Essentials of interventional cancer pain management 1st ed 2019 edition ebook pdf

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Amitabh Gulati Vinay Puttanniah Brian M. Bruel William S. Rosenberg Joseph C. Hung Editors

Essentials of Interventional Cancer Pain Management

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Contents

Part I Perspectives on Cancer Pain Medicine 1 Perspectives on Interventional Cancer Pain Management ������������������������������������� 3 Arvider Gill and Oscar A. de Leon-Casasola 2 The Practice of Cancer Pain: A Case Series ������������������������������������������������������������� 5 Sana Shaikh Part II Cancer Pain Syndromes 3 Pathophysiology of Cancer Pain ������������������������������������������������������������������������������� 13 Stephen Lawrence Thorp 4 Chemotherapy ������������������������������������������������������������������������������������������������������������� 19 Karina Gritsenko and Michael Lubrano 5 Postsurgical Pain Syndromes ������������������������������������������������������������������������������������� 29 Thomas J. Van de Ven and Amitabh Gulati 6 Radiation-Induced Pain Syndromes ������������������������������������������������������������������������� 39 Jasmit Brar, Grant H. Chen, and Amitabh Gulati Part III Paradigms in Cancer Pain Syndromes 7 General Pain Management Concepts ����������������������������������������������������������������������� 47 Dhanalakshmi Koyyalagunta, Maureen J. Simmonds, and Diane M. Novy 8 Head and Neck Cancer Pain ������������������������������������������������������������������������������������� 55 Vinay Puttanniah and Elena V. Zininberg 9 Breast Cancer Pain: A Review of Pathology and Interventional Techniques ����������������������������������������������������������������������������������� 63 Ali Valimahomed, Jennifer Zocca, and Amitabh Gulati 10 Thoracic Cancer Pain ������������������������������������������������������������������������������������������������� 85 Joseph C. Hung, Rajiv Shah, and Amitabh Gulati 11 Gastrointestinal Cancer Pain ������������������������������������������������������������������������������������� 97 Daniel Pak and Joseph C. Hung 12 Genitourinary Cancer Pain Syndromes ������������������������������������������������������������������� 107 Ilan Margulis and Amitabh Gulati 13 Pediatric Cancer Pain Management ������������������������������������������������������������������������� 113 Stephen L. Long and Anurag K. Agrawal

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14 Pain in Hematologic Malignancies ��������������������������������������������������������������������������� 123 Kanu Sharan 15 Dermatologic Cancer Pain Syndromes ��������������������������������������������������������������������� 133 Katerina Svigos, Viswanath Reddy Belum, and Mario E. Lacouture Part IV Percutaneous Pain Techniques and Anatomy 16 Ablative Techniques ��������������������������������������������������������������������������������������������������� 141 Simon Guo and Jack W. Lam 17 Sympathetic Nervous System Blocks for the Treatment of Cancer Pain ��������������� 145 Nadya M. Dhanani, Wilson A. Almonte, and Mitchell P. Engle 18 Peripheral Nerve Blocks ��������������������������������������������������������������������������������������������� 167 Nantthasorn Zinboonyahgoon, Christopher R. Abrecht, and Sanjeet Narang 19 Cranial Nerve Targets ������������������������������������������������������������������������������������������������� 183 Jill E. Sindt 20 Vertebroplasty, Kyphoplasty, and Sacroplasty ��������������������������������������������������������� 201 Dawood Sayed and Shervin Razavian 21 Treatment Considerations for Cancer Pain Syndromes ����������������������������������������� 213 Devin Peck and Gendai J. Echezona Part V Surgical Techniques and Neuromodulation 22 Intracranial Neuroablation ��������������������������������������������������������������������������������������� 225 Roy Hwang, Ashwin Viswanathan, Ahmed M. Raslan, and Erich Richter 23 Spinal Neuroablation for Cancer Pain ��������������������������������������������������������������������� 231 William S. Rosenberg, Parag G. Patil, and Ahmed M. Raslan 24 Radiosurgery ��������������������������������������������������������������������������������������������������������������� 235 Simon S. Lo, Tithi Biswas, Rodney J. Ellis, and Peter C. Gerszten 25 Deep Brain Stimulation and Motor Cortical Stimulation for Malignant Pain ����� 241 Joshua M. Rosenow and Jonathan Miller 26 Spinal Cord Stimulation and Oncologic Pain Management ����������������������������������� 247 Neel D. Mehta and Mohammad M. Piracha 27 Peripheral Nerve Stimulation for the Treatment of Cancer Pain ��������������������������� 255 Jennifer A. Sweet and Nicholas M. Boulis 28 Transcutaneous Electrical Nerve Stimulation for Cancer Pain ����������������������������� 261 Jeffrey Loh Part VI Intrathecal Drug Delivery 29 Indications for Intrathecal Pump Therapy �������������������������������������������������������������� 269 Mercy A. Udoji and Helen M. Blake 30 Intrathecal Drug Delivery System Trialing for Cancer Pain Management ����������� 273 Namrata Khimani and Sanjeet Narang 31 Intrathecal Pump Implantation Technique ������������������������������������������������������������� 277 Shane E. Brogan and Christina Bokat

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32 Medications in Intrathecal Pumps ��������������������������������������������������������������������������� 287 Grant H. Chen 33 Compounding Drugs for Intrathecal Use ����������������������������������������������������������������� 293 Shalini Shah Part VII Interventional Oncology 34 Image Guidance and Planning ����������������������������������������������������������������������������������� 301 Ramon Go and Jeffrey Prinsell Jr. 35 Ablative Techniques for Painful Metastasis (Radiofrequency ablation, Microwave ablation, Cryoablation, Chemical ablation, and HIFU) ��������������������� 307 Hooman Yarmohammadi 36 Introduction to Radiation Therapy ��������������������������������������������������������������������������� 319 Shayna E. Rich and Kavita V. Dharmarajan 37 Palliative Radiation Therapy ������������������������������������������������������������������������������������� 329 Shayna E. Rich and Kavita V. Dharmarajan 38 External Beam Radiotherapy in the Treatment of Painful Bone Metastases ��������������������������������������������������������������������������������������������������������� 339 Candice Johnstone, Amol J. Ghia, and Anussara Prayongrat 39 Non-opioid Intravenous Infusions for Management of Cancer-Associated Pain ����������������������������������������������������������������������������������������� 353 Yury Khelemsky and Mourad M. Shehabar Part VIII Interventional Physiatry 40 Cancer Rehabilitation ������������������������������������������������������������������������������������������������� 363 Ameet Nagpal, Jacob Fehl, Brittany Bickelhaupt, Maxim S. Eckmann, Brian Boies, and Jon Benfield 41 Neuromuscular Medicine: Cancer Pain ������������������������������������������������������������������� 375 Eric Leung 42 Cancer-Related Pelvic Pain ��������������������������������������������������������������������������������������� 385 Sarah Hwang and Megan Clark 43 Exercise Therapy and Fatigue Management ����������������������������������������������������������� 395 Jack B. Fu and Arash Asher 44 Physical Therapy ��������������������������������������������������������������������������������������������������������� 403 Monica Verduzco-Gutierrez, Roy Rivera Jr., and Prathap Jayaram 45 Occupational Therapy ����������������������������������������������������������������������������������������������� 417 Meilani Mapa and Jason Chen 46 Cancer Pain and Physical Modalities ����������������������������������������������������������������������� 427 Joel Frontera and Amy Cao 47 Osteopathic Treatment for Cancer-­Related Pain ����������������������������������������������������� 433 Ryan K. Murphy and Jonas M. Sokolof 48 Rehabilitation-Bracing as a Conservative Treatment Option ��������������������������������� 443 Lisa Marie Ruppert and Michelle Yakaboski

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Part IX Complementary and Psycho-Behavioral Therapies 49 Psychosocial Assessment and Treatment for Patients with Cancer Pain ��������������� 451 Laura M. van Veldhoven and Diane M. Novy 50 Relaxation Techniques and Biofeedback for Cancer Pain Management ��������������� 463 Asimina Lazaridou and Robert R. Edwards 51 Mood and Anxiety in Cancer Pain ��������������������������������������������������������������������������� 473 R. Garrett Key and William S. Breitbart 52 Acupuncture and Cancer Pain ����������������������������������������������������������������������������������� 485 Yan Cui Magram and Gary E. Deng 53 Creative Therapies and Mind-Body Health Systems ����������������������������������������������� 489 Veena Sankar 54 Botanical Treatments in Cancer Pain Management ����������������������������������������������� 503 Helen M. Blake 55 Integrative Therapies for Pain Modulation ������������������������������������������������������������� 507 Joan Pope and Aron Legler Index ������������������������������������������������������������������������������������������������������������������������������������� 513

Contents

Contributors

Christopher R. Abrecht, MD Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Anurag K. Agrawal, MD Department of Hematology/Oncology, UCSF Benioff Children’s Hospital Oakland, Oakland, CA, USA Wilson A. Almonte, MD Victoria Pain and Rehabilitation Center, Victoria, TX, USA Arash Asher, MD Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los Angeles, CA, USA Viswanath Reddy Belum, MD Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Jon Benfield, DO South Texas Spinal Clinic, San Antonio, TX, USA Brittany Bickelhaupt, MD University of Texas Health Science Center at San Antonio (UTHSCSA), Department of Physical Medicine and Rehabilitation, San Antonio, TX, USA Tithi Biswas, MD University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Department of Radiation Oncology, Cleveland, OH, USA Helen M. Blake, MD Pain and Rehabilitation Specialists of Saint Louis, LLC, St. Louis, MO, USA Brian Boies, MD University of Texas Health Science Center at San Antonio (UTHSCSA), UT Medicine Pain Consultants, Department of Anesthesiology, San Antonio, TX, USA University of Texas Health Science Center at San Antonio (UTHSCSA), Department of Anesthesiology, San Antonio, TX, USA Christina Bokat, MD, MPhil University of Utah, Department of Anesthesiology, Salt Lake City, UT, USA Nicholas M. Boulis, MD Neurosurgery, Emory University Hospital, Atlanta, GA, USA Jasmit Brar, MD New York Presbyterian-Weill Cornell Medicine, Department of Anesthesiology, New York, NY, USA William S. Breitbart, MD Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA Shane E. Brogan, MD, MPhil University of Utah, Department of Anesthesiology, Salt Lake City, UT, USA Amy Cao Baylor St. Luke’s Medical Center, Physical medicine and rehabilitation, Houston, TX, USA Grant H. Chen, MD Memorial Sloan Kettering Cancer Center, Department of Anesthesiology and Critical Care Medicine, New York, NY, USA

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Jason Chen, DO McGovern Medical School at UT Health, Department of Physical Medicine and Rehabilitation, The University of Texas Health Science Center at Houston, Houston, TX, USA Megan Clark, MD University of Kansas, Department of Physical Medicine and Rehabilitation, Kansas City, KS, USA Yan Cui Magram, MD New York Presbyterian Hospital-Weill Cornell Medicine, Department of Anesthesiology, New York, NY, USA Oscar A. de Leon-Casasola, MD The Jacobs School of Medicine and Biomedical Sciences, Department of Anesthesiology, Buffalo, NY, USA Division of Pain Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Gary E. Deng, MD, PhD Memorial Sloan Kettering Cancer Center, Department of Integrative Medicine Service, New York, NY, USA Nadya M. Dhanani, MD Memorial Hermann Hospital/Mischer Neuroscience Institute, Department of Pain Management/Neurosurgery, Houston, TX, USA Kavita V. Dharmarajan, MD, MSc Icahn School of Medicine at Mount Sinai, New York, NY, USA Gendai J. Echezona, MD Eagle Consulting Services,White Plains, NY, USA Maxim S. Eckmann, MD University of Texas Health Science Center at San Antonio (UTHSCSA), UT Medicine Pain Consultants, Department of Anesthesiology, San Antonio, TX, USA University of Texas Health Science Center at San Antonio (UTHSCSA), Department of Anesthesiology, San Antonio, TX, USA Robert R. Edwards, PhD Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women’s Hospital and Harvard Medical School, BWH Pain Management Center, Chestnut Hill, MA, USA Rodney J. Ellis, MD University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Department of Radiation Oncology, Cleveland, OH, USA Mitchell P. Engle, MD, PhD Institute of Precision Pain Medicine, Corpus Christi, TX, USA Jacob Fehl, MD Kansas City VA Medical Center, Kansas City, MO, USA Joel Frontera, MD McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA Jack B. Fu, MD Department of Palliative Care & Rehabilitation Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA R. Garrett Key, MD University of Texas at Austin Dell Medical School, Austin, TX, USA Peter C. Gerszten, MD, MPH, FACS University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Department of Radiation Oncology, Cleveland, OH, USA Amol J. Ghia, MD University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX, USA Arvider Gill, DO The Jacobs School of Medicine and Biomedical Sciences, Department of Anesthesiology, Buffalo, NY, USA Ramon Go, MD Pain Management, Memorial Sloan Kettering Cancer Center, New York, NY, USA Karina Gritsenko, MD Montefiore Medical Center – Albert Einstein College of Medicine, Bronx, NY, USA Amitabh Gulati, MD, FIPP Department of Anesthesiology and Critical Care, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Contributors

Contributors

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Simon Guo, MD Northport Veterans Affairs Medical Center, Department of Anesthesia, Northport, NY, USA Joseph C. Hung, MD Memorial Sloan Kettering Cancer Center, Anesthesiology and Critical Care Medicine, New York, NY, USA Roy Hwang West Virginia University, Department of Neurosurgery, Morgantown, WV, USA Sarah Hwang, MD Shirley Ryan AbilityLab, Chicago, IL, USA Prathap Jayaram, MD Baylor College of Medicine, Department of Physical Medicine and Rehabilitation, Houston, TX, USA Candice Johnstone, MD, MPH Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA Yury Khelemsky, MD Icahn School of Medicine at Mount Sinai, Department of Anesthesiology, New York, NY, USA Namrata Khimani, MD Department of Anesthesiology, Perioperative and Pain Medicine, The Pain Management Center at Brigham and Women’s Hospital, Chestnut Hill, MA, USA Dhanalakshmi Koyyalagunta, MD Department of Pain Medicine, UTMD Anderson Cancer Center, Houston, TX, USA Mario E. Lacouture, MD Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Jack W. Lam, MD Rex Hospital, Wake Med Cary Hospital, Duke Raleigh Hospital, Department of Anesthesia, Raleigh, NC, USA Asimina Lazaridou, PhD Department of Anesthesiology, Brigham & Women’s Hospital and Harvard Medical School, BWH Pain Management Center, Chestnut Hill, MA, USA Aron Legler, MD Memorial Sloan Kettering, Department of Anesthesiology, New York, NY, USA Eric Leung, MD Department of Physical Medicine and Rehabilitation, Northwell Health, Manhasset, NY, USA Jeffrey Loh, MD, MS Queen’s Medical Center, Department of Anesthesiology & Pain Management, Honolulu, HI, USA Stephen L. Long, MD Department of Anesthesiology, UCSF Benioff Children’s Hospital Oakland, Oakland, CA, USA Simon S. Lo, MD, FACR University of Washington School of Medicine, Department of Radiation Oncology, Seattle, WA, USA Michael Lubrano, MD, MPH Department of Anesthesia & Perioperative Care, University of California San Francisco (UCSF) Medical Center, San Francisco, CA, USA Meilani Mapa, MD Memorial Rehabilitation Institute, Memorial Healthcare Systems, Division of Physical Medicine and Rehabilitation, Hollywood, FL, USA Ilan Margulis Department of Anesthesiology, New York-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA Neel D. Mehta, MD Joan and Sanford I. Weill Cornell Medical College of Cornell University, New York Presbyterian Hospital, Division of Pain Management, Department of Anesthesiology, New York, NY, USA Jonathan Miller, MD, FAANS, FACS University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA Ryan K. Murphy, DO Valley Medical Group, Waldwick, NJ, USA

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Ameet Nagpal, MD, MS, MEd University of Texas Health Science Center at San Antonio (UTHSCSA), UT Medicine Pain Consultants, Department of Anesthesiology, San Antonio, TX, USA University of Texas Health Science Center at San Antonio (UTHSCSA), Department of Anesthesiology, San Antonio, TX, USA Sanjeet Narang, MD Department of Anesthesiology, Perioperative and Pain Medicine, The Pain Management Center at Brigham and Women’s Hospital, Harvard Medical School, Chestnut Hill, MA, USA Diane M. Novy, PhD Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Daniel Pak, MD Massachusetts General Hospital, Boston, MA, USA Parag G. Patil, MD, PhD University of Michigan Medical Center, Ann Arbor, MI, USA Devin Peck, MD Physician, Austin Interventional Pain, Austin, TX, USA Mohammad M. Piracha, MD Joan and Sanford I. Weill Cornell Medical College of Cornell University, New York Presbyterian Hospital, Division of Pain Management, Department of Anesthesiology, New York, NY, USA Joan Pope, MSN Memorial Sloan Kettering, New York, NY, USA Anussara Prayongrat, MD King Chulalongkorn Memorial Hospital and Chulalongkorn University, Department of Radiation Oncology, Bangkok, Thailand Jeffrey Prinsell Jr., MD Pain Management, Memorial Sloan Kettering Cancer Center, New York, NY, USA Vinay Puttanniah, MD Memorial Sloan Kettering Cancer Center, Anesthesiology and Critical Care Medicine, New York, NY, USA Ahmed M. Raslan, MD Oregon Health & Science University, Department of Neurosurgery, Portland, OR, USA Portland VA Medical Center, Neurological Surgery, Portland, OR, USA Shervin Razavian, MD Anesthesia Associates of Kansas City, Overland Park, KS, USA Shayna E. Rich, MD, PhD, MA Haven Hospice, Gainesville, FL, USA Erich Richter, MD, FAANS New Orleans Neurosurgical Associates, Marrero, LA, USA Roy Rivera Jr., PT, PhD, DPT, CHES Crom Rehabilitation, LLC, Department of Outpatient Sports Medicine, Houston, TX, USA William S. Rosenberg, MD, FAANS Center for the Relief of Pain, Kansas City, MO, USA Joshua M. Rosenow, MD Northwestern Memorial Hospital, Department of Neurosurgery, Neurology and Physical Medicine and Rehabilitation, Chicago, IL, USA Lisa Marie Ruppert, MD Memorial Sloan Kettering Cancer Center, New York, NY, USA Veena Sankar, MD Austin Anesthesiology Group, Austin, TX, USA Dawood Sayed, MD University of Kansas Medical Center, Department of Anesthesiology and Pain Medicine, Kansas City, KS, USA Rajiv Shah, MD Washington University School of Medicine, Saint Louis, MO, USA Shalini Shah, MD University of California, Irvine, Department of Anesthesiology and Perioperative Care, Irvine, CA, USA Sana Shaikh, MD Memorial Sloan Kettering Cancer Center, New York, NY, USA

Contributors

Contributors

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Kanu Sharan, MD MD Anderson Cancer Center at Cooper, Department of Hematology/ Oncology, Camden, NJ, USA Mourad M. Shehabar, MD Icahn School of Medicine at Mount Sinai, Department of Anesthesiology, New York, NY, USA Maureen J. Simmonds, PhD, PT University of Texas, Physical Therapy Department, San Antonio, TX, USA Jill E. Sindt, MD University of Utah, Department of Anesthesiology, Salt Lake City, UT, USA Jonas M. Sokolof, DO Department of Rehabilitative Medicine, Weill College of Medicine Cornell University, New York, NY, USA Department of Neurology – Rehabilitation Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Katerina Svigos, BA New York University School of Medicine, New York, NY, USA Jennifer A. Sweet, MD University Hospitals Case Medical Center, Cleveland, OH, USA Stephen Lawrence Thorp, MD Pain Medicine, Northwell Health Phelps Hospital, Sleepy Hollow, NY, USA Mercy A. Udoji, MD Emory University/Atlanta Veterans’ Administration, Department of Anesthesiology, Decatur, GA, USA Ali Valimahomed, MD Department of Physical Medicine and Rehabilitation, New YorkPresbyterian Hospital, Weill Cornell Medical College/Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA Laura M. van Veldhoven, PhD, MPH Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, USA Thomas J. Van de Ven, MD, PhD Duke University Medical Center and Durham VAMC, Department of Anesthesiology, Durham, NC, USA Monica Verduzco-Gutierrez, MD Department of Physical Medicine and Rehabilitation, University of Texas Health Science Center, Houston, TX, USA Ashwin Viswanathan Baylor College of Medicine, Department of Neurosurgery, Houston, TX, USA Michelle Yakaboski, CPO Certified Prosthetist Orthotist at Boston Orthotics and Prosthetics, Stony Brook, NY, USA Hooman Yarmohammadi, MD Certified Prosthetist Orthotist at Boston Orthotics and Prosthetics, Stony Brook, NY, USA Nantthasorn Zinboonyahgoon, MD Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Elena V. Zininberg, MD Weill Cornell School of Medicine, Department of Anesthesiology, New York, NY, USA Department of Anesthesiology/Pain Management, Memorial Sloan Kettering, New York, NY, USA Jennifer Zocca, MD Department of Anesthesiology, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA

Part I Perspectives on Cancer Pain Medicine

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Perspectives on Interventional Cancer Pain Management Arvider Gill and Oscar A. de Leon-Casasola

As of January 2012, approximately 13.7 million Americans with a history of cancer were alive [1]. It is unclear how many of these individuals were cancer-free and how many had evidence of cancer and may have been undergoing treatment. Regardless, the burden of disease is significant; about 1,665,540 new cancer cases, not including cancer in situ, are expected to be diagnosed in 2014 [1]. If 30–50% of individuals with advanced cancer experience significant pain, then one can understand the high prevalence of pain affecting this population. Moreover, the 5-year relative survival rate for all cancers diagnosed between 2003 and 2009 is 68%, up from 49% in 1975–1977 [1]. These numbers explain the high number of patients experiencing pain due to their cancer treatments, including chemotherapy-induced peripheral neuropathy, postradiation visceral and neuropathic pain, and postsurgical pain syndromes. These survivors have increased the need for resources to treat these patients at cancer centers, as they have complex pain syndromes that are not managed by community physicians.

Despite advances in the understanding of the neurobiology of pain in cancer, the translation of this information to multimodal pharmacologic analgesic therapy and the advent of new interventional techniques for the management of cancer pain have not shown a dramatic reduction in the prevalence of patients experiencing cancer pain.

Recently, a group in the Netherlands reported that 55% of the 1429 respondents with a diagnosis of cancer had experienced moderate to severe pain in the week prior to the

A. Gill The Jacobs School of Medicine and Biomedical Sciences, Department of Anesthesiology, Buffalo, NY, USA O. A. de Leon-Casasola (*) The Jacobs School of Medicine and Biomedical Sciences, Department of Anesthesiology, Buffalo, NY, USA Division of Pain Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA e-mail: Oscar.deleon@roswellpark.org

survey and that 42% of patients were experiencing pain despite receiving pharmacological treatment for it [2]. In the United States, 3,123 ambulatory patients with breast, prostate, colorectal, or lung cancer were evaluated for pain at their first visit and then 4–5 weeks later. Of those patients, 67% had pain and ongoing pharmacological treatment with opioids at the first visit. However, 33% did not have adequate pain control at that time despite their treatment with opioids [3]. At the follow-­up visit, though they continued treatment with opioids, there was no reduction in the number of patients experiencing inadequate pain control [3].

This study also showed that the prevalence of pain due to solid tumors has not changed in the United States in more than 20 years, despite the wide availability and increased consumption of opioids [3]. In contrast, a randomized clinical trial comparing intrathecal therapy (IT) to comprehensive medical management (CMM) in the treatment of refractory cancer pain showed that once the patients were enrolled into the study, and then treated by a pain specialist, there was a further 39% pain reduction in patients allocated to the CMM group versus a 51% in those receiving IT therapy [4]. The difference was not statistically significant illustrating the power of pharmacological therapy in the hands of pain specialists.

These findings suggest that the involvement of a pain specialist may have a significant impact in the quality of pain control experienced by cancer patients. This difference may be the result of the implementation of multimodal therapy with topical analgesics [5], judicious opioid use [6], anticonvulsants with modulating capabilities of the voltage-gated calcium channel [7], tricyclic antidepressants [7], and titration to doses associated with therapeutic effects [8]. The importance of adequate pain management in cancer patients needs to be underscored because there is evidence in the oncology literature that survival rates are proportionally related to symptom control and that pain management contributes to better psychosocial functioning and quality of life [9]. Because of the interactions of psychosocial issues and

© Springer Nature Switzerland AG 2019 A. Gulati et al. (eds.), Essentials of Interventional Cancer Pain Management, https://doi.org/10.1007/978-3-319-99684-4_1

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pain, care for these patients is best provided in a multidisciplinary environment where psychological support includes emotional support, coping skills training, and cognitive behavioral therapy [10].

As noted, evaluation of pain is critically important in the oncology patient. Pain intensity must be quantified, and quality must be characterized by the patient (whenever possible based on patient communication capacity). The brief pain inventory is an appropriate tool for this purpose [11], while the short form McGill Pain Questionnaire may be used in cancer patient to evaluate the multidimensionality of pain [12]. A comprehensive pain assessment should be performed if new pain is present and regularly performed for persisting pain. Moreover, the quality of pain must be evaluated to determine if there is a neuropathic pain component. There are several neuropathic pain scales that may be implemented for this purpose, including the Douleur Neuropathique (DN4) [13] and the Leeds assessment of neuropathic symptoms and signs (LANSS) [14], which are easy to use, and may be applied in a short period of time. The patient impression of adequate pain relief and the healthcare provider assessment of adequacy of function, and any special issues for the patient relevant to pain treatment, is also necessary to have a complete evaluation of the success of therapy. Because patients with cancer pain will likely need opioid therapy, it is also important to evaluate the patient for the risk of abuse and diversion. Several tools have been created for this purpose and can be easily implemented [15, 16].

Pharmacological pain therapy is very successful in cancer pain [6, 17]. However, invasive techniques are sometimes needed because patients cannot tolerate pharmacologic titration to therapeutic levels or because inadequate analgesia is achieved despite maximum doses of these agents. In these individuals, there are several options. These include neurolytic blocks of the sympathetic axis for those patients with a visceral pain component [18, 19], intrathecal therapy for both somatic and neuropathic pain components [20–22], peripheral and spinal cord stimulation [23], and other interventional procedures performed in the non-cancer population, as noncancer-related pain may also occur in this population.

In summary, the use of pharmacological multimodal therapy and interventional procedures may result in successful pain control in the great majority of patients afflicted by cancer-related pain when implemented by practitioners well versed in the use of these alternative therapies.

References 1. American Cancer Society. Cancer facts & figures 2014. Atlanta: American Cancer Society; 2014.

2. van den Bueuken-van Everdingen MHJ, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Parjin J. High prevalence of pain in patients with cancer in a large population-based study in the The Netherlands. Pain. 2007;132:312–20.

3. Fisch MJ, Lee J-W, Weiss M, Wagner LI, Chang VT, Cella V, Manola JB, Minasian LM, McCaskill-Stevens W, Mendoza TR,

A. Gill and O. A. de Leon-Casasola Cleeland CS. Prospective, observational study of pain and analgesic prescribing in medical oncology outpatient with breast, colorectal, lung, or prostate cancer. J Clin Oncol. 2012;30:1980–91.

4. Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, Boortz-Marx RL, Buchser E, Catala E, Bryce DA, Coyne PJ, Pool GE. Randomized clinical trial of an implantable drug delivery sytem compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol.

2002;20:4040–9.

5. de Leon-Casasola OA. Multimodal approaches to the management of neuropathic pain: the role of topical analgesia. J Pain and Symp Manag. 2007;33:356–64.

6. de Leon-Casasola OA. Current developments in opioid therapy for the management of cancer pain. Clin J Pain. 2008;24(Suppl 10):S3–7.

7. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;122:S22–32.

8. de Leon-Casasola OA. Multimodal, multiclass, multidisciplinary therapy: the key to better analgesia in the 21st century? Clin J Pain.

2010;26(Suppl 10):S1–2.

9. Temel JS, Greer JA, Muzikansky A. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733–42.

10. Morley S, Eccleston C, Williams A. Systematic review and meta-­ analysis of randomized controlled trials of cognitive behavior therapy and behavior therapy for chronic pain in adults, excluding headache. Pain. 1999;80:1–13.

11. Cleeland CS, Ryan KM. Pain assessment: global use of the brief pain inventory. Ann Acad Med Singapore. 1994;23:129–38.

12. Gauthier LR, Young A, Dworkin RH, Rodin G, Zimmermann C, Warr D, Librach SL, Moore M, Sheperd FA, Riddell RP, Macpherson A, Melzack R, Gagliese L. Validation of the short-­ form Mc Gill pain questionnaire-1 in younger and older people with cancer pain. J Pain. 2014;15:756–70.

13. Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, Cunin G, Fermanian J, Ginies P, Grun-Overdyking A, Jafari-­ Schluep H, Lanteri-Minet M, Laurent B, Mick G, Serrie A, Valade D, Vicaut E. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005;114:29–36.

14. Bennett M. The LANSS pain scale: the Leeds assessment of neuropathic symptoms and signs. Pain. 2001;92:147–57.

15. Moore TM, Jones T, Browder JH, Daffron S, Passik SD. A comparison of common screening methods for predicting aberrant drug-­ related behavior among patients receiving opioids for chronic pain management. Pain Med. 2009;10:1426–33.

16. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-­ treated patients: preliminary validation of the opioid risk tool. Pain Med. 2005;6:432–42.

17. de Leon-Casasola OA. Implementing therapy with opioids in cancer pain. Oncol Nurs Forum. 2008;35(6):S1–6.

18. Wong GY, Schroeder DR, Carns PE, Wilson JI, Martin DP, Kinney MO, Mantilla CB, Warner DO. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer. A randomized controlled trial.

JAMA. 2004;291:1092–9.

19. de Leon-Casasola OA, Kent E, Lema MJ. Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer. Pain. 1993;54:145–51.

20. Lozano J, de Leon-Casasola OA. Indications for intrathecal therapy in cancer patients. Tech Reg Anesth Pain Manag. 2011;15:147–9.

21. de Leon-Casasola OA. Implementing and managing intrathecal pumps. Tech Reg Anesth Pain Manag. 2011;15:155–7.

22. Sparlin J, de Leon-Casasola OA. Intrathecal pump implantation techniques. Tech Reg Anesth Pain Manag. 2011;15:158–61.

23. de Leon-Casasola OA. Spinal cord and peripheral nerve stimulation techniques for neuropathic pain. J Pain Symp Manag.

2009;38:S28–38.

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The Practice of Cancer Pain: A Case Series Sana Shaikh

Introduction Surviving cancer is just the beginning. Often the struggle for many patients is thriving after treatment which may be limited by pain. While strategies to treat pain in the chronic pain population exist, implementing pharmacologic and interventional therapies for the cancer pain patient may be challenging. The following case series illustrate a framework that chronic pain physicians may use to treat cancer pain syndromes.

The clinical practice of pain management can vary from one practice to another based on patient population and referrals. In community-based practices, practitioners may have a consistent population base with similar anatomy and pathophysiology. A distinct challenge to the practice of cancer pain medicine is that each patient’s tumor pathology and metastatic disease leads to evolving sources of pain. It is important to consistently reevaluate imaging as the primary and secondary diseases result in changing pain syndromes.

Choosing interventions is often balanced with oncologic treatment protocols and life expectancy.

Case 1: Oncologic Diagnosis in the Community Setting The incidence of cancer is 454.8 cases per 100,000 men and women per year (based on 2008–2012 cases) [1].

The epidemiology of cancer pain among diagnosed cases of cancer is variable depending on the source. A systematic review of 52 articles showed that pain was prevalent in 64% of patients with metastatic or advanced-stage disease, 59% in patients on anticancer treatment, and 33% in patients after curative treatment [2]. Another study estimated the prevalence of pain in cancer at 25% for those newly diagnosed, 33% for those undergoing active treatment, and greater than 75% for those with advanced-stage disease[3, 4]. Due to the

S. Shaikh (*) Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: shaikhs@mskcc.org

high prevalence of pain as a symptom in cancer patients, it is important to consider an underlying oncologic process in the differential diagnosis when evaluating the initial presentation of pain.

Case 1: A 75-year-old female with a distant history of non-small cell lung cancer presents with right shoulder pain.

The pain in the right-sided shoulder is a constant, sharp pain with radiation to the lateral aspect of the deltoid, elbow, and anterior chest wall over the right pectoralis muscle. She denies any numbness or tingling in the arm. Upon initial presentation of pain, the patient was evaluated at a community-­ based pain practice where she was given a prescription for physical therapy for the right shoulder and an intraarticular steroid injection.

The patient noted that physical therapy exacerbated her shoulder pain and that the injection resulted in minimal improvement of her symptoms. Multiple opioid regimens were tried with dose-limiting nausea noted and a lack of adequate pain relief achieved. Despite the addition of steroids, nerve pain-modulating medications, and muscle relaxants, the pain progressively worsened at which time she presented to the hospital with severe pain and limited ability to move the right shoulder.

CT examination of the right shoulder revealed a lytic lesion in the glenoid process of the right scapula along with a complete supraspinatus tear (Fig. 2.1). A PET scan showed a large lytic lesion within the right coracoid process extending into the glenoid process. She was started on a regimen of steroids and radiation therapy to the right glenoid process.

After 2 weeks of radiation with minimal improvement in symptoms, both the interventional pain service and orthopedic surgery were consulted for possible interventions to improve patient’s shoulder pain.

Given her the anatomy and location of her pathology, the patient would unlikely benefit from an additional intraarticular shoulder joint injection. A consultation and discussion with orthopedic surgery led to a recommendation of

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and the non-cancer patients [6]. A systematic review demonstrated that home, hospital, and inpatient specialist palliative care significantly improved patient outcomes in the domains of pain and symptom control, anxiety, and reduced hospital admissions [7]. Overall the treatment of palliative and pain symptoms is crucial to the quality of life patients experience as part of their cancer treatment.

Fig. 2.1 CT scan of the right upper extremity is demonstrating a lytic metastasis in the superior glenoid (arrows) with new cortical breakthrough and an extraosseous soft tissue component and new probable nondisplaced, pathologic fracture

surgical resection of the coracoid and scapula fracture along with rotator cuff tendon repairs. After pain management, anesthesia, and surgical discussion, it was decided to proceed with the surgery with preoperative nerve blocks to help with postoperative pain control and rehabilitation.

Ultrasound guidance was used to target right cervical C5 and C6 for neural blockade in combination with the PECSII nerve block. Perioperatively, the patient was noted to have excellent pain relief with regional analgesia lending to an overall perceived decrease in oral opioid regimen requirements.

Patients undergoing orthopedic surgery for tumor resection often have anatomical considerations unique to their tumor location. Surgical incisions and planning can often be unpredictable and cross multiple dermatomes in comparison with orthopedic surgery for nonmalignant pain. Careful planning between the acute pain specialist, anesthesiologist, and surgical teams is important to ensure adequate perioperative pain relief.

Case 2: Symptom Management in Oncologic Pain Treatment A systematic review of palliative symptoms in cancer patients showed that their most prevalent symptoms were fatigue, excretory symptoms, urinary incontinence, asthenia, pain, constipation, and anxiety which occurred in at least 50% of patients [5]. In a comparison between palliative care in cancer and non-cancer geriatric patients, cancer patients were found to have more pain, digestive symptoms, psychological symptoms, and fatigue than non-cancer patients. The study also found that the prevalence of digestive symptoms, pain, and psychological symptoms was higher in younger and in cancer patients than in the elderly

Case 2: A 57-year-old male with metastatic colon cancer involving the liver and lungs presents with intractable hiccups. His hiccups started after a CT scan and have occurred every few minutes consistently with some periods of pause not lasting longer than 20 min. As an outpatient, his oncologist tried a regimen of baclofen twice a day dosing with no change in symptoms. He was also given a single dose of fluconazole to empirically treat esophageal candidiasis. As part of the workup for this patient’s new onset of hiccups, the patient had reimaging of the body including CT of the chest, abdomen, and pelvis (Fig. 2.2). This imaging showed an increase in size and number of multiple bilateral pulmonary metastases and persistent splenomegaly, with portal venous hypertension. It was suspected that diaphragmatic irritation secondary to pulmonary metastatic disease was the likely etiology of the patient’s persistent hiccups.

A trial of bilateral sphenopalatine ganglion blocks was performed which resulted in only a 20 min resolution of the hiccups. A trial of gabapentin 300 milligrams daily was initiated and titrated to three times a day dosing along with a regimen of oral viscous lidocaine to be swallowed instead of rinsed three times a day. The patient had complete resolution of hiccups after therapeutic titration of oral viscous lidocaine and Neurontin at three times a day. The patient was discharged on maintenance gabapentin therapy and oral viscous lidocaine on an as-needed basis.

Fig. 2.2 CT of the chest, abdomen, and pelvis with contrast showed slightly increased size of bilateral pulmonary metastases in the right upper and lower lobes. The picture above showed the right peri-hilar mass increased marked narrowing of the right upper lobe bronchus (arrows)

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Localized treatments for pain including directed topical treatments can often be helpful to treat novel causes of pain.

Case 3: Changing Pain States in Oncologic Patients The symptoms of cancer often change over time, and there is a need for practitioners to have a low threshold for reevaluation of the underlying disease process. New symptoms can manifest from treatment or from progression of cancer, either locally or to distant sites. Diagnostic workup of these possibilities is important in determining the treatment plan.

Collaboration between interventional pain and other service may offer patients a wide variety of options to treat different pain and non-pain symptoms during cancer treatment.

Ultimately, it is most important to consider a wide array of therapies to optimize symptom manage and quality of life.

Case 3: A 41-year-old male with multifocal peripheral schwannoma involving the pleura and liver presents with right-sided chest wall pain. Interventional radiology recommended cryoablation of this lesion on the anterior aspect of the seventh rib. The patient was also referred for consultation with the pain service for possible interventional options for pain relief.

On initial assessment, patient noted pain as a sharp, tingling, and burning in the right upper quadrant of the abdomen. Despite the use of opioids, the patient found the pain to cause significant daily disability. Upon physical exam, there was tenderness to palpation across the right seventh and eighth rib in an anterolateral location This correlated with a seventh rib schwannoma (Fig. 2.3). A right-sided intercostal nerve block of the seventh and eighth ribs under ultrasound guidance was performed.

The patient’s noted significant improvement from baseline and that relief lasted for 11 weeks. At that time, pain

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returned with the same presentation and severity. Given the positive response from first procedure, the intercostal nerve blocks were repeated; however the patient had minimal relief from this procedure. Given this response, imaging with an MRI of the thoracolumbar spine was repeated to evaluate for extension of disease into the spinal cord. MRI of the spine revealed paraspinal masses abutting exiting nerve roots at the right T7–T8 level. A thoracic epidural was performed with significant relief of the patient’s pain. Patient’s pain relief lasted for 6 weeks with significant progression of the original disease. Due to the rate of disease growth, we planned for intrathecal pump placement to treat the neuraxial source of the pain.

Though various nerve blocks can make sense clinically based on the history and physical exam, it is often necessary to correlate these findings with relevant and up-to-date imaging in order to optimize efficacy and safety of a planned intervention. It’s important to consider the possibility that an initial intervention that was helpful may not be possible given changes in anatomy related to progression of disease.

It is crucial to always reassess patients given the aggressive nature of some of the baseline etiologies.

Case 4 and 5: Considerations for Intrathecal Drug Delivery in the Oncologic Population The goal of interventional pain physician is to consider intervening in someone’s pain outcome as early as possible to treat a patient’s pain and improve their quality of life and function. The intrathecal delivery of opioids and other adjuvant medications is an effective way to treat refractory cancer pain while minimizing systemic side effects and allowing for a greater ability to address increased pain medication requirements. A randomized clinical trial of implantable drug systems showed better clinical pain relief, less systemic side effects, and a tendency toward increased survival in the treatment of cancer pain [8].

The following two cases describe clinical scenarios where directed drug delivery via an intrathecal pump would be indicated and how the progression of disease ultimately was the reason to proceed or the reason to not proceed with an intrathecal pump placement. Intrathecal drug delivery is an especially useful method to very quickly adjust and meet increasing opioid requirements while minimizing side effects.

Case 4: A 35-year-old woman who was recently diagnosed with adenocarcinoma of the rectum in the setting of Crohn’s disease presents for consultation with the interventional pain team 6 months after being diagnosed. The patient’s pain first started with increasing perineal discomfort and pain. She underwent imaging studies with MRI of Fig. 2.3 CT of the chest and abdomen with contrast showing right-­ sided chest wall mass responsible for patient’s first onset of chest wall the abdomen and pelvis which showed enlarged perirectal pain (arrows) lymph nodes and three irregular hypodense masses in the

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liver which were suspicious for metastatic disease. Liver biopsy would confirm metastatic disease and rectal cancer.

Further imaging showed perirectal nodal disease and distant mets to the liver, pleura, left adrenal, and bone.

The patient’s perirectal pain progressed to include saddle anesthesia, with pain in the right buttock radiating around laterally into the right groin and intermittent right first toe paresthesia. Additional workup was consistent with extensive disease from T12 through the sacrum, an L5 fracture, left foraminal narrowing due to metastasis at L4–L5 and L5– S1, and presacral extraosseous disease with right S2–S3 sacral nerve root impingement (Fig. 2.4a and b). She denies bowel or bladder incontinence and noted no weakness in the lower extremities. Interventional radiology and the pain service were consulted for on input on symptomatic treatment of the pain in conjunction with ongoing chemotherapy.

Radiation therapy to the sacral spine was started along with an oral steroid regimen.

The patient and pain practitioner’s initial goal was to alleviate as much of the patient’s perineal paresthesias and radicular pain as possible. Review of the MRI showed no disease at the sacral hiatus, and a caudal epidural steroid injection was planned. The patient’s INR was elevated likely due to hepatic involvement and was treated with vitamin K. Once the coagulopathy improved, a caudal epidural steroid injection was performed with moderate relief of radicular pain.

She continued to have midline sacral pain. Directed drug delivery via an intrathecal pump was discussed given the fast progression of the disease after completion of radiation therapy. Unfortunately, the patient’s disease would continue to progress aggressively and left her with a limited prognosis affecting her risk and benefit profile for intrathecal pump placement. The benefits of the procedure did not outweigh the risks and costs for placement of an intrathecal pump.

Further goals of care were discussed with the patient, and a plan for hospice initiation was determined. The patient’s pain was managed with hydromorphone PCA. Patient’s may often have pain that is amenable to directed drug delivery via intrathecal pump; however it is important to reconcile the patient’s wishes and beliefs regarding palliation with the risks and benefits of the procedure. An intrathecal pump placement can improve patient’s ability to be functional, and often pain is a short-term setback before the benefits are achieved.

Case 5: A 36-year-old male with a history of sacral spindle cell sarcoma metastatic to the pelvis presented to the inpatient pain service after having had a left-sided hind-quarter amputation (Fig. 2.5). The consultation is called for acutely worsened pain in the left groin and pelvis on an inpatient basis. An epidural catheter had been placed perioperatively for acute pain control, but a plan for intrathecal drug delivery had simultaneously been discussed with the patient.

The epidural was dosed with a combination of hydromorphone and bupivacaine solution. An epidural trial of medica-

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a

b

Fig. 2.4 (a) Left MRI sacrum showing bilateral sacral metastases have increased with bilateral presacral extraosseous disease. The right sacral ala with metastasis infiltrates into the S2 and to a greater extent the S3 neural foramina (arrows). (b) Right MRI lumbar spine consistent with osseous metastases involving almost every level throughout the cervical, thoracic, and lumbar spine (arrows at L1, L2, and L5 vertebral disease with epidural extension at L5)

tion can often be considered when considering the efficacy of neuraxial medicine prior to intrathecal pump placement.

The patient noted improved pain control and side effect pro-

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The Practice of Cancer Pain: A Case Series

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and adjust the therapeutic plan as patients’ underlying pathology, treatments, and goals of care change. Most important is having a low threshold to consider that an initial underlying pathology has changed and may require new diagnostics or a change in management. Ultimately the goal is optimal pain relief and to give patients a chance to enhance their quality of life and functionality. Each patient has personal goals, and it is these benchmarks that should guide therapy. Each patient’s case provides an opportunity for reflection and reminds pain practitioners to learn, advance, and develop algorithms to best treat each patient.

References Fig. 2.5 CT of the chest, abdomen, and pelvis shows necrotic left pelvic mass centered at the left iliopsoas muscle and extending into the peritoneum (arrows)

file from decrease in systemic opioid treatment. An intrathecal pump was placed without any side effects or complications, and the patient returned for subsequent outpatient visits and for adjustment of dose over the next few months. Ultimately the cancer progressed, and various combinations and doses of intrathecal medications were titrated to alleviate the pain.

A retrospective case study of 46 cancer patients who had an epidural trial discussed how to use a patient’s pre-pump systemic opioid requirements to calculate an appropriate intrathecal dose without having to do an epidural trial [8].

There are several ways to trial a patient for neuraxial directed drug delivery, but epidural trial can be a reasonable option for patients who are in the hospital.

Conclusion This chapter highlights several different cases that can represent challenges to interventional pain physicians when treating cancer patients. It is crucial to continuously challenge

1. NIH: National Cancer Institute. Cancer statistics. https://www.cancer.gov/about-cancer/understanding/statistics 2. Van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007;18(9):1437–49.

3. American Pain Society (APS). Principles of analgesic use in the treatment of acute pain and cancer pain. 6th ed. Glenview: American Pain Society; 2008.

4. National Comprehensive Cancer Network. Clinical practice guidelines in oncology for adult cancer pain. V. 1.2010. Fort Washington: National Comprehensive Cancer Network. 2010. Available at: www.nccn.org. Accessed 1 Nov 2010.

5. Van Lancker A, Velghe A, Van Hecke A, Verbrugghe M, Van Den Noortgate N, Grypdonck M, Verhaeghe S, Bekkering G, Beeckman D. Prevalence of symptoms in older cancer patients receiving palliative care: a systematic review and meta-analysis. J Pain Symptom Manag. 2014;47(1):90–104. https://doi.org/10.1016/j. jpainsymman.2013.02.016.

6. Borgsteede SD, et al. Symptoms in patients receiving palliative care: a study on patient-physician encounters in general practice.

Palliat Med. 2007;21:417–23.

7. Higginson IJ, Evans CJ. What is the evidence that palliative care teams improve outcomes for cancer patients and their families? Cancer J. 2010;16(5):423–35. https://doi.org/10.1097/ PPO.0b013e3181f684e5.

8. Malhotra VT, Root J, Kesselbrenner J, Njoku I, Cubert K, Gulati A, Puttanniah V, Bilsky M, Kaplitt M. Intrathecal pain pump infusions for intractable cancer pain: an algorithm for dosing without a neuraxial trial. Anesth Analg. 2013;116(6):1364–70.

Part II Cancer Pain Syndromes

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Pathophysiology of Cancer Pain Stephen Lawrence Thorp

Introduction The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [1]. Pain is prevalent among patients with cancer, with a systematic review finding pain prevalence to be 66.4% in advanced metastatic or terminal disease, 55% during anticancer treatment, 39.3% after curative treatment, and moderate to severe pain being reported in 38.0% of all patients [2]. Adequate control of pain can improve patient’s quality of life through improved mood, functional status, and rest, among other things. Pain may even be related to survival [3]. Cancer-related pain is unique and may be related to the anatomic location of the tumor, pathophysiology of the tumor, or treatment of the tumor. Similarly, the origin of the pain itself can be somatic, visceral, neuropathic, or mixed in nature. Given the complexity of cancer pain and its multiple etiologies, it is critical to assess the pathophysiology of the cancer and its role in creating a pain syndrome.

Anatomic Location of Tumors Pathophysiology of Bone Tumor Pain The location of a tumor is often the direct cause of significant pain for patients. As an example, tumors in the bone are one of the most common sources of pain in patients with cancer.

There are multiple types of primary benign and malignant bone tumors, and metastasis to bone is common [4]. When tumors metastasize to the bone, the route is most commonly hematogenous but can also be due to contiguous spread or

via lymphatics. The vertebrate is the most common site of metastasis; however the pelvis, ribs, femur, and skull are also common sites. Patients typically present with well-localized pain that worsens with weight bearing and activity and is tender to palpation on physical examination.

The etiology of bone pain is complex and not fully understood [5]. The periosteum and marrow cavity are both innervated by peripheral nociceptors capable of causing pain. In animal studies, it has been shown that sensory and sympathetic neurons innervate the bone, with the periosteum having the densest innervation followed by the bone marrow [6]. The sensory fibers that innervate the bone differ from more well-characterized afferents that innervate the skin. Bone is innervated primarily by A-delta fibers, and there is very little innervation by either C-fibers or A-β fibers [7]. Sharp nociceptive bone pain is likely transmitted by the A-δ fibers, and the dull ache is transmitted from the C-fibers that become sensitized. Bone pain likely has a neuropathic component as well, as invading tumor cells injure sensory fibers [8].

When bone is invaded by cancer cells, a release of inflammatory mediators such as prostaglandin E2 (PGE2) sensitizes the peripheral nociceptors. This mechanism underlies the role for nonsteroidal anti-inflammatory (NSAIDS) agents in treating bone pain. Metastasis and primary tumors can be lytic, due to increased osteoclastic activity, or sclerotic, due to increased osteoblastic activity, both of which induce mechanical instability in the bone [9]. The instability in the bone may eventually manifest as a vertebral compression fractures (VCF) if the tumor is located in the vertebral body.

Fractures localized within the vertebral body may be treated with vertebral augmentation techniques such as kyphoplasty; however, more severe fractures resulting in neurological dysfunction and severe pain may require surgical stabilization.

S. L. Thorp (*) Pain Medicine, Northwell Health Phelps Hospital, Sleepy Hollow, NY, USA e-mail: sthorp@northwell.edu © Springer Nature Switzerland AG 2019 A. Gulati et al. (eds.), Essentials of Interventional Cancer Pain Management, https://doi.org/10.1007/978-3-319-99684-4_3

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Etiologies of Neuropathic Pain Accordingly, tumor location in close proximity to neural structures can lead to neurological impairment and neuropathic pain. Neoplastic plexopathy represents a severe and difficult to treat form of cancer pain. Neoplastic plexopathy arises when a tumor progresses to involve one of the main plexuses; the cervical, brachial, or lumbosacral plexus. Treatment for tumor-induced plexopathies may involve surgical or radiation therapy, in addition to neuropathic pain medications.

The cervical plexus contains contributions from the C1, C2, C3, and C4 spinal nerves and provides innervation for the muscles of the neck as well as the prevertebral muscles.

Impingement upon this plexus by tumor can result in cervical plexopathy, which typically presents with pain in the neck, shoulder, or throat. Weakness in the shoulder is related to weakness in the trapezius and sternocleidomastoid muscles, which are innervated by the spinal accessory nerve. The patient may also have shortness of breath, particularly if there is underlying pulmonary pathology, due to involvement of the phrenic nerve and hemidiaphragmatic paralysis.

Cervical plexopathy is most commonly associated with head and neck tumors and lymphomas but may also be due to lung and breast cancers [10]. The cervical plexus can be blocked superficially resulting in cutaneous analgesia, or by anesthetizing the C2, C3, and C4 spinal nerves as they exit their respective cervical foramina, or the deep cervical plexus.

Far more common than tumors impacting the cervical plexus are tumors compressing the brachial plexus. The brachial plexus is composed of the ventral rami of C5–T1 in most individuals, with occasional contributions from C4 and T2 spinal nerves. The nerve roots exit the foramina and travel anterolateral between the anterior and middle scalene muscles, where they combine to form superior, middle, and interior trunks. At approximately the level of the first rib, these trunks again divide into an anterior and posterior division, which then form the lateral, medial, and posterior cords, so-­ named for their relation to the axillary artery. The three cords then divide into the peripheral nerves which supply innervation to the upper extremities.

Brachial plexopathy is most commonly associated with lung and breast cancer. Superior sulcus, or Pancoast, tumors are located at the apex of the lung and may impinge upon the brachial plexus. The clinical presentation of the plexopathy is related to where the plexus is impacted. The most commonly affected portion of the brachial plexus is the lower roots, and patients often present with radicular pain and radiculopathies in an ulnar nerve distribution. When head and neck neoplasms impact the brachial plexus, they typically affect the upper cervical roots and superior trunk, causing pain more commonly in a median or radial nerve distribution.

The lumbar and sacral plexus provide innervation to the lower extremity. The lumbar plexus is comprised of the ven-

S. L. Thorp

tral rami of the L1–L4 spinal nerves, with variable contributions from the T12 and L5 spinal nerves. The plexus lies in the psoas compartment located between the quadratus lumborum and psoas muscles and is composed of dorsal and ventral divisions. The main branches of the lumbar plexus include the femoral, obturator, and lateral femoral cutaneous nerves as well as the iliohypogastric, ilioinguinal, and genitofemoral nerves. The sacral plexus arises from S1–S3 giving rise to the sciatic nerve posteriorly, which then forms the common peroneal and tibial nerves, as well as the pudendal nerve which provides sensation to the perineal area.

The most common tumors invading this plexus are colorectal, sarcomas, and genito-ureteral tumors, with the sacral plexus being involved more commonly than the lumbar plexus. When the lumbar plexus is involved, the most common presenting symptom is leg pain, followed by numbness and weakness [11]. As the plexus lies in the psoas compartment, tumors affecting the psoas muscle can cause significant pain, termed malignant psoas syndrome [12].

When the sacral plexus is involved, the clinical picture can present with pain down the posterior aspect of the leg and weakness in the foot, similar to an S1 radiculopathy. The patient may also present with perineal pain and incontinence in later stages. Diagnosis of neoplastic plexopathy is confirmed with magnetic resonance imaging (MRI) and positron emission tomography (PET) to identify areas of active neoplasm in or abutting the plexus. Electromyography (EMG) can be used to further elucidate which nerves are most affected and guide treatment.

ther Associated Pathophysiology O for Anatomic Cancer-Related Pain While pain related to tumor in the bone and nervous system structures is the most common cause of anatomical pain, other anatomical locations may generate pain as well.

Tumors in the brain are well known to cause headaches, as are metastasis to the spinal meninges [13]. Distension of capsular organs is another well-known cause of tumor-­ related pain as occurs when liver tumors distend Glisson’s capsule causing abdominal pain [14]. In all of these examples, the primary treatment of cancer pain is treatment of the cancer and any therapies that remove or reduce the size of the tumor.

Chemical Mediators of Pain The tumor microenvironment (TME) is composed of tumor cells and stromal cells and has a substantial role in tumor progression and cancer-mediated pain [15]. Tumor and stromal cells communicate with each other, their microenviron-

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Pathophysiology of Cancer Pain

ment, as well as the tissue they are invading by secreting multiple noxious chemical factors, inflammatory mediators, and immunomodulators. These stimuli are transduced at peripheral nociceptors and transmitted via an action potential to the spinal cord and travel via ascending tracts to the supraspinal processing centers. While this likely plays a role in all cancers, the details of a few specific examples have been elucidated.

athophysiology of Pain in Patients P with Multiple Myeloma Multiple myeloma is a malignant cancer of plasma cells that results in a unique pain syndrome referred to as myeloma bone disease. Bone pain is the most common symptom reported at presentation, in more than two-thirds of patients, and 80–90% of patients with multiple myeloma will develop bone lesions during their disease [16]. The etiology of this bone pain is likely dysregulation in bone remodeling. Normal bone remodeling is a continuous process of old bone resorption stimulated by osteoclasts and new bone formation through collagen synthesis and mineralization by osteoblasts. When multiple myeloma metastasizes to the bone, it induces bone resorption by activating osteoclasts. The myeloma cells release and stimulate cells in the bone marrow microenvironment to release osteoclastogenic activating factors such as RANKL, MIP-1α, TNF-α, interleukin 3 (IL-­ 3), and IL-6 [17]. In addition to the stimulation of osteoclast formation and activity, many of these factors are also involved in the inhibition of osteoblastic activity as well as a supportive role for myeloma cells themselves.

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In addition to inflammatory cytokines inducing inflammation and sensitization of peripheral nociceptors, cytokines may also be involved in noninflammatory pain. TGF-β is a cytokine that has been implicated in regulating osteoclasts and mediating bone resorption, as occurs with metastasis to bone. TGF-β is released by chondrocytes during bone injury and may mediate the production of nerve growth factor (NGF) in chondrocytes as well [19]. Further, TGF-β has been shown to be inhibited by proinflammatory cytokines and, as such, may be a noninflammatory mediator of pain in metastatic bone pain. The stimulation of osteoclastogenesis may also lead to the release of growth factors and other mediators that may cause the growth of the invading tumor cells.

Novel Therapies for Cancer-Related Pain

The treatment of cancer pain is multifaceted and discussed throughout this text. The most important treatment of cancer pain is treatment of the cancer itself. Treatments in the form of surgery, radiation therapy, chemotherapy, interventional treatments, and medication management are at the forefront of treatment. These treatments may be the cause of, or contribute to, the patient’s pain as well, as with chronic postsurgical pain, radiation-induced neuritis, or chemotherapy-induced peripheral neuropathy, to name a few examples. In recent years there has been increased interest in treatments that target the pathophysiology of the cancer. These same molecular targets are also potential targets for the treatment of pain, as these therapies that target the cytokine and inflammatory mediators released by tumors and inhibit tumor growth also decrease tumor-related pain.

Bone-related pain and the molecular causes of the pain are now being targeted as pain therapies. One such molecule is Src, a protein tyrosine kinase non-receptor that is associ Pathophysiology of Cancer Pain in Patients with Breast Cancer ated with the N-methyl-D-aspartate (NMDA) receptor complex. Found in neurons, Src has been shown to be associated Breast cancer, in addition to causing pain with metastasis to with pain and maintaining inflammatory hyperalgesia [20]. sites such as the bone and compressing neural structures as Further, Src has a vital role in osteoclast activity. By targetdiscussed previously, causes pain through the release of ing this molecule involved in bone resorption, there is potenchemical mediators as well. The tumor and stromal cells tial to decrease the breakdown of bone and thus one aspect of release and induce host release of numerous mediators of the bone pain itself. Bisphosphates are another well-known pain. The amount and content of circulating cytokines have treatment that inhibits osteoclast-mediated bone resorption been shown to be not only distinct to subtype of breast can- by reducing osteoclast activity [21]. While effective in reduccer but potentially to the amount of pain suffered by patients ing osteoclastic activity, bisphosphonates do not impact as well. Luminal type A and B breast cancers exhibit higher osteoblastic activity and have numerous potential side effects levels of TGF-β1 and TNF-α than healthy controls, and TGF-­ including renal impairment and osteonecrosis of the jaw. β1 levels are higher in HER2-amplified tumors than luminal Further, bisphosphonates have been shown to inhibit the types [18]. In contradistinction, triple-negative tumors have ability of the metastasis to interact with the osteoblasts and lower circulating levels of TGF-β1 when compared with inhibit their secretion of chemokine CCL2 [22].

The treatment of myeloma bone disease is multifaceted other subtypes and healthy volunteers. While the different cytokine profiles of tumors are currently under investigation, and involves mediation management, radiation therapy, chemotherapy, vertebral augmentation, and surgery. The underthe direct relationship with pain is still being elucidated.

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S. L. Thorp

Table 3.1 Potential targets for the treatment of myeloma bone disease

References

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2. Van Den Beuken-Van Everdingen MHJ, Hochstenbach LMJ, Joosten BEAJ, Tjan-Heijnen VCG, Janssen DJA. Update on prevalence of pain in patients with Cancer: systematic review and meta-­ analysis. J Pain Symptom Manag. 2016;51(6):1070–90. n. pag.

OPG osteoprotegerin, RANK receptor activator of nuclear factor kappaWeb. ­B, MIP-1 alpha macrophage inflammatory protein-1 alpha, VEGF vas3. Koizumi M, Yoshimoto M, Kasumi F, Iwase T, Ogata E. Post-­ cular endothelial growth factor, SDF-1 alpha stromal-derived factor-1 operative breast Cancer patients diagnosed with skeletal metastasis alpha, WIF-1 wnt inhibitory factor-1, SFRPs secreted frizzled-related without bone pain had fewer skeletal-related events and deaths than proteins, Dkk Dickkorf family of secreted proteins, Runx2 runt-related those with bone pain. BMC Cancer. 2010;10(1):423. Web. transcription factor 2, TGF-beta transforming growth factor-beta 4. Fletcher CDM. WHO classification of tumours of soft tissue and bone. Lyon: IARC; 2013. Print.

5. Nencini S, Ivanusic JJ. The physiology of bone pain. How much do we really know? Front Physiol Front Physiol. 2016;7:157. n. pag. lying pathophysiology discussed previously has also become Web. a target for therapy. Bisphosphonates, discussed previously, 6. Mach DB, Rogers SD, Sabino MC, Luger NM, Schwei MJ, are a mainstay of therapy for multiple myeloma. In addition Pomonis JD, Keyser CP, Clohisy DR, Adams DJ, O’Leary P, Mantyh PW. Origins of skeletal pain: sensory and sympathetic to bisphosphonates, a number of mediators known to be innervation of the mouse femur. Neuroscience. 2002;113(1):155– involved in the pathogenesis of myeloma bone pain are cur66. Web. rently being investigated as potential therapeutic targets, and 7. Jimenez-Andrade JM, Mantyh WG, Bloom AP, Haili X, Ferng AS, there is tremendous potential for such agents (Table 3.1).

Dussor G, Vanderah TW, Mantyh PW. A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus One such agent, bortezomib, is a proteasome inhibitor that skin: therapeutic opportunity for treating skeletal pain. Bone. has been found to improve the survival of patients with mul2010;46(2):306–13. Web. tiple myeloma [23].

8. Ohtori S, Orita S, Yamashita M, Ishikawa T, Ito T, Shigemura Pain related to breast cancer may be related to many of the T, Nishiyama H, Konno S, Ohta H, Takaso M, Inoue G, Eguchi Y, Ochiai N, Kishida S, Kuniyoshi K, Aoki Y, Arai G, Miyagi topics discussed previously, including compression of neural M, Kamoda H, Suzkuki M, Nakamura J, Furuya T, Kubota G, structures and metastasis to bone. As in the treatment of Sakuma Y, Oikawa Y, Suzuki M, Sasho T, Nakagawa K, Toyone myeloma bone pain, there are many potential novel therapies T, Takahashi K. Existence of a neuropathic pain component in being investigated that may be used to not only treat the cancer patients with osteoarthritis of the knee. Yonsei Med J Yonsei Med J. 2012;53(4):801. Web. but the pain it causes as well. It has been shown that altered 9. Arrington SA, Schoonmaker JE, Damron TA, Mann KA, Allen glutamatergic signaling can disrupt the normal cycle of bone MJ. Temporal changes in bone mass and mechanical properties in a remodeling and cause significant pain [24]. Utilizing inhibimurine model of tumor osteolysis. Bone. 2006;38(3):359–67. Web. tors of glutamate release from the cancer cells is one such 10. Jaeckle K. Neurologic manifestations of neoplastic and radiation-­ induced Plexopathies. Semin Neurol. 2010;30(03):254–62. Web. novel therapeutic approach. Sulfasalazine is an inhibitor of glutamate release that has been shown to reduce nociceptive 11. Jaeckle KA, Young DF, Foley KM. The natural history of lumbosacral plexopathy in cancer. Neurology. 1985;35(1):8. Web. behavior in a mouse model of breast cancer bone pain [25]. 12. Stevens MJ, Atkinson C, Broadbent AM. The malignant psoas synThe continued investigation of further treatments related to the drome revisited: case report, mechanisms, and current therapeutic options. J Palliat Med. 2010;13(2):211–6. Web. pathophysiology of breast cancer pain will continue to change 13. Fizazi K, Asselain B, Vincent-Salomon A, Jouve M, Dieras the management of the cancer itself and the pain it causes.

V, Palangie T, Beuzeboc P, Dorval T, Pouillart P. Meningeal Carcinomatosis in patients with breast carcinoma: clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer. 1996;77(7):1315–23. Web. Conclusion 14. Mehrabi A, Kashfi A, Fonouni H, Schemmer P, Schmied BM, Hallscheidt P, Schirmacher P, Weitz J, Friess H, Buchler Cancer pain is difficult to treat and a terrible malady for MW, Schmidt J. Primary malignant hepatic epithelioid those suffering from cancer. Traditional therapies continue to Hemangioendothelioma. Cancer. 2006;107(9):2108–21. Web. be the standard of care and involve medication management, 15. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423–37. Web. radiation therapy, chemotherapy, vertebral augmentation, 16. Hameed JB, Dowling P, Clynes M, O’Gorman P. Bone disease and surgery, among other therapies. New studies that eluciin multiple myeloma: pathophysiology and management. CGM date the pathophysiology of individual cancers open the door Cancer Growth Metastasis. 2014;7:33. Web. for novel therapies that may target the cancers as never done 17. Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease of multiple myeloma. Bone. 2008;42(6):1007–13. Web. before. As new therapies evolve, the treatment of cancer-­ 18. Panis C, Pavanelli WR. Cytokines as mediators of pain-related prorelated pain will evolve as well, ushering in a new paradigm cess in breast cancer. Mediat Inflamm. 2015;2015:1–6. Web. Osteoclast mediators OPG RANK MIP-1 alpha VEGF SDF-1 alpha

of treatment for our patients.

Osteoblast mediators WIF-1 SFRPs Dkk Runx2 TGF-beta

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Pathophysiology of Cancer Pain

19. Davidson ENB, Van Caam APM, Vitters EL, Bennink MB, Thijssen E, Van Den Berg WB, Koenders MI, Van Lent PLEM, Van De Loo FAJ, Van Der Kraan PM. TGF-β is a potent inducer of nerve growth factor in articular cartilage via the ALK5-Smad2/3 pathway. Potential role in OA related pain? Osteoarthr Cartil.

2015;23(3):478–86. Web. 20. De Felice M, Lambert D, Holen I, Escott KJ, Andrew D. Effects of Src-kinase inhibition in cancer-induced bone pain. Mol Pain.

2016;12(0): n. pag. Web. 21. Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest. 1996;97(12):2692–6. Web. 22. Kaiser T, Teufel I, Geiger K, Vater Y, Aicher WK, Klein G, Fehm T. Bisphosphonates modulate vital functions of human osteoblasts

17 and affect their interactions with breast Cancer cells. Breast Cancer Res Treat. 2013;140(1):35–48. Web. 23. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2007;111(5):2516–20.

Web. 24. Fazzari J, Lin H, Murphy C, Ungard R, Singh G. Inhibitors of glutamate release from breast Cancer cells; new targets for Cancer-­ induced bone-pain. Sci Rep Sci Rep. 2015;5:8380. Web. 25. Ungard RG, Seidlitz EP, Singh G. Inhibition of breast Cancer-cell glutamate release with sulfasalazine limits Cancer-induced bone pain. Pain. 2014;155(1):28–36. Web.

4

Chemotherapy Karina Gritsenko and Michael Lubrano

Introduction In this chapter, the most common chemotherapeutic agents, a number of their uses, and most of their relevant side effects are addressed. For some compounds, their uses may extend further than just neoplastic therapies as a number of inflammatory diseases benefit from immune modulation. For the purposes of our review, only antineoplastic uses and their adverse effects will be mentioned.

affect all phases of the cell cycle, with the majority focusing on S phase (antimetabolites) or M phase (taxanes and vinca alkaloids) [2–5]. A summary of antineoplastic agents, by class, is included in Table 4.1.

Alkylating Agents

Alkylating agents are a large and diverse class of agents that actively cross-link DNA strands in order to reduce the synthesis of DNA during all steps of the cell cycle. Subcategories Chemotherapeutic Classes include alkyl sulfonates, bioreductives, nitrogen mustards, nitrosoureas, and triazenes. Alkyl sulfonate (busulfan) priChemotherapeutic agents are subdivided into major classes marily interacts with guanosine at the N-7 position in order and then subcategories. Therapies are grouped according to to disrupt RNA transcription and the replication of DNA. It which component of the cell cycle they impair and the mech- is especially effective in hematologic cells with considerable anism by which this occurs. Tumor cells are rapidly growing, efficacy on myeloid cells compared to lymphoid cells. Alkyl and dividing entities thus are more susceptible to interven- bioreductives (mitomycin C) are most active during late-G1 tions that impair cellular division, triggering a cascade and early-S phases of the cell cycle. It is converted to an toward cell destruction. The cycle for somatoform non-­ alkylating metabolite and functions as such by cross-linking gamete developing cells begins with G1 phase. The cell pre- nucleotides, primarily guanine and cytosine, thus disrupting pares for division by expressing RNA and proteins which cell activity. DNA and RNA syntheses are also impaired. allow the cell to grow in anticipation of future cell division. Reduced environments, such as hypoxic tumor cells, increase The next phase, S, allows for DNA replication. G2 phase the effectiveness of this agent. Nitrogen mustards (cyclosubsequently occurs with a number of checkpoints to assure phosphamide, mechlorethamine, melphalan, chlorambucil) the cell is ready to appropriately divide. The final phase is M include a myriad of agents that are effective in cross-linking phase, which occurs directly before cell division, with its DNA strands to impair DNA synthesis. As such, they are hallmark mitotic spindle that develops down the center of a active during all phases of the cell cycle. Nitrosoureas (carcell prior to division, aligning and separating chromosomes mustine, lomustine, semustine, streptozocin) also cross-link to opposite, cellular poles [1]. Chemotherapeutic agents may DNA and RNA strands but may have a secondary function of modifying and disrupting proteins as well. Given their lipid-­ soluble nature, nitrosoureas are able to cross the blood-brain K. Gritsenko (*) barrier in order to treat tumors of the central nervous Montefiore Medical Center – Albert Einstein College of Medicine, system.

Bronx, NY, USA Busulfan is an alkylating agent used in chronic myelogeM. Lubrano nous leukemia with up to 90% remission. Seizures have been Department of Anesthesia & Perioperative Care, University of reported in patients who are predisposed to them, and proCalifornia San Francisco (UCSF) Medical Center, San Francisco, CA, USA phylactic anticonvulsants may be administered prior to e-mail: Michael.Lubrano@ucsf.edu

© Springer Nature Switzerland AG 2019 A. Gulati et al. (eds.), Essentials of Interventional Cancer Pain Management, https://doi.org/10.1007/978-3-319-99684-4_4

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K. Gritsenko and M. Lubrano

Table 4.1 Summary of agents Class Alkyl sulfonate

Agent Busulfan

Bioreductive

Mitomycin C

Uses CML

Nitrosourea

Adenocarcinomas of the stomach/pancreas, anal carcinoma, bladder cancer, cervical cancer, esophageal cancer, non-small cell lung cancer Cyclophosphamide Breast cancer, ALL/AML/CLL/CML, Ewing’s sarcoma, Hodgkin’s/non-Hodgkin’s lymphoma, multiple myeloma, mycosis fungoides, pheochromocytoma, small-cell lung cancer, Wilm’s tumor Carmustine Astrocytomas, ependymomas, glioblastomas, medulloblastomas, multiple myeloma, Hodgkin’s/ non-Hodgkin’s lymphoma, mycosis Streptozocin Adrenal carcinoma, pancreatic islet cell carcinoma

Triazene

Dacarbazine

Triazene Folate

Temozolomide Methotrexate

Folate

Pemetrexed

Platinum analog

Cisplatin

Platinum analog

Carboplatin

Platinum analog

Oxaliplatin

Purine analog

Mercaptopurine

Purine analog

Thioguanine

Purine analog

Hydroxyurea

Pyrimidine analog

5-Fluorouracil (5-FU)

Pyrimidine analog

Capecitabine

Pyrimidine analog

Cytarabine

Nitrogen mustard

Nitrosourea

Melanoma, Hodgkin’s lymphoma, medullary carcinoma pheochromocytoma, medullary carcinoma Gliomas, refractory astrocytoma Acute lymphoblastic leukemia, breast cancer, central nervous system tumors, head and neck cancer, lung cancers, meningeal leukemia, trophoblastic neoplasms

Adverse effects Adrenal insufficiency, bone marrow suppression, seizures, pulmonary fibrosis, hepatic sinusoidal obstruction syndrome, cardiac tamponade Bladder fibrosis, hemolytic uremic syndrome, pulmonary toxicity Acute respiratory distress syndrome, bladder cancer, cardiotoxicity, hemorrhagic cystitis, infertility, pneumonitis Bone marrow suppression, ocular toxicity, pulmonary toxicity, renal impairment Bone marrow suppression, glucose intolerance, confusion/lethargy, depression Anaphylaxis, extravasation

Pneumocystis jirovecii pneumonia Acute kidney injury, bone marrow suppression, dermatologic reactions, diarrhea/stomatitis, infertility, hepatotoxicity, neurotoxicity, pneumonitis, tumor lysis syndrome Bone marrow suppression, Bladder cancer, cervical cancer, ovarian cancer, pleural mesothelioma, non-squamous non-small cell lung cancer, dermal reactions, GI toxicity, hepatotoxicity, interstitial pneumonitis thymus cancer Bladder cancer, breast cancer, cervical cancer, endometrial Anaphylaxis, extravasation, hyperuricemia, cancer, esophageal and gastric cancer, hepatobiliary cancer, gastroenteric toxicity, neurotoxicity, ototoxicity, renal toxicity, posterior Hodgkin’s lymphoma, testicular cancer, ovarian cancer, reversible leukoencephalopathy syndrome neuroblastoma, neuroendocrine tumors (PRES) Similar to cisplatin with less gastrointestinal Advanced ovarian cancer, Merkel cell carcinoma, small-cell lung cancer, thymic malignancies, others similar and renal toxicity to cisplatin Anaphylaxis, GI toxicity, neuropathy, Colorectal cancer, esophageal cancer, gastric cancer, hepatic toxicity, pulmonary fibrosis, pancreatic cancer, hepatobiliary cancer, ovarian/testicular posterior reversible leukoencephalopathy cancer syndrome (PRES) Acute lymphoblastic leukemia, acute promyelocytic Bone marrow suppression, hepatotoxicity, leukemia, non-Hodgkin’s lymphoma immunosuppression, secondary malignancies Adult acute myelogenous leukemia Bone marrow suppression, hepatotoxicity, malignancies, tumor lysis syndrome Chronic myelocytic leukemia, ovarian cancer, melanoma, Bone marrow suppression, megaloblastic meningiomas, squamous head and neck cancer erythropoiesis, vascular ulceration, gangrene, secondary malignancy, tumor lysis syndrome Breast cancer, bladder cancer, colon cancer, gastric cancer, Palmar-plantar erythrodysesthesia (hand-­ foot) syndrome, diarrhea, neurotoxicity, head and neck cancers, hepatobiliary cancers, neutropenia neuroendocrine cancers, pancreatic cancer Metastatic colon cancer, similar tumor profile as 5-FU Bone marrow suppression, cardiotoxicity, gastrointestinal toxicity, hand-foot syndrome, hepatotoxicity Acute lymphocytic leukemia, acute myelocytic leukemia, Acute pancreatitis, bone marrow suppression, hypersensitivity, respiratory chronic myelocytic leukemia in blast phase, chronic arrest, tumor lysis syndrome lymphocytic leukemia, meningeal leukemia, refractory Hodgkin’s lymphoma

4 Chemotherapy

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Table 4.1 (continued) Class Pyrimidine analog

Agent Gemcitabine

Anthracycline Doxorubicin

Antibiotic

Bleomycin

Vinca alkaloid Vincristine

Vinca alkaloid Vinblastine

Taxane

Paclitaxel

Uses Bladder cancer, cervical cancer, Hodgkin’s/non-Hodgkin’s lymphoma, metastatic breast cancer, non-small cell lung cancer, ovarian cancer, pancreatic adenocarcinoma, renal cell cancer, small-cell lung cancer, sarcomas, testicular cancer, thymic malignancies Acute lymphocytic leukemia, acute myeloid leukemia, breast cancer, sarcomas of the soft tissues and bone, thyroid cancer, small-cell lung cancer, gastric cancer, neuroblastoma, Wilm’s tumor Cervical cancer, penis carcinoma, head and neck squamous cell carcinoma, Hodgkin’s/non-Hodgkin’s lymphoma, ovarian germ cell tumors, testicular carcinoma Acute lymphocytic leukemia, chronic lymphocytic leukemia, Ewing’s sarcoma, gestational trophoblastic tumors, Hodgkin’s/non-Hodgkin’s lymphoma, multiple myeloma, small-cell lung cancer, Wilm’s tumor, neuroblastoma, retinoblastoma, rhabdomyosarcoma Bladder cancer, breast cancer, choriocarcinoma desmoid tumors, Hodgkin’s/non-Hodgkin’s lymphoma, Kaposi’s sarcoma, melanoma, ovarian cancer, testicular cancer Adenocarcinoma, bladder cancer, breast cancer, head and neck cancers, Kaposi’s sarcoma, non-small cell lung cancer, ovarian cancer, small-cell lung cancer

t­herapy initiation in cases where high doses may be anticipated. Pulmonary fibrosis and bronchopulmonary dysplasia can occur with an average of 4 years after treatment in up to 4% of patients. Hepatic sinusoidal obstruction syndrome may occur and is associated with high concentrations as a result of rapid infusion. This risk is increased with doses over 16 mg/kg based on ideal body weight. With pulmonary symptoms, it is important to rule out opportunistic infections as well as leukemic infiltrates before diagnosing busulfan toxicity. This may require biopsy of the lung. If toxicity is diagnosed, busulfan should be discontinued immediately.

Mitomycin C is an alkylating agent effective against a number of GI adenocarcinomas. It can be used alongside 5-fluorouracil for squamous cell cancer of the anus. As a vesicular infusion, it may also be used to topically treat bladder cancer. Bladder fibrosis is a common side effect. Patient may also experience pulmonary toxicity and hemolytic uremic syndrome.

Cyclophosphamide is a nitrogen mustard most frequently utilized clinically in a large number of oncologic and inflammatory settings, including hematologic, adrenal, and lung cancers. Hepatocytes metabolize cyclophosphamide to aldophosphamide, which is further converted into toxic compounds by cells throughout the body, including target tumor cells. These toxic compounds thus function as alkylating agents. High doses of cyclophosphamide may cause cardiotoxicity by damaging endothelial capillaries. This can lead to pericarditis or pericardial effusions and may eventually develop into a cardiac tamponade [6]. ACE inhibitors, inotropes, beta-blockers, and diuretics can help to manage car-

Adverse effects Bone marrow suppression, capillary leak syndrome (CLS), hemolytic uremic syndrome (HUS), pulmonary toxicity

Bone marrow suppression, cardiac toxicity, secondary malignancy, skin extravasation, tumor lysis syndrome Hepatotoxicity, renal toxicity, pulmonary toxicity, idiosyncratic reaction Gastrointestinal toxicity, neurotoxicity, respiratory complications, uric acid nephropathy

Disabling neurotoxicity, peripheral sensory neuropathy Bone marrow suppression, cardiovascular toxicity, hypersensitivity reactions, peripheral neuropathy

diotoxicity. Pneumonitis is rare and can be reversed with early discontinuation within the first several months of use.

Pleural thickening is associated with late-onset pneumonitis which may become a chronic, progressive condition [7].

Interstitial cystitis and bladder cancer are additional concerns, as acrolein (a toxic metabolite of cyclophosphamide) may accumulate in the bladder, thus predisposing transitional bladder cells to oncogenicity. In order to avoid these toxic side effects, clinicians should consider pulse doses as well as giving 2-mercaptoethanesulfonate, a compound that conjugates acrolein in the urine. Patients should also be advised to drink fluids to maintain adequate hydration. Of note, some individuals with a G516 T variant of CYP2B6 metabolize cyclophosphamide much more rapidly and therefore may require lower doses in order to avoid the toxic effects of this agent.

Carmustine is similar to other nitrosoureas as it cross-­ links DNA and RNA strands. It may also carbamylate amino acids which modify proteins. This agent is lipid soluble, thus allowing it to cross the blood-brain barrier in order to combat malignancies in the central nervous system (including astrocytomas, ependymomas, glioblastomas, and medulloblastomas). Cumulative doses greater than 1400 mg/m2 place patient at risk for delayed-onset pulmonary fibrosis typically in those who have had prolonged treatment.

Streptozocin is a nitrosourea that functions similarly to carmustine by cross-linking DNA, modifying proteins, and crossing the blood-brain barrier. It is typically used to treat metastatic islet cell carcinoma of the pancreas and metastatic adrenal carcinomas. Patients experience less bone marrow

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suppression for this agent than for carmustine, although it has been associated with psychiatric side effects such as depression and confusion.

Dacarbazine is a triazene that is activated by the cytochrome P450 system by conversion to methyl-triazene-1-limidazole-­4-carboxamide (MTIC). As MTIC, it functions by methylating the O6 and N6 positions of guanine in DNA. This subsequently causes breaks in the DNA double strand and eventual triggers apoptosis. It may be used for treating melanoma and adrenal malignancies. Extravasation is a serious consequence that results in extreme pain and tissue damage.

Temozolomide: This prodrug is converted to MTIC nonenzymatically through a spontaneous and rapid process in bodily tissues after redistributing. It functions similar to dacarbazine as a triazene. Typically, this agent is reserved for refractory astrocytoma and a number of additional, off-label uses in the central nervous system tumors. Radiotherapy in conjunction with this agent increases risk for Pneumocystis jirovecii pneumonia, thus warranting prophylactic antibiotics in select patient populations.

K. Gritsenko and M. Lubrano

metabolite that allows for its elimination. Tumor lysis syndrome is another severe side effect that may lead to acute kidney injury and/or failure, especially when tumor burden is high.

Pemetrexed functions similarly to methotrexate but also inhibits thymidylate synthase and two other enzymes that play roles in the reduction of folate. Its uses include treating pleural mesothelioma and thymus cancer. Bone marrow suppression and interstitial pneumonitis are concerning adverse effects; however, hepatic toxicity is especially concerning with pemetrexed with several case reports identifying this as a cause of mortality. Folate and vitamin B12 are essential for reducing bone marrow and gastrointestinal toxicity.

Nucleotide and Platinum Analogs

Nucleotide analogs are broken down into two subgroups.

Purine analogs (mercaptopurine, thioguanine, hydroxyurea) mimic adenosine and guanine. They typically deceive intracellular machinery in order to be inappropriately placed into DNA. Once present, DNA replication is impaired, and tumor cells are unable to undergo S phase and replicate. This trig Folates gers a number of mechanisms that lead to apoptosis.

Folates participate in a disruption of the folate cycle (metho- Pyrimidine analogs (fluorouracil, capecitabine, cytaragine, trexate, pemetrexed). These agents irreversibly inhibit dihy- gemcitabine) either mimic cytosine, thymine, and uracil or drofolate reductase (DHFR), an enzyme that donates methyl entirely block pyrimidine synthesis within cells. These groups to folate, thus impairing an essential step for intracel- agents commonly are administered as prodrugs that require lular production of purines and thymidylic acid. DNA, RNA, activation by either hepatic cells or cellular machinery within and various proteins require this in order to function. While the tumor of interest.

Platinum analogs (carboplatin, cisplatin, and oxaliplatin) folates may also be used in inflammatory diseases, the mecheffectively treat malignancies by interacting with tumors in a anism of action is unknown.

Methotrexate is a folate that is especially useful in treat- number of ways. They actively bind the DNA of target cells ing solid tumors found in a myriad of organ systems. It is and form intra-strand and inter-strand DNA covalent cross-­ often the agent of choice for trophoblastic neoplasms and links. These cross-links inhibit DNA synthesis and denature may be given as a sole agent for hydatidiform moles or ecto- the double helix.

Mercaptopurine is a purine analog converted by pic pregnancies of small enough sizes. The hepatotoxic side effects of methotrexate are related to a cumulative dose of hypoxanthine-­guanine phosphoribosyl transferase (HGPRT) greater than 1.5 grams. Hepatic biopsies are recommended into monophosphate and triphosphate forms. The monoin patients with prolonged exposure. Other hepatotoxic risk phosphate form inhibits purine synthesis. The triphosphate factors include ethanol consumption, diabetes, hyperlipid- form is falsely incorporated into DNA and RNA by cellular emia, family history of liver disease, and obesity. machinery to inhibit replication. Xanthine oxidase (XO) is Methotrexate elimination is renal based, with greater than the enzyme that metabolizes its active forms, as well as 50% not metabolized. Neurotoxicity includes seizures that purines themselves. By co-administering allopurinol, a XO occur predominantly in children who are being treated for inhibitor, the dose of mercaptopurine can be reduced by ALL, as well as encephalopathy from high doses or concur- 50–70%. Mercaptopurine is mainly used for hematologic rent radiation. Intrathecal administration raises concerns for cancers and thus has a number of side effects involving the arachnoiditis, chronic leukoencephalopathy, and myelopa- manipulation of hematologic cell lines. This includes bone thy. Administering leucovorin (5-formyltetrahydrofolate) marrow suppression, immunosuppression, and subsequent may reduce the toxicity of methotrexate and spares non-­ secondary malignancies. Hepatotoxicity occurs at any dose, tumor cells. Another treatment modality for overexposure but increased risk occurs above 2.5 mg/kg/day. includes glucarpidase, an enzyme that rapidly hydrolyzes Discontinuation may resolve hepatic symptoms after about methotrexate in the extracellular space into an inactive 1–2 months. Secondary malignancies are a major concern,

4 Chemotherapy

especially hepatosplenic T-cell lymphomas (HSTCL) which are a rare and frequently fatal cancer.

Thioguanine is a purine analog closely related to mercaptopurine and has a similar function and metabolism. Its primary use is for adult acute myelogenous leukemia. Side effects parallel those of mercaptopurine with concern for tumor lysis syndrome. Some patients have genetic polymorphism that results in a deficiency of thiopurine methyltransferase (TPMT). Medications that are salicylic acid derivatives are able to inhibit TPMT and may lead to significant myelosuppression while taking this agent for some patients. This would require considerable dose reduction to avoid serious toxicity.

Hydroxyurea is another purine analog that disrupts DNA synthesis by inhibiting ribonucleoside-diphosphate reductase. This blocks the development of deoxyribonucleotides from ribonucleotides, thus freezing target cells in the G1 phase. It is effective in leukemias, melanoma, and squamous cancers. In addition to tumor lysis syndrome, concerning adverse effects include bone marrow suppression, megaloblastic erythropoiesis, vascular ulceration, and gangrene.

Erythrocyte abnormalities may erupt displaying megaloblastic erythropoiesis that is typically self-limiting. Hydroxyurea has also been associated with the development of skin cancer with long-term use.

5-Fluorouracil (5-FU) is a pyrimidine analog requiring activation in order to inhibit thymidylate synthase. This enzyme is necessary for generating thymidine triphosphate, an essential factor for synthesizing DNA. A second metabolite of 5-FU is generated that may be inappropriately incorporated in RNA and effectively disrupt translation. This is a very useful agent to treat solid tumors found throughout multiple organ systems. Palmar-plantar erythrodysesthesia (hand-foot) syndrome is a side effect that 5-FU may precipitate that involves tingling in the hands and feet. It has the potential for developing into pain associated with erythema.

The resolution typically occurs within a week of discontinuing 5-FU. Toxicity can also occur in the 5% of patients who are deficient in dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for metabolizing 5-FU. Without DPD, 5-FU toxicity can cause neutropenia, diarrhea, and neurotoxicity. Overdose of 5-FU may be treated with uridine triacetate if administered within 4 days, with multiple, small cohort studies showing full recovery in all patients who received this rescue agent [8, 9].

Capecitabine is another pyrimidine analog (prodrug) that must be hydrolyzed by the liver as well as other bodily tissues to become 5-FU. Its uses are therefore similar to 5-FU, but it is capable of oral administration. Its side effect profile is similar; although bone marrow suppression is significant, patients with platelets less than 100,000 or neutrophils less than 1500 are not candidates for this medication.

Dysrhythmia, angina, myocardial infarction, cardiac arrest,

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cardiac myopathy, and sudden death have all occurred in patients receiving capecitabine.

Cytarabine, a pyrimidine analog, utilizes cellular transporters to enter tumors prior to being converted to aracytidine triphosphate. In this phosphorylated form, it may be placed into DNA. Unlike other analogs, cytarabine functions by directly inhibiting DNA polymerase, both alpha and beta, thus impairing DNA replication and repair, primarily useful to treat hematologic malignancies. In addition to acute pancreatitis and tumor lysis syndrome, a hypersensitivity reaction with acute cardiopulmonary arrest is a rare side effect.

Sudden respiratory arrest syndrome is also a subsequent concern that may take up to 12 h to precipitate following treatment. This involves malaise, maculopapular rash, fever, myalgia, bone pain, and chest pain and requires immediate administration of corticosteroids to manage. Patients receiving doses that exceed 1.5 g/m2 may experience conjunctivitis.

Gemcitabine is also a pyrimidine analog that functions similarly to cytarabine. It is metabolized to gemcitabine diphosphate and works to inhibit ribonucleotide reductase and DNA synthesis. Its triphosphate form is effective in incorporating itself into DNA directly to inhibit DNA polymerase. This agent is used to treat metastatic breast cancer and solid and hematopoietic tumors from a number of organ systems. Capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS) are serious, adverse events.

Gemcitabine should be discontinued if CLS precipitates.

HUS may result in considerable morbidity and mortality.

Any patient on this agent must therefore have an established renal baseline that is continuously monitored. Adult respiratory distress syndrome and pneumonitis and fibrosis are other observed effects although symptoms may not precipitate for 2 weeks after a patient’s gemcitabine dose.

Cisplatin is a platinum analog that exists in two isomer forms, with the cis form actively functioning at 14 times the cytotoxic level as its trans-isomer counterpart. Both isomers function similarly, but cellular mechanisms are less capable of recognizing and repairing the cis-isomer form. It is effective in eradicating a number of tumor cells, most notably solid tumors. Adverse effects are also numerous and considerable – perhaps the most notable including ototoxicity and renal toxicity. Neurotoxicity is an additional concern for all platinum agents. Hyperuricemia may also occur with cisplatin due to tumor lysis. Neuropathies that are severe and potentially irreversible can occur when administration is too frequent or recommended doses are exceeded. A number of neurologic sequelae have been described, including posterior reversible leukoencephalopathy syndrome (PRES), seizures, and loss of taste or motor function. Children with thiopurine S-methyltransferase (TPMT) polymorphisms are more susceptible to ototoxicity, which is also dose dependent and perpetuated by aminoglycoside use.

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DANCE ON STILTS AT THE GIRLS’ UNYAGO, NIUCHI

Newala, too, suffers from the distance of its water-supply—at least the Newala of to-day does; there was once another Newala in a lovely valley at the foot of the plateau. I visited it and found scarcely a trace of houses, only a Christian cemetery, with the graves of several missionaries and their converts, remaining as a monument of its former glories. But the surroundings are wonderfully beautiful. A thick grove of splendid mango-trees closes in the weather-worn crosses and headstones; behind them, combining the useful and the agreeable, is a whole plantation of lemon-trees covered with ripe fruit; not the small African kind, but a much larger and also juicier imported variety, which drops into the hands of the passing traveller, without calling for any exertion on his part. Old Newala is now under the jurisdiction of the native pastor, Daudi, at Chingulungulu, who, as I am on very friendly terms with him, allows me, as a matter of course, the use of this lemon-grove during my stay at Newala.

FEET MUTILATED BY THE RAVAGES OF THE “JIGGER” (Sarcopsylla penetrans)

The water-supply of New Newala is in the bottom of the valley, some 1,600 feet lower down. The way is not only long and fatiguing, but the water, when we get it, is thoroughly bad. We are suffering not only from this, but from the fact that the arrangements at Newala are nothing short of luxurious. We have a separate kitchen—a hut built against the boma palisade on the right of the baraza, the interior of which is not visible from our usual position. Our two cooks were not long in finding this out, and they consequently do—or rather neglect to do—what they please. In any case they do not seem to be very particular about the boiling of our drinking-water—at least I can attribute to no other cause certain attacks of a dysenteric nature, from which both Knudsen and I have suffered for some time. If a man like Omari has to be left unwatched for a moment, he is capable of anything. Besides this complaint, we are inconvenienced by the state of our nails, which have become as hard as glass, and crack on the slightest provocation, and I have the additional infliction of pimples all over me. As if all this were not enough, we have also, for the last week been waging war against the jigger, who has found his Eldorado in the hot sand of the Makonde plateau. Our men are seen all day long—whenever their chronic colds and the dysentery likewise raging among them permit—occupied in removing this scourge of Africa from their feet and trying to prevent the disastrous consequences of its presence. It is quite common to see natives of this place with one or two toes missing; many have lost all their toes,

or even the whole front part of the foot, so that a well-formed leg ends in a shapeless stump. These ravages are caused by the female of Sarcopsylla penetrans, which bores its way under the skin and there develops an egg-sac the size of a pea. In all books on the subject, it is stated that one’s attention is called to the presence of this parasite by an intolerable itching. This agrees very well with my experience, so far as the softer parts of the sole, the spaces between and under the toes, and the side of the foot are concerned, but if the creature penetrates through the harder parts of the heel or ball of the foot, it may escape even the most careful search till it has reached maturity.

Then there is no time to be lost, if the horrible ulceration, of which we see cases by the dozen every day, is to be prevented. It is much easier, by the way, to discover the insect on the white skin of a European than on that of a native, on which the dark speck scarcely shows. The four or five jiggers which, in spite of the fact that I constantly wore high laced boots, chose my feet to settle in, were taken out for me by the all-accomplished Knudsen, after which I thought it advisable to wash out the cavities with corrosive sublimate. The natives have a different sort of disinfectant—they fill the hole with scraped roots. In a tiny Makua village on the slope of the plateau south of Newala, we saw an old woman who had filled all the spaces under her toe-nails with powdered roots by way of prophylactic treatment. What will be the result, if any, who can say?

The rest of the many trifling ills which trouble our existence are really more comic than serious. In the absence of anything else to smoke, Knudsen and I at last opened a box of cigars procured from the Indian store-keeper at Lindi, and tried them, with the most distressing results. Whether they contain opium or some other narcotic, neither of us can say, but after the tenth puff we were both “off,” three-quarters stupefied and unspeakably wretched. Slowly we recovered—and what happened next? Half-an-hour later we were once more smoking these poisonous concoctions—so insatiable is the craving for tobacco in the tropics.

Even my present attacks of fever scarcely deserve to be taken seriously. I have had no less than three here at Newala, all of which have run their course in an incredibly short time. In the early afternoon, I am busy with my old natives, asking questions and making notes. The strong midday coffee has stimulated my spirits to

an extraordinary degree, the brain is active and vigorous, and work progresses rapidly, while a pleasant warmth pervades the whole body. Suddenly this gives place to a violent chill, forcing me to put on my overcoat, though it is only half-past three and the afternoon sun is at its hottest. Now the brain no longer works with such acuteness and logical precision; more especially does it fail me in trying to establish the syntax of the difficult Makua language on which I have ventured, as if I had not enough to do without it. Under the circumstances it seems advisable to take my temperature, and I do so, to save trouble, without leaving my seat, and while going on with my work. On examination, I find it to be 101·48°. My tutors are abruptly dismissed and my bed set up in the baraza; a few minutes later I am in it and treating myself internally with hot water and lemon-juice.

Three hours later, the thermometer marks nearly 104°, and I make them carry me back into the tent, bed and all, as I am now perspiring heavily, and exposure to the cold wind just beginning to blow might mean a fatal chill. I lie still for a little while, and then find, to my great relief, that the temperature is not rising, but rather falling. This is about 7.30 p.m. At 8 p.m. I find, to my unbounded astonishment, that it has fallen below 98·6°, and I feel perfectly well. I read for an hour or two, and could very well enjoy a smoke, if I had the wherewithal—Indian cigars being out of the question.

Having no medical training, I am at a loss to account for this state of things. It is impossible that these transitory attacks of high fever should be malarial; it seems more probable that they are due to a kind of sunstroke. On consulting my note-book, I become more and more inclined to think this is the case, for these attacks regularly follow extreme fatigue and long exposure to strong sunshine. They at least have the advantage of being only short interruptions to my work, as on the following morning I am always quite fresh and fit.

My treasure of a cook is suffering from an enormous hydrocele which makes it difficult for him to get up, and Moritz is obliged to keep in the dark on account of his inflamed eyes. Knudsen’s cook, a raw boy from somewhere in the bush, knows still less of cooking than Omari; consequently Nils Knudsen himself has been promoted to the vacant post. Finding that we had come to the end of our supplies, he began by sending to Chingulungulu for the four sucking-pigs which we had

bought from Matola and temporarily left in his charge; and when they came up, neatly packed in a large crate, he callously slaughtered the biggest of them. The first joint we were thoughtless enough to entrust for roasting to Knudsen’s mshenzi cook, and it was consequently uneatable; but we made the rest of the animal into a jelly which we ate with great relish after weeks of underfeeding, consuming incredible helpings of it at both midday and evening meals. The only drawback is a certain want of variety in the tinned vegetables. Dr. Jäger, to whom the Geographical Commission entrusted the provisioning of the expeditions—mine as well as his own—because he had more time on his hands than the rest of us, seems to have laid in a huge stock of Teltow turnips,[46] an article of food which is all very well for occasional use, but which quickly palls when set before one every day; and we seem to have no other tins left. There is no help for it—we must put up with the turnips; but I am certain that, once I am home again, I shall not touch them for ten years to come.

Amid all these minor evils, which, after all, go to make up the genuine flavour of Africa, there is at least one cheering touch: Knudsen has, with the dexterity of a skilled mechanic, repaired my 9 × 12 cm. camera, at least so far that I can use it with a little care.

How, in the absence of finger-nails, he was able to accomplish such a ticklish piece of work, having no tool but a clumsy screw-driver for taking to pieces and putting together again the complicated mechanism of the instantaneous shutter, is still a mystery to me; but he did it successfully. The loss of his finger-nails shows him in a light contrasting curiously enough with the intelligence evinced by the above operation; though, after all, it is scarcely surprising after his ten years’ residence in the bush. One day, at Lindi, he had occasion to wash a dog, which must have been in need of very thorough cleansing, for the bottle handed to our friend for the purpose had an extremely strong smell. Having performed his task in the most conscientious manner, he perceived with some surprise that the dog did not appear much the better for it, and was further surprised by finding his own nails ulcerating away in the course of the next few days. “How was I to know that carbolic acid has to be diluted?” he mutters indignantly, from time to time, with a troubled gaze at his mutilated finger-tips.

Since we came to Newala we have been making excursions in all directions through the surrounding country, in accordance with old habit, and also because the akida Sefu did not get together the tribal elders from whom I wanted information so speedily as he had promised. There is, however, no harm done, as, even if seen only from the outside, the country and people are interesting enough.

The Makonde plateau is like a large rectangular table rounded off at the corners. Measured from the Indian Ocean to Newala, it is about seventy-five miles long, and between the Rovuma and the Lukuledi it averages fifty miles in breadth, so that its superficial area is about two-thirds of that of the kingdom of Saxony. The surface, however, is not level, but uniformly inclined from its south-western edge to the ocean. From the upper edge, on which Newala lies, the eye ranges for many miles east and north-east, without encountering any obstacle, over the Makonde bush. It is a green sea, from which here and there thick clouds of smoke rise, to show that it, too, is inhabited by men who carry on their tillage like so many other primitive peoples, by cutting down and burning the bush, and manuring with the ashes. Even in the radiant light of a tropical day such a fire is a grand sight.

Much less effective is the impression produced just now by the great western plain as seen from the edge of the plateau. As often as time permits, I stroll along this edge, sometimes in one direction, sometimes in another, in the hope of finding the air clear enough to let me enjoy the view; but I have always been disappointed.

Wherever one looks, clouds of smoke rise from the burning bush, and the air is full of smoke and vapour. It is a pity, for under more favourable circumstances the panorama of the whole country up to the distant Majeje hills must be truly magnificent. It is of little use taking photographs now, and an outline sketch gives a very poor idea of the scenery. In one of these excursions I went out of my way to make a personal attempt on the Makonde bush. The present edge of the plateau is the result of a far-reaching process of destruction through erosion and denudation. The Makonde strata are everywhere cut into by ravines, which, though short, are hundreds of yards in depth. In consequence of the loose stratification of these beds, not only are the walls of these ravines nearly vertical, but their upper end is closed by an equally steep escarpment, so that the

western edge of the Makonde plateau is hemmed in by a series of deep, basin-like valleys. In order to get from one side of such a ravine to the other, I cut my way through the bush with a dozen of my men.

It was a very open part, with more grass than scrub, but even so the short stretch of less than two hundred yards was very hard work; at the end of it the men’s calicoes were in rags and they themselves bleeding from hundreds of scratches, while even our strong khaki suits had not escaped scatheless.

NATIVE PATH THROUGH THE MAKONDE BUSH, NEAR MAHUTA

I see increasing reason to believe that the view formed some time back as to the origin of the Makonde bush is the correct one. I have no doubt that it is not a natural product, but the result of human occupation. Those parts of the high country where man—as a very slight amount of practice enables the eye to perceive at once—has not yet penetrated with axe and hoe, are still occupied by a splendid timber forest quite able to sustain a comparison with our mixed forests in Germany. But wherever man has once built his hut or tilled his field, this horrible bush springs up. Every phase of this process

may be seen in the course of a couple of hours’ walk along the main road. From the bush to right or left, one hears the sound of the axe— not from one spot only, but from several directions at once. A few steps further on, we can see what is taking place. The brush has been cut down and piled up in heaps to the height of a yard or more, between which the trunks of the large trees stand up like the last pillars of a magnificent ruined building. These, too, present a melancholy spectacle: the destructive Makonde have ringed them— cut a broad strip of bark all round to ensure their dying off—and also piled up pyramids of brush round them. Father and son, mother and son-in-law, are chopping away perseveringly in the background—too busy, almost, to look round at the white stranger, who usually excites so much interest. If you pass by the same place a week later, the piles of brushwood have disappeared and a thick layer of ashes has taken the place of the green forest. The large trees stretch their smouldering trunks and branches in dumb accusation to heaven—if they have not already fallen and been more or less reduced to ashes, perhaps only showing as a white stripe on the dark ground.

This work of destruction is carried out by the Makonde alike on the virgin forest and on the bush which has sprung up on sites already cultivated and deserted. In the second case they are saved the trouble of burning the large trees, these being entirely absent in the secondary bush.

After burning this piece of forest ground and loosening it with the hoe, the native sows his corn and plants his vegetables. All over the country, he goes in for bed-culture, which requires, and, in fact, receives, the most careful attention. Weeds are nowhere tolerated in the south of German East Africa. The crops may fail on the plains, where droughts are frequent, but never on the plateau with its abundant rains and heavy dews. Its fortunate inhabitants even have the satisfaction of seeing the proud Wayao and Wamakua working for them as labourers, driven by hunger to serve where they were accustomed to rule.

But the light, sandy soil is soon exhausted, and would yield no harvest the second year if cultivated twice running. This fact has been familiar to the native for ages; consequently he provides in time, and, while his crop is growing, prepares the next plot with axe and firebrand. Next year he plants this with his various crops and

lets the first piece lie fallow. For a short time it remains waste and desolate; then nature steps in to repair the destruction wrought by man; a thousand new growths spring out of the exhausted soil, and even the old stumps put forth fresh shoots. Next year the new growth is up to one’s knees, and in a few years more it is that terrible, impenetrable bush, which maintains its position till the black occupier of the land has made the round of all the available sites and come back to his starting point.

The Makonde are, body and soul, so to speak, one with this bush.

According to my Yao informants, indeed, their name means nothing else but “bush people.” Their own tradition says that they have been settled up here for a very long time, but to my surprise they laid great stress on an original immigration. Their old homes were in the south-east, near Mikindani and the mouth of the Rovuma, whence their peaceful forefathers were driven by the continual raids of the Sakalavas from Madagascar and the warlike Shirazis[47] of the coast, to take refuge on the almost inaccessible plateau. I have studied African ethnology for twenty years, but the fact that changes of population in this apparently quiet and peaceable corner of the earth could have been occasioned by outside enterprises taking place on the high seas, was completely new to me. It is, no doubt, however, correct.

The charming tribal legend of the Makonde—besides informing us of other interesting matters—explains why they have to live in the thickest of the bush and a long way from the edge of the plateau, instead of making their permanent homes beside the purling brooks and springs of the low country.

“The place where the tribe originated is Mahuta, on the southern side of the plateau towards the Rovuma, where of old time there was nothing but thick bush. Out of this bush came a man who never washed himself or shaved his head, and who ate and drank but little.

He went out and made a human figure from the wood of a tree growing in the open country, which he took home to his abode in the bush and there set it upright. In the night this image came to life and was a woman. The man and woman went down together to the Rovuma to wash themselves. Here the woman gave birth to a stillborn child. They left that place and passed over the high land into the valley of the Mbemkuru, where the woman had another child, which

was also born dead. Then they returned to the high bush country of Mahuta, where the third child was born, which lived and grew up. In course of time, the couple had many more children, and called themselves Wamatanda. These were the ancestral stock of the Makonde, also called Wamakonde,[48] i.e., aborigines. Their forefather, the man from the bush, gave his children the command to bury their dead upright, in memory of the mother of their race who was cut out of wood and awoke to life when standing upright. He also warned them against settling in the valleys and near large streams, for sickness and death dwelt there. They were to make it a rule to have their huts at least an hour’s walk from the nearest wateringplace; then their children would thrive and escape illness.”

The explanation of the name Makonde given by my informants is somewhat different from that contained in the above legend, which I extract from a little book (small, but packed with information), by Pater Adams, entitled Lindi und sein Hinterland. Otherwise, my results agree exactly with the statements of the legend. Washing?

Hapana—there is no such thing. Why should they do so? As it is, the supply of water scarcely suffices for cooking and drinking; other people do not wash, so why should the Makonde distinguish himself by such needless eccentricity? As for shaving the head, the short, woolly crop scarcely needs it,[49] so the second ancestral precept is likewise easy enough to follow. Beyond this, however, there is nothing ridiculous in the ancestor’s advice. I have obtained from various local artists a fairly large number of figures carved in wood, ranging from fifteen to twenty-three inches in height, and representing women belonging to the great group of the Mavia, Makonde, and Matambwe tribes. The carving is remarkably well done and renders the female type with great accuracy, especially the keloid ornamentation, to be described later on. As to the object and meaning of their works the sculptors either could or (more probably) would tell me nothing, and I was forced to content myself with the scanty information vouchsafed by one man, who said that the figures were merely intended to represent the nembo—the artificial deformations of pelele, ear-discs, and keloids. The legend recorded

by Pater Adams places these figures in a new light. They must surely be more than mere dolls; and we may even venture to assume that they are—though the majority of present-day Makonde are probably unaware of the fact—representations of the tribal ancestress.

The references in the legend to the descent from Mahuta to the Rovuma, and to a journey across the highlands into the Mbekuru valley, undoubtedly indicate the previous history of the tribe, the travels of the ancestral pair typifying the migrations of their descendants. The descent to the neighbouring Rovuma valley, with its extraordinary fertility and great abundance of game, is intelligible at a glance—but the crossing of the Lukuledi depression, the ascent to the Rondo Plateau and the descent to the Mbemkuru, also lie within the bounds of probability, for all these districts have exactly the same character as the extreme south. Now, however, comes a point of especial interest for our bacteriological age. The primitive Makonde did not enjoy their lives in the marshy river-valleys.

Disease raged among them, and many died. It was only after they had returned to their original home near Mahuta, that the health conditions of these people improved. We are very apt to think of the African as a stupid person whose ignorance of nature is only equalled by his fear of it, and who looks on all mishaps as caused by evil spirits and malignant natural powers. It is much more correct to assume in this case that the people very early learnt to distinguish districts infested with malaria from those where it is absent.

This knowledge is crystallized in the ancestral warning against settling in the valleys and near the great waters, the dwelling-places of disease and death. At the same time, for security against the hostile Mavia south of the Rovuma, it was enacted that every settlement must be not less than a certain distance from the southern edge of the plateau. Such in fact is their mode of life at the present day. It is not such a bad one, and certainly they are both safer and more comfortable than the Makua, the recent intruders from the south, who have made USUAL METHOD OF good their footing on the western edge of the CLOSING HUT-DOOR plateau, extending over a fairly wide belt of country. Neither Makua nor Makonde show in their dwellings anything of the size and comeliness of the Yao houses in the plain, especially at Masasi, Chingulungulu and Zuza’s. Jumbe Chauro, a Makonde hamlet not far from Newala, on the road to Mahuta, is the

most important settlement of the tribe I have yet seen, and has fairly spacious huts. But how slovenly is their construction compared with the palatial residences of the elephant-hunters living in the plain.

The roofs are still more untidy than in the general run of huts during the dry season, the walls show here and there the scanty beginnings or the lamentable remains of the mud plastering, and the interior is a veritable dog-kennel; dirt, dust and disorder everywhere. A few huts only show any attempt at division into rooms, and this consists merely of very roughly-made bamboo partitions. In one point alone have I noticed any indication of progress—in the method of fastening the door. Houses all over the south are secured in a simple but ingenious manner. The door consists of a set of stout pieces of wood or bamboo, tied with bark-string to two cross-pieces, and moving in two grooves round one of the door-posts, so as to open inwards. If the owner wishes to leave home, he takes two logs as thick as a man’s upper arm and about a yard long. One of these is placed obliquely against the middle of the door from the inside, so as to form an angle of from 60° to 75° with the ground. He then places the second piece horizontally across the first, pressing it downward with all his might.

It is kept in place by two strong posts planted in the ground a few inches inside the door. This fastening is absolutely safe, but of course cannot be applied to both doors at once, otherwise how could the owner leave or enter his house? I have not yet succeeded in finding out how the back door is fastened.

MAKONDE LOCK AND KEY AT JUMBE CHAURO

This is the general way of closing a house. The Makonde at Jumbe Chauro, however, have a much more complicated, solid and original one. Here, too, the door is as already described, except that there is only one post on the inside, standing by itself about six inches from one side of the doorway. Opposite this post is a hole in the wall just large enough to admit a man’s arm. The door is closed inside by a large wooden bolt passing through a hole in this post and pressing with its free end against the door. The other end has three holes into which fit three pegs running in vertical grooves inside the post. The door is opened with a wooden key about a foot long, somewhat curved and sloped off at the butt; the other end has three pegs corresponding to the holes, in the bolt, so that, when it is thrust through the hole in the wall and inserted into the rectangular opening in the post, the pegs can be lifted and the bolt drawn out.[50]

MODE OF INSERTING THE KEY

With no small pride first one householder and then a second showed me on the spot the action of this greatest invention of the Makonde Highlands. To both with an admiring exclamation of “Vizuri sana!” (“Very fine!”). I expressed the wish to take back these marvels with me to Ulaya, to show the Wazungu what clever fellows the Makonde are. Scarcely five minutes after my return to camp at Newala, the two men came up sweating under the weight of two heavy logs which they laid down at my feet, handing over at the same time the keys of the fallen fortress. Arguing, logically enough, that if the key was wanted, the lock would be wanted with it, they had taken their axes and chopped down the posts—as it never occurred to them to dig them out of the ground and so bring them intact. Thus I have