Dermatologic Principles and Practice in Oncology: Conditions of the Skin, Hair, and Nails in Cancer Patients

By Mario E. Lacouture

The first book focusing specifically on frequent and frequently disabling side effects involving the skin, hair and nails in cancer patients

According to the World Health Organization, there are approximately thirty million people living with a diagnosis of cancer – the majority of whom will receive surgery, systemic therapy, and/or radiation, and who will suffer from dermatologic adverse events. Dermatologists and oncologists are only beginning to grapple with these events, which pose serious quality-of-life issues with so many patients, and will become more prevalent as survival rates improve, thanks in part to new cancer treatments and drug regimens.

Concentrating on a topic that has only been briefly touched upon by other texts, this book offers a focused perspective on the clinical presentation, underlying pathophysiologic mechanisms, and management of skin, hair, and nail conditions for oncologists, dermatologists, and allied practitioners.
Dermatologic Principles and Practice in Oncology: Conditions of the Skin, Hair, and Nails in Cancer Patients:

• Covers in detail the dermatologic adverse events of oncologic therapies, clinical presentations, and treatment recommendations

• Enables dermatologists and other practitioners to significantly improve the care of patients with cancer
• Addresses the dermatologic adverse events of cancer therapies used globally, of which a large number are found in developing countries

• Emphasizes prophylactic measures – based on treatments used and type of cancer – to prevent the appearance of adverse events

• Provides built-in discussions on patient education for practical counseling during therapies

• Offers rapid-reference sections on topical dermatology drugs

The first book to present dermatologic conditions in cancer patients and survivors in a uniform and in-depth manner, Dermatologic Principles and Practice in Oncology is ideal for oncologists, oncology nurses, and dermatologists who wish to take better care of those with adverse skin, hair, and nail conditions.

• Language: English
• Publisher: Wiley
• Release date: Nov 26, 2013
• ISBN: 9781118590607

Book preview

1

Dermatology and Oncology

1

Epidemiology and Burden of Disease

Beth N. McLellan¹, Devika Patel² and Mario E. Lacouture³,⁴

¹The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA

²Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA

³Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

⁴Department of Dermatology, Cornell University, New York, NY, USA

Introduction

Due to recent advances in cancer therapies, patients are now living longer than ever before. For all diagnosed cancers, the 5-year relative survival has increased from 50% in 1975–1977 to 66% in 1996–2004 [1]. From 1990 to 2003, all-site cancer deaths in the United States decreased by 1% per year and these declines were especially pronounced for some of the most common malignancies including breast, prostate, colorectal, and lung cancers [2]. In the United States in 2009, there were 1 479 350 new cancers expected to be diagnosed [1], of which 52–87% were treated with surgery, 24–35% with chemotherapy, and 47–51% with radiation therapy (based on 2002 data for breast, lung, and colorectal cancers) [3]. Fifty to sixty thousand hematopoietic stem cell transplants are performed worldwide per year [4].

The large number of people being diagnosed with cancer in combination with increased survival rates have led to an increased number of patients living with a history of cancer, estimated to be 11.1 million in 2005 in the United States [1], of which 270 000 are survivors of pediatric cancers [5]. The increased number of patients living with and after cancer has revealed a number of dermatologic issues specific to this population: affecting cutane­ous health, causing a financial burden, decreasing health-related quality of life, and impairing consistent drug dosing.

Dermatologic health in cancer patients and survivors

The relationship between the skin, hair, and nails and internal malignancies is manifested in various ways and in all phases of a patient's experience with cancer (Figure 1.1) . Even before a diagnosis of cancer is made, the skin may be affected by genetic syndromes with an increased cancer risk, environmental carcinogens leading to both skin conditions and internal malignancies, or paraneoplastic syndromes. Before treatment begins, patients can be affected by a number of dermatologic problems, most commonly tinea pedis/onychomycosis, pruritus, and xerosis [6]. After the diagnosis of cancer is made, cancer treatments (systemic agents, radiation, therapeutic transplants, and surgeries) can result in a number of skin, hair, and nail adverse events (AEs) that develop either as a result of idiosyncratic reactions or as an effect on rapidly proliferating cells (of which the skin, hair, and nails are prototypical structures).

Figure 1.1 Dermatologic events in the life of the cancer patient and/or survivor [7]. GVHD, graft versus host disease. Adapted from Agha, 2007 [7].

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The number of dermatologic AEs of chemotherapeutic agents is large and continues to expand as new agents come into use (see Appendix 1.1). In 2008, of approximately 384 000 routine AEs for phase I and II studies were reported to the Cancer Therapy Evaluation Program (CTEP) via the Clinical Data Update System (CDUS), 30 834 (8.04%) were dermatologic in nature (personal communication, Clinical Data Update System). Actual numbers of dermatologic AE to therapy may be higher than these estimates because of underreporting and inaccurate grading of AEs [14]. These inaccuracies have at least partly been brought about by difficulty applying existing grading systems to distinct dermatologic AEs, as has been demonstrated with other toxicities [15]. Another difficulty is grading AEs that are of low grade but prolonged duration [16]. Improved reporting of dermatologic AE is expected as focused grading scales are created [17].

In addition to the primary dermatologic toxicity of therapy, secondary skin infections are a frequent complication. In one study of patients receiving epidermal growth factor receptor inhibitors (EGFRIs), 38% of patients showed evidence of infection at sites of dermatologic toxicities [18]. Treatment modalities other than chemotherapy including radiation therapy, cancer-related surgery, and hematologic transplants are associated with distinct dermatologic toxicities and secondary infections (Figure 1.2).

Figure 1.2 Locations of therapy-induced dermatologic toxicities.

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Financial burden

In addition to the psychosocial effects (discussed in Chapter 6 ), dermatologic AEs also result in a financial cost to patients. Overall costs of treating cancer have increased by 75% from 1995 to 2004 [3]. A portion of this cost can be attributed to supportive dermatologic care. Median medical costs per patient treated for head and neck or nonsmall cell lung cancer with radiochemotherapy are $39 313 per patient with mucositis/pharyngitis and $20 798 per patient without mucositis/pharyngitis [19]. Much of the increased cost was attributed to increased length of hospital stay [19]. For dermatologic AEs in patients treated with EGFRIs or platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitors, mean cost of treatment for dermatologic toxicities was $2496 per patient [20]. Costs associated with stem cell transplantation can be increased by as much as $28,100 by development of acute graft versus host disease (GVHD) [21]. It is plausible that a prophylactic approach to managing treatment-induced AEs could decrease these associated costs.

Health-related quality of life

All of the described dermatologic toxicities due to cancer treat­ment can have a significant impact on a patient's health-related quality of life (HRQL). Patients most frequently report dermato­logic AE as carrying a negative impact and of being unanticipated prior to therapy, with 67% of patients reporting that dermatologic AEs are worse than their initial belief [22]. Fifty-eight percent of patients rate chemotherapy-induced alopecia as the most traumatic side effect from their therapy and 8% of patients would decline chemotherapy because of fear of hair loss [23]. In a study of breast cancer patients receiving radiation therapy, the skin changes induced by radiotherapy were found to negatively impact physical well-being, body image, emotional well-being, functional well-being, and treatment satisfaction [24]. Scars resulting from oncologic surgical pro­cedures can lead to psychologic problems in 15% of survivors of childhood cancers [25]. In a prospective study measuring the frequency and impact on quality of life of dermatologic toxicities in women receiving chemotherapy, 34% of women reported dermatologic AEs as most important during treatment and they were the most common significant contributor to overall HRQL [26]. Of those who develop dermatologic AEs, 69% feel significantly limited in their daily activities [26].

Dosing of chemotherapy

Perhaps the most imposing challenge offered by dermatologic AE is their ability to result in dose modifications of anticancer therapies. Although the effects of anticancer therapy dose modification on progression-free survival or overall survival have not been evaluated, one can surmise that by reducing dose intensity, clinical outcome will be negatively affected. Studies linking the frequency and severity of dermatologic AEs to a longer median survival underscore the importance of managing dermatologic events, as patients who develop these untoward events are those most likely to benefit from their antineoplastic therapy [27]. Most notably, the papulopustular (acneiform) eruption to the EGFRIs (e.g., erlotinib, cetuximab, and panitumumab) has been shown to correlate with increased progression-free and overall survival in a variety of solid tumors [28,29].

In patients receiving cetuximab for example, up to 11.3% will develop a grade 3 or higher skin rash, necessitating dose reductions [30]. The development of mucositis is shown to lead to a twofold increased risk of chemotherapy dose reduction and limits the ability to give methotrexate for prevention of GVHD following autologous stem cell transplants [31]. Effectively recognizing and treating dermatologic toxicities to chemotherapy can minimize dose reductions and treatment interruptions as shown in the STEPP trial in which 12 doses were delayed in the prophylactic skin treatment arm, compared to 21 doses in the reactive arm [32].

Conclusions

The increasing number of cancer patients and survivors has led to an increased awareness of the HRQL components and treatment-related dermatologic manifestations seen in this patient population. These dermatologic toxicities are diverse and can have an enormous impact on the cutaneous health of patients, overall costs of treatment, healthcare-related quality of life, and consistent anticancer therapy. The recognition of all of these factors has led to a new field within dermatology: supportive oncoderma­tology, which is focused on the addressing the aforementioned dermatologic issues facing cancer patients and survivors.

References

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2 Byers, T. (2008) Changes in cancer mortality. In: V.T. DeVita, T.S. Lawrence & S.A. Rosenberg (eds), Cancer Principles and Practice of Oncology, 8th ed., pp. 275–282. Lippincott Williams & Wilkins, Philadelphia.

3 Warren, J.L., Yabroff, K.R., Meekins, A. et al. (2008) Evaluation of trends in the cost of initial cancer treatment. Journal of the National Cancer Institute, 100, 888–897.

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5 Oeffinger, K.C., Mertens, A.C., Sklar, C.A. et al. (2006) Chronic health conditions in adult survivors of childhood cancer. New England Journal of Medicine, 355, 1572–1582.

6 Kiliç, A., Gül, Ü. & Soylu, S. (2007) Skin findings in nternal malignant diseases. International Journal of Dermatology, 46, 1055–1060.

7 Agha, R., Kinahan, K., Bennett, C.L. & Lacouture, M.E. (2007) Dermatologic challenges in cancer patients and survivors. Oncology, 21, 1462–1472.

8 Litt, J.Z. (2009) Litt's Drug Eruption Reference Manual, 15th ed., Informa Healthcare, New York.

9 Kantarjian, H., Giles, F., Wunderle, L. et al. (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. New England Journal of Medicine, 354, 2542–2551.

10 Iwamoto, F.M., Lamborn, K.R., Robins, H.I. et al. (2010) Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro-Oncology, 12, 855–861.

11 Teneriello, M.G., Tseng, P.C., Crozier, M. et al. (2009) Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer. Journal of Clinical Oncology, 27, 1426–1431.

12 Molife, L.R., Attard, G., Fong, P.C. et al. (2010) Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Annals of Oncology, 21, 109–113.

13 Montero, A.J., Estrov, Z., Freireich, E.J. et al. (2006) Phase II study of low-dose interleukin-11 in patients with myelodysplastic syndrome. Leukemia and Lymphoma, 47, 2049–2054.

14 Bauer, K.A., Hammerman, S., Rapoport, B. & Lacouture, M.E. (2008) Completeness in the reporting of dermatologic adverse drug reactions associated with monoclonal antibody epidermal growth factor report inhibitors in phase II and III colorectal cancer clinical trials. Clinical Colorectal Cancer, 7, 209–214.

15 Basch, E. (2010) The missing voice of patients in drug-safety reporting. New England Journal of Medicine, 362, 865–869.

16 Edgerly, M. & Fojo, T. (2008) Is there room for improvement in the era of targeted therapies? Journal of the National Cancer Institute, 100, 240–242.

17 Lacouture, M.E., Maitland, M.L., Segaert, S. et al. (2010) A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Supportive Care in Cancer, 18, 509–522.

18 Eilers, R.E. Jr, Gandhi, M., Patel, J.D. et al. (2010) Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy. Journal of the National Cancer Institute, 102, 47–53.

19 Nonzee, N.J., Dandade, N.A., Patel, U. et al. (2008) Evaluating the supportive care costs of severe radiochemotherapy-induced mucositis and pharyngitis: results from a Northwestern University Costs of Cancer Program pilot study with head and neck and nonsmall cell lung cancer patients who received care at a county hospital, a Veterans Administration hospital, or a comprehensive cancer care center. Cancer, 113, 1446–1452.

20 Borovicka, J.H., Hensley, J.R., Calahan, C. et al. (2010) Economic burden associated with the management of dermatologic toxicities induced by targeted anticancer therapies. Presented at American Academy of Dermatology 68th Annual Meeting, March 2010.

21 Redaelli, A., Botteman, M.F., Stephens, J.M. et al. (2004) Economic burden of acute myeloid leukemia: a literature review. Cancer Treatment Reviews, 30, 237–247.

22 Gandhi, M., Oishi, K., Zubal, B. & Lacouture, M.E. (2010) Unanticipated toxicities from anticancer therapies: survivors' perspectives. Supportive Care in Cancer, 18, 1461–1468.

23 McGarvey, E.L., Baum, L.D., Pinkerton, R.C. & Rogers, L.M. (2001) Psychological sequelae and alopecia among women with cancer. Cancer Practice, 9, 283–289.

24 Schnur, J.B., Oullette, S.C., DiLorenzo, T.A. Green, S. & Montgomery, G.H. (2011) A qualitative analysis of acute skin toxicity among breast cancer radiotherapy patients. Psycho-Oncology, 20, 260–268.

25 Pinter, A.B., Hock, A., Kajtar, P. & Dóber, I. (2003) Long-term follow-up of cancer in neonates and infants: a national survey of 142 patients. Pediatric Surgery International, 19, 233–239.

26 Hackbarth, M., Haas, N., Fotopoulou, C., Lichtenegger, W. & Sehouli, J. (2008) Chemotherapy-induced dermatological toxicity: frequencies and impact on quality of life in women's cancers. Results of a prospective study. Supportive Care in Cancer, 16, 267–273.

27 Li, T. & Perez-Soler, R. (2009) Skin toxicities associated with epidermal growth factor receptor inhibitors. Targeted Oncology, 4, 107–119.

28 Wacker, B., Nagrani, T., Weinberg, J., Witt, K., Clark, G. & Cagnoni, P.J. (2007) Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clinical Cancer Research, 13, 3913–3921.

29 Peréz-Soler, R. & Saltz, L. (2005) Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? Journal of Clinical Oncology, 23, 5235–5246.

30 Su, X., Lacouture, M.E., Jia, Y. & Wu, S. (2009) Risk of high-grade skin rash in cancer patients treated with cetuximab: an antibody against epidermal growth factor receptor: systemic review and meta-analysis. Oncology, 77, 124–133.

31 Murphy, B.A. (2007) Clinical and economic consequences of mucositis induced by chemotherapy and/or radiation therapy. Journal of Supportive Oncology, 5, 13–21.

32 Lacouture, M.E., Mitchell, E.P., Piperdi, B. et al. (2010) Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. Journal of Clinical Oncology, 28, 1351–1357.

33 Kwak, E.L., Bang, Y.J., Gamidge, D.R., et al. (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine, 363, 1693–1703.

34 Mitchell, E.P. (2013) Targeted therapy for metastatic colorectal cancer: role of afibercept. Clinical Colorectal Cancer, 12, 73–85.

35 Robinson, B.G., Paz-Ares, L., Krebs, A., Vasselli, J. & Haddad, R. (2010) Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism, 95, 2664–2671.

36 Cortes, J.E., Kantarijan, H., Shah, N.P., et al. (2012) Ponatinib in refractory Philadelphia chromosome-positive leukemias. New England Journal of Medicine, 367, 2075–2088.

37 Rini, B.I., Escudier, B., Tomczak, P. et al. (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet, 378, 1931–1939.

38 Smith, D.C., Smith, M.R., Sweeny, C. et al. (2013) Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. Journal of Clinical Oncology, 31, 412–419.

39 Cortes, J.E., Kim, D.W., Kantarjian, H.M. et al. (2012) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. Journal of Clinical Oncology, 30, 3486–3492.

40 Demetri, G.D., Reichardt, P., Kang, Y.K. et al. (2013) Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet, 381, 295–302.

41 Chapman, P.B., Hauschild, A., Robert, C. et al. (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine, 364, 2507–2516.

42 Anderson, L., Schmieder, G.J., Werschler, W.P. et al. (2009) Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. Journal of the American Academy of Dermatology, 60, 934–943.

43 Von Hoff, D.D, LoRusso, P.M., Rudin C.M. et al. (2009) Inhibition of hedgehog pathway in advanced basal-cell carcinoma. New England Journal of Medicine, 361, 1164–1172.

44 Axelson, M., Liu, K., Jiang, X. et al. (2013) U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clinical Cancer Research, 19, 2289–2293.

45 Bissler, J.J., Kingswood, J.C., Radzikowska, E. et al. (2013) Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomized, double blind, placebo-controlled trial. Lancet. Epub ahead of print.

46 Hodi, F.S., O'Day, S.J., McDermott, D.F. et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363, 711–723.

47 Swain, S.M., Kim, S.B., Cortés, J. et al. (2013) Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncology, 14, 461–471.

Appendix 1.1 Anticancer agents and associated adverse events affecting the skin, mucosa, hair, and nails. Based on data from Litt JZ, 2009 [8].

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2

The History of Supportive Oncodermatology

Yevgeniy Balagula¹, Steven T. Rosen²,³ and Mario E. Lacouture¹

¹Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

²Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

³Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA

The vast array of anticancer treatment modalities including surgical interventions, radiotherapy, stem cell transplantation, conventional cytotoxic chemotherapy, and novel targeted agents has drastically changed the lives of oncology patients throughout the last century. Nevertheless, this remarkable progress in therapeutics has not been devoid of significant systemic adverse events (AEs) affecting hematopoietic, gastrointestinal, and der­matologic organ systems. While the advent of systemic antibiotics and blood transfusions has reduced the high morbidity associated with bone marrow suppression and an altered immune system, AE affecting the skin and its adnexae have not attracted the same attention, and there has been a relative paucity of effective management strategies.

The major shift in chemotherapeutics in the last decade has been driven by the development of targeted agents. Although this has resulted in improved patient survival and a lower in­­cidence of acute nonspecific AE, a wide spectrum of dermatologic toxicities affecting the majority of patients has been recognized. Their significant burden on patients' quality of life (QoL), with impact on consistent administration of anticancer therapy, has heightened the importance of dermatologic health in cancer patients. Subsequent multidisciplinary research efforts have made considerable strides toward elucidating underlying mechanisms, better understanding of impact on QoL, and the development of evidence-based management strategies, leading to the emergence of supportive oncodermatology – a discipline dedicated to dermatologic health in cancer patients undergoing therapy, as well as cancer survivors (Figure 2.1).

Figure 2.1 Timeline of selected key events and clinical trials in supportive oncodermatology. BMJ, British Medical Journal; EGFR, epidermal growth factor receptor; EGFRI, epidermal growth factor receptor inhibitor; FDA, Food and Drug Administration; HFS, hand-foot syndrome; MASCC, Multinational Association of Supportive Care in Cancer; QOL, quality of life; RCT, randomized controlled trial; SCC, squamous cell carcinoma.

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Evolution of anticancer therapeutics

Evidence of cancer identified in Peruvian and Egyptian mum­­mies dates back to approximately 2500

bc

. The early treatment approach consisted of tumor eradication with a hot iron [1]. The Ebers papyrus, 1500

bc

, contains descriptions of arsenic paste used against ulcerated tumors [2], and surgical removal of breast carcinomas was performed by Celsus in 30

bc

to 38

ad

[3]. Besides physical destruction, oral remedies were also used, with Pliny the Elder (

ad

23–79) utilizing several compounds (e.g., amygdaline or vitamin B17) [4]. An array of chemicals including mercury, lead, iron, potassium, and iodine were utilized by Paracelsus (1493–1541) to treat a spectrum of internal diseases including cancer [5].

Only 2 months after the discovery of X-rays in November 1895 by William Conrad Röntgen, Emil Grubbe, at the time a Chicago medical student, was allegedly the first to utilize radiation to treat breast cancer [6]. The first successful application of radiotherapy for a dermatologic indication (a giant hairy nevus) was performed by Leopold Freund in 1896 [7]. The term chemotherapy was coined by the Nobel laureate Paul Ehrlich (1854–1915), with the era of modern chemotherapy emerging in the 1940s when nitrogen mustard, a nonspecific DNA alkylating agent, was shown to induce regression in lymphoma patients [8,9].

As the list of chemotherapy agents continued to expand, it was realized that combining different agents yielded better results. In 1965, a combination of methotrexate, vinca alkaloid (vincristine), 6-mercaptopurine, and prednisone (POMP) was demonstrated to achieve long-term remissions in children with acute lymphocytic leukemia [10]. The addition of 5-fluorouracil to the arsenal of chemotherapeutics in 1957 was a significant step forward in the treatment of solid malignancies [11]. Driven by discoveries of intricate mechanisms responsible for tumorigenesis, an abundance of chemotherapy agents were synthesized and approved in the latter part of the twentieth century, including alkylating agents (busulfan), plant alkaloids (paclitaxel), antitumor antibiotics (doxorubicin), antimetabolites (capecitabine), and topoisomerase inhibitors (irinotecan).

The last two decades of the twentieth century were highlighted by the identification and improved understanding of carcinogenic mutations involving cell membrane tyrosine kinase receptors and intracellular signaling pathway enzymes. The ability to inhibit specific molecular targets launched oncology into an era of targeted therapy. Agents such as rituximab, a chimeric monoclonal IgG1 antibody targeting the B-cell CD20 surface receptor, were at the forefront of therapy for patients with non-Hodgkin lymphoma [12,13]. Subsequently, a wide spectrum of agents inhibiting cell membrane epidermal growth factor receptors (EGFRs), tyrosine kinases of the Raf-Mek-Erk cascade, and other mitogen activated protein kinase (MAPK) signaling pathways have been synthesized [14].

Spectrum of dermatologic adverse events stemming from conventional cytotoxic chemotherapy agents

An early insightful observation was made in the sixteenth century by Paracelsus, who noted: All things are poison and nothing is without poison, only the dose permits something not to be poisonous [15]. The rapid evolution of anticancer therapeutics has been paralleled by the concomitant emergence of an expanding spectrum of dermatologic AEs, with at least 50 distinct AEs affecting the skin and its adnexae which have been described in association with more than 30 therapies or agents [16–19].

The hematologic and gastrointestinal AEs associated with nitrogen mustard were evident since its introduction in the 1940s. In contrast, a maculopapular rash has only rarely been reported with this agent [20], and in 1967 the first case report of erythema multiforme was published in the Archives of Internal Medicine [21]. In 1974, Zuehlke presented a clinical syndrome as a reaction to mitotane, characterized by an erythematous eruption on the palms and soles [22]. Almost a decade later, a similar presentation was documented in a patient with acute myelogenous leukemia undergoing treatment with a combination of doxorubicin, vincristine, and cytarabine [23]. In 1984, this distinct clinical presentation was also attributed to a protracted infusion of 5-fluorouracil and doxorubicin, now termed palmar-plantar erythrodysesthesia [24]. Liposomal doxorubicin and capecitabine (a prodrug that is enzymatically converted to 5-fluorouracil) have also been identified as triggers of what is currently referred to as hand-foot syndrome (HFS) [25]. The first large randomized double-blind placebo-controlled trial for the prevention of HFS was published in 2010 [26]. However, it failed to demonstrate efficacy of oral pyridoxine in prevention of capecitabine-associated HFS.

Oral mucositis, usually manifesting within the first week of therapy and characterized by erythema, edema, and ulceration of the oropharyngeal mucosa, has been reported to affect 40–70% of patients receiving standard chemotherapy regimens [27], of which 10% are severe (grade 3–4) [28,29]. The incidence of severe mucositis is 30–50% in the setting of high-dose conditioning chemotherapy in preparation for hematopoietic stem cell transplantation [30]. It is associated with clinically significant sequelae including pain, nutritional deficiencies, weight loss, feeding tube placement, infection, and increases the risk of hospitalization [27,31,32]. In 1991, oral cryotherapy, utilizing ice chips placed in the mouth for 30 minutes during 5-fluorouracil infusion, was shown to be a simple but effective intervention diminishing the severity and duration of oral mucositis [33]. In 2004, a randomized double-blind placebo-controlled phase III trial demonstrated that palifermin, a recombinant human keratinocyte growth factor, significantly reduced the incidence and duration of severe mucositis compared with placebo in recipients of autologous stem cell transplantation undergoing intensive conditioning therapy (63% vs. 98%, p < 0.001) [34]. These results have led to the approval of this intravenous agent for the prevention of mucositis in this patient population. Oral glutamine in a novel proprietary formulation has also been shown to diminish severe oral mucositis significantly in a 2007 randomized trial of patients receiving anthracycline-based chemotherapy (1.2% vs. 6.7%, p = 0.005) [35].

In addition to cutaneous and mucosal surfaces, adnexal structures (e.g., hair, nails) can also be significantly affected by conventional cytotoxic chemotherapy agents. Since the initial description of chemotherapy-induced alopecia (CIA) in the 1950s [36,37], this particular adverse event has remained one of the most significant and prevalent toxicities [38]. Fifty-eight percent of women undergoing alopecia-inducing therapy consider it the most distressing AE and 8% would potentially avoid chemo­therapy in anticipation of this toxicity [39]. Multiple agents are known to cause alopecia, including paclitaxel (>80%), doxoru­bicin (60–100%), cyclophosphamide (>60%), and 5-fluorouracil (10–50%) [40]. The use of cold caps has been attempted in numerous trials, but has not been widely adopted [41,42]. In 1996, a randomized trial of topical 2% minoxidil demonstrated some benefit in reducing the duration of CIA in breast cancer patients [43].

Any component of a nail unit (nail plate, nail bed, and periungual tissues) can be affected by multiple cytotoxic agents with resultant manifestations such as leukonychia, onycholysis, Beaus lines, and paronychia [44,45]. For example, docetaxel commonly results in nail toxicities affecting up to 88% of patients [46]. Additionally, taxanes (paclitaxel and docetaxel) can induce painful subungual hemorrhages that contribute to separation of the nail plate from the nail bed (onycholysis), and subsequent development of a painful subungual abscess, which can cause cessation of therapy [47]. Frozen gloves, worn by patients during docetaxel infusion, have been demonstrated to represent an effective strategy diminishing the incidence (51% vs. 11%, p = 0.0001) and severity of nail toxicity [48].

Necrotizing and irritating properties of certain intravenous chemotherapy agents can cause significant tissue destruction upon their extravasation. Localized pain, edema, necrosis, and ulceration have been reported in association with early agents such as nitrogen mustard (1940s) and doxorubicin (1970s) [8,49,50]. Significant morbidity from anthracycline-associated soft tissue necrosis prompted investigations that attempted to describe the clinical course, histopathology, and management as early as 1976 [51]. At present, partly because of improved intravascular access, extravasation injuries are observed in up to 6% of patients undergoing intravenous treatments, but nevertheless may have significant clinical sequelae [52]. The first antidote for anthracycline extravasation has been approved by the Food and Drug Adminstration (FDA) in 2007, more than 30 years after the recognition of its necrotizing properties [53]. Dexrazoxane, a topoisomerase II inhibitor and iron chelator, was shown to significantly reduce the incidence of necrosis requiring surgery.

Radiation and surgery-induced mucocutaneous toxicities

Less than a year after the discovery of ionizing radiation, in 1896 radiation-induced burns affecting the hands were reported in the British Medical Journal [54]. In 1902, Frieben described a squamous cell carcinoma arising on the dorsal hand of a radiation technician [55], and, after the discovery of radium, experiments in 1900 showed that when in contact with skin, inflammation was induced [56,57]. At present, radiotherapy is a fundamental component of numerous treatment protocols and both acute and chronic mucocutaneous AEs are frequently observed. Acute toxicities range from radiation dermatitis, characterized by erythema, edema, moist desquamations, and ulceration in severe cases, to oropharyngeal mucositis. Severe mucositis can affect up to 56% of patients treated with altered fractionation radiation [32], and acute radiation dermatitis is seen in up to 90% of breast and head and neck cancer patients [58,59]. Although improved patient responses may be obtained through utilization of combination therapies, concomitant administration of epidermal growth factor receptor inhibitors (EGFRIs), or conventional cytotoxic chemotherapy agents with radiation enhances the severity of mucocutaneous toxicities, which has been referred to as radiation enhancement [60,61]. Telangiectasias, fat necrosis, skin fibrosis, pigmentary changes, and atrophy represent the changes of chronic radiation dermatitis, which may manifest several years after the initial insult [62,63]. While numerous topical and systemic interventions for prevention and management of acute radiation dermatitis have been investigated, there is currently insufficient clinical evidence to support the use of any specific agent [64]. However, the use of high potency corticosteroids has been demonstrated to be effective in ameliorating the severity of acute skin reactions [64,65].

Radiation and surgical interventions can sever delicate lymphatic channels with subsequent accumulation of interstitial fluids and the development of lymphedema. The cumulative 5-year incidence of lymphedema in breast cancer survivors can reach 42% [66]. The vast majority of breast cancer survivors (80%) develop lymphedema within 2 years of diagnosis, with signs and symptoms that can persist for more than a decade following surgery [67].

Mucocutaneous toxicities induced by novel targeted agents

Following the approval of the tyrosine kinase inhibitor imatinib in 2001, numerous agents have been approved by regulatory agencies, and their AE profiles have emerged. EGFRIs represent one such class of agents. The most characteristic cutaneous toxicity of these agents, which has become known as a class effect, is a papulopustular (acneiform) rash, which affects up 90% of treated patients [68]. Other commonly observed dermatologic toxicities include xerosis, pruritus, nail and hair alterations, paronychia, and mucosal changes [69]. With the introduction of sorafenib and sunitinib, small molecule multikinase inhibitors (MKIs) for treatment of renal cell carcinomas and gastrointestinal stromal tumors, a new entity that clinically mimics HFS has been described. In an attempt to distinguish this from HFS associated with conventional cytotoxic agents, it has been referred to as hand-foot skin reaction (HFSR) [70]. Similar to EGFRIs, MKIs are associated with a wide spectrum of mucocutaneous toxicities including xerosis, pruritus, seborrheic dermatitis-like rash, scalp dysesthesias, alopecia, subungual hemorrhages, and mucosal inflammation [71].

Emergence of supportive oncodermatology and future directions

The remarkable deveopments in cancer therapies have been possible, at least in part, because of improved management of toxicities from cancer treatment. In the late 1950s, the utilization of transfusions has led to a reduction in hemorrhagic complications in leukemic patients [72]. In addition, prompt empiric antibiotic therapy in immunosuppressed patients has resulted in a significant decrease in early mortality from infectious complications [73]. In contrast, mucocutaneous toxicities have not attracted the same level of interest. There has been a relative paucity of research efforts to quantify the impact of dermatologic toxicities on patients' QoL and their management strategies [42].

The spectrum of dermatologic toxicities resulting from an array of novel targeted therapies, which affect the majority of treated patients in cosmetically sensitive areas, and the contin­ued emergence of new mucocutaneous AE, has highlighted the importance of dermatologic health in cancer patients throughout the last decade. As a result, significant progress has been made in our understanding of the underlying mechanisms of certain toxicities and the ability to diminish their severity and quantify their impact on patients' QoL. Since 2007, multiple randomized controlled trials have been conducted investigating the management strategies of EGFRI-induced papulopustular rash and provide evidence-based data supporting the prophylactic use of antibiotics to mitigate the significant impact of this specific toxicity [74–77]. In 2006, a referral center at the Robert H. Lurie Comprehensive Cancer Center and the Department of Dermatology of Northwestern University in Chicago was created through the multidisciplinary effort of dermatologists, oncologists, and ophthalmologists [78]. Spe­cializing in dermatologic health of cancer patients, this SERIES (Skin and Eye Reactions to Inhibitors of EGFR and kinaseS) clinic has set the stage for specialized dermatologic care for cancer patients. Similarly, in the same year, the Multinational Association for Supportive Care in cancer (MASCC) established the Skin Toxicity Study group which serves to motivate continued research efforts and to develop effective management approaches. Only two years following its inception, a comprehensive classification system was created, the MASCC EGFR Inhibitor Skin Toxicity tool, which it is hoped will improve the ability to quantify the impact of EGFRI-associated toxicities in the setting of clinical trials and routine care [79]. Multidisciplinary efforts have also yielded several management guidelines for dermatologic toxicities associated with EGFRIs and MKIs [69,80,81].

This global effort has contributed to the emergence of supportive oncodermatology as a new discipline within derma­tology, which specifically addresses dermatologic health in cancer patients and survivors. One of the fundamental principles of oncodermatology is to ensure timely and early intervention to maintain QoL and anticancer therapy dose intensity. Driven by a multidisciplinary approach and improved global awareness of dermatologic health in cancer patients, significant progress has been made in our understanding of mucocutaneous AEs, their impact on patient care, and treatment strategies. However, much remains to be accomplished and future efforts should emphasize the development of accurate classification schemes, further understanding of underlying pathophysiology, management strategies, and identifying potential risk factors, which will assist in selecting the most appropriate patient population for pre-emptive therapy. The field of supportive oncodermatology can facilitate improved awareness of derma­tologic toxicities and research efforts, with the mutual goal of maximizing patient QoL and optimizing utilization of potentially life-prolonging anticancer interventions.

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3

Structure and Function of the Integumentary System and the Dermatology Lexicon

Emmy Graber¹ and Amit Garg²

¹Boston University School of Medicine, Boston, MA, USA

²Hofstra School of Medicine North Shore-LIJ Health System, New York, USA

Introduction

The integument, comprised of three layers of skin and its appendages, represents the largest organ of the body (Figure 3.1). In its most basic of functions, the integument serves to protect the body from the external environment and to maintain an internal homeostasis of temperature, fluid, and nutrients. The ability to diagnose and treat skin disease in oncology patients may be enhanced by the clinician's understanding of the structure and function of the integumentary system and by an appreciation of the primary and sequential lesions that arise as a result of aberrances of its components. Certain conditions have a predilection for the palms and soles rather than other locations on the body. The skin on the palms and soles is thicker than on other areas, lacks sebaceous glands, but is copious in eccrine (sweat) glands. There are no hair follicles on the palms and soles. However, cutaneous nerves abound in these areas. In this chapter, we introduce the essential components of the integument and describe the dermatology lexicon of morphologic terms.

Figure 3.1 Basic skin anatomy and cellular structures.

c3-fig-0001

Skin

Epidermis

The epidermis is a continually renewing structure made up primarily of ectodermally derived keratinocytes and organized into four layers: the stratum germinativum, stratum spinosum, stratum granulosum, and the stratum corneum. Its thickness varies depending on location, being thinnest on the eyelids (0.05 mm) and thickest on the palms and soles (1.5 mm). Mitotically active basal layer keratinocytes attached to the basement membrane differentiate upward until reaching a terminally differentiated stage in which they are called corneocytes. These anucleate corneocytes comprise the keratinized stratum corneum, the lipid (ceramide) and protein (loricrin) rich surface barrier of the skin. The epidermal barrier regulates desquama­tion, permeation of water and environmental solubles, activity of antimicrobial peptides, and initiation of cytokine-mediated inflammation, among other critical functions. Keratinocytes throughout the epidermis are tightly intercalated through calcium-dependent cell surface adhesion molecules known as desmosomes.

Immigrant cells of the epidermis include melanocytes, Langerhans cells and Merkel cells. Melanocytes are neural crest-derived dendritic cells largely residing in the basal layer of the epidermis. These cells synthesize pigment and are primarily responsible for imparting color to the skin. Langerhans cells are the marrow derived dendritic antigen presenting cells of the epidermis whose cytoplasm contains characteristic racket-shaped structures known as Birbeck granules. Tumor antigens presented by Langerhans cells mount a tumor-specific immune response and, as such, these cells have been evaluated as vehicles of antitumor and vaccine therapies. Merkel cells are slow-adapting type I mechanoreceptors located in sites of high tactile sensitivity, including the lips, oral cavity, digits, and around hair follicles. Merkel cell carcinoma has been a focus of attention in dermatology and oncology given its aggressive and recalcitrant nature.

Dermal–epidermal junction

The dermal–epidermal junction, also known as the basement membrane zone, is the interface between the epidermis and the uppermost portion of the dermis. This junction contains interconnecting layers of proteins (hemidesmosomes, basal lamina, lamina densa, anchoring fibrils) that secure the epidermis to the dermis and form a semipermeable barrier. Blistering diseases, some of which are induced by medications, are caused by antibody mediated disruptions to basement membrane zone proteins resulting in clefts separating the epidermis and dermis.

Dermis

The dermis provides pliability, elasticity, and tensile strength to the skin, with a thickness ranging from 0.3 mm on the eyelid and 3.0 mm on the back. It is organized into two portions:

1. The upper papillary dermis, which hugs the epidermis and is made up of loosely arranged collagen fibers; and

2. The reticular dermis, which makes up almost the entire thickness of the dermis.

The connective tissue matrix of the reticular dermis is composed of interwoven bundles of densely packed helical collagen fibrils surrounded by elastic fibers. Type I collagen makes up 80–90% of dermal collagen. The matrix also contains glycoproteins, proteoglycans, and glycosaminoglycans that form the water binding ground substance of the dermis. Vascular and nerve networks as well as appendages are also housed in the dermis.

The predominant cell types within the dermis include fibroblasts, macrophages, mast cells, and circulating cells of the immune system. Mesenchymally derived fibroblasts synthesize and degrade connective tissue matrix proteins which provide the structural framework for the dermis. Bone marrow derived macrophages differentiate into circulating monocytes and migrate to the dermis before differentiating further in tissue. Macrophages in the skin serve a number of important functions including antigen processing and presentation, phagocytosis, and wound healing. Mast cells are integral to the initiation of immediate-type hypersensitivity reactions in the skin (e.g., urticaria). Preformed histamine, which is initially confined to secretory granules within mast cells, is the major mediator of these reactions, although tryptase, chymase, carboxypeptidase, and other mast cell mediators are frequently involved.

Vasculature

Oxygen and nutrition delivery, temperature and blood pressure regulation, wound repair, and immunologic progression represent just some of the roles of the cutaneous vasculature. There are two main horizontal plexuses of vessels that run through the upper and lower portions of the dermis. The vasculature tree in the skin advances from arterioles to precapillary sphincters to arterial and venous capillaries which become postcapillary venules, and ultimately venules. Cutaneous vessels of various sizes can be affected by inflammatory diseases (e.g., leukocytoclastic vasculitis, urticaria) or by bland occlusive vasculopathies (e.g., antiphospholipid antibody syndrome).

Lymph channels of the skin regulate interstitial pressure through resorption of released fluids and debris from vessels and tissue. Lymphatics begin as blind endings in the papillary dermis and drain into a horizontal plexus of lymph vessels that run below the papillary dermal venous plexus. Lymph flows vertically downward through the dermis to a deeper collecting plexus located at the base of the dermis. Cancer patients are susceptible to pathologic conditions involving the lymphatic vessels, including lymphedema and lymphangitis. Additionally, the importance of lymphatics in the progression and spread of cancer is now well documented.

Nerves

The skin contains a network of sensory and sympathetic autonomic fibers which regulate a number of critical functions in the skin. Cutaneous nerves arise segmentally from spinal nerves and follow a pattern in the skin similar to the vasculature. Pencillate sensory fibers and specialized corpuscular structures function as the receptors of touch, pain, temperature, and itch. The type and density of these receptors vary, and this accounts for the differences in sensation and acuity across body sites.

After primary infection with the varicella zoster virus, the virus migrates along sensory nerve fibers to the satellite cells of dorsal root ganglia and becomes dormant. The virus may become reactivated by conditions of decreased cellular immunity and result in herpes zoster, a dermatomal eruption of grouped vesicles on an erythematous base.

Subcutaneous tissue

Beneath the dermis lies a layer of subcutaneous adipose tissue, also known as the panniculus, which is subject to a number of inflammatory and neoplastic disorders. The subcutaneous tissue insulates and cushions the body and serves as one of its energy reserves. It is federated with the dermis through networks of vessels, nerves, and appendages. Synthesis and storage of fat result from accumulation of lipid within adipocytes and from proliferation of existing adipocytes. Regulatory feedback signaling in this process is mediated by leptin, a hormone secreted by adipocytes. Adipocytes are organized into lobules separated by septa of fibrous connective tissue containing vessels, lymphatics, and inflammatory cells.

Appendages

Eccrine sweat glands

Eccrine sweating represents a physiologic response to increased body temperature. There are 2–4 million eccrine glands, capable of producing up to 10 L of sweat per day distributed over almost the entire body surface. They are most numerous on the forehead, axillae, palms, and soles. The eccrine sweat gland is made up of a secretory coil and a duct. Clear (secretory), dark (mucoid), and myoepithelial cells comprise the secretory coil to generate an ultrafiltrate of an isotonic precursor fluid in response to cholinergic stimulation. The duct reabsorbs sodium and chloride to produce hypotonic sweat which is secreted on the surface of the skin.

Apocrine sweat glands

The physiologic role of apocrine sweat glands in humans is unclear. These glands are found in the axillae, perineum, and areolae, and begin to secrete a milky odorless fluid around the time of puberty. Though sweat secreted by apocrine glands is odorless, it emits odor when acted upon by bacteria upon reaching the surface of the skin. Apocrine glands have a coiled structure located at the border of the deep dermis and the subcutaneous fat. This coiled structure extends upward into a straight tubular structure that drains into the mid-portion of the hair follicle and shares a common secretory opening to the surface with sebaceous glands.

Sebaceous glands

Sebaceous glands are composed of lobules of lipid-producing sebocytes lining sebaceous ducts associated with hair follicles throughout the body. A sebaceous gland and the associated hair follicle are termed a pilosebaceous unit. Nonhair-bearing sites including the mouth (Fordyce spots), the eyelids (meibomian glands), the nipples (Montgomery glands), and the genitals (Tyson glands) also have sebaceous glands. The greatest density of these glands is noted on the face and scalp. Only the palms and soles, which also have no hair follicles, are completely devoid of sebaceous glands.

Sebaceous glands release lipids through holocrine secretion, a process in which the entire cell disintegrates to extrude its contents. Human sebum reaching the surface of the skin consists of a mixture of lipids including cholesterol, squalene, triglycerides, and free fatty acids. Sebum is speculated to maintain hydration of the skin's surface, to keep the skin soft, and to protect it from infection by bacteria and fungi, perhaps because of its immunoglobulin A content.

Hair

Hair in humans has cosmetic and social significance, and this accounts for the considerable psychologic impact among patients suffering from hair loss (alopecia).

The hair follicle is divided into the infundibulum and the isthmus which comprise the upper portion of the follicle, as well as the suprabulbar area and the bulb which make up the lower follicle. While the upper follicle is permanent, the lower follicle regenerates with each follicular cycle. Rapidly dividing keratinocytes in the bulb's matrix form the hair shaft. Also residing within the matrix are melanocytes which produce pigment that forms the basis of hair color. The cuticle of the hair shaft covers and protects the hair once it exits the shaft.

Hair follicles perpetually cycle through three phases: anagen (growth), catagen (involution), and telogen (rest). On the scalp, about 90% of the approximately 100,000 follicles are in anagen and the rest primarily in telogen. Hairs are in the anagen phase for about 3 years, the catagen phase for a few days, and the telogen phase for about 3 months. Approximately 1% of telogen hairs (100–150 hairs) are normally shed from the scalp daily. Scalp hairs in anagen grow at a rate of 0.37–0.44 mm/day or approximately 1 cm/month. Chemotherapeutics represent the most common causes of anagen effluvium. As most hair follicles are in the anagen stage at any given time, anagen effluvium affects the majority of scalp hair.

Hair is further classified according to size. Terminal hairs are at least 60 μm in diameter and are found on the scalp, eyebrows, and eyelashes at birth. The length of the terminal hair is determined by the duration of the anagen growth phase. Vellus hairs are less than 30 μm in diameter and typically do not achieve a length greater than 2 cm. These hairs are found throughout the body and become terminal hairs in the beard area, trunk, axillae, and genitalia under the influence of male sex hormones at puberty.

The bottom of the hair root is known as the hair matrix. The hair matrix cells divide and move up the follicle, differentiating into either hair cells or inner epithelial sheath cells (hair lining). Interspersed amongst matrix stem cells are melanocytes, which produce hair pigment. The pigment is synthesized from the amino acid tyrosine (catalyzed by the enzyme phenol-oxidase) and transformed to dopa and then to dopaquinone. Further transformation of dopaquinone proceeds in two directions: either directly to indolquinone or through the addition of the amino acid cysteine. Further polymerization of indolquinone alone produces the dark pigment, eumelanin. Polymerization of indolquinone and dopaquinone with an added cysteine produces the yellow pigment, pheomelanin. Hair matrix cells phagocytose eumelanin or pheomelanin from dendritic elongations of melanocytes. This is how hair assumes its color: black if eumel­anin is dominant, and yellow or red if pheomelanin is the major pigment.

Nails

In addition to serving an aesthetic purpose, nails enhance tactile senses and the biomechanics of fingers and toes. Nails can be affected in a number of disease states or responses to therapy, and a basic appreciation for the structure and function of nails may aid the clinician in detecting abnormal physiologic states.

The nail apparatus consists of the nail plate, proximal nail fold, nail matrix, nail bed, and the hyponychium (Figure 3.2). The nail plate is a