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Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp. 1953-1954 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.8252
Skin Squamous Cell Cancer: The Time Is Right for Greater Involvement of the Medical OncologistMemorial Sloan-Kettering Cancer Center, New York, NY Squamous cell cancer (SCC) of the skin is a paradox for the medical oncologist. It is one of the most common malignancies, yet medical oncologists are involved infrequently in the management of most skin SCCs. Most patients with the disease have an excellent prognosis and are treated by a dermatologist, surgeon, or radiation oncologist. There has been no established role for systemic therapy in the adjuvant setting, either alone or with radiation, with the recent exception of the potential use of oral retinoids with preventive intent in selected patients at increased risk for the development of new skin cancers.1 Historically, the medical oncologist's role has been relegated largely to the palliative treatment and symptom management of patients with recurrent locoregional or distant disease not amenable to further local treatment measures. Although chemotherapy has limited efficacy in this setting, relatively little attention has been paid to the prospective evaluation of promising new agents in patients with cutaneous SCC. Oncologists have regularly relied on low-quality evidence from the literature, preclinical data, expert opinion, experience with the treatment of SCC from other primary sites such as the aerodigestive tract or cervix, and clinical judgment to assist in chemotherapy drug selection. However, several factors point toward the need for more investigations into the pathogenesis, molecular biology, prevention, developmental therapeutics, and combined-modality therapy of SCC of the skin, as well as a growing awareness of the disease and its management among medical oncologists. Because the incidence of SCC of the skin increases after age 40,2,3 an aging population of baby boomers will contribute to a further increase in the incidence of the disease. A number of risk factors have been identified that predispose one to developing cutaneous SCC—exposure to sunlight and related ultraviolet radiation is the most important and best characterized risk factor.3 A prior diagnosis of SCC of the skin is associated with an increased likelihood of subsequent skin cancer,4 as well as cancer at other sites.5 Many such factors lend themselves to risk-reduction strategies, so there is a keen interest in preventive interventions, including chemoprevention.6,7 Skin cancer preventive education warrants broad-based attention across all age groups,1 and it certainly has relevance to newer survivorship initiatives. Successes in organ transplantation have been associated with an increase in SCC of the skin among these patients,8 attributed to the need for chronic immunosuppression. Similarly, the incidence is increased among individuals with leukemia or lymphoma.9 The skin cancers that occur in such populations are more aggressive, and there is a growing appreciation that their management poses special challenges. Indeed, the International Transplant-Skin Cancer Collaborative (Milwaukee, WI) has a new initiative, After Transplantation—Reduce Incidence of Skin Cancer (www.at-risc.org). There are other poor prognostic subgroups of patients in addition to the immunosuppressed, identified by a variety of established clinical and pathological factors,1 in whom SCC of the skin is more likely to behave aggressively, with adverse consequences for both the quality and quantity of survival and, thus, a need for better therapy. In that context, several newer agents have a sound basis for efficacy in the disease, and lessons learned from combined modality approaches in other settings, particularly the integration of chemotherapy and radiation, have a good rationale for further evaluation as well. With this background, the randomized trial reported by Brewster et al10 from the M.D. Anderson Cancer Center (Houston, TX) in this issue of the Journal of Clinical Oncology is both timely and of great interest. The question being asked was whether 6 months of the combination of 13-cis-retinoic acid and interferon alfa administered with adjuvant intent after primary treatment of aggressive skin SCC could decrease the combined end point of time to recurrence or second primary skin cancer in patients, compared with no therapy. The trial built on previous work identifying high-risk factors for recurrence of the disease, as well as prior evaluation of these drugs as both preventive and therapeutic agents. Sixty-six patients were randomly assigned; the primary treatment was surgery and radiation in most (75%). Overall, 28% of patients developed recurrence, and 17% developed a second primary tumor. Grade 3 or 4 toxicities prompted dose reduction in 29% of patients treated on the experimental arm. Unfortunately, the added toxicity did not translate into a proven benefit, as there was no significant difference between the treatment arms in time to recurrence, the incidence of second primary tumors, or the composite end point of these outcomes considered together. The study had certain limitations that deserve consideration when interpreting its results and in planning future investigations. As the authors note, the trial was underpowered to detect smaller differences, given the modest sample size and the less-than-predicted observed incidence of recurrence or second primary cancer. The median follow-up for the study was 21.5 months, and as such, a subsequent report with longer follow-up and more information on survival outcomes will be of interest. Experience with the composite end point of recurrence or second primary cancer is limited. A more detailed description of the skin cancer second primaries that did occur would be useful, as such tumors will run the gamut from easily detected and addressed trivial lesions to ones that are more worrisome prognostically and for which successful prevention with adjuvant systemic therapy will provide a benefit of significant magnitude to offset the anticipated added toxicity. Among the recurrences, most (61%) were locoregional. Based on data from other settings,11,12 many would argue that incorporating chemotherapy in a concurrent fashion with radiation as an adjuvant is likely more effective than drug therapy alone in addressing this type of failure. Nonetheless, the trial reported by Brewster et al—to our knowledge, the first of its kind for patients with aggressive skin SCC—remains an important contribution, providing disease-specific and randomized data in a disease and setting that historically has received little attention within the medical oncology community. The M.D. Anderson investigators note the rationale for the use of 13-cis-retinoic acid and interferon alfa in skin SCC and premalignant actinic keratoses. Another potential mechanism for the effect of retinoids is their impact on the background epithelium, which, in turn, exerts an effect on the neoplastic process. Other metabolic pathways are also of potential importance in the disease, and newer, targeted therapies that have already received considerable attention in other solid tumors have a good rationale for further study in SCC of the skin. For example, the epidermal growth factor receptor (EGFR) plays a central role in normal physiology of the epidermis, and it may be important in the biology of cutaneous SCC. High levels of EGFR expression have been detected in metastatic cutaneous SCC.13,14 A phase II study of the EGFR tyrosine kinase inhibitor gefitinib in patients with metastatic/recurrent cutaneous SCC reported partial responses in three (15%) of 20 patients assessable for response.15 Angiogenesis is another area of active research in cutaneous SCC. Vascular density, an indicator of angiogenesis, is higher in cutaneous SCC lesions compared with normal skin.16 In a clinical study of cutaneous SCC patients treated with topical imiquimod, tretinoin, calcipotriene, diclofenac, hydrocortisone, and valerate (OLCAT-005), durable complete responses were common and attributed to the antiangiogenic effect of this treatment.17 Combined inhibition of EGFR and vascular endothelial growth factor receptor 2–induced apoptosis in a cutaneous SCC xenograft model,18 and this observation presents an opportunity for further clinical study. Cutaneous SCC is an entity well suited for the further evaluation of new drug therapies. Many of these tumors will be superficially accessible and lend themselves for sampling as part of correlative studies, adding to the richness of data that can be derived from thoughtfully designed clinical trials. Well-done, prospective clinical studies evaluating promising new agents will be instrumental in moving the field forward, but they require cooperation among investigators to accrue adequate numbers of patients in a timely fashion. Given the very limited nature of available evidence to guide the use of systemic therapy, such initiatives deserve our support. Otherwise, opportunities to identify and quantitate the activity of new agents that improve outcome, or conversely to document inactivity of drugs that offer no benefit and should not be used, will be missed. Considering the evolving clinical picture of SCC of the skin and the need to rigorously evaluate drug therapies in the disease, the time is certainly right for greater involvement of the medical oncologist. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES 1. National Comprehensive Cancer Network: Non-melanoma skin cancers: NCCN Clinical Practice Guidelines in Oncology. http://www.nccn.org/professionals/physician_gls/default.asp 2. Miller DL, Weinstock MA: Nonmelanoma skin cancer in the United States: Incidence. J Am Acad Dermatol 30: 774-778, 1994[Medline] 3. Alam M, Ratner D: Cutaneous squamous-cell carcinoma. N Engl J Med 344: 975-983, 2001 4. Marcil I, Stern RS: Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: A critical review of the literature and meta-analysis. Arch Dermatol 136: 1524-1530, 2000 5. Hemminki K, Dong C: Subsequent cancers after in situ and invasive squamous cell cancer of the skin. Arch Dermatol 136: 647-651, 2000 6. Otley CC, Statsko T, Tope WD, et al: Chemoprevention of nonmelanoma skin cancer with systemic retinoids: Practical dosing and management of adverse effects. Dermatol Surg 32: 562-568, 2006[CrossRef][Medline] 7. Chen K, Craig JC, Shumack S: Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: A systematic review of randomized controlled trials. Br J Dermatol 152: 518-523, 2005[CrossRef][Medline] 8. Euvrard S, Kanitakis J, Claudy A: Skin cancers after organ transplantation. N Engl J Med 348: 1681-1691, 2003 9. Weimar VM, Ceilley RI, Goeken JA: Aggressive biologic behavior of basal- and squamous-cell cancers in patients with chronic lymphocytic leukemia or chronic lymphocytic lymphoma. J Dermatol Surg Oncol 5: 609-614, 1979[Medline] 10. Brewster AM, Lee JJ, Clayman GL, et al: Randomized trial of adjuvant 13-cis-retinoic-acid and interferon alpha for patients with aggressive skin squamous cell carcinoma. J Clin Oncol 25: 1974-1978, 2007 11. Peters WA III, Liu PY, Barrett RJ II, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18: 1606-1613, 2000 12. Bernier J, Vermorken JB, Koch WM: Adjuvant therapy in patients with resected poor-risk head and neck cancer. J Clin Oncol 24: 2629-2635, 2006 13. Shimuzu T, Izumi H, Oga A, et al: Epidermal growth factor receptor overexpression and genetic aberrations in metastatic cutaneous squamous-cell carcinoma of the skin. Dermatology 202: 203-206, 2001[CrossRef][Medline] 14. Maubec E, Duvillard P, Velasco V, et al: Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res 25: 1205-1210, 2005[Medline] 15. Glisson BS, Kim ES, Kies MS, et al: Phase II study of gefitinib in patients with metastatic/recurrent squamous cell carcinoma of the skin. J Clin Oncol 24: 18S, 2006 (abstr 5531)[CrossRef] 16. Strieth S, Hartschuh W, Pilz L, et al: Angiogenic switch occurs late in squamous cell carcinomas of the skin. Br J Cancer 82: 591-600, 2000[CrossRef][Medline] 17. Li VW, Ball RA, Vasan N, et al: Antiangiogenic therapy for squamous cell carcinoma using combinatorial agents. J Clin Oncol 23: 16S, 2005 (abstr 3032) 18. Park YW, Younes MN, Jasser SA, et al: AEE788, a dual tyrosine kinase receptor inhibitor, induces endothelial cell apoptosis in human cutaneous squamous cell carcinoma xenografts in nude mice. Clin Cancer Res 11: 1963-1973, 2005 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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