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© 2002 American Society for Clinical Oncology
Searching for a StandardThe University of Chicago, Chicago, IL IF ONE WERE TO search the pages of a recent edition of any medical oncology or dermatology textbook, the information on the treatment of advanced cutaneous squamous cell carcinoma (SCC) would be very sparse. Compared with SCC of other primary sites, advanced cutaneous SCC has received little attention with respect to clinical data and definition of standard therapy, reflecting the high curability of early-stage SCC and its relatively low metastatic potential. Nevertheless, this is an entity that is certainly encountered in clinical practice, that often poses a dilemma to the treating physician, and that, as the prevalence of cutaneous SCC is increasing, will likely become more common in the first half of the 21st century.1,2 These difficulties and realities make the study by Shin et al3 in this issue of the Journal of Clinical Oncology particularly intriguing. As an extension of their previous work in this area,4 this group was able to complete the largest study to date involving patients with advanced cutaneous SCC. The 6 years it took to enroll 39 patients reflects the obstacles in conducting clinical trials with this population and the dedication of the researchers. Using a strategy of biologic agents (interferon-alfa [IFN] and 13-cis-retinoic acid [13cRA]) and cytotoxic chemotherapy (cisplatin), the authors were able to demonstrate activity of this regimen, especially in patients with local recurrence. Although only three patients (7.6%) in their study had received prior chemotherapy, most were previously treated with local control measures, implying a high degree of biologic aggressiveness of these tumors. The response rate for the entire cohort was 34%, whereas those with local disease had a 67% response rate. Median survival in the study was 14.6 months but was not reported separately for patients with previously untreated local or metastatic disease. The authors conclude that this is a promising regimen that warrants further examination in the phase III setting. Without decrying the study itself, there are many reasons to suggest that this will never happen. The logistics of conducting a phase III trial in this setting with enough power to demonstrate a statistically or clinically significant benefit of any treatment regimen are daunting. One would have to envision involvement of multiple cooperative groups in a trial that would accrue over many years, with the risk that the agents used and the conclusions drawn would be dated by the time the study was completed. In the decade since Shin et al undertook the present trial, there has been growing skepticism regarding the utility of retinoic acids and IFN in solid tumors5 and the potential of 13cRA as a prophylactic agent.6 Moreover, although cisplatin remains one of the most active agents in SCC, it can be difficult to tolerate and administer. Practical trial design issues aside, the data presented offer few compelling reasons to pursue this strategy. The in vitro results on two SCC cell lines reveal that the inhibitory effects of the agents are additive or "subadditive" rather than synergistic. There are several other novel agents that do demonstrate synergy with cisplatin in SCC cell lines. Furthermore, adding IFN and/or 13cRA to cisplatin did not increase growth inhibition in the cisplatin-sensitive cell line, and adding 13cRA to cisplatin/IFN did not improve results in either cell line. There is no evidence presented in the preclinical data that would suggest the triple combination is superior to cisplatin/IFN. This leads to speculation about the utility of the triple combination. Preclinical data suggest that retinoids can modulate the cellular response to IFN, which supports their use in combination.7-9 The authors cite elegant studies from their institution investigating the expression and effects of retinoids and IFN in human cutaneous SCC specimens.10-12 However, the article from Xu et al10 demonstrated suppression of retinoic acid receptor (RAR) expression from normal skin to SCC, and Clifford et al12 concluded that SCC might be less responsive to IFN compared with adjacent nonmalignant epithelium. Other investigators have demonstrated that RAR expression is positively correlated with the growth inhibitory response to retinoids.13,14 Therefore, SCC, as opposed to earlier dysplastic lesions, may actually be less responsive to retinoids and IFN. Whether IFN and 13cRA interact in vivo to reverse this phenomenon and restore susceptibility has yet to be explored. In 1992, Lippman et al4 suggested that "future studies of this combined-agent therapy (IFN and 13cRA) in cutaneous SCC . . . certainly will include serial biopsies to evaluate these mechanisms of action as well as to evaluate histologic changes." A trial that utilizes serial biopsies may help to further our understanding of the molecular biology of cutaneous SCC as it relates to retinoid and IFN therapy. Indeed, such a trial may aid in explaining the reasons why metastatic disease is less responsive to these agents and may also direct the rational planning of future approaches. A critical review of the clinical data also highlights certain shortcomings. Comparing response rates between this group’s earlier study of IFN/13cRA4 and the present study, it would seem that the former combination was superior to cisplatin/IFN/13cRA. The authors offer the argument that the current research enrolled a more advanced or refractory group of patients, but it is difficult to ascertain what therapies patients received before or after enrollment, such as the number and types of surgical procedures, dose and extent of radiotherapy, and chemotherapy doses and regimens. It is also unclear how patients were selected and whether all those who met eligibility criteria were enrolled. Were these consecutive patients? Were any eligible patients not enrolled and for what reasons? A 34% response rate in a heavily pretreated cohort could indeed be more impressive than a 68% response rate in selected patients who were exposed to little or no therapy. However, these data are not presented. In addition the reader is given little insight on predictors of response, such as tumor size, bone invasion, and number and size of lymph nodes involved. Were there any other clinical parameters that influenced efficacy? Did RAR status influence outcome? Furthermore, no information is presented on subsequent care. Since the great majority of responders were those with localized disease, it would seem reasonable that they received further therapy. This treatment would be likely to impact time to progression and survival to a greater extent than the initial chemotherapy. Future directions will likely include cytotoxic therapy, as there is evidence from the current study and past reports that cisplatin, fluorouracil, bleomycin, doxorubicin, and vindesine may have activity in cutaneous SCC.15-22 One should note that the largest of these trials, except for the current publication by Shin et al, enrolled only 28 patients,19 and many of these articles amount to little more than case cohorts. In fact, the data do not allow comparisons between different regimens, and a standard therapy in this disease does not exist. Nevertheless, there is little doubt that cisplatin, the most commonly studied agent, can induce responses and remissions in this disease. Moreover, strategies that use IFN and cisplatin have proven efficacy in SCC at other sites, including the head and neck.23-26 In addition to cytotoxic therapeutic agents, an emerging and promising target is the epidermal growth factor receptor (EGFR).27 EGFR, together with its most common ligand, transforming growth factor-alpha, forms an autocrine loop that is highly expressed in cutaneous SCC and is active in cell proliferation and transformation.28 Several agents are being introduced into clinical trials that have synergistic activity with cytotoxic agents in SCC preclinical models, including an anti-EGFR antibody, cetuximab,29,30 and two small molecule inhibitors of EGFR tyrosine kinase, ZD-183931,32 and OSI-774.33 Early trials have confirmed their safety,34 with data accumulating regarding their efficacy.35 It would seen from the in vitro and in vivo evidence thus far that these agents should be utilized in future trials of patients with cutaneous SCC. Notwithstanding the above, Shin et al3 have overcome several impediments to clinical research in cutaneous SCC and should be commended for their achievements. It is time to view the data critically and objectively. Doing so, one might conclude that the curtain is setting on 13cRA, and possibly IFN. It is time for new names to appear on the marquee. The decade since Shin et al began enrolling patients in this trial has seen the emergence of several novel targets and agents. This number will likely multiply over the next decade. Future research needs to establish a more effective regimen before embarking on randomized trials. Incorporating these newer agents could fulfill the hope of meaningful increases in response rates and survival. REFERENCES 1. Strom SS, Yamamura Y: Epidemiology of nonmelanoma skin cancer. Clin Plast Surg 24: 627–636, 1997[Medline] 2. Miller DL, Weinstock MA: Nonmelanoma skin cancer in the United States: Incidence. J Am Acad Dermatol 30: 774–778, 1994[Medline]
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Lippman SM, Parkinson DR, Itri LM, et al: 13-Cis-retinoic acid and interferon alpha-2a: Effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 84: 235–241, 1992 5. Agarwala SS: Interferon-alpha and -beta: Clinical applications—Epithelial cancers, in Rosenberg SA (ed): Principles and Practice of the Biologic Therapy of Cancer, ed 3. Philadelphia PA, Lippincott Williams and Wilkins, 2000, pp 275–285 6. Pinto H, Li Y, Loprinzi C, et al: Phase III trial of low-dose 13-cis-retinoic acid for prevention of second primary cancers in stage I-II head and neck cancer: An Eastern Cooperative Oncology Group study. Proc Am Soc Clin Oncol 20: 222a, 2001 (abstr 886)
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Clifford JL, Menter DG, Yang X, et al: Expression of protein mediators of type I interferon signaling in human squamous cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev 9: 993–997, 2000 13. Klaassen I, Brakenhoff RH, Smeets SJ, et al: Expression of retinoic acid receptor gamma correlates with retinoic acid sensitivity and metabolism in head and neck squamous cell carcinoma cell lines. Int J Cancer 92: 661–665, 2001[CrossRef][Medline] 14. Le Q, Dawson MI, Soprano DR, et al: Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids. Oncogene 19: 1457–1465, 2000[CrossRef][Medline] 15. Khansur T, Kennedy A: Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin. Cancer 67: 2030–2032, 1991[CrossRef][Medline] 16. Denic S: Preoperative treatment of advanced skin carcinoma with cisplatin and bleomycin. Am J Clin Oncol 22: 32–34, 1999[CrossRef][Medline] 17. Goldberg H, Tsalik M, Bernstein Z, et al: Cisplatin-based chemotherapy for advanced basal and squamous cell carcinomas. Harefuah 127: 217–221, 286, 1994[Medline] 18. Guthrie TH Jr, McElveen LJ, Porubsky ES, et al: Cisplatin and doxorubicin: An effective chemotherapy combination in the treatment of advanced basal cell and squamous carcinoma of the skin. Cancer 55: 1629–1632, 1985[CrossRef][Medline] 19. Guthrie TH Jr, Porubsky ES, Luxenberg MN, et al: Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: Results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol 8: 342–346, 1990[Abstract] 20. Merimsky O, Neudorfer M, Spitzer E, et al: Salvage cisplatin and Adriamycin for advanced or recurrent basal or squamous cell carcinoma of the face. Anticancer Drugs 3: 481–484, 1992[Medline] 21. Ikegawa S, Saida T, Obayashi H, et al: Cisplatin combination chemotherapy in squamous cell carcinoma and adenoid cystic carcinoma of the skin. J Dermatol 16: 227–230, 1989[Medline] 22. Sadek H, Azli N, Wendling JL, et al: Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer 66: 1692–1696, 1990[CrossRef][Medline] 23. Vokes EE, Kies M, Haraf DJ, et al: Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: Impact on the natural history of the disease. J Clin Oncol 13: 876–883, 1995[Abstract]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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