Evidence Based Analysis on Cisplatin in Treating Patients with Cutaneous Squamous Cell Carcinoma

Skin cancer contains melanoma, basal cell cancer and cutaneous squamous cell carcinoma (CSCC) (Veness et al., 2005). Lifetime risk for SCC is estimated to be 7%-11%, and demonstrates an increasing trend in these 30 years (Miller et al., 1994). CSCC is generally more aggressive, and potentially life threatening, than BCC. Most patients with CSCC who are not cured by local therapies require systematic treatment. Investigation on systemic therapy is relatively limited. A number of systemic therapies are used to treat patients with advanced CSCC, including cytotoxic chemotherapeutic (cisplatin, 5-fluorouracil [5-FU], bleomycin, and doxorubicin), 13-cis-retinoic acid (13cRA), immunotherapy (interferon _2a [IFN-_], etc), and molecularly targeted agents (gefitinib, cetuximab, and erlotinib). Sadek et al. (1990) reported on 14 patients (13 evaluable) from a prospective observational study for patients with advanced CSCC treated with cisplatin, 5-FU, and bleomycin for 1-4 months. Two case series reported patients achieving a CR with the combination of cisplatin and 5-FU (Khansur et al., 1991; Fujisawa et al., 2006). Khansur et al. (1991) reported on seven patients with primary CSCC and locoregional progression treated with cisplatin and 5-FU. A CR was achieved in three of seven patients and a PR was achieved in three of seven patients.


Introduction
Skin cancer contains melanoma, basal cell cancer and cutaneous squamous cell carcinoma (CSCC) (Veness et al., 2005). Lifetime risk for SCC is estimated to be 7%-11%, and demonstrates an increasing trend in these 30 years (Miller et al., 1994). CSCC is generally more aggressive, and potentially life threatening, than BCC. Most patients with CSCC who are not cured by local therapies require systematic treatment.
Investigation on systemic therapy is relatively limited. A number of systemic therapies are used to treat patients with advanced CSCC, including cytotoxic chemotherapeutic (cisplatin,, bleomycin, and doxorubicin), 13-cis-retinoic acid (13cRA), immunotherapy (interferon _2a [IFN-_], etc), and molecularly targeted agents (gefitinib, cetuximab, and erlotinib). Sadek et al. (1990) reported on 14 patients (13 evaluable) from a prospective observational study for patients with advanced CSCC treated with cisplatin, 5-FU, and bleomycin for 1-4 months. Two case series reported patients achieving a CR with the combination of cisplatin and 5-FU (Khansur et al., 1991;Fujisawa et al., 2006). Khansur et al. (1991) reported on seven patients with primary CSCC and locoregional progression treated with cisplatin and 5-FU. A CR was achieved in three of seven patients and a PR was achieved in three of seven patients.
Xiao-Hong Shao 1 , Yun-Sheng Xu 1 , Xue-Qi Zhang 1 , Wen-Feng Li 2 * The median duration of CR was 1 year. Two of the three patients with a CR were disease free at a 13-month and 24-month follow up. Fujisawa et al. (2006) reported on two patients achieving a CR after one or two cycles of cisplatin and 5-FU. In one of the patients, therapy was discontinued after achieving a surgically confirmed CR. d in four of 13 patients with a complete response (CR) and seven of 13 with a partial response (PR) (Miller et al., 1981). Guthrie et al. (1985) treated three SCC patients with cisplatin and doxorubicin. One patient had a CR for 17 months, one had a PR for 3 months, and one had stable disease (SD). The authors suggested that the combination of cisplatin and doxorubicin had activity in cutaneous SCC. However, no large clinical trial was published to demonstrate the efficacy of cisplatin in CSCC. On this background, we report a pooled analysis on cisplatin in treating patients with refractory or relapsed CSCC.

Search strategy
We searched PUBMED, by using the following search term: (cisplatin) and (cutaneous squamous cell carcinoma). All clinical studies evaluating the impact of cisplatin on the response or survival and side effects for cutaneous squamous cell carcinoma published in English prior to November 1st, of 2014 were identified. If samples of two studies overlap, only the latest one was included. Additional articles were obtained from references within the articles identified by the electronic search. We did not consider meeting abstracts or unpublished reports.

Inclusion and exclusion criteria
We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (1) clinical studies, combined with paclitaxel or pirarubicin; (2) The study was performed in accordance with the Helsinki Declaration (1964, amended in 1975 and 1983) of the World Medical Association. Eligibility criteria included histologically or cytologically verified metastatic and/or locally advanced cutaneous squamous cell carcinoma, the presence of at least one bidimensionally measurable lesion, a performance status (WHO) 2, age< 18 years. Studies were excluded if one of the following existed: (1) duplicate data; (2) no sufficient data were reported.

Data collection and analysis
Selection of trials and data extraction: The titles and abstracts of publications identified according to the above search strategy were assessed independently for inclusion by two authors; the full text was selected for further assessment if the abstract suggests relevance. Disagreement was resolved by discussion. Data was extracted by independent authors. The following recorded data were extracted: author, publication data, and country of the first or corresponding author, the number of patients.

Results
There were 65 papers relevant to the search words by the end of November 1st, of 2014. Via steps of screening the title and reading the abstract, 4 studies were identified (Ikegawa et al., 1989;Guthrie et al., 1990;Goldberg et al., 1994;Nakamura et al., 2013) when cisplatin was used in combination of chemotherapy. These studies had been carried out in Japan, Israel, and the United States. The following outcomes were presented in at least all studies and extracted for combined analysis: response rate, including the rate of complete or partial response (CR or PR) and toxicities. When cisplatin was used in combined chemotherapy with cyclophosphamide, and/or doxorubicin, 4 studies included in this study are presented and the short-term outcomes suggested that the response rate of Nakamura et al. was 25%, of Ikegawa et al. was 50%, of Guthrie et al. was 67.9%, and of Goldberg et al. was 75%. Totally, 50 patients were enrolled and 30 patients achieved CR or PR, the pooled response rate thus was 30/50 (60%). Observation on toxicities: Nausea and vomiting were the main side effects. No grade III or IV renal or liver toxicity were observed. No treatment related death occurred in these cisplatin based treatment.

Discussion
Skin cancer is an important research topic in China (Deng et al., 2013;Hao et al., 2013;Wang et al., 2013;Wu et al., 2013). CSCC with distant metastasis, while rare, is more common than metastatic basal cell cancer. A 10-year cohort study involving 985 patients with SCC found a 3.7% risk of metastasis and 2.1% risk of disease-specific death. Patients with metastatic CSCC should receive appropriate therapy although participation in a clinical trial is encouraged. Possible agents for patients in this setting include cisplatin monotherapy, cisplatin plus 5-FU, or epidermal growth factor receptor (EGFR) inhibitors, eg., cetuximab. At present, few evidence is available regarding systemic therapy for this condition, and no prospective phase III studies were available (Cranmer et al., 2010).
Cisplatin as a single agent or combined with 5-FU is a widely used regimen in clinical. A phase II study with biochemotherapy and interferon alfa, cis-retinoic acid, as well as cisplatin, were assessed for response in 35 patients, and among them, 11 patients had distant metastases (Shin 2002). One of these 11 patients experienced complete response, and among 12 patients with only regional lymph node metastases, 2 had partial and 1 had complete response (Shin, 2002). Nakamura et al retrospectively examined the response rate of combination platinum and anthracycline chemotherapy for metastatic CSCC. They recruited 8 patients, and all these 8 patients received combination chemotherapy: cisplatin (60-90 mg/m 2 /day, day 1) and adriamycin (20-40 mg/m 2 /day, day 1 or 2) was administered in 5 patients; cisplatin (10-15 mg/m 2 /day, days 1-5) and epirubicin (10-15 mg/m 2 /day, days 1-5) was administered in 2 patients; and carboplatin (200-400 mg/m 2 /day, day 1) and adriamycin (20-40 mg/m 2 /day, day 1 or 2) was administered in one patient. They found complete response in 2 patients (cisplatin + adriamycin for lung metastasis, cisplatin + epirubicin for lymph node metastasis), partial response in 1 (cisplatin + adriamycin for lymph node metastasis), stable disease in 2, and progressive disease in 3. A durable response was observed in 2 patients showing complete responses (Nakamura et al., 2013). Goldberg et al. also treated 8 patients (4 men and 4 women; mean age 70, range 49-86) with advanced CSCC with cisplatin-based chemotherapy. The disease was local in 4, local with regional lymph node involvement in 2, involved regional lymph nodes in 1 and was local with distant metastases in 1 patient. All were treated with a combination of cisplatin and 5-Fu, 2 patients were treated in addition with a combination of cyclophosphamide, doxorubicin, and cisplatin. Complete pathological response was seen in 2/8 and partial response in 4/8 with an overall response rate of 75%. Tumor progression was observed in 2 patients. Survival of patients who responded was from 3-47 months (mean 12). Two patients who did not respond to chemotherapy died within 1 and 3 months after treatment. Significant side-effects in 6 included myelotoxicity and transient renal toxicity (Goldberg et al., 1994). They concluded that cisplatin based chemotherapy is effective in treating patients with advanced CSCC and may have curative potential when combined with local therapy (Goldberg et al., 1994).
Our results suggested that when cisplatin was used in combination with chemotherapy. Totally, 50 patients could be enrolled and 30 patients achieved CR or PR, the pooled response rate thus was 30/50 (60%). Observation on toxicities: Nausea and vomitting were the main side effects. No grade III or IV renal or liver toxicity were observed. No treatment related death occurred in these cisplatin based treatment.
Thus, in conclusion, we suggested that cisplatin based regimens are associated with good response rate and accepted toxicities for treating patients with CSCC.