In locoregionally advanced disease (large/inoperable primary tumor, N2/N3 or extra nodal extension), survival rates are poor despite extensive surgical treatment so new treatment strategies are required. As described in the previous sections surgery, radiotherapy and chemotherapy are all effective modalities in the treatment of penile cancers. Therefore, a multimodality approach with combinations of these modalities seems a logical step.

Radiotherapy (RT) in combination with concurrent chemotherapy is an established approach to improve RT efficacy. Concurrent chemo-radiotherapy (CRT) has been proven to be effective in the treatment of squamous cell carcinomas such as lung, cervical and head and neck cancer. Currently there are no studies investigating the value of CRT for locally advanced penile cancers. The situation is different for the other squamous cell carcinomas such as cancer of the vulva and the anal canal.

For (locally advanced) anal squamous cell carcinoma the current standard is CRT with 5-fluorouracil (5-FU) and mitomycin (MMC), surgery is reserved for poor and non-responders to CRT. This standard is set by several controlled randomized phase III trials. In 1996 the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Anal Cancer Trial Working Party reported on a randomized phase III trial of RT alone versus CRT with 5-FU + MMC. In this trial the clinical response was assessed 6 weeks after initial treatment: good respond-ers were recommended for boost radiotherapy and poor responders for salvage surgery. The CRT arm showed a 46% reduction in local failure compared to the RT arm (p < 0.0001). The risk of CRT patients to develop local failure was 36% at 3 years. Early morbidity was significantly more frequent in the CRT arm (p = 0.03), but late morbidity occurred at similar rates. Similar outcome was reported in 1997 by the EORTC in a phase III randomized trial between RT versus CRT with 5-FU + MMC.4 7 Also in this trial clinical response was assessed 6 weeks after initial treatment: good responders were recommended for boost radiotherapy. Surgical resection was performed in patients who had not responded 6 weeks after RT or patients with residual palpable disease after the completion of treatment. The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for RT alone to 80% for CRT. This led to a significant improvement of loco regional control and colostomy-free interval (p = 0.02 and p = 0.002, respectively), both in favor of CRT. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. In the CRT group approximately 70% of the patients remained free from colostomy at 5 years. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The added value of MMC to 5-FU was examined in a RTOG/ECOG randomized phase III trial.48 Patients were randomized to receive either CRT + 5-FU versus CRT + 5-FU + MMC. At 4 years, colostomy rates were lower (9% vs. 22%;

Fig. 12.3 The possible role of CRT for penile cancer

p = 0.002), colostomy-free survival higher (71% vs. 59%; p = 0.014), and disease-free survival higher (73% vs. 51%; p = 0.0003) in the MMC arm. RTOG 98-11, a multicenter, phase 3, randomized controlled trial compared treatment with CRT + 5-FU + MMC versus CRT + 5-FU + cisplatin in patients with anal canal carcinoma.49 Cisplatin-based therapy failed to improve disease-free survival compared with MMC-based therapy, but cisplatin-based therapy resulted in a significantly worse colostomy rate.

In locally advanced cancer of the vulva, treatment seems to focus on preopera-tive CRT with 5-FU + MMC or 5-FU + cisplatin followed by surgery. Prospective randomized trials to assess the benefit of adding chemotherapy to radiation therapy have not been done. Although there are no prospective randomized controlled trials, there are many reports addressing the feasibility and safety of preoperative CRT for advanced vulvar carcinoma.50 Most studies use CRT with 5-FU + MMC or CRT with 5-FU + cisplatin. Bleomycin appears to be less effective and may result in severe toxicity.5 0,51 Preoperative CRT reduces tumor size and improves operability. With CRT using 5-FU + CDDP or 5-FU and MMC operability is achieved in 63-92% of cases.51 More than half of the patients (50-95%) become free of disease following surgery and remain free of recurrence during follow-up.50 Essentially different from CRT in anal cancer is the toxicity profile. Many patients experience severe intestinal, vaginal, or urologic complications. Even among selected patients who were fit for surgery treatment related deaths are reported.50,51 In a recent critical review by the Cochrane Gynaecological Cancer Group the current status of neoadjuvant CRT for advanced vulvar cancer is summarized.51 It was concluded that patients with a large or inoperable primary tumor or lymph nodes may benefit from chemoradiation.

Given the excellent outcome of CRT in the other squamous cell carcinomas of perineal origin, CRT for locally advanced penile cancer seems a valid option. There are two options, CRT in a preoperative setting, as used in vulvar cancer, or CRT as primary treatment and surgery reserved for poor and nonresponders (Fig. 12.3).

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