Sequential complete responses to chemoradiation and subsequent chemotherapy in giant vulvar squamous cell carcinoma

Dear Editors, Chemoradiation can be considered a treatment option for patients with locally or locoregionally advanced squamous cell carcinoma (SCC) who are not candidates for curative surgery. Although chemoradiation has been reported to achieve a high rate of local control, its efficacy is greatly influenced by tumor size. 1, 2 In contrast, achieving complete response (CR) in metastatic SCC with chemotherapy alone is uncommon.3 Here, we report an unusual case of giant vulvar SCC that initially achieved CR with chemoradiation, subsequently recurred, and then achieved CR again with chemotherapy alone. A 43-year-old woman presented with a progressively enlarging vulvar tumor that had initially developed 15 years prior to referral. Physical examination revealed a firm 17 × 10 × 4 cm tumor in the left vulva (Figure 1a). A skin biopsy showed diffuse dermal infiltration of atypical squamous cells with keratin pearl formation, some of which were continuous with the overlying epidermis, consistent with SCC (Figure 1b). Computed tomography (CT) revealed multiple enlarged lymph nodes (LNs) in the left inguinal and pelvic regions (Figure 1c, d). These enlarged LNs were fluorodeoxyglucose-avid on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), indicating metastases. The primary tumor was strongly suspected to have infiltrated the urethra, rendering it unresectable without removal of the proximal urethra. The International Federation of Gynecology and Obstetrics (FIGO) classifies cases with metastatic pelvic LNs as stage IVB, grouping them with those having hematogenous metastases.4 However, patients with positive pelvic LNs are suggested to have better survival than those with metastatic disease beyond the pelvis, and radiotherapy has been associated with improved outcomes.4 The current NCCN guidelines for vulvar cancer recommend chemoradiation for locally unresectable tumors with pelvic LN metastases.5 Therefore, we initiated concurrent chemoradiotherapy using 5-fluorouracil and cisplatin (FP). The FP regimen consisted of 5-fluorouracil (800 mg/m2) and cisplatin (15 mg/m2), administered for five consecutive days followed by a 2-day rest, repeated every four weeks. Radiotherapy was delivered to a total dose of 74 Gy, including 62 Gy of intensity-modulated radiation therapy to the primary tumor and bilateral inguinal and pelvic regions, and 12 Gy of interstitial brachytherapy to the primary tumor. Although chemotherapy continued after completion of radiotherapy, the dose was reduced to 80 % from the 6th cycle onward due to decreased creatinine clearance, diarrhea and fatigue. The locoregional lesions rapidly regressed after treatment. Eight months after initiation of therapy, both the primary tumor and the enlarged LNs had completely regressed, indicating CR (Figure 1e–g). Chemotherapy was discontinued due to concerns about cumulative nephrotoxicity. However, 13 months later, PET-CT revealed recurrence, with FDG-avid masses in the inguinal, pelvic and paraaortic LNs as well as in the left rectus abdominis and adductor muscles (Figure 2a–d). Re-administration of FP led to gradual regression of all recurrent tumors, and CR was achieved one year after resumption of chemotherapy (Figure 2e, f). The patient has remained on chemotherapy for eight months to date, with no evidence of recurrence. Given that SCC is radiosensitive and chemotherapy acts as a radiosensitizer, concurrent chemoradiation is widely employed for treating locally or locoregionally advanced disease.6 Indeed, previous studies have demonstrated that chemoradiation is associated with better outcomes than radiotherapy alone.7 However, the efficacy of chemoradiation negatively correlates with tumor size,1, 2 and there have been no reports of CR in cases with giant tumors larger than 10 cm treated with chemoradiation. Thus, our case may represent the largest tumor to achieve CR with chemoradiation. The effects of radiotherapy can be long-lasting and may take several months to become fully apparent. Therefore, during chemoradiation therapy, the antitumor activity is primarily attributed to radiation, whereas concurrent chemotherapy is generally considered to act mainly as a radiosensitizer.8 However, the rapid and marked tumor regression observed in our case suggests that FP may have exerted a direct antitumor effect beyond radiosensitization. This is further supported by the fact that CR was achieved again upon recurrence with FP chemotherapy alone in our case. Recently, anti-PD-1 antibodies have been introduced for the treatment of advanced SCC, demonstrating higher response rates compared to conventional chemotherapies.9 Nevertheless, in patients who respond well to chemoradiation, the same chemotherapy regimen used during chemoradiation may represent a viable and effective option for treating recurrent disease, as illustrated in our case. Currently, there is no consensus on whether chemotherapy should be continued after achieving CR with chemoradiation, or the optimal duration of such treatment. However, given the recurrence observed in our case and the relatively high relapse rates reported after CR in previous studies,10 extended chemotherapy may be warranted in high-risk cases, such as those with large tumors or multiple LN metastases. We thank Cosmin Florescu (Medical English Communications Center, Faculty of Medicine, University of Tsukuba) for useful comments. None.