Long-term outcome of concurrent chemotherapy and re-irradiation for recurrent and second primary head-and-neck squamous cell carcinoma

Locoregional failure remains a serious problem in the management of head-and-neck cancer. Recent reports have demonstrated improved locoregional control (LRC) and survival rates with definitive or adjuvant concomitant chemoradiotherapy over radiotherapy (RT) alone. Despite these advances, local recurrences affect a large number of patients, especially with those with advanced primary stage disease. Furthermore, many patients treated with combined modality therapy develop second primary tumors.

When recurrences occur in previously radiated fields, patients and oncologists have limited salvage options. For low-volume resectable disease, surgery is the standard of care. However, many patients are medically unfit for surgery, refuse surgery, or have unresectable disease.

Nonsurgical candidates are usually offered chemotherapy, with a median survival of 6–8 months and little chance for cure . However, isolated locoregional recurrences in nonmetastatic patients can potentially be eradicated with aggressive treatment. Long-term survival rates of 37–50% have been reported after reirradiation of recurrent and second primary head-and-neck cancer. However, tumor clonogenic cells persisting through a course of RT are likely to be radioresistant. Adding radiosensitizing chemotherapy offers a method of enhancing the cell kill.

At the University of Chicago, concomitant chemotherapy and reirradiation have been investigated for two decades. Most regimens have incorporated concurrent 5-fluorouracil (5-FU), hydroxyurea (HU), and RT as the base regimen (FHX). Both 5-FU and HU exhibit single-agent activity and radiosensitization of squamous cell head-and-neck cancer. Furthermore, 5-FU and HU act synergistically in vivo.

We have previously reported the outcomes with FHX and regimens containing third agents paired with FHX for recurrent and second primary head-and-neck cancers. Studies from the Institute Gustave Roussy, the University of Alabama-Birmingham, and the Radiation Therapy Oncology Group have corroborated our results with FHX . The 4-year overall survival (OS) rates in these studies have been 22–43%.

Some have questioned whether reirradiation toxicity outweighs the potential benefits, because the median survival of reirradiated patients marginally exceeds that of chemotherapy alone. However, the 2–3-year OS rates appear superior. We sought to identify subgroups of patients with nonmetastatic squamous cell cancer undergoing concurrent chemotherapy and reirradiation who were more likely to benefit from an aggressive approach. Therefore, we analyzed patient- and treatment-related factors across several similarly designed Phase I and II trials investigating novel chemoradiotherapy regimens to determine their impact on OS, progression-free survival (PFS), LRC, and freedom from distant metastasis (FFDM).

Purpose: To define favorable pretreatment characteristics for overall survival (OS), progression-free survival (PFS), locoregional control, and freedom from distant metastasis for patients with recurrent and second primary head-and-neck cancer treated with concomitant chemotherapy and reirradiation.

Methods and Materials: Our study population comprised a subset of 115 previously irradiated patients without overt metastases from 304 poor-prognosis head-and-neck cancer patients treated in seven consecutive phase I-II protocols. Of the 115 patients, 49, who had undergone surgical resection, were treated with a median of four cycles of concurrent chemotherapy and reirradiation and 66, who had not undergone surgical resection, were treated with a median of five cycles. The following regimens were used: 5-fluorouracil and hydroxyurea concurrent with reirradiation (FHX) (n = 14), cisplatin plus FHX (n = 23), paclitaxel plus FHX (n = 42), gemcitabine plus paclitaxel and 5-fluorouracil concurrent with reirradiation (n = 26), and irinotecan plus FHX (n = 10).

Results: The median lifetime radiation dose was 131 Gy. The median follow-up for surviving patients was 67.4 months (range, 18.5–158.7). The median OS and PFS was 11 and 7 months (range, 0.2–158.7), respectively. The 3-year OS, PFS, locoregional control, and freedom from distant metastasis rate was 22%, 33%, 51%, and 61%, respectively. Multivariate analysis identified reirradiation dose, triple agent (cisplatin-, paclitaxel-, or gemcitabine-containing chemotherapy), and surgery before protocol treatment as independently prognostic for OS, PFS, and locoregional control. Triple-agent chemotherapy was prognostic for freedom from distant metastasis. Nineteen patients died of treatment-related toxicity, five of these of carotid hemorrhage.

Conclusion: For recurrent and second primary head-and-neck cancer, trimodality therapy with surgery, concurrent chemotherapy, and reirradiation for a full second dose offers potential for long-term survival. Owing to the substantial toxicity and lack of an optimal regimen, reirradiation of recurrent head-and-neck cancer should be limited to clinical trials.