A non-randomized comparison of gemcitabine-based chemoradiation with or without induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck

Two thirds of the squamous cell carcinoma of the head and neck (SCCHN) are in a locoregionally advanced disease stage at time of diagnosis. Locoregionally advanced SCCHN is generally treated by a combination of chemotherapy and irradiation with or without surgery [1]. Concurrent chemotherapy and radiotherapy (chemoradiation) is widely adopted as standard of care for locoregionally advanced SCCHN after the publication of a large meta-analysis including individual data on 10.741 patients in 63 randomized trials [2, 3]. Concurrent chemoradiation conferred an absolute survival benefit of 8% at 2 and 5 years. In contrast, the meta-analysis failed to demonstrate a survival advantage for induction chemotherapy followed by local treatment compared to local treatment alone. However when the meta-analysis was restricted to trials using the standard cisplatin/infusional 5-fluorouracil (PF) regimen, the absolute benefit at 5 years was 5% (p = 0.05). Recently, the addition of a taxane, docetaxel or paclitaxel, to cisplatin and 5-fluorouracil induction chemotherapy has shown to further improve response rates and survival outcomes when compared to the standard PF combination [4‐6].

Moreover, induction chemotherapy reduces the risk of distant metastasis and offers the opportunity of assessing tumor chemosensitivity and selecting the patients who are candidate for organ preservation [7]. Sequential administration of induction chemotherapy followed by concurrent chemoradiation might combine the benefits of both [8]. Several cooperative groups are currently comparing this sequential approach to standard chemoradiation. However, definitive results of these randomized trials will not be available for several years. We therefore decided to perform a historical comparison of two cohorts of patients who were treated at our institution either by gemcitabine-based chemoradiation or induction chemotherapy followed by the same chemoradiation regimen.

Twenty-seven patients were treated in the concurrent chemoradiation cohort and 31 patients in the sequential cohort.

Patient and tumor characteristics are summarized in table 1 and 2. Median age was similar in both cohorts. There were slightly more male patients in the sequential cohort. Hypopharynx tumors predominated in the concurrent cohort wile oropharynx tumors constituted the largest group in the sequential cohort. Almost all tumors were stage IV in both cohorts while all patients had a good or excellent performance status.

Admittedly, the results of our analysis are to be interpreted with extreme caution as this is a non-randomized historical comparison of a relatively small number of patients treated at a single institution. Moreover, although the chemoradiation regimen was the same in both cohorts, it was not the currently widely accepted standard which is cisplatin-based. However, gemcitabine is a potent radiosensitizer which ensures excellent local control rates when added to radiation as treatment for locally advanced head and neck cancer, albeit at the cost of acute and late toxicity in excess of what is usually seen with cisplatin-based chemoradiation [9]. The median overall survival in our CRT cohort (20.2 months) was very similar to that observed in the chemoradiation arm of the Intergroup Study conducted in patients with unresectable squamous cell carcinoma of the head and neck (19.1 months) [10], at least suggesting that the difference between the two cohorts in our comparison was not due to a worse than expected outcome in the CRT cohort. In that Intergroup Study the standard cisplatin regimen (100 mg/m² on day 1, 22 and 42) was used. The locoregional control rate in our patients was promising and not significantly affected by the administration of induction chemotherapy. Induction chemotherapy did not preclude timely administration of radiotherapy, which is crucial as a protracted duration of radiation has a negative impact on treatment outcome [11‐14]. The use of induction chemotherapy was associated with a statistically significant reduced risk of distant metastases. The reduction in distant metastasis translated into a better overall survival in a multiple Cox regression analysis taking into account age, T and N stage and tumor site. A reduced risk of distant metastasis has been a consistent observation in induction chemotherapy trials [2, 15‐17]. Graf et al [18] published the results of a non-randomised comparison of chemoradiation and sequential therapy performed at the Charité Medical School in Berlin. In contrast to our findings, local control was significantly worse in the sequential cohort. They observed a difference in overall survival in favor of the concomitant cohort which approached statistical significance. However, the radiation regimen in that study differed between the two cohorts: patients in the chemoradiation cohort received a hyperfractionated course up to 72 Gy while the patients in the sequential cohort received conventionally fractionated chemotherapy up to 70 Gy. Moreover, mean radiation dose achieved in the sequential cohort (65.3 Gy) was substantially lower than in the chemoradiation cohort (71.6 Gy). Finally, patients in the sequential cohort received only two cycles of PF induction chemotherapy and only one additional course of chemotherapy during radiation.

In our study, patients received a median of 4 cycles of chemotherapy which was a taxane containing triplet in 93%. Indeed, taxane containing triplets have demonstrated clear superiority over PF when administered as induction regimen. In our patients, induction chemotherapy did not jeopardize the subsequent radiation therapy as the median cumulative dose was 70 Gy in both cohorts. All these factors taken together may explain the discordant results of the analysis by Graf et al and ours.

Sequential treatment is associated with an increased toxicity. Hematological toxicity dominates during the induction phase of the therapy. Some of the hematological toxicity carries over to the chemoradiation phase. Of greater concern is the difference of long term feeding tube dependency rate between the two cohorts. Admittedly, the numbers in our study are small and the outcome might be different if cisplatin is used instead of gemcitabine. Nevertheless, we think this observation is noteworthy.

Thus far, the sequential administration of induction chemotherapy followed by chemoradiation should still be considered experimental and should not be used outside clinical trials. The short term feasibility of this paradigm has been demonstrated both in phase II and in phase III trials, but long term toxicity data are still lacking. Moreover, the superiority of this approach over chemoradiation alone in terms of efficacy has not been demonstrated in a phase III direct comparison. At least four large randomized phase III trials comparing TPF induction chemotherapy followed by chemoradiation to chemoradiation alone are currently planned or underway [7]. Data of one of these phase III trials were presented by Hitt et al [19]. TPF followed by irradiation and concurrent cisplatin 100 mg/m² every 3 weeks was associated with a higher CR rate and a better time to treatment failure than the same concurrent chemoradiation regimen alone. Paccagnella presented the final results of the phase II portion of an Italian randomized trial which compares TPF followed by irradiation in combination with cisplatin and 5-FU or the same chemoradiation alone [20]. TPF induction chemotherapy did not compromise the delivery of the subsequent chemoradiation and did not increase the incidence of severe radiation dermatitis or mucositis. The higher CR rate in the sequential arm justified the initiation of the phase III portion of the study.

In conclusion, our non-randomized comparison mirrors the outcome of randomized trials which demonstrated a reduced risk of distant metastasis with induction chemotherapy in LA-SCCHN. In a multiple Cox regression analysis, this reduced risk of distant metastasis translated in a better overall survival. Locoregional control was not significantly affected by induction chemotherapy. Notwithstanding the limitations of a non-randomized single-centre comparison, the results are in line with the very preliminary data of randomized comparisons, mentioned above. Nevertheless, we suggest that the outcome of the large randomized trials need to be awaited before the sequential approach of induction chemotherapy followed by chemoradiation can replace cisplatin-based chemoradiation as the new standard treatment.