The trend in the treatments for advanced head and neck squamous cell carcinoma (HNSCC) has shifted from radical surgery to organ preservation due, in large part, to the two milestone studies conducted in the 1990s: The Department of Veterans Affairs Laryngeal Cancer Study Group (VALCSG) (1) and European Organization for Research and Treatment of Cancer (EORTC) 24891 (2). These two studies clearly demonstrated that laryngeal preservation is feasible with combined use of induction chemotherapy and radiation without compromising patients' survival in advanced laryngeal and hypopharyngeal carcinoma. As a result, organ-preservation was adopted as the main goal of the clinical studies and whereby unprecedented dose-intensification has been conducted mainly through two forms of modalities: Concurrent chemoradiotherapy (CRT) (e.g., clinical trials led by the Radiation Therapy Oncology Group [RTOG]) or sequential therapy (ST) composed of induction chemotherapy and CRT (e.g., GORTEC and Tax 324 protocols) (3–6). Because of the further improved laryngeal preservation, these dose-intensified organ-preserving strategies (DIOPSs) are currently proposed as the standard for organ preservation (7,8). However, it is becoming apparent that DIOPSs involve critical issues. Firstly, only a limited number of advanced HNSCC patients benefit from DIOPSs, because these types of experimental therapies are feasible only in a select subset of patients (i.e., patients with good general condition) who can tolerate these heavy regimens. This limitation may be related to the recent surprising results of large surveys based on the Surveillance, Epidemiology, and End Results (SEER) or the National Cancer Data Base (NCDB), which demonstrated a worsening survival trend in patients with laryngeal cancer and only a marginal improvement in those with hypopharyngeal cancer (9,10). Secondly, it is obvious that current DIOPSs have reached the upper limit of human tolerance in terms of late toxicitiy, as exemplified in the recently published long-term results of RTOG 91–11. On this regimen, which employs concurrent 100 mg/m² of CDDP tri-weekly, as much as 43% of the patients with preserved larynx developed laryngo-esophageal dysfunction, and which eventually accounted for the high rate of tumor-unrelated deaths (11–13). Thirdly, it became practically infeasible to compare the treatment results of radical surgery with organ-preserving treatments in randomized control studies, due to the strong dogma: Similar survival is achievable by either DIOPS or radical surgery on the basis of VALCSG and EORTC 24891 studies (1,2) conducted more than 20 years ago. Consequently, the survival benefit of radical surgery appears to have been overly underestimated despite considerable technical advancements and the improved multimodality setting in which surgery is conducted.

Contrary to the trend of DIOPSs, we have treated HNSCC patients using a distinctive platform, in which 30–40 GY of induction CRT is used as a selection tool for organ preservation (14,15). In this algorithm-based ‘chemoradioselection’ strategy, only patients who demonstrate good response to induction CRT (i.e., ‘chemoradioselected’: CRS), proceed to organ preservation arm and then receive further CRT up to 60–70 Gy. For the remaining non-responders (i.e., ‘non-chemoradioselected’: N-CRS), radical surgery is recommended. Mainly using moderate intensity CRT regime, we obtained quite satisfactory laryngeal preservation and survival in T2 glottic carcinoma and overall survival in oropharyngeal carcinoma with minimal toxicity (14,16–18). In a recent pilot study on advanced hypopharyngeal carcinoma (19), we reported the utility of this protocol; chemoradioselection can segregate tumors for organ-preservation with use of moderate intensity CRT from those that would be better treated by radical surgery. Interestingly irrespective of clinical stage, CRS patients demonstrated quite favorable survival and organ preservation with moderate intensity CRT that seldom caused laryngo-esophageal-dysfunction, whereas radical surgery appeared to exhibit survival benefit in the N-CRS. In this context, the aim of this study is to verify the utility of this strategy in a larger scale study employing patients with advanced hypopharyngeal and laryngeal cancer and to explore the potential of this strategy as a novel platform for the treatment of advanced HNSCC which may address the issues associated with the current DIOPSs mentioned above.

Over the last decade, there has been a hot debate about the superiority of CRT and ST as DIOPS for treatment of advanced HNSCC (8,23,24). However, a recent meta-analysis clearly demonstrated that induction chemotherapy has no survival benefit over CRT in advanced HNSCC (25) and therefore CRT is expected to be the future mainstay of treatment. On the other hand, it is obvious that current standard CRT with high-dose CDDP, in which 100 mg/m² of CDDP is administered every three weeks, needs to be optimized to reduce the severe toxicity, which is frequently observed in both the acute and the long-term phase (11–13). In this context, the quite favorable 5-year OS (73%) and 5-year LEDFS (69%) observed in this CRS cohort in the present study appears to offer one solution. Thus, for those who show good response to induction CRT, total 150 (split regimen) or 160 (bolus regimen) mg/m² of CDDP may be sufficient to achieve favorable survival without impairment of laryngeal function. Interestingly these CDDP doses were considerably lower than the 200 mg/m² dose recommended for maintenance of the oncological results in the standard tri-week CDDP or in the recently proposed weekly (40 mg/m²) CDDP protocol (26–28) and therefore more applicable to the elderly patients and/or patients with poor general condition. This result suggests that a majority of the CRS tumors are composed of less aggressive tumors which are amenable to cure with the moderate intensity CRT alone; this inference is also supported by the significantly lower rates of tumor-related death in the CRS arm as compared to that in the N-CRS arm. Thus, chemoradioselection provides an accurate measure of the biological aggressiveness of each tumor, and may be a useful strategy for optimization of the intensity of CRT. This method is comparable with chemoselection, which entails one or a few cycles of induction chemotherapy as a tool to select patients for organ preservation (20,21,29). However, given the conclusions of the above-mentioned meta-analysis (25) and the time- and cost-effectiveness, chemoradioselection is thought to be a better method than chemoselection.

In this study, the premise of VALCSG and EORTC (1,2), i.e., DIOPS is a better option than radical surgery in patients with advanced laryngeal and hypopharyngeal cancer, because of better quality of life and comparable survival rates, was questioned. The N-CRS-ope showed markedly better 5-year OS (70%) at the expense of the larynx, which otherwise remained at 47% as shown by the N-CRS-ref, which indicates that under selected conditions, radical surgery confers survival benefit over CRT. Because similar rates of distant metastases were observed in these two populations, the rates of loco-regional failure appear to be the main cause of this difference; the N-CRS-refu demonstrated as high as the 32% of loco-regional failure, which probably caused by the high local recurrence (56%) and poor salvage (43%), whereas in the N-CRS-ope arm the incidence of loco-regional failure was only 9%. Interestingly, only refusal of surgery (and not T, N, and primary site) was an independent predictor of adverse prognosis in the N-CRS population, as was clearly demonstrated in our multivariate analysis. This result implies that independent of the tumor stage and site, chemoradioselection can accurately segregate patients who would be better treated with curative-intent surgery at a relatively early phase of treatment. Moreover, in a similar analysis of the overall population, the refusal of surgery alone correlated with increased risks of death, which validates our algorithm-based treatment decision (i.e., organ preservation vs. surgery). In the cohort of patients who were initially treated with CRT alone (i.e., the CRS plus CRS-ref), hypopharyngeal cancer and refusal of surgery was associated with poor prognosis. The former result confirms a general fact that when treated with similar modalities hypopharyngeal cancer shows poorer prognosis than laryngeal cancer. Whereas the latter finding indicates that irrespective of the tumor stage and site, continuation of CRT for poor responders eventually culminates in poor survival. Given that this similar phenomenon has long been recognized in the field of ST and has been used as the logical basis for chemoselection (20,21,29), it is quite puzzling that CRT strategy has stuck to the policy of definitive CRT and salvage surgery without adequate attention to the biological selection so far. Collectively, our results suggest that poor responders should be treated by radical surgery with curative-intent at a relatively early phase of CRT rather than by definitive CRT, which increases the risk of the local failure and eventually compromises survival.

In this algorithm-based strategy, improvement of the overall LEDFS (41%), which is mainly worsened by poor results of T3 tumors (25%), is an essential issue to be addressed. We altered the regimen from split to bolus CDDP, with the expectation that a substantial increase in the rate of chemoradioselection may lead to the improved results including an increase in LEDFS in T3 cases. Our preliminary data suggests that this alteration succeeded in increasing the rate of chemoradioselection and improved overall OS and LEDFS. However, in T3 cases the improvement in LEDFS was not observed. These results indicate the superiority of bolus CDDP as well as its limitation for laryngeal preservation, particularly in advanced T. It is obvious that further dose-intensification inevitably leads to the enhanced toxicity and tends to diminish the utility of chemoradioselection. Thus, addition of a molecular-targeted approach to our strategy seems to be a rational method to address this problem. Recently we found that induction of a putative cancer stem cell marker, CD44 variant 9 (CD44v9), was a major hurdle to chemoradioselection. Thus, addition of CD44v9 targeting (e.g., sulfasalazine) to chemoradioselection may be a promising approach to enhance the efficacy of chemoradioselection and thereby improve survival and laryngeal preservation (30).

In conclusion, our algorithm-based ‘chemoradioselection’ might provide a novel platform for the treatment of advanced HNSCC and help optimize the currently employed excessive treatment intensity. We have started a multi-institutional prospective study to verify the utility of this protocol on a larger scale.