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Revisiting Induction Chemotherapy for Head and Neck Cancer

Revisiting Induction Chemotherapy for Head and Neck Cancer

Squamous cell carcinomas of the head and neck are highly responsive to induction chemotherapy. However, randomized trials have failed to demonstrate a survival advantage with the addition of induction chemotherapy to locoregional therapy consisting of surgery and/or radiation therapy. Currently, concomitant radiation and chemotherapy has emerged as a standard and has optimized locoregional control in head and neck cancer. In this setting, the addition of induction chemotherapy may further improve outcome by enhancing both locoregional and distant control. As interest in induction regimens is renewed, we elected to conduct a systematic review of trials of induction chemotherapy for locoregionally advanced head and neck cancer. The most studied combination— cisplatin plus fluorouracil (5-FU)—achieves objective response rates of about 80%. In a meta-analysis, induction with platinum/ 5-FU resulted in a small survival advantage over locoregional therapy alone. The introduction of a taxane into induction chemotherapy regimens has produced promising results. Induction chemotherapy should be the subject of further clinical research in head and neck cancer. Randomized clinical trials in which the control arm is concurrent chemoradiotherapy and the experimental arm is induction chemotherapy followed by concurrent chemoradiotherapy are planned. Platinum/taxane combinations are the preferred regimens for further study in the induction setting and a suitable platform with which to investigate the addition of novel targeted agents.

Head and neck cancer affects about 39,000 persons and results in 11,000 deaths annually in the United States.[1] Patients with head and neck cancer commonly have locoregionally advanced disease at presentation, which is associated with a poor long-term outcome: Traditional treatment with surgery and/ or radiation produces a 5-year survival rate of 40% or less.[2] Historically, disease recurrence has been predominantly locoregional, whereas distant failure occurs in 20% to 30% of patients. The use of chemotherapy has been introduced with a binary objective- to achieve organ preservation and improve survival. Indeed, in recent years, chemotherapy has been successfully employed in a variety of clinical settings and has established an integral role in the curative management of locoregionally advanced head and neck squamous cell carcinoma. The timing of chemotherapy in this setting can be either (1) prior to locoregional therapy (ie, induction, neoadjuvant, or preoperative), (2) concurrent with definitive radiation therapy, or (3) after locoregional therapy with or without concomitant radiation therapy (ie, adjuvant or postoperative). Currently, the data strongly support the use of chemotherapy concurrently with radiation therapy either as primary therapy or in the postoperative setting. Concurrent chemoradiotherapy has become the standard nonsurgical treatment for locoregionally advanced head and neck cancer. However, the optimal chemotherapeutics for use concurrently with radiation to treat head and neck cancer have not yet been determined. A favored regimen, supported by results of cooperative group randomized trials in the United States, is cisplatin at 100 mg/m2 every 3 weeks during conventional fractionation radiation. In unresectable disease and nasopharyngeal cancer, a survival advantage was demonstrated with the use of the above regimen over radiotherapy alone,[3,4] whereas in laryngeal cancer, concurrent chemoradiotherapy with cisplatin resulted in a higher rate of organ preservation.[5] Finally, the combination of cisplatin and radiation therapy was superior to radiation therapy alone after a potentially curative surgical resection.[6,7] In addition to single-agent cisplatin, a number of combination chemotherapy regimens, predominantly platinum/fluorouracil (5-FU), have been studied concurrently with radiation and produced superior results over radiation alone in randomized trials.[8]

Induction Chemotherapy: Rationale and Controversy

Squamous cell carcinomas of the head and neck are highly responsive to induction chemotherapy. A complete response (CR) to induction chemotherapy, and especially a pathologic CR, is predictive of improved survival.[9-13] It is reasonable to hypothesize that induction chemotherapy can improve patient outcome by downstaging the primary tumor and eradicating locoregional and distant micrometastases. Nevertheless, with a few notable exceptions, multiple randomized trials conducted in the 1980s and 1990s that used standard locoregional therapy- surgery and/or radiation-as a control failed to demonstrate that the addition of induction chemotherapy to locoregional treatment results in survival benefit.[14,15] In several of these studies, the addition of induction chemotherapy decreased the rate of distant metastasis, which usually did not translate into a survival benefit. Moreover, a deleterious effect on survival from induction chemotherapy was suggested in some studies.[16,17] Domenge et al reported the only positive trial, a study that enrolled 318 patients with locally advanced oropharyngeal cancer.[18] Disease-free survival was improved in the induction chemotherapy arm, but the difference did not reach statistical significance (P = .11); however, overall survival was superior in the induction chemotherapy arm (P < .05).[18] A study by Paccagnella et al, comparing induction chemotherapy with cisplatin/ 5-FU followed by surgery and/ or radiation, showed a survival benefit for induction therapy but only in patients with unresectable tumors.[19] In a meta-analysis by Pignon et al, when all induction chemotherapy studies were examined together, there was no survival benefit with induction chemotherapy.[ 20] However, when the subset of trials with cisplatin (or carboplatin) plus 5-FU was examined, a small (3%) but statistically significant improvement in survival was observed with the addition of induction chemotherapy (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.79-0.97). Nevertheless, the superior treatment was concomitant delivery of chemotherapy and radiation, which resulted in a meaningful survival benefit of 8% at 5 years (HR = 0.81, 95% CI = 0.76-0.88). A number of studies have directly compared induction chemotherapy followed by single-modality radiotherapy to concurrent chemoradiotherapy.[5,21] A study by Taylor et al showed that concurrent therapy on an alternate-week schedule produced better disease control than induction chemotherapy followed by radiation.[21] Furthermore, Forastiere et al reported that locoregional control and laryngeal preservation rates were superior with concurrent vs sequential chemotherapy and radiation.[ 5] Therefore, concurrent chemoradiotherapy has emerged as the preferred treatment strategy for locally advanced head and neck cancer. However, it is unknown whether induction chemotherapy would be of benefit when the primary therapy is concurrent chemoradiotherapy. When the patterns of failure in randomized trials of concurrent chemotherapy and radiation vs radiation alone were analyzed, it was evident that the survival benefit was most likely a result of improved locoregional control.[8] More recently, phase II studies have reported that high rates of local control approaching 90% can be achieved with intensive chemoradiotherapy regimens.[22,23] A reversal of the historical pattern of relapse (ie, local more common than distant) was observed, with a predominance of distant failure.[24] In that context, eradication of distant micrometastasis that is potentially achievable with induction chemotherapy may become critical. In conclusion, the potential role of induction chemotherapy in improving the survival of patients treated with concurrent chemoradiotherapy needs to be revisited. We conducted a review of the activity and toxicity profile of various induction chemotherapy regimens. The review of these clinical trials may assist in the identification of the most efficacious regimens for use in future trials of induction chemotherapy.

Methods

We performed a computerized search of Cancerlit, Medline, and American Society of Clinical Oncology website databases in order to identify phase II and III clinical studies of induction chemotherapy for locoregionally advanced head and neck cancer. Trials in the English literature that included previously untreated patients with locoregionally advanced squamous cell cancer of the head and neck were selected and included in this review. We recorded the objective response rates, pathologic response rates (when reported), and toxicities of the regimens. Survival data were primarily reviewed in randomized trials. It should also be noted that most studies included heterogeneous patient populations usually without eligibility restrictions by site or resectability. Moreover, there were significant differences in the methods used to assess and report objective response rates between trials. Although survival end points may be relevant to the efficacy of induction chemotherapy regimens,[ 25] subsequent locoregional therapy is a major confounding factor. Therefore, we elected to use objective response rates as a surrogate of chemotherapy efficacy, acknowledging the limitations of this assumption.

Differences in Response Among Head and Neck Sites

Some reports have suggested differences in chemotherapy responsiveness among squamous cell carcinomas that arise from different head and neck sites. Nasopharyngeal cancer may be different biologically and appears to be the most chemotherapy-responsive head and neck tumor.[26-33] Separate clinical trials of induction chemotherapy for nasopharyngeal cancer are warranted. The oral cavity was shown to be a less responsive site in one study,[34] but contradicting results have also been reported.[35] A recent trial reported an objective response rate of 82% in the primary tumor among patients with resectable oral cavity squamous cell carcinoma.[36] Limited experience has been reported for other less common sites of head and neck cancer[37] such as the paranasal sinuses, but it is likely that squamous cell carcinomas arising from these sites and other more common sites are equally chemotherapy responsive. In this review, the studies examined mainly enrolled patients with tumors affecting four major primary sites: oral cavity, oropharynx, hypopharynx, and larynx.

Optimal Number of Treatment Cycles

Although no randomized trial data have suggested an optimal number of chemotherapy cycles in this setting, it is widely accepted that two to four cycles are optimal as induction therapy.Studies with cisplatin and 5-FU have shown that the response rate is higher with three vs two cycles,[38,39] whereas a plateau may be reached after three cycles.[14] Di Blasio et al observed no further increase in the rate of objective response with the extension of induction chemotherapy to five cycles; however, there the CR rate improved (see Table 1).[14]

Shin et al reported that the rate of complete response to carboplatin/ ifosfamide/paclitaxel at the primary sites increased from 23% after two cycles to 60% after four cycles.[40] Moreover, the Department of Veterans Affairs (VA) laryngeal cancer study and the European Organization for Research and Treatment of Cancer (EORTC) trial in resectable laryngeal and hypopharyngeal cancers, respectively,[41,42] as well as other randomized trials[36] have employed three cycles of induction chemotherapy with cisplatin and 5-FU. Finally, a recent phase III, randomized EORTC trial in patients with unresectable head and neck cancer incorporated four cycles of induction chemotherapy in both arms-cisplatin/5-FU/docetaxel [Taxotere] or cisplatin/5-FU (Figure 1).[43]

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