David M. Brizel and David J. Adelstein
Approximately 50,000 patients are diagnosed annually with squamous cell head and neck cancer (HNC) in the United States. Worldwide, approximately 600,000 patients are afflicted. Nearly 60% of this population presents with locally advanced but nonmetastatic disease. Locoregional failure constitutes the predominant recurrence pattern, and most fatalities result from uncontrolled local and/or regional disease.
Radiotherapy (RT) alone was long the standard nonsurgical therapy for locally advanced disease. The state of the art regarding radiation dose fractionation has evolved from once-daily treatment to hyperfractionation and accelerated fractionation.1,2,3–4 These newer strategies lead to a 7% to 10% improvement in locoregional control relative to once-daily treatment schemes. A recent meta-analysis of randomized trials testing modified fractionation schemes against conventional once-daily fractionation demonstrated that hyperfractionation was the most effective strategy, leading to an 8% absolute improvement in 5-year survival.5 Nonetheless, even the most effective RT regimens result in local control rates of 50% to 70% and disease-free survivals (DFSs) of 30% to 40%.
This circumstance has stimulated the investigation of treatments combining RT and chemotherapy. Review articles describe in detail the different chemotherapeutic agents and RT schemes of these treatment programs.6,7 Most trials have used sequential or neoadjuvant (induction) chemotherapy followed by RT. Randomized trials of induction cisplatin and 5-fluorouracil (5-FU) chemotherapy followed by standard fractionation versus laryngectomy and postoperative RT in advanced larynx and hypopharynx cancer performed by the Veterans Administration Cooperative Group8 and the European Organization for the Research and Treatment of Cancer (EORTC), respectively, initially showed that larynx preservation could be achieved without compromising overall survival.
Most randomized clinical trials show the superiority of combined RT and chemotherapy to RT alone for the treatment of locally advanced, nonmetastatic HNC. A meta-analysis of individual patient data from >17,346 participants in 93 trials conducted from 1965 to 2000 (Meta-Analysis of Chemotherapy on Head and Neck Cancer [MACH-NC]) demonstrated that the use of radiotherapy and concurrent chemotherapy (CRT) resulted in a 19% reduction in the risk of death and an overall 6.5% improvement in 5-year survival compared to treatment with RT alone (p < .0001).9 This benefit was predominantly attributable to a 13.5% improvement in local regional control. The 2.9% reduction in the risk of distant metastases was not statistically significant (Fig. 40.1).
FIGURE 40.1. Data from the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) illustrating that the major therapeutic benefit of platinum-based chemotherapy results from an improvement in local-regional disease control when the drugs are given concurrently with radiotherapy. No significant improvement occurs with induction chemotherapy followed by radiotherapy.
The MACH-NC also demonstrated a 2% improvement in 5-year survival from the use of induction chemotherapy followed by RT, which was not significant. A subset analysis of trials that used cisplatin and 5-FU as the induction regimen did show a 4% improvement in overall survival.10
Randomized comparisons of concurrent chemoradiation versus induction chemotherapy followed by radiotherapy alone are few but confirm that the former strategy is superior.11,12 The Radiation Therapy Oncology Group (RTOG) conducted a three-arm trial of radiation alone versus radiation and concurrent cisplatin versus induction cisplatin followed by irradiation in larynx carcinoma. Concurrent therapy constituted the most effective means of larynx preservation and provided the best disease control, albeit without a statistically significant survival benefit.12 Neoadjuvant chemotherapy followed by RT was no more efficacious than RT alone. Despite the lack of evidence supporting sequential chemoradiation strategies, this strategy was the most common method of integrating the two modalities in the community practice setting until recently.13 A more contemporary survey has demonstrated that concurrent RT and chemotherapy is now used more frequently.14
RT and concurrent chemotherapy represents the most commonly used strategy and is a more attractive approach because some chemotherapeutic agents may both radiosensitize cells and provide additive cytotoxicity. The superiority of concurrent CRT relative to RT alone has been demonstrated in randomized trials in squamous cell carcinoma of other anatomic sites including the esophagus and uterine cervix.15–17
Certain issues must be considered when evaluating randomized trials of CRT for advanced head and neck cancer. The first consideration relates to the effectiveness of the RT-alone control arm. Specifically, does it represent optimal single-modality treatment? If the CRT regimen is more effective than RT alone but the radiation is suboptimal, then it is difficult to accurately gauge whether or not the combined-modality regimen represents a true improvement in therapy. The second consideration concerns the toxicity of CRT itself. Typically, both acute and late toxicity from CRT are greater than from RT alone.18–20
Acute mucositis constitutes the most significant impediment to the timely delivery of concurrent therapy. Because prolongation of total treatment time adversely affects the success of RT in HNC,21,22–23 a major challenge has been the development of treatment schedules that integrate RT and chemotherapy and yet do not excessively increase total treatment time. A thorough understanding of toxicity is mandatory as avoidance of the functional morbidity associated with surgery in advanced head and neck cancer is one of the main reasons for the utilization of concurrent therapy in the first place.
HISTORICAL DEVELOPMENT OF RADIATION AND CONCURRENT CHEMOTHERAPY
CRT may be administered in synchronous or alternating schemes. Synchronous administration results in the delivery of RT and chemotherapy (CT) on the same days. Typically, chemotherapy will be given for 1 or more days at the initiation of RT and then repeated in the same fashion several weeks later. Alternating regimens usually sandwich RT and CT around one another. Radiation and drugs are therefore not necessarily given on the same days. In such a scheme, CT would be given during the first week of treatment with RT following in subsequent week(s) before CT is given again.
TABLE 40.1 RANDOMIZED TRIALS OF ONCE-DAILY IRRADIATION AND CONCURRENT CHEMOTHERAPY IN ADVANCED HEAD AND NECK CANCER
Synchronous Radiation and Single-Agent Chemotherapy
Synchronous treatment is completed more quickly than alternating treatment. It is therefore preferable from a theoretical standpoint in terms of addressing the issue of accelerated repopulation, albeit at the expense of increased acute side effects. Early randomized trials of conventionally fractionated RT and CT used single-agent chemotherapy. These studies are summarized in Table 40.1. The experimental arms of RTOG 90-03,1 EORTC 22791,3 and DAHANCA 6-74 are included to provide a basis for comparison with optimal regimens of RT alone.
Both the Northern California Oncology Group (NCOG) and the EORTC tested radiation and synchronous bleomycin against radiation therapy alone.24,25 Acute toxicity was worse in the combined-modality arm in both trials, but the outcomes were quite different with respect to efficacy. The EORTC trial showed no improvement in DFS or survival and the RT/bleomycin combination in the NCOG program led to a statistically significant doubling of locoregional control and DFS, as well as a near-significant improvement in overall survival from 24% to 43%.
Differences in study design and execution may explain the discrepancy between outcomes in the EORTC and NCOG trials. Fractionation was similar in the two studies, but patients in the EORTC trial received 15 mg of bleomycin twice weekly during the first 5 weeks of RT for a total dose of 150 mg, whereas the NCOG patients received 5 mg twice weekly for a total dose of 70 mg. Acute mucosal and skin toxicity was worse in the RT/bleomycin arm in both trials. Toxicity significantly prolonged the RT delivery time in 30% of the combined-modality patients in the EORTC trial but not in any of the RT-alone patients. This prolongation of treatment time and associated tumor repopulation in such a large proportion of patients may have negated any benefit accrued from the use of concurrent therapy. There were no differences in overall treatment time between the two treatment arms in the NCOG trial. An important lesson from these two studies is that the dose administration schedules of concurrent chemotherapy must be carefully designed so that toxicity does not adversely affect overall treatment compliance.
The Christie Hospital in Great Britain evaluated RT and 100 mg/m2 of single-agent methotrexate (MTX) given at the commencement of and after 2 weeks of a 3-week course of treatment.26 Most of the 313 patients in this protocol received 50 to 55 Gy in 15 or 16 fractions. Mucositis was significantly greater in the patients receiving MTX, but there was no difference in long-term toxicity. The addition of MTX increased local control from 50% to 70% (p = .02) and survival from 37% to 47% (p = .07). The greatest benefit was seen in patients with oropharyngeal primary tumors who constituted one-third of the study population. Local control with RT/MTX was 78% versus 38% with RT alone (p = .002) in this patient subset. Survival was 25% with RT alone and 50% with RT/MTX (p = .009). Unfortunately, the data from this trial are not generally applicable to current clinical practice because of the large radiation fraction sizes that were used.
5-FU has been used in conjunction with RT more frequently than any other chemotherapeutic agent. Lo et al.27 reported the first study to show a significant improvement in local control and survival with the addition of bolus 5-FU to RT in squamous carcinoma of the oral cavity. Browman et al.28 compared RT and continuous infusion 5-FU against RT alone in a placebo-controlled randomized trial sponsored by the National Cancer Institute of Canada. All 175 patients received 66 Gy in 2-Gy fractions. 5-FU was given at 1,200 mg/m2/day for the first 3 days of the first and third weeks of irradiation. Confluent mucositis was more frequent in the 5-FU arm than in the placebo arm (32% vs. 11%; p = .001), as was weight loss >15% from pretreatment baseline (41% vs. 11%; p < .0001). This increased acute toxicity did not prolong the delivery of RT in the RT/5-FU arm relative to the RT/placebo arm. Two-year DFS and survival were 30% and 50% for RT/placebo patients and 50% and 63% for RT/5-FU patients (p = .06 and .08), respectively.
The relative radioresistance of hypoxic cells in vitro is well understood.29 Clinically, the existence of hypoxia both in head and neck primary tumors and metastatic lymph nodes has been described, and its adverse impact on the prognosis of patients treated with RT has been demonstrated.30,31 Investigators from Yale University designed their treatment strategy around this principle. They treated 195 patients in two randomized trials with mitomycin-C (MMC). This agent is predominantly metabolized in and preferentially cytotoxic to hypoxic cells. The Yale treatment program consisted of 68 Gy ± MMC on days 1 and 43 of RT. Local control was improved with the addition of MMC from 54% to 76% (p = .003). Survival improved from 42% to 48%, but this was not statistically significant. The majority of patients in these trials received adjuvant postoperative or preoperative irradiation, however. Only 74 (38%) received definitive, primary RT, and the benefit from the addition of MMC in this subset is unclear.32
Synchronous Radiation and Multiagent Chemotherapy
Cisplatin (CDDP) is a radiosensitizer, too.33 The combination of CCDP and 5-FU is also one of the most active cytotoxic drug combinations against squamous cell HNC. Consequently, investigators have incorporated both of these drugs into a variety of concurrent treatment strategies. A randomized trial from the Cleveland Clinic assigned patients to receive 66 to 72 Gy ± two cycles of synchronous CDDP (20 mg/m2/day é 4) and infusional 5-FU (1,000 mg/m2/d é 4) during weeks 1 and 4 of RT.34 The main objective of this study was primary site organ preservation. Surgical salvage was allowed for patients with persistent disease. Acute toxicity was significantly greater in the combined-modality treatment arm, especially with respect to weight loss. Mucosal recovery usually required 8 to 12 weeks after completion of RT and chemotherapy. There were no differences in the total time required for RT delivery, however. Three-year DFS was significantly better for the patients receiving chemoradiotherapy (67% vs. 52%; p = 0.03). Three-year survival with primary site preservation was also higher in the combined-modality group (57% vs. 35%, p = .02), although there was no significant difference in overall survival.
MMC and 5-FU were used together in a trial of 209 patients conducted at the Princess Margaret Hospital.35 Patients were treated with continuous course RT alone at 2.5 Gy/day to 50 Gy in 28 days. Patients randomized to receive RT/chemotherapy received the same dose fractionation scheme as those receiving RT alone but over a total time of 56 days due to a planned 4-week treatment interruption after 25 Gy. Bolus MMC (10 mg/m2) was given on days 1 and 43. Two cycles of continuous infusion 5-FU (1,000 mg/m2/day) were given on days 1 to 4 and 43 to 46. The intent of the treatment break was to maintain comparable levels of acute toxicity in the two treatment arms. Acute toxicity was, in fact, equivalent in the two groups. Unfortunately, however, there was no difference in 4-year local control (~40%) or survival (~40%).
The Princess Margaret trial raises an important question: can one quantify the contribution provided by concurrent chemotherapy in terms of the delivery of an equivalent dose of irradiation? Approximately 0.6 Gy/day is necessary to compensate for the tumor repopulation that transpires with each day of prolongation of standard course RT.23 Thus, the total dose in the Princess Margaret Hospital RT/chemotherapy arm would have to have been about 67 Gy [(2.5 Gy é 20) + (0.6 Gy/day é 28 days)] in order to have been isoeffective with the 50-Gy regimen in the RT-alone arm. The equivalent efficacy of the two treatments in this trial therefore suggests that the chemotherapy compensated for the tumor repopulation that occurred during the treatment break. Thus, one could argue that the chemotherapy was equivalent to approximately 17 Gy of additional irradiation. There can be no doubt as to the inferiority of the split-course fractionation scheme in this trial had it been delivered without chemotherapy and compared head to head against the continuous course RT regimen. Conversely, if the combined-modality treatment had been given with continuous course RT, it would quite probably have been more efficacious than the RT-only regimen.
A Spanish three-arm randomized trial (N = 859) provides additional information that is pertinent to the estimation of the radiotherapeutic dose equivalent provided by the delivery of concurrent chemotherapy.36 Patients were assigned to receive one of the following regimens:
A. 2 Gy/day to 60 Gy/42 days,
B. 1.1 Gy twice daily to 70.4 Gy/44 days, or
C. 2 Gy/day to 60 Gy/42 days with concurrent bolus 5-FU 250 mg/m2 given every other day.
Progression-free survival and overall survival were significantly worse in arm A as compared with arms B and C, as one would expect. Arms B and C were equally efficacious. Not accounting for the different fractionation in arms B and C and the unconventional administration of chemotherapy, it is still clear that the addition of 5-FU was comparable to dose escalation of approximately 10 Gy. A recent modeling analysis of phase III trials comparing CRT with RT only suggests that concurrent chemotherapy provides the equivalent of a 10- to 12-Gy dose escalation.37
Neither the Princess Margaret nor the Spanish trial delivered maximally intensive radiotherapy in their respective control arms. The rationale for treatment intensification with the addition of concurrent chemotherapy as opposed to simple RT dose escalation is weak in such a context. The situation may be dramatically different, however, when the RT-alone arm is maximally intensive such as in RTOG 90-03 or EORTC 22791. Dose escalations of 10 to 12 Gy are not possible with accelerated regimens that already deliver 72 Gy during 6 weeks or with hyperfractionated regimens delivering 79 Gy in 7 weeks (see Radiation Fractionation Scheme section). Concurrent chemotherapy, however, can be added to modified fractionation regimens ≥70 Gy.
Alternating Radiotherapy and Chemotherapy
Alternating therapy produces less acute mucosal toxicity than synchronous therapy but may prolong the overall treatment time by several weeks. Although longer treatment times adversely affect efficacy in programs of standard RT alone due to tumor repopulation, the significance of overall treatment time (for RT) in a continuous course of alternating RT and chemotherapy is controversial. Some investigators have suggested that the usual time–dose relationships do not apply.38
The National Institute for Cancer Research in Italy conducted a phase III trial comparing RT with alternating RT and chemotherapy in 157 patients with unresectable head and neck cancer.39,40 The RT arm was designed to give 70 Gy/7 weeks via standard fractionation. The combined-therapy arm scheduled chemotherapy on weeks 1, 4, 7, and 10 and radiation (60 Gy) on weeks 2 to 3, 5 to 6, and 8 to 9. Each 2-week cycle of radiation consisted of 20 Gy/10 fractions. Each cycle of chemotherapy included 5 days of bolus CDDP (20 mg/m2/day) and bolus 5-FU (200 mg/m2/day). The incidence of grade 3/4 mucositis (18% to 19%) was the same in both treatment groups. However, RT treatment delays occurred more often in the RT-alone patients: 32% with a 1-week prolongation and 25% with a ≥2-week prolongation. Corresponding delays in the combined-modality treatment group were 11% and 15%, respectively. The median dose of RT delivered in the combined-modality-treatment group matched the planned dose of 60 Gy, but it was only 62 Gy in the RT-alone group. Five-year actuarial survival was significantly better in the combined-modality-treatment patients (24% vs. 10%; p = .01), as were DFS (21% vs. 9%; p = .008) and local control (64% vs. 32%; p = .04).
Given the similar levels of acute toxicity, it is unclear why treatment times were prolonged and total doses reduced so extensively in the RT-only patients. Better protocol compliance in the control arm might well have changed the outcome of this trial. There are no other randomized trials of RT and alternating chemotherapy. Further randomized trials of alternating therapy will be necessary to determine its true value because the deficiencies of the National Institute for Cancer Research study prevent definitive conclusions.
Despite its drawbacks, the Italian study, like the Princess Margaret Hospital trial, strongly reinforces the idea that in some settings, chemotherapy counteracts tumor repopulation during treatment. The total RT treatment time was prolonged in the combined-modality arms in both studies. The fundamental difference between these two trials is that patients received no treatment during the RT break in the Princess Margaret Hospital trial and the patients in the Italian trial received chemotherapy during each interruption of RT.
CONTEMPORARY RANDOMIZED TRIALS OF RADIOTHERAPY AND CONCURRENT CHEMOTHERAPY
Curative Intent Treatment
The French cooperative group trial, GORTEC 94-01, was performed in patients who had stage III/IV oropharyngeal carcinoma.19,41 Radiotherapy consisted of conventional 2 Gy, once-daily fractionation to 70 Gy. Patients on the CRT arm also received three cycles of concurrent carboplatin (70 mg/m2) and continuous infusion 5-FU (600 mg/m2/day é 4 days). Two hundred twenty-six patients were enrolled in the trial. CRT resulted in significant improvement in 5-year locoregional control (48% vs. 25%; p = .002), DFS (27% vs. 15%; p = .01), and survival (23% vs. 16%; p = .05). This improvement in efficacy was accompanied by a significant increase in acute mucositis (grade ≥2) from 39% to 71% (p = .005). Severe acute cutaneous and hematologic toxicity and worse nutritional status were also significantly more prevalent in the patients who received combined-modality therapy. Severe late toxicity, primarily cervical fibrosis, occurred in 27% of the combined-modality patients and in 12% of those treated with RT alone (p = .04). Severe dental complications were twice as frequent in the combined-modality patients (37% vs. 18%; p = .01).
Wendt et al.42 conducted a multi-institutional trial of CRT versus RT for patients with unresectable stage III/IV head and neck cancer. CRT patients received three cycles of cisplatin, 5-FU, and leucovorin during a 7-week period. Cisplatin was given as a 60 mg/m2 bolus. 5-FU was given as an initial 350 mg/m2 bolus followed by a 4-day continuous infusion of 350 mg/m2/day. Leucovorin was also given for 4 days at 100 mg/m2/day. Radiotherapy was given as three cycles of 23.4 Gy at 1.8 Gy bid in both treatment arms. It coincided with the chemotherapy on the CRT arms. Planned treatment breaks were given between the cycles of treatment to ameliorate treatment-induced mucositis. The cumulative dose of radiation therapy in both treatment arms was 70.2 Gy in 7 weeks.
One-third of the 270 patients enrolled had oropharynx primary tumors. CRT doubled both 3-year local control (35% vs. 17%; p < .004) and survival (49% vs. 24%; p < .003) (Fig. 40.2). As in the GORTEC 94-01 oropharyngeal trial, confluent mucositis was significantly higher (38% vs. 16%; p < .001) with the use of CRT.
Treatment of advanced nasopharynx carcinoma with radiation and concurrent chemotherapy was the subject of an intergroup study in which patients in both arms received conventionally fractionated RT (1.8 to 2.0 Gy/day) to a total dose of 70 Gy.43 Those patients who were randomized to concurrent chemotherapy also received three cycles of cisplatin during RT at a dose of 100 mg/m2. After the completion of RT, they received an additional three cycles of cisplatin at 80 mg/m2 as well as 4-day continuous infusions of 5-FU at 1,000 mg/m2/day. All patients had stage III/IV, M0 disease. In spite of the initial plan of enrolling 270 patients, the trial was terminated early when an interim analysis demonstrated the superiority of the combined-modality regimen. One hundred ninety-three patients were enrolled, and the median follow-up is 2.7 years. Three-year progression-free survival favored the combined-modality patients (69% vs. 24%; p < .001). Similarly, 3-year survival was 78% versus 47% (p = .005) in favor of the patients who received concurrent chemotherapy (Fig. 40.3). Table 40.1 summarizes the data from the trials of conventionally fractionated irradiation and concurrent chemotherapy.
FIGURE 40.2. Data from the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC), which demonstrates that adding concurrent chemotherapy to radiotherapy provides a significant improvement in survival but that induction chemotherapy does not. A:Concomitant chemotherapy. B:Induction chemotherapy.
FIGURE 40.3. Three-year survival in the Intergroup Nasopharynx Carcinoma Trial was significantly better (p = .005) for those patients who received concurrent cisplatin and postirradiation adjuvant cisplatin/5-fluorouracil (78%) than for those who received radiotherapy alone (47%). These results led to early trial closure.
One must ask not only whether CRT is more effective than conventionally fractionated RT, but also whether it is superior to hyperfractionated or accelerated fractionation irradiation as these strategies represent the most efficacious single-modality treatment strategies. A prospective randomized trial from Duke University provides some insight into this issue.44 Patients with locally advanced head and neck cancer were randomized to hyperfractionated irradiation alone versus split-course hyperfractionation with concurrent CDDP/5-FU chemotherapy. Patients in the RT-alone arm received 1.25 Gy bid continuous course to 75 Gy in 6 weeks, whereas those patients on the CRT arm received 1.25 Gy bid split course to 70 Gy in 7 weeks. Chemotherapy was given during weeks 1 and 6 of irradiation (CDDP 12 mg/m2/day é 5 days; 5-FU continuous infusion was 600 mg/m2/day é 5 days).
The time–dose aspects of the RT in the combined-modality arm are similar to those of the previously discussed trials. The time–dose characteristics of the RT in the control arm were similar to certain aspects of both the concurrent boost arm (decreased treatment time) and the hyperfractionation arm (increased total dose) of RTOG 90-03. Most importantly, these characteristics made the RT more intensive in the control arm than in the experimental CRT arm. This study design was intentional because a primary objective of the trial was to determine whether a lower dose of RT with concurrent chemotherapy would be superior to maximally intensive/effective RT alone.
Fifty-four percent of the patients presented with unresectable disease, and approximately 40% of the primaries were located in the oropharynx. One hundred sixteen patients were enrolled, and the updated median follow-up now exceeds 5 years. Locoregional control was 70% versus 44% (p = .006), favoring the combined-modality patients. An unpublished update of the 5-year survival revealed superiority in the combined-modality patients (42% vs. 27%; p= .04) (Fig. 40.4). Confluent (grade 3) mucositis was seen in approximately 75% of the patients in both arms, the main difference being that the mean time to resolution of mucositis was 50% longer in the patients receiving radiation and concurrent chemotherapy (6 vs. 4 weeks).
Jeremic et al.45 evaluated hyperfractionated irradiation (1.1 Gy bid to 77 Gy) with or without concurrent low-dose daily cisplatin (6 mg/m2) in stage III/IV patients. One hundred thirty patients were enrolled; primary tumors originated in the oropharynx in approximately one-third of the population. Fifty-nine percent presented with T3 or T4 primaries, and 80% had nodal involvement. Five-year locoregional control (50% vs. 36%; p = .04), progression-free survival (46% vs. 25%; p = .007), and overall survival (46% vs. 25%; p = .007) (Fig. 40.5) were all significantly improved with the addition of concurrent chemotherapy. Of note, the distant metastasis-free survival was also improved in the concurrent therapy patients (86% vs. 57%; p = .01).
A German multicenter trial also confirmed that CRT is superior to maximally intensive single-modality irradiation.18 Three hundred eighty-four patients, 93% of whom had either stage III or IV oropharyngeal or hypopharyngeal primaries, were enrolled. As in the Duke trial, the total dose of RT delivered in the CRT arm was lower than that in the RT control arm. RT patients received 77.6 Gy in 6 weeks (14 Gy at 2 Gy once daily followed by 63.6 Gy at 1.4 Gy twice daily), and CRT patients received 70.6 Gy during 6 weeks (30 Gy at 2 Gy per day followed by 40.6 Gy at 1.4 Gy twice daily). Chemotherapy consisted of mitomycin-C (10 mg/m2) on days 5 and 35 and 5-FU given as a single bolus of 350 mg/m2 and a 5-day continuous infusion of 600 mg/m2/day. Two-year survival was significantly better in the combined-modality arm (54% vs. 45%; p = .05), as was locoregional control (61% vs. 45%; p = .001). Acute and chronic toxicity were equivalent in the two treatment populations.
A French cooperative group (FNLCC-GORTEC) tested a related concept in 163 patients with technically unresectable carcinomas of the oropharynx and hypopharynx.46 RT was administered at 1.2 Gy twice daily to a total dose of 80.4 Gy/46 days to oropharyngeal primary tumors and 75.6 Gy/44 days to hypopharyngeal primary tumors. The experimental arm received the same RT and concurrent CDDP (100 mg/m2) on days 1, 22, and 43 of RT. Three 5-day cycles of continuous infusion 5-FU were also administered. The first cycle was 750 mg/m2/day and the second and third cycles were 430 mg/m2/day. Three-year DFS favored the concurrent chemoradiation arm (48% vs. 25%; p = .002), as did overall survival (38% vs. 20%; p = .04). Post hoc subset analyses demonstrated that the larger (and statistically significant) benefit was confined to the patients with oropharyngeal carcinomas. However, the trial was not designed to compare treatment efficacy in these two different primary sites of origin.
A three-armed randomized trial from the University of Vienna compared conventionally fractionated RT (2 Gy daily to 70 Gy) against continuous hyperfractionated accelerated RT with and without mitomycin C (V-CHART + MMC and V-CHART, respectively).47 Radiotherapy was given as an initial 2.5-Gy fraction followed by 1.65 Gy twice daily to a total dose of 55.3 Gy in 17 days. MMC was given as a 20 mg/m2 bolus on day 5 of RT. Of the 239 patients enrolled, 85% had T3/4 primary tumors, and 79% had nodal involvement.
Three-year actuarial locoregional control was 48% for V-CHART + MMC versus 32% for V-CHART and 31% for conventional fractionation (CF) (p = .05 and.03, respectively). Survival including death from all causes was also improved to 41% in the V-CHART + MMC arm as compared with 31% for V-CHART and 24% for CF (p = .03).
The incidence of confluent mucositis was 90% in both experimental arms as compared with 33% in the CF arm. The median time to complete resolution of mucositis was 6 to 7 weeks in all three arms. Grade 3/4 hematologic toxicity, primarily thrombocytopenia, developed in 18% of the V-CHART + MMC patients. Table 40.2 summarizes the data from the trials that used modified fractionation and concurrent chemotherapy and includes the RTOG 90-03 and EORTC 22791 data as a point of reference for optimally delivered RT alone.
FIGURE 40.4. Five-year locoregional control in the Duke University randomized trial of continuous course accelerated hyperfractionation (44%) versus split-course accelerated hyperfractionation and concurrent cisplatin/5-fluorouracil (p = .01). Extended follow-up has demonstrated that the survival benefit of combined-modality treatment is also statistically significant.
FIGURE 40.5. Five-year survival in the Yugoslavian trial of hyperfractionated irradiation alone (25%) or with daily low-dose concurrent cisplatin (46%) ( p = .007).
TABLE 40.2 RANDOMIZED TRIALS OF ACCELERATED OR HYPERFRACTIONATED RADIOTHERAPY AND CONCURRENT CHEMOTHERAPY IN ADVANCED HEAD AND NECK CANCER
Adjuvant Postoperative Irradiation
The role of chemotherapy for patients receiving primary resection and postoperative irradiation has been studied less extensively than in the definitive irradiation setting. The National Cancer Institute Head and Neck Contracts Program48 conducted a three-arm trial that evaluated the addition of one cycle of preoperative cisplatin and bleomycin with or without six cycles of sequential cisplatin (80 mg/m2) maintenance chemotherapy after surgery and postoperative irradiation. The control arm consisted of surgery and postoperative irradiation alone. This trial enrolled 443 patients and demonstrated no benefit with respect to locoregional control or survival from the addition of chemotherapy. Nearly half of the patients who were randomized to receive maintenance chemotherapy never received it. Despite this flaw in study execution, the incidence of distant metastases as the site of first relapse was 9% in the patients assigned to maintenance chemotherapy as opposed to 19% in those who were not (p = .02).
Intergroup Study 0034 readdressed the issue of postoperative chemotherapy in a trial that randomized patients after surgery to three 21-day cycles of sequential cisplatin (100 mg/m2) and infusion 5-FU (1,000 mg/m2/day for 5 days) followed by 50 to 60 Gy versus 50 to 60 Gy alone with no chemotherapy.49 Again, there was no significant improvement in locoregional control or overall survival associated with the use of chemotherapy, but the incidence of distant metastases was reduced from 30% to 20% (p = .02).
In contrast to the use of sequential postoperative RT and chemotherapy, the EORTC conducted a randomized trial in which patients were given either postoperative RT alone (2 Gy daily to 66 Gy) or the same RT with three cycles of cisplatin (100 mg/m2) on days 1, 22, and 43 of irradiation.50 Three hundred thirty-four patients were enrolled. Two-thirds of patients in the combined-modality arm received all three cycles of chemotherapy. The median follow-up is 5 years. Three-year DFS was increased from 41% to 59% (p = .001), and 3-year survival was increased from 49% to 65% (p = .006) in favor of the group of patients receiving concurrent therapy. Acute mucosal toxicity greater than grade 3 was significantly higher in the concurrent treatment arm (41% vs. 21%; p = .001). An analysis of 10-year outcomes is in progress.
The RTOG led an intergroup trial that randomized 459 high-risk postoperative patients to receive 60 to 66 Gy with or without concurrent CDDP in the same dose and schedule as in the EORTC study.51 Sixty-one percent of patients in the concurrent therapy arm received all three cycles of CDDP. The median follow-up for this study is 4 years; 2-year actuarial local regional control favored the combined-modality arm by 82% versus 72% (hazard ratio [HR], 0.61; p = .61), with only eight local or regional recurrences occurring beyond the 2-year point. DFS also favor concurrent therapy (HR, 0.78; p = .04). There was no statistically significant difference in survival (HR, 0.84; p = .19). Acute toxicity grade 3 or higher was higher in the concurrent therapy patients (77% vs. 34%; p < .001), but late toxicity was similar (21% vs. 17%).
PRINCIPLES FOR THE CHOICE OF CONCURRENT TREATMENT REGIMENS
Three general statements can summarize the previously reviewed randomized trials:
a. RT with concurrent chemotherapy is more efficacious than conventionally fractionated RT alone in advanced head and neck cancer;
b. Concurrent therapy appears to be more effective than maximally intensive single-modality RT administered via a modified fractionation regimen; and
c. Acute and late toxicity are increased with the use of concurrent chemotherapy.
No consensus exists, however, regarding either the optimal radiation dose fractionation scheme or the optimal scheduling of chemotherapy in these concurrent regimens. These controversies pose a decision-making dilemma to the physician when it is time to devise a treatment plan. The application of certain principles may serve as a guide in this selection process, though. The radiochemotherapy regimen should be more effective than maximally effective single-modality radiation. The use of an RT/chemotherapy regimen, which is superior to a suboptimal RT-alone regimen, does not offer the potential for a therapeutic gain to the patient.36
Radiation Fractionation Scheme
One rational approach to the choice of radiation dose fractionation within the context of concurrent chemotherapy would start with the selection of an optimal single-modality therapy and a definition of both its clinical efficacy and toxicity. Different dose-fractionation schemes in concurrent treatment programs could then be normalized to one another using the biologically equivalent dose (BED) concept.52 The BED = nd[1 + d/(α/β)], where n = the number of fractions delivered, d = the dose per fraction, and α/β = 10 for tumors and acute responding normal tissues and 2 for late-responding tissues. The intent of this normalization process is to allow a comparison of these different treatment programs in order to identify those having a favorable profile in terms of maximizing the probability of tumor control while minimizing the risk of late toxicity. Kasibhatla et al.37 evaluated prospective trials of CRT in order to estimate the radiotherapeutic dose equivalence of the concurrent chemotherapy. They concluded that, with respect to the tumor, the administration of concurrent chemotherapy was equivalent to the delivery of an additional 10 to 12 Gy. Subsequently, Lee and Eisbruch53 estimated that concurrent chemotherapy was equivalent to the delivery of an additional 8 Gy when the development of acute mucositis was used as the end point.
Whether modified fractionation irradiation and concurrent chemotherapy is superior to conventionally fractionated irradiation and concurrent chemotherapy has been addressed in the RTOG 0129 clinical trial. Both RT and chemotherapy constituted experimental variables in this trial. Patients (N = 720) were randomized to receive accelerated fractionation/concomitant boost to 72 Gy/6 weeks as per RTOG 90-03 and two cycles of concurrent bolus cisplatin (100 mg/m2) or conventionally fractionated RT 70 Gy/7 weeks and three cycles of concurrent bolus cisplatin (100 mg/m2). A preliminary report has revealed no differences in outcome between the two arms, suggesting that one could compensate for the elimination of the third dose of cisplatin by the more intensive radiation schedule. It should also be pointed out that on the conventionally fractionated arm only 69% of patients could tolerate all three doses of CDDP, a common occurrence with the use of high-dose CDDP regimens.54 Outcome was also the same in the conventionally fractionated arm patients who only received two cycles of CDDP versus all three cycles.
Chemotherapy Scheduling Considerations
Many investigators consider 100 mg/m2 bolus dosing of CDDP on days 1, 22, and 43 of RT to be standard. This schedule was originally developed for use in clinical trials of induction chemotherapy and later incorporated into CRT regimens. This traditional cyclical approach to delivery of concurrent CDDP has not been compared directly with schedules that use smaller, more frequent doses. In fact, randomized clinical trials comparing so-called nonstandard schedules of platinum-based CRT against RT alone42,43,55,56 have treated large numbers of patients with efficacy that compares favorably with bolus CDDP CRT regimens.12,43,57
Schedules that deliver smaller and more frequent doses of chemotherapy are also quite effective in improving outcome.45 Given the efficacy of these nonstandard platinum schedules, they may be preferable to cyclical bolus administration on two counts. More frequent administration could provide radiosensitizing chemotherapy during a larger proportion of the course of RT. Smaller individual doses of drug may lead to less chemotherapy-induced morbidity without compromise of efficacy.58,59 Concurrent CRT using such schedules has proven very effective and become the standard of care in squamous carcinoma of the uterine cervix.16,60–62
Compliance is a significant problem with the standard three-cycle concurrent CDDP paradigm. Nearly one-third of patients do not receive all cycles, and subset analyses suggest that two cycles are as effective as three.12,46,50,51RTOG 0129 and other studies have suggested that there may be a minimum cumulative threshold dose of approximately 200 mg/m2 of cisplatin that is required to achieve maximal benefit when used concomitantly with radiation.63–64,65 Schedules that administer chemotherapy more frequently throughout the course of RT deliver approximately the same cumulative dose as would result from two cycles of bolus CDDP, with treatment-related morbidity being the outcome that is most affected by drug administration schedule and cumulative dose >200 mg/m2.63
Weekly cisplatin regimens have been increasingly used, in large part because of their relative ease of administration and the clinical impression of reduced toxicity. It is important to stress the limitations of this experience. No direct comparison has been made between the weekly and the every-three-week regimens. The randomized data justifying weekly drug administration are equivocal. The North American Head and Neck Intergroup, in an older trial, compared radiation alone with radiation and weekly cisplatin (20 mg/m2/week) in patients with unresectable disease. This study was recently updated and reported by Quon et al.66 No survival difference was observed between the two treatment arms, but it is very important to recognize that the total cisplatin dose was only 140 mg/m2.
In nasopharyngeal cancer, Chan et al.67 reported a comparison of radiation with radiation and concurrent cisplatin (40 mg/m2/week). Progression-free survival was not different between the two treatment arms and a marginal overall survival difference was only appreciated after adjustment for stage and age. This survival difference was restricted to those patients with T3 or T4 tumors, and no difference was observed in the likelihood of distant metastatic disease. Thus, despite the enthusiasm for weekly cisplatin dosing regimens, there is little objective evidence supporting their use, and the every-three-week regimen must still be considered standard.
Recently, a Chinese trial compared 70 Gy of conventionally fractionated irradiation against the same regimen given with weekly concurrent cisplatin (30 mg/m2) in 230 patients with World Health Organization stage II nasopharynx cancer.68 No adjuvant chemotherapy was given. Five-year overall survival was significantly better in the combined-modality arm (95% vs. 86%; p = .007). The benefit was due to an improvement in distant metastases–free survival (95% vs. 84%; p = .007). Interestingly, concurrent chemotherapy did not improve local-regional control most likely because of the excellent results in the control arm (93% vs. 91%).
Phase III comparisons of platin- and non-platin-based concurrent treatment regimens are almost nonexistent, and the relative benefit of concurrent platin versus fluorouracil or taxane therapy is unknown. Meta-analysis data have suggested that fluorouracil or cisplatin regimens are more successful than carboplatin- or mitomycin-based treatments69 and that concurrent platin monotherapy is better than non-platin monotherapy.9 In a single small phase III trial, a weekly paclitaxel concurrent regimen appeared equivalent to a weekly cisplatin concurrent schedule.70 Overall, however, the data must be considered limited.
Most concurrent chemotherapy regimens use a single agent, an approach that, in general, suboptimally exploits the potential systemic adjuvant benefits of this modality. In most other diseases multiagent chemotherapy has been considered a better approach in controlling distant disease. In head and neck cancer multiagent induction chemotherapy regimens have clearly demonstrated an impact on distant metastases, a benefit observed both from single trials and in large meta-analyses.9 This same meta-analysis demonstrated a significant but less pronounced impact on distant metastases from concurrent treatment schedules. No clear survival difference has been identified when comparing concurrent single-agent platin regimens and concurrent multiagent schedules.
Radiation has also been administered in conjunction with concurrent high-dose intra-arterial cisplatin. This approach has the hypothetical advantage of allowing selective delivery of chemotherapy to the tumor while sparing uninvolved organs and allowing for the administration of intravenous sodium thiosulfate, a systemic cisplatin neutralizing agent designed to protect the kidneys. Although the procedure proved technically challenging, a phase II multi-institutional trial proved feasible.71 A phase III trial comparing concurrent radiation and intra-arterial versus intravenous cisplatin revealed no benefit, however, and enthusiasm for this regimen has waned.72
The most frequently utilized regimen for concurrent chemoradiotherapy remains single-agent high-dose cisplatin given every 3 weeks, despite strong feelings and considerable rhetoric. Limited evidence suggests that cisplatin may be more effective than carboplatin.73 Taxanes are also active agents against squamous head and neck cancer but have not been studied extensively as components of CRT regimens.
Radiotherapy and Molecularly Targeted Agents
Recent efforts to integrate radiation and systemic therapy have focused on molecularly targeted agents. The epidermal growth factor receptor (EGFR) is the target most often addressed and best studied in head and neck cancer. The EGFR is up-regulated in approximately 90% of patients with squamous cell head and neck cancer and has been associated with a poor prognosis.74,75–76 In patients with recurrent or metastatic disease, a modest response rate has been observed with the anti-EGFR monoclonal antibody cetuximab, both with and without systemic chemotherapy, as well as with the oral tyrosine kinase inhibitors gefitinib and erlotinib.77,78–79,80,81 Even more impressive is the disease stability that has been identified after treatment with these agents. This experience has prompted further exploration of these agents in definitive management.
Bonner et al.82 reported the results of the first phase III randomized trial exploring the role anti-EGFR therapy in the definitive management of a solid tumor. This trial compared the use of radiation therapy alone with radiation and concurrent cetuximab in the treatment of patients with stage III or IV nonmetastatic squamous cell carcinoma of the oropharynx, hypopharynx, or larynx. Cetuximab therapy consisted of a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2 for the duration of the radiation therapy. An updated analysis reported in 2010 confirmed the initial results.83 The addition of cetuximab to radiation therapy improved the median overall survival from 29 months to 49 months (p = .018), and the 5-year overall survival from 36% to 46%. The incidence of grade 3 or greater toxicity including mucositis did not differ between the two groups, except for a greater incidence of acneiform rash and infusion reactions in those patients treated with cetuximab. An interesting but unplanned subgroup analysis suggested that the benefit was greater in the cetuximab-treated patients with oropharynx cancers, smaller primary tumors, and more advanced nodal involvement. Males, patients with a better performance status, and patients who were younger also seemed to do better. This demographic distribution suggested the possibility that the drug was more effective in those patients with human papillomavirus (HPV)-associated disease, although HPV testing of the tumor specimens was not performed. It was also notable that survival was better in the cetuximab-treated patients who developed a cetuximab-induced rash.
It is important to recognize that the control arm of this trial, radiation therapy alone, is no longer considered a treatment standard for most patients with stage III and IV locoregionally advanced squamous cell head and neck cancer. Consequently, the relative benefit of cetuximab and radiation compared to a more standard radiation and concurrent chemotherapy combination is unknown. RTOG attempted to define this better in its 0522 trial reported preliminarily at the 2011 meeting of the American Society of Clinical Oncology.84 This study compared concurrent radiation, cetuximab, and cisplatin with radiation and cisplatin alone. As expected, the skin reactions were worse in those patients given cetuximab. No differences were observed in any survival outcome including progression-free survival, overall survival, or patterns of disease failure. Approximately 50% of the patients were p16 positive (and by inference HPV positive), but somewhat unexpectedly, no outcome differences were observed as a function of p16 status either. Given the results of this study, there is currently no justification for adding cetuximab to the standard radiation and cisplatin regimens used in definitive management outside of a clinical trial.
The findings in RTOG 0522 conflict with the observation made in the metastatic disease setting. There, a phase III randomized trial compared cisplatin and fluorouracil with cisplatin, fluorouracil, and cetuximab.80 This study demonstrated an improvement in survival from the addition of cetuximab to standard chemotherapy, and it remains unclear why the RTOG 0522 trial did not demonstrate a similar outcome improvement.
The question also remains unanswered as to whether concurrent radiation and cetuximab is equivalent or even superior to radiation and cisplatin. This issue is currently being addressed by the RTOG 1016 study, which compares these two regimens in a more selected patient population with HPV-positive oropharynx cancer. It is anticipated that the survival outcomes on the two treatment arms will be equivalent but that a difference may emerge in terms of late toxicity, function, or quality of life. It is of note that a retrospective study reported from Memorial Sloan-Kettering Cancer Center suggested the possibility that locoregional control and survival were better in patients treated with radiation and cisplatin when compared to patients given radiation and cetuximab.85 Although these results were upheld on multivariate analysis, prospective validation is required given the very significant differences in patients selected for these treatments. The randomized phase II TREMPLIN study prospectively compared the two regimens administered after three-drug induction chemotherapy. Given the nature and size of this trial, however, it is difficult to interpret any outcome comparisons.86
DEVELOPMENTAL ASPECTS OF COMBINED-MODALITY THERAPY
Induction Chemotherapy and Sequential Chemoradiation
The use of induction chemotherapy for locoregionally advanced squamous cell head and neck cancer continues to be an attractive treatment option. The dramatic tumor shrinkage seen in previously untreated patients after cisplatin-based chemotherapy regimens would intuitively suggest that an improvement in locoregional control and even survival should also result. Multiple phase III clinical trials, however, have failed to demonstrate any reproducible impact from induction treatment schedules on overall outcome.87,88 A marginal survival benefit was identified by the large Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC) using fluorouracil and platin induction chemotherapy, but this survival improvement was dwarfed by that obtained with the use of concurrent treatment regimens (Fig. 40.2).9,89
A frequent observation from these induction trials, however, has been a reduction in distant metastases.8,90,91 The fact that this did not impact on overall survival likely reflects the historically limited importance of distant metastases in the natural history of this disease. Recently, however, with the increasing locoregional control achieved by concurrent treatment regimens, distant metastases have emerged as a more frequent cause of treatment failure.92,93 This observation has led to the suggestion that there may be a role for the reintroduction of chemotherapy into current multimodality treatment schedules.94
Coincident with this resurgent interest in induction schedules has been the recognition that the widely used and very successful cisplatin and fluorouracil combination may not be the optimal induction regimen. Considerable phase III experience now exists demonstrating the superiority of three-drug fluorouracil, cisplatin, and taxane–containing regimens when compared to fluorouracil and cisplatin alone95–98 (Table 40.3). In these studies, successful induction was followed by definitive radiation therapy with or without concurrent chemotherapy.
It is important to note that three of these studies demonstrated a survival benefit favoring the three-drug induction regimen. This should not be interpreted as evidence that three-drug induction chemotherapy is a new standard of care. Induction chemotherapy followed by definitive radiation or chemoradiation is not a generally established sequence of treatment modalities, and the superiority of one induction regimen over another does not define induction chemotherapy as a standard of care.
Nonetheless, there are several situations where induction chemotherapy may have a role. In the larynx preservation setting, induction fluorouracil and cisplatin followed by definitive radiation in responders has been compared directly with concurrent chemoradiation with single-agent cisplatin and with radiation therapy alone.12 Although the laryngeal preservation and locoregional control were superior in the concurrent chemoradiotherapy arm, laryngectomy-free survival and distant metastatic control were equivalent between the two chemotherapy regimens.99 It is of note that overall survival was unchanged by the addition of chemotherapy. Thus, induction chemotherapy can be considered an acceptable larynx preservation strategy. The superiority of the three-drug docetaxel, cisplatin, and fluorouracil regimen when compared to fluorouracil and cisplatin in the larynx preservation setting has been established,98 although the subsequent use of concurrent treatment regimens after three-drug induction has proven difficult.86
Of greater interest has been the use of induction chemotherapy in what has been termed sequential treatment regimens, that is, induction chemotherapy followed by concurrent chemoradiotherapy.100 The rationale for this approach is that the addition of induction chemotherapy can, by improving the distant metastatic control, improve upon the overall survival achieved after concurrent chemoradiotherapy alone. These treatment schedules are intensive and require considerable commitment from both patient and physician. Toxicity, when compared to concurrent chemoradiotherapy alone, will be increased, and the administration of multiple doses of both induction and concurrent cisplatin is challenging.86
A preliminary report by Hitt and Lopez-Pousa101 from their study of three-drug induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone suggested a benefit for the induction arm. Significant methodologic flaws existed in this initial report, and the results may ultimately prove to be uninterpretable. A successful phase II randomized experience has been reported by Paccagnella et al.102 comparing induction docetaxel, cisplatin, and fluorouracil before chemoradiotherapy with chemoradiotherapy alone. This experience has now been expanded to a phase III trial, which also includes an assessment of the role of concurrent cetuximab. Similarly, a phase III trial comparing induction followed by concurrent chemoradiotherapy with concurrent treatment alone has been completed by the University of Chicago consortium, and the results are eagerly anticipated.
A third rationale for induction chemotherapy has been explored by University of Michigan investigators. Their premise is that induction chemotherapy can serve as a predictive tool and allow for the appropriate selection of the subsequent definitive head and neck cancer management strategy. Patients responding to induction chemotherapy can be approached nonoperatively, while those in whom induction is unsuccessful should proceed to surgical resection. This strategy is based on the long-standing recognition that patients responding to induction chemotherapy are also those who respond best to radiation therapy.103
TABLE 40.3 TAXANE, CISPLATIN, AND FLUOROURACIL (TPF) VERSUS CISPLATIN AND FLUOROURACIL (PF) INDUCTION CHEMOTHERAPY: RANDOMIZED TRIALS
This approach has been used successfully in patients with advanced larynx cancer.104 The treatment schedule began with a single cycle of induction cisplatin and fluorouracil, followed by concurrent chemoradiotherapy with high-dose single-agent cisplatin in responders. At least a partial response to single-cycle induction was achieved in 75% of patients, and larynx preservation ultimately proved possible in 70% of the entire patient cohort. It was of particular import that those patients requiring laryngectomy because of a failure to respond to induction chemotherapy achieved an overall survival equivalent to the chemotherapy responders.
This experience proved less successful in their patients with oropharynx and oral cavity cancer, however.105,106 Furthermore, the relegation of induction chemotherapy to a purely predictive tool is disquieting to both medical and radiation oncologists. Induction adds significant cost and toxicity, and one would hope that it might provide an additional survival benefit or an improvement in distant metastatic disease control. Perhaps other less toxic predictive “biomarkers” than responsiveness to induction chemotherapy might emerge in the future.
Thus, induction chemotherapy, particularly using the three-drug cisplatin, fluorouracil, and taxane combination, remains a very active but incompletely developed tool. Its ultimate impact on survival, distant metastases, and our treatment paradigms remains to be seen. The results of current phase III trials must be awaited before sequential treatment schedules can be considered standard treatment approaches. Toxicity considerations will play an important role in the choice of therapeutic strategies. Overall, more treatment means more toxicity as treatment is escalated along the continuum from conventional once-daily RT only to the most intensive combined-modality regimens. The total toxicity burden imposed upon a patient may increase as much as fivefold.107 These considerations are particularly relevant to sequential therapy programs. Compliance rates with an entire course of treatment with these regimens is only 65% to 70% in the most experienced hands.95,97,108
Other Targeted Agents
Other EGFR monoclonal antibodies are also being explored in the head and neck cancer patient population, both in the metastatic setting and in conjunction with radiation, including panitumumab and zalutumumab.109,110 The oral tyrosine kinase inhibitors including gefitinib, erlotinib, and others have undergone limited phase II testing as part of definitive treatment schedules. Results from these studies have been mixed and enthusiasm restrained.71,111–114
Treatments directed against other molecular targets, most notably the vascular endothelial growth factor receptor (VEGFR), are also now being integrated with definitive radiation therapy schedules.115,116 Overexpression of VEGF in head and neck cancer is associated with a twofold increase in the risk of death from disease.117 Yoo et al.118 performed a pilot study in 29 patients that integrated dual targeting of EGFR with erlotinib and VEGFR with the antibody bevacizumab into a regimen of platinum-based chemoradiation for newly diagnosed, locally advanced, nonmetastatic disease. Three-year progression-free survival was 82%. One of the most important facets of this trial was that it utilized functional metabolic imaging with the performance of serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans to assess response to treatment. DCE-MRI quantitatively measures tumor perfusion and vascular permeability, which is expressed by the parameter Ktrans. Patients whose disease recurred after treatment had lower baseline pretreatment median Ktrans values, which rose during the earliest phases of therapy. Patients who did not fail, however, had higher baseline median Ktrans values that decreased during therapy. These data suggest that Ktrans could potentially serve as an imaging biomarker to guide initial treatment selection based on pretreatment prognosis or to guide treatment modification based on a favorable or unfavorable response to the early phases of treatment.119
Hypoxia is one of the most important characteristics of the aggressive malignant phenotype.120–123 Poorly oxygenated tumors are less likely to respond to surgery,124 radiotherapy,120,125–127 and chemotherapy. Hypoxic primary tumors are more likely to develop distant metastases after treatment.128 A recent review of nearly 400 HNC patients who underwent tumor oxygenation measurement demonstrated that hypoxia was strongly associated with treatment failure independently of stage and therapeutic modality.31
Tirapazamine, a bioreductively activated compound, is one to two orders of magnitude more cytotoxic to hypoxic cells than well-oxygenated cells and also potentiates the activity of cisplatin.129–131 Phase I/II studies in advanced squamous HNC demonstrated efficacy with acceptable toxicity when this drug was incorporated into cisplatin-containing CRT regimens and suggested that the benefit of the drug was restricted to those patients who had hypoxic tumors as assessed by 18F-misonidazole positron emission tomography (PET) scanning.132,133
Two phase III trials were conducted to determine whether targeting of hypoxic cells with tirapazamine/cisplatin CRT was superior to cisplatin CRT. The first trial (HeadSTART) enrolled 880 patients. No benefit was observed from the addition of tirapazamine.134 A large number of patients had significant protocol deviations with respect to the delivery of radiotherapy, however. A subset analysis of patients who correctly received all of their treatment according to the protocol guidelines did demonstrate an advantage in patients who received tirapazamine.135 Another important consideration is that patients enrolled into this trial were not selected according to whether or not they had hypoxic tumors, which would have increased the power to detect a benefit from the drug if in fact one existed. A second trial with the same treatment schema was launched with a planned enrollment of 550 patients but was prematurely closed because of an unexplainable excess of deaths during treatment in the tirapazamine arm.
SUMMARY
The use of modified daily fractionation as opposed to conventional once-daily fractionation improves the prognosis of patients who receive curative intent RT for advanced head and neck cancer. Radiation therapy and concurrent chemotherapy in turn are superior to both single-modality conventional and modified fractionation radiation therapy in the nonsurgical management of advanced head and neck cancer. Anti-EGFR-targeted therapy also enhances the effectiveness of RT. The role of EGFR inhibition in a chemoradiation setting is under investigation. Likewise, the benefit of adding induction chemotherapy to a platform of chemoradiation is being tested. Hypoxia-targeted therapy remains investigational.
The increased acute and late toxicity that results from combining these multiple modalities poses immediate challenges. These include the need to develop criteria for a priori selection of those patients with advanced-stage disease who can still be adequately treated with radiotherapy alone and the need to create effective strategies for toxicity prophylaxis and management. These efforts will allow for the optimal integration of radiotherapy, chemotherapy, and biologically targeted therapy for those patients requiring combined modality therapy.
REFERENCES
1. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7–16.
2. Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:111–121.
3. Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol1992;25:231–241.
4. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet2003;362:933–940.
5. Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368:843–854.
6. Fu KK. Combined-modality therapy for head and neck cancer. Oncology (Williston Park) 1997;11:1781–1790, 96; discussion 96, 179.
7. Lamont EB, Vokes EE. Chemotherapy in the management of squamous-cell carcinoma of the head and neck. Lancet Oncol 2001;2:261–269.
8. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med1991;324:1685–1690.
9. Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14.
10. Monnerat C, Faivre S, Temam S, et al. End points for new agents in induction chemotherapy for locally advanced head and neck cancers. Ann Oncol 2002;13:995–1006.
11. Taylor SGt, Murthy AK, Vannetzel JM, et al. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol1994;12:385–395.
12. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091–2098.
13. Harari PM. Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 1997;15:2050–2055.
14. Harari PM, Cleary JF, Hartig GK. Evolving patterns of practice regarding the use of chemoradiation for advanced head and neck cancer patients. Proceedings ASCO 2001;20:226a.
15. Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593–158.
16. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–1613.
17. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA1999;281:1623–1627.
18. Budach V, Stuschke M, Budach W, et al. Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 Prospective Randomized Trial. J Clin Oncol 2005;23:1125–1135.
19. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69–76.
20. Denis F, Garaud P, Bardet E, et al. Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys 2003;55:93–98.
21. Cox JD, Pajak TF, Marcial VA, et al. Interruptions adversely affect local control and survival with hyperfractionated radiation therapy of carcinomas of the upper respiratory and digestive tracts. New evidence for accelerated proliferation from Radiation Therapy Oncology Group Protocol 8313. Cancer 1992;69:2744–2748.
22. Overgaard J, Hjelm-Hansen M, Johansen LV, et al. Comparison of conventional and split-course radiotherapy as primary treatment in carcinoma of the larynx. Acta Oncol 1988;27:147–152.
23. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988;27:131–146.
24. Eschwege F, Sancho-Garnier H, Gerard JP, et al. Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycin to radiotherapy alone in epidermoid carcinomas of the oropharynx: experience of the European Organization for Research and Treatment of Cancer. NCI Monogr 1988:275–278.
25. Fu KK, Phillips TL, Silverberg IJ, et al. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial. J Clin Oncol 1987;5:1410–1418.
26. Gupta NK, Pointon RC, Wilkinson PM. A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer. Clin Radiol 1987;38:575–581.
27. Lo TC, Wiley AL Jr, Ansfield FJ, et al. Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study. AJR Am J Roentgenol1976;126:229–235.
28. Browman GP, Cripps C, Hodson DI, et al. Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol1994;12:2648–2653.
29. Gray LH, Conger AD, Ebert M, et al. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 1953;26:638–648.
30. Brizel DM, Dodge RK, Clough RW, et al. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999;53:113–117.
31. Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol2005;77:18–24.
32. Haffty BG, Son YH, Papac R, et al. Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials. J Clin Oncol 1997;15:268–276.
33. Bartelink H, Kallman RF, Rapacchietta D, et al. Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cis-diamminedichloroplatinum (II) and irradiation. Radiother Oncol 1986;6:61–74.
34. Adelstein DJ, Lavertu P, Saxton JP, et al. Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 2000;88:876–883.
35. Keane TJ, Cummings BJ, O’Sullivan B, et al. A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma. Int J Radiat Oncol Biol Phys 1993;25:613–618.
36. Sanchiz F, Milla A, Torner J, et al. Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 1990;19:1347–1350.
37. Kasibhatla M, Kirkpatrick JP, Brizel DM. How much radiation is the chemotherapy worth in advanced head and neck cancer? Int J Radiat Oncol Biol Phys 2007;68:1491–1495.
38. Wong WW, Mick R, Haraf DJ, et al. Time-dose relationship for local tumor control following alternate week concomitant radiation and chemotherapy of advanced head and neck cancer. Int J Radiat Oncol Biol Phys1994;29:153–162.
39. Merlano M, Benasso M, Corvo R, et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996;88:583–589.
40. Merlano M, Vitale V, Rosso R, et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992;327:1115–1121.
41. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst1999;91:2081–2086.
42. Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16:1318–1324.
43. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol1998;16:1310–1317.
44. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998;338:1798–1804.
45. Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000;18:1458–1464.
46. Bensadoun RJ, Benezery K, Dassonville O, et al. French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: results at 2 years (FNCLCC-GORTEC). Int J Radiat Oncol Biol Phys 2006;64:983–994.
47. Dobrowsky W, Naude J. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers. Radiother Oncol 2000;57:119–124.
48. Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. Cancer 1987;60:301–311.
49. Laramore GE, Scott CB, al-Sarraf M, et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys1992;23:705–713.
50. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–1952.
51. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–1944.
52. Fowler JF. Modelling altered fractionation schedules. BJR Suppl 1992;24:187–192.
53. Lee IH, Eisbruch A. Mucositis versus tumor control: the therapeutic index of adding chemotherapy to irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 2009;75:1060–1063.
54. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35.
55. Bernier J. Alteration of radiotherapy fractionation and concurrent chemotherapy: a new frontier in head and neck oncology? Nat Clin Pract Oncol 2005;2:305–314.
56. Huguenin P, Beer KT, Allal A, et al. Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. J Clin Oncol2004;22:4665–4673.
57. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92–98.
58. Nagai N, Ogata H. Quantitative relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-time curve (AUC) as the major toxicodynamic determinant in vivo. Cancer Chemother Pharmacol 1997;40:11–18.
59. Kurihara N, Kubota T, Hoshiya Y, et al. Pharmacokinetics of cis-diamminedichloroplatinum (II) given as low-dose and high-dose infusions. J Surg Oncol 1996;62:135–138.
60. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137–1143.
61. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153.
62. Thomas GM. Improved treatment for cervical cancer–concurrent chemotherapy and radiotherapy. N Engl J Med 1999;340:1198–1200.
63. Ang KK. Concurrent radiation chemotherapy for locally advanced head and neck carcinoma: are we addressing burning subjects? J Clin Oncol 2004;22:4657–4659.
64. Loong HH, Ma B, Mo F, et al. The effect of cisplatin dose administered during concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol2011;29:abstr 5532.
65. Ghi MG, Paccagnell A, Floriani I, et al. Concomitant chemoradiation in locally advanced head and neck squamous cell carcinoma: a literature-based meta-analysis on the platinum concomitant chemotherapy. J Clin Oncol2011;29:abstr 5534.
66. Quon H, Leong T, Haselow R, et al. Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382). Int J Radiat Oncol Biol Phys 2011;81:719–725.
67. Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst2005;97:536–539.
68. Chen QY, Wen YF, Guo L, et al. Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial. J Natl Cancer Inst 2011;103:1761–1770.
69. Budach W, Hehr T, Budach V, et al. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer 2006;6:28.
70. Jain RK, Kirar P, Gupta G, et al. A comparative study of low dose weekly paclitaxel versus cisplatin with concurrent radiation in the treatment of locally advanced head and neck cancers. Indian J Cancer2009;46:50–53.
71. Robbins KT, Kumar P, Harris J, et al. Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin Oncol 2005;23:1447–1454.
72. Rasch CR, Hauptmann M, Schornagel J, et al. Intra-arterial versus intravenous chemoradiation for advanced head and neck cancer: results of a randomized phase 3 trial. Cancer 2010;116:2159–2165.
73. Fountzilas G, Ciuleanu E, Dafni U, et al. Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study. Med Oncol 2004;21:95–107.
74. Temam S, Kawaguchi H, El-Naggar AK, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol 2007;25:2164–2170.
75. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002;62:7350–7356.
76. Chung CH, Ely K, McGavran L, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol2006;24:4170–4176.
77. Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646–8654.
78. Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980–1987.
79. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004;22:77–85.
80. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116–1127.
81. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol2009;27:1864–1871.
82. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578.
83. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21–28.
84. Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). J Clin Oncol 2011;29:360s.
85. Koutcher L, Sherman E, Fury M, et al. Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;81:915–922.
86. Lefebvre J, Pointreau Y, Rolland F. Sequential chemoradiotherapy (SCRT) for larynx preservation (LP): results of the randomized phase II TREMPLIN study. J Clin Oncol 2011;29:360s.
87. Adelstein DJ. Induction chemotherapy in head and neck cancer. Hematol Oncol Clin North Am 1999;13:689–698, v–vi.
88. Cohen EE, Lingen MW, Vokes EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 2004;22:1743–1752.
89. Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949–955.
90. Schuller DE, Metch B, Stein DW, et al. Preoperative chemotherapy in advanced resectable head and neck cancer: final report of the Southwest Oncology Group. Laryngoscope 1988;98:1205–11.
91. Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994;86:265–272.
92. Adelstein DJ, Saxton JP, Lavertu P, et al. Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol2002;20:1405–1410.
93. Vokes EE, Kies MS, Haraf DJ, et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 2000;18:1652–1661.
94. Brockstein B, Haraf DJ, Rademaker AW, et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol 2004;15:1179–1186.
95. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005;23:8636–8645.
96. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695–1704.
97. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705–1715.
98. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498–506.
99. Forastiere AA, Maor M, Weber RS. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 2006;24:284s.
100. Posner MR, Haddad RI, Wirth L, et al. Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: evolution of the sequential treatment approach. Semin Oncol 2004;31:778–785.
101. Hitt R, Grau JJ, Lopez-Pousa A. Final results of a randomized phase III trial comparing induction chemotherapy with cisplatin/5-FU or docetaxel/cisplatin/5-FU follow by chemoradiotherapy (CRT) versus CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC). J Clin Oncol 2009;27:abstr 6000.
102. Paccagnella A, Ghi MG, Loreggian L, et al. Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. Ann Oncol 2010;21:1515–1522.
103. Ensley JF, Jacobs JR, Weaver A, et al. Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck. Cancer 1984;54:811–814.
104. Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm. J Clin Oncol2006;24:593–598.
105. Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol 2008;26:3138–146.
106. Urba S, Worden F, Carey TE. One cycle of induction chemotherapy (IC) to select for organ preservation for patients (PTS) with advanced squamous carcinoma of the oral cavity (SCCOC). J Clin Oncol2005;23:513s.
107. Bentzen SM, Trotti A. Evaluation of early and late toxicities in chemoradiation trials. J Clin Oncol 2007;25:4096–4103.
108. Adelstein DJ, Moon J, Hanna E, et al. Docetaxel, cisplatin, and fluorouracil induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin in patients with advanced squamous cell head and neck cancer: a Southwest Oncology Group phase II trial (S0216). Head Neck 2010;32:221–228.
109. Wirth LJ, Allen AM, Posner MR, et al. Phase I dose-finding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck. Ann Oncol 2010;21:342–347.
110. Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011;12:333–343.
111. Caponigro F, Romano C, Milano A, et al. A phase I/II trial of gefitinib and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck. Anticancer Drugs2008;19:739–744.
112. Chen C, Kane M, Song J, et al. Phase I trial of gefitinib in combination with radiation or chemoradiation for patients with locally advanced squamous cell head and neck cancer. J Clin Oncol2007;25:4880–4886.
113. Hainsworth JD, Spigel DR, Burris HA 3rd, et al. Neoadjuvant chemotherapy/gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients with locally advanced squamous carcinoma of the head and neck. Cancer 2009;115:2138–2146.
114. Harrington KJ, El-Hariry IA, Holford CS, et al. Phase I study of lapatinib in combination with chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27:1100–1107.
115. Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol 2012;13:172–180.
116. Seiwert TY, Haraf DJ, Cohen EE, et al. Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol 2008;26:1732–1741.
117. Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 2005;11:1434–1440.
118. Yoo D, Kirkpatrick J, Craciunescu O, et al. Prospective trial of synchronous bevacizumab, erlotinib, and concurrent chemoradiation in locally advanced head and neck cancer. Clin Cancer Res2012;18:1404–1414.
119. Brizel DM. Head and neck cancer as a model for advances in imaging prognosis, early assessment, and posttherapy evaluation. Cancer J 2011;17:159–165.
120. Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys2002;53:1192–1202.
121. Graeber TG, Osmanian C, Jacks T, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379:88–91.
122. Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy. Clin Cancer Res2001;7:3399–3403.
123. Moeller BJ, Cao Y, Li CY, et al. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004;5:429–441.
124. Hockel M, Schlenger K, Aral B, et al. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509–4515.
125. Fyles A, Milosevic M, Pintilie M, et al. Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 2006;80:132–137.
126. Brizel DM, Dodge RK, Clough RW, et al. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999;53:113–117.
127. Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285–289.
128. Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996;56:941–943.
129. Gatzemeier U, Rodriguez G, Treat J, et al. Tirapazamine-cisplatin: the synergy. Br J Cancer 1998;77(Suppl 4):15—17.
130. Tuttle SW, Hazard L, Koch CJ, et al. Bioreductive metabolism of SR-4233 (WIN 59075) by whole cell suspensions under aerobic and hypoxic conditions: role of the pentose cycle and implications for the mechanism of cytotoxicity observed in air. Int J Radiat Oncol Biol Phys 1994;29:357–362.
131. Peters KB, Brown JM. Tirapazamine: a hypoxia-activated topoisomerase II poison. Cancer Res 2002;62:5248–5253.
132. Rischin D, Peters L, Fisher R, et al. Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin, and Radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol 2005;23:79–87.
133. Rischin D, Peters L, Hicks R, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 2001;19:535–542.
134. Rischin D, Peters LJ, O’Sullivan B, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 2010;28:2989–2995.
135. Peters LJ, O’Sullivan B, Giralt J, et al. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. J Clin Oncol2010;28:2996–3001.