The first prospective randomized controlled clinical trial that integrated chemotherapy into the curative treatment of patients with advanced head and neck cancer was the Head and Neck Contracts Program, a multi-institutional collaboration of surgeons, medical oncologists, and radiation oncologists (12
). This trial randomized 462 patients into a control group of surgery and postoperative radiotherapy, an experimental arm of one cycle of induction chemotherapy with cisplatin and bleomycin followed by surgery and postoperative radiotherapy or a second experimental arm of induction chemotherapy with cisplatin and bleomycin followed by surgery and postoperative radiotherapy, followed by six cycles of adjuvant cisplatin. Study results were reported in 1987 and demonstrated that the group that received adjuvant cisplatin after definitive therapy had a lower rate of distant metastases; however, the addition of chemotherapy in both experimental arms did not impact survival (13
). However, some laryngectomy specimens in patients with an apparent complete response to induction chemotherapy were found to be histologically free of tumor after resection. These findings drove subsequent studies of the feasibility of larynx preservation with induction chemotherapy followed by radiotherapy, with surgery reserved for patients without a response to induction chemotherapy or for salvage of patients with persistent or recurrent disease following radiotherapy.
The current era of chemoradiation was ushered in by the Veterans Affairs (VA) Laryngeal Cancer Study Group, who performed a landmark randomized controlled clinical trial to determine if induction chemotherapy followed by definitive radiation, with laryngectomy reserved for salvage, was a viable option to the gold standard of total laryngectomy with postoperative radiotherapy for patients with advanced stage laryngeal cancer (14
). Patients with stage III or IV laryngeal cancer who would have required total laryngectomy for cure were randomized to receive either three cycles of induction chemotherapy with cisplatin and 5-FU followed by radiotherapy, or surgery and postoperative radiotherapy. Clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response to induction received a third cycle followed by definitive radiation therapy. Patients without a tumor response or patients with progressive disease, including nodal disease, underwent immediate surgical resection followed by postoperative radiotherapy; patients with recurrent disease following chemotherapy and radiation underwent salvage laryngectomy.
The VA study results were published in 1991 and showed that organ preservation could be attempted in patients with advanced laryngeal cancer with chemoradiation without reducing survival in patients who would otherwise have undergone total laryngectomy, with laryngeal preservation in 64% of patients. Patterns of failure did differ between treatment groups, with significantly more patients in the induction chemotherapy group failing locally and significantly fewer patients failing at distant sites, in comparison with the surgical control group. Rates of second primary cancers were significantly higher in the surgery group. This study demonstrated that for some patients with advanced laryngeal cancer, laryngeal preservation with chemoradiation was feasible. Significant predictors of the need for salvage surgery were T4 and stage IV disease. Salvage laryngectomy was required in 56% of T4 lesions compared with 29% of smaller primary tumors, and in 44% of patients
with stage IV disease compared with 29% for stage III disease. Patients with T4 lesions comprised 26% of participants in the VA study, with T4N0 disease present in 12% of patients. The subset of patients with T4N0 disease had significantly reduced survival in the nonoperative treatment arm compared to the surgical arm (15
), suggesting that the encouraging results of organ preservation do not apply to this subgroup.
Advanced stage nodal disease is a known adverse prognostic factor and was related to the poorer survival of stage IV disease in the VA study, which includes N2 and N3 nodal disease by definition. When organ preservation therapy is used in patients with advanced neck disease, the response in the neck may be independent of the response at the primary site. A follow-up study of patients in the VA study showed poorer survival in patients with N2 or N3 disease and a partial response in the neck following induction chemotherapy, who subsequently required salvage neck dissection because of inability to control disease in the neck, compared to those with a complete response to induction therapy (16
). The incorporation of early, planned posttreatment neck dissection after induction but prior to radiotherapy in such patients resulted in improved regional control and no difference in survival between patients with a partial response compared to complete responders (17
A follow-up phase III study designed by the Radiation Therapy Oncology Group (RTOG) was designed to determine the contribution of chemotherapy and radiotherapy to larynx preservation to investigate three radiation-based treatments: induction cisplatin and 5-FU followed by radiotherapy in responders, similar to the induction arm of the VA study; chemotherapy with cisplatin administered concurrently with radiotherapy; and radiotherapy alone (18
). Unlike the VA study, there was no primary surgical arm. The concurrent treatment arm was designed to test observations of the enhancement of radiation effects on tumor by concurrent treatment with cisplatin. Patients with stage III or IV laryngeal cancer, excluding T1 disease, were included. As a result of the poorer outcomes for patients with T4 disease in the VA study, patients with large volume T4 disease, defined as extension through cartilage or greater than 1 cm of base of tongue involvement, were excluded from the RTOG 91-11 trial. Patients with low volume T4 disease were incorporated into RTOG 91-11 and represented 10% or less of patients in each arm.
The RTOG 91-11 study demonstrated that overall survival rates were similar in all three treatment groups; however, locoregional control rates were significantly better in the concurrent chemoradiation arm (78%) compared with induction (61%) and radiation alone (56%) and 2-year laryngeal preservation rates were higher for concurrent therapy (88%) compared with induction (75%) or radiation alone (70%). Induction chemotherapy had the same rate of acute toxicity as concurrent chemotherapy; however, acute mucosal toxicity was twice as frequent in the concurrent chemotherapy arm as in the induction or radiotherapy alone arms and was associated with delayed recovery of swallowing function at 1-year assessment.
These data established concurrent chemoradiation with cisplatin as the standard of care for organ preservation in advanced laryngeal cancer, excluding T4 tumors with tongue base or cartilage invasion. A follow-up of RTOG 91-11 evaluating the subset of patients who required salvage laryngectomy confirmed that salvage laryngectomy was required significantly less often following concurrent chemoradiation (16%), compared with the induction (28%) and radiotherapy alone (31%) arms (19
). However, among patients surviving at least 1 year, overall survival was significantly worse for patients who required salvage laryngectomy compared to those who did not, by approximately 10%. There was no statistically significant difference in survival among patients undergoing salvage total laryngectomy as a function of initial nonoperative treatment.
Severe late toxicity after concurrent chemoradiation causing dysphagia secondary to dysfunction of the larynx and/or pharynx is progressive over time and in an RTOG analysis of several RTOG studies, including 91-11, was present in as many as 43% of patients at 3 years, after excluding patients with pretreatment severe laryngopharyngeal dysfunction (20
). On multivariate analysis, older age, advanced primary tumor stage and laryngeal or hypopharyngeal primary site disease were significant predictors of late toxicity, emphasizing the importance of careful patient selection for aggressive organ-sparing treatment and swallowing exercises.
Taken together, these landmark randomized controlled clinical trials established concurrent chemoradiation as the standard of care for laryngeal preservation in advanced laryngeal cancer, with the caveat that patient selection should consider whether survival and function with an organ-sparing approach can be anticipated to be equivalent to the standard of laryngectomy with postoperative radiotherapy. Patients with T4 disease have poorer survival with chemoradiation and should undergo primary laryngectomy. Patients with pretreatment organ dysfunction are inappropriate for organ preservation because of predicted laryngopharyngeal dysfunction and feeding tube dependence resulting from severe late toxicities associated with chemoradiation. The cohort of patients with advanced primary stage disease and evidence of pretreatment organ dysfunction are better served with primary surgery and reconstruction rather than attempting to preserve a dysfunctional organ. Finally, patients should be aware that salvage laryngectomy is associated with a decrease in survival.
Organ preservation strategies for hypopharyngeal cancer are associated with a lower laryngeal preservation rate than those reported for advanced laryngeal cancer. The
only randomized, prospective trial to date comparing chemoradiation to surgery with postoperative radiotherapy in hypopharyngeal cancer was conducted by the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Cooperative group (21
). Modeled after the VA laryngeal cancer study, patients with T2-T4 lesions who required total laryngectomy as part of definitive surgical treatment were randomized to receive either induction chemotherapy with cisplatin and 5-FU followed by definitive radiotherapy, or surgery with postoperative radiotherapy. Patients with T4 lesions comprised 6% of participants. This trial found no significant difference between the induction chemotherapy arm and the surgery arm in local (12% and 17%, respectively) or regional (19% and 23%) recurrence rates and 5-year disease-free survival (25% and 27%).Overall survival was less than 30% and did not differ between treatment groups. Successful organ preservation was far less likely when compared with laryngeal cancer, with only 17% of patients treated with induction chemotherapy followed by radiation alive and laryngectomy-free at 5 years.
A subsequent phase III study, also conducted by the EORTC, directly compared induction cisplatin and 5-FU followed by radiotherapy in patients with a complete response at the primary site with a regimen of alternating cisplatin and 5-FU and radiotherapy (22
). No significant difference in laryngeal preservation or survival rates was demonstrated, and at the present time, induction chemotherapy followed by radiotherapy is the evidence-based standard of care for laryngeal preservation in hypopharyngeal cancers, in the absence of site-specific trials evaluating concurrent chemoradiation.
A third trial was conducted by the European Groupe Oncologie Radiothérapie Tête et Cou (GORTEC) study group for organ preservation in patients with advanced cancer of the larynx or hypopharynx who, similar to the EORTC study, would be candidates for total laryngectomy for cure (23
). A total of 220 patients were randomly assigned, and of those, just more than one-half had a hypopharynx primary tumor. The majority of patients had T3 primary tumors. The two treatment arms consisted of standard cisplatin and 5-FU for three cycles (control group) or combination docetaxel, cisplatin, and 5-FU for three cycles. Following induction of both therapies, responding patients received 70 Gy of standard radiation; patients without a response to induction chemotherapy underwent surgery. The three-drug therapy was shown to be statistically superior for the endpoints of response to the induction regimen (80% vs. 59%) and preservation of a functional larynx at 3 years (70% vs. 58%). Based on these data, induction therapy with the triple-drug combination of docetaxel, cisplatin, and 5-FU is superior to cisplatin and 5-FU for organ preservation in advanced hypopharyngeal cancer.
While subsite analysis was not described in the EORTC report, others have shown in retrospective studies that survival is better with surgery and postoperative radiotherapy compared with chemoradiation, and in such series the volume of disease and laryngeal involvement were factors that adversely impacted survival (24
). As for advanced laryngeal cancer, patients with severe pretreatment organ dysfunction are inappropriate for chemoradiation because permanent laryngeal dysfunction and gastrostomy tube dependence are expected sequelae of nonoperative treatment. Hypopharyngeal cancer is a significant predictor of pharyngoesophageal stricture, with rates of gastrostomy tube dependence following chemoradiation twice as high as for laryngeal primary tumors (27
). The hypopharynx is particularly predisposed to stricture formation because the dose to the pharyngeal constrictors cannot be reduced as the structures related to swallowing dysfunction are the primary target. Taken together, these data suggest that organ preservation in hypopharyngeal cancer should be reserved for those patients with stage III disease with low volume primary tumors. As for laryngeal cancer, patients with T4 disease have poorer survival with chemoradiation and should undergo primary laryngectomy (28
Concurrent chemoradiation has increasingly replaced surgery in the initial treatment of advanced stage oropharyngeal cancer, despite a lack of trials directly comparing surgery with postoperative radiation to concurrent chemoradiation. In contrast to the data for larynx and hypopharyngeal cancer, there are no clinical trial data that compare control rates and survival for patients with advanced oropharyngeal cancer treated with surgery with postoperative radiation versus chemoradiation, and therefore equivalence cannot be shown. Surgery with postoperative radiation therapy results in superior survival compared with radiation therapy alone, and has been the standard of care for patients with advanced stage oropharyngeal cancer. There has been one randomized controlled trial limited to patients with oropharyngeal cancer (29
) and several nonrandomized or mixed primary site trials (31
) that demonstrate improved locoregional control and survival rates with concurrent chemoradiation (cisplatin and 5-FU) of approximately 20% compared to radiation alone for advanced stage disease, which are comparable to the historical results of surgery and postoperative radiation (34
) with organ preservation rates of 77% to 84%. No difference was observed between chemoradiation and radiation alone in the distant metastatic rate. Mucositis, related weight loss and need for a feeding tube, and hematologic toxicity occurred more frequently in the chemoradiotherapy group.
Despite the absence of level I evidence comparing concurrent chemoradiation to primary surgery, most oncologists consider these data sufficient evidence to offer
organ preservation using concurrent cisplatin and 5-FU to patients with oropharyngeal cancer. Exceptions are stage I or II disease, which is treated with either surgery or radiotherapy, and a subset of stage III oropharyngeal cancers with T1 or T2 lesions and N1 disease, who do not appear to receive significant benefit from the addition of chemotherapy and may be treated with primary radiation therapy alone (43
). A major topic of debate is the influence of human papillomavirus (HPV) associated tumors on clinical trial results, which primarily involves males under age 65, and is increasing in incidence in the United States and Europe (44
). The favorable response of oropharyngeal cancer to chemoradiation may be due to a subset of patients with HPV-associated disease, who have improved response rates to chemoradiation primarily due to improved disease-free survival (45
). HPV-positive tumors have been shown to have improved survival and disease control rates compared to HPV-negative tumors, and this survival benefit is independent of treatment modality (46
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