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Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1064-1071 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.5867 Multiagent Concurrent Chemoradiotherapy for Locoregionally Advanced Squamous Cell Head and Neck Cancer: Mature Results From a Single InstitutionFrom the Departments of Hematology and Medical Oncology, Radiation Oncology, Biostatistics, and Otolaryngology and Communicative Disorders, The Cleveland Clinic Foundation; and the Department of Otolaryngology and Head and Neck Surgery, University Hospitals of Cleveland, Cleveland, OH Address reprint requests to David J. Adelstein, MD, Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk R-35, Cleveland, OH 44195; e-mail: adelstd{at}ccf.org
PURPOSE: A retrospective review with long-term follow-up is reported from the Cleveland Clinic Foundation studying radiation and concurrent multiagent chemotherapy in patients with locoregionally advanced squamous cell head and neck cancer. PATIENTS AND METHODS: Between 1989 and 2002, 222 patients were treated with 4-day continuous infusions of fluorouracil (1,000 mg/m2/d) and cisplatin (20 mg/m2/d) during weeks 1 and 4 of either once daily or twice daily radiation therapy. Primary site resection was reserved for patients with residual or recurrent primary site disease after chemoradiotherapy. Neck dissection was considered for patients with N2 or greater disease, irrespective of clinical response, and for patients with residual or recurrent neck disease. RESULTS: With a median follow-up of 73 months, the Kaplan-Meier 5-year projected overall survival rate is 65.7%, freedom from recurrence rate is 74.0%, local control without the need for surgical resection rate is 86.7%, and overall survival rate with organ preservation is 62.2%. Including patients undergoing primary site resection as salvage therapy, the overall local control rate is 92.4%. Regional control rate at 5 years is 92.4%. Among patients with N2-3 disease, regional control was significantly better if a planned neck dissection was performed. Distant control at 5 years was achieved in 85.4% of patients and was significantly worse in patients with hypopharyngeal primary sites and patients with poorly differentiated tumors. CONCLUSION: Concurrent multiagent chemoradiotherapy can result in organ preservation and cure in the majority of appropriately selected patients with locoregionally advanced, nonmetastatic, squamous cell head and neck cancer. Distant metastatic disease was the most common cause of treatment failure. Late functional outcomes will require further investigation.
The past 15 years have seen extensive exploration of concurrent chemotherapy and radiation therapy as definitive management for patients with locoregionally advanced squamous cell head and neck cancer.1,2 Both single-institution3,4 and multi-institutional5,6 phase III trials, as well as several large meta-analyses,7,8 now allow us to make evidence-based recommendations supporting this treatment approach. Radiation therapy and concurrent high-dose single-agent cisplatin has become a standard of care in selected patients with nasopharyngeal cancer,9 laryngeal cancer,10 and unresectable squamous cell head and neck tumors11 and in the postoperative adjuvant setting.12,13 In theory, the use of multiple chemotherapeutic agents in combination would seem more attractive than monotherapy with cisplatin alone, and several of the positive phase III trials have used concurrent multiagent chemotherapy regimens.3-6 Combination chemotherapy also seems attractive given the increasing concern about distant metastases as a clinically important pattern of recurrence in this disease. However, only one study has compared single-agent and multiagent concurrent chemoradiotherapy.11 This three-arm, randomized, Intergroup trial compared radiation and cisplatin; radiation, fluorouracil, and cisplatin; and radiation therapy alone in patients with unresectable disease. Although the results of this study favored the single-agent cisplatin arm, the radiation therapy schedules used were radically different, and the value of this comparison is quite limited. Thus, the role of multiagent concurrent chemoradiotherapy schedules remains ill defined. Since 1989 at the Cleveland Clinic Foundation, a single disease-management team has used a consistent treatment approach of radiation and concurrent multiagent chemoradiotherapy with fluorouracil and cisplatin.3,14,15 We report mature results from this patient cohort in an effort to better define both survival expectations and patterns of treatment failure.
Since 1989, all patients presenting with locoregionally advanced, nonmetastatic (M0), squamous cell carcinoma of the head and neck have been considered for treatment with definitive concurrent multiagent chemoradiotherapy, with the goal of improving survival and preserving organ function. Patients with resectable oral cavity tumors and patients with tumor invasion into bone or cartilage are usually not considered appropriate for this treatment approach. Patients presenting with marked tumor-induced organ dysfunction are also, in general, not considered candidates for organ function–preservation therapy. Patients treated for primary tumors of the nasopharynx, paranasal sinus, or salivary gland are not included in this report. All patients treated in this fashion have been entered into the Cleveland Clinic Foundation Institutional Review Board (IRB) –approved and monitored Head and Neck Cancer Chemoradiotherapy Tumor Registry. All patients, if deemed appropriate and eligible, were also offered participation in one of several sequentially conducted IRB-approved clinical trials exploring the use of this treatment modality. These studies included a phase III trial conducted from 1990 to 1995 that compared radiation therapy alone with concurrent chemoradiotherapy in patients with resectable head and neck cancer,3 a phase II trial conducted from 1996 to 2001 for patients with locoregionally advanced disease using concurrent chemotherapy and hyperfractionated radiation,15 and a phase II trial conducted from 1999 to 2001 assessing the role of adoptive immunotherapy after completion of definitive management (including definitive chemoradiotherapy) for stage III to IV disease. Because of administrative and technical difficulties, the last study was terminated before completion and was never reported. Since 1995, on the basis of the positive results from our phase III trial, patients have been routinely offered this same chemoradiotherapy if clinical trial enrollment was not possible. Therefore, this report includes data gathered both from patients treated on IRB-approved clinical trials and from patients treated off study for one of several reasons. Pretreatment evaluation in all patients included a medical history, a direct and endoscopic examination under anesthesia, and a chest radiograph. Computed tomography or magnetic resonance imaging scans of the involved head and neck region or other staging procedures for distant metastases were obtained if clinically indicated. Positron emission tomography scans were not routinely obtained. Pretreatment laboratory evaluation included a CBC count and serum chemistry tests including urea nitrogen, creatinine, calcium, phosphorus, alkaline phosphatase, AST, albumin, total protein, bilirubin, and uric acid. Adequate hematologic, renal, and hepatic function was required before treatment. Patients with other uncontrolled malignancies or with active infection were not treated in this fashion. Tumor and lymph node classification was assigned according to the American Joint Committee on Cancer staging system in effect at the time of diagnosis.16 Patients with hematogenous metastases (M1) were not approached in this fashion. No patient previously administered definitive treatment for their head and neck cancer was included in this series. Patient care was provided by a multidisciplinary management team that included head and neck surgeons; medical, radiation, and nurse oncologists; dentists; and speech therapists. All patients underwent a pretreatment dental evaluation with appropriate preventative care, and all patients received a pretreatment audiogram. The treatment schema is detailed in Figure 1. All patients received a continuous course of radiation therapy administered either in once-daily fractions of 1.8 to 2 Gy to a total dose of 68 to 72 Gy or in twice-daily fractions of 1.2 Gy to a total dose of 72 Gy. Concurrently with this radiation therapy, patients were administered two courses of chemotherapy using 4-day continuous infusions of fluorouracil (1,000 mg/m2/d) and cisplatin (20 mg/m2/d) during the first and the fourth weeks of radiation.
Patients were hospitalized for hydration and antiemetic therapy during chemotherapy administration. No chemotherapy dose modifications were made irrespective of nadir blood counts or blood counts at the time of treatment, although the second course of chemotherapy was delayed until recovery if a neutropenic fever had developed. Peripheral intravenous catheters were used for drug administration. Megavoltage radiotherapy was generated by a 6-MV linear accelerator. Opposed lateral fields were generally used, with an electron beam boost administered to selected lymph node regions as indicated. There were no planned or toxicity-mandated breaks scheduled during the radiation therapy, and there were no toxicity-mandated delays in the administration of the second course of chemotherapy. Patients were monitored at least weekly during their therapy in an effort to manage treatment-induced adverse effects, particularly mucositis and myelosuppression. Neutropenia with fever resulted in mandatory hospitalization and appropriate antibiotic therapy. Hospitalization was also required when mucosal injury precluded an adequate oral intake. Percutaneous endoscopic gastrostomy feeding tubes or nasogastric feeding tubes were placed as needed. Tracheostomies were performed in patients with significantly compromised airways, either at presentation or, if required, during the course of their treatment. Between 6 and 12 weeks after completion of definitive chemoradiotherapy, a formal response analysis was undertaken. This assessment included an examination under anesthesia if clinically appropriate. A biopsy was performed if there was clinical evidence of residual tumor. Patients were not routinely biopsied to confirm the absence of tumor. A complete response required the disappearance of all clinical, radiographic, and, if applicable, pathologic evidence of disease. Any response that was less than complete and pathologically confirmed would result in appropriate surgical resection, if possible. Primary site resection was reserved for patients with histologically verified residual primary site disease after completion of chemoradiotherapy. Neck dissection was performed if clinical evidence of residual neck node disease was present after completion of nonoperative management. Neck dissection was also recommended for patients with N2-3 disease at presentation, irrespective of clinical response, and for patients undergoing primary site resection. Salvage surgery was recommended for all patients, if appropriate, for local or regional disease recurrence. Patients were observed by all members of the multidisciplinary team after completion of therapy. Careful clinical examination was performed at 2- to 3-month intervals, and any suspected local, regional, or distant recurrence underwent biopsy for confirmation. Chest x-rays were obtained yearly, and other radiographic studies were performed as clinically indicated. Aggressive attempts were made to obtain follow-up information on each patient, even when their follow-up care was provided at another institution. Survival times were calculated from the date radiation therapy was initiated, and the results were analyzed as of September 30, 2005. The Kaplan-Meier method was used to estimate the events of interest, including overall survival, freedom from recurrence, local control both with and without surgery, overall survival with organ preservation, regional control, and distant control. Except for the overall survival calculations, a patient was considered censored at death if the event in question had not occurred. The log-rank test was used to compare outcomes between subgroups. Cox proportional hazards analysis was used to identify multivariable risk factors for distant metastatic failure. The following 13 variables were considered in the analysis: age, race, sex, performance status, treatment on or off study, number of chemotherapy courses, radiation therapy schedule, primary site, planned neck dissection, tumor stage, nodal stage, overall stage, and tumor differentiation. A stepwise selection procedure was used with a variable entry criterion of P < .10 and a variable retention criterion of P < .05. All analyses were performed with SAS software (SAS Institute, Cary, NC). All statistical tests were two sided, and P < .05 was used to indicate statistical significance.
Between November 1, 1989 and September 30, 2002, 222 patients with locoregionally advanced squamous cell head and neck cancer were entered onto our IRB-approved Head and Neck Cancer Chemoradiotherapy Tumor Registry and were treated with multiagent concurrent chemoradiotherapy regimen. One hundred sixteen of these patients were formally consented and enrolled onto one of several IRB-approved clinical trials. One hundred six patients were treated off study. These two patients groups are analyzed both separately and together. The reasons for treating patients off study varied depending on the clinical trial open at the time of patient presentation. Overall, 59 of the 106 off-study patients were ineligible for the clinical trial available, mostly because of disease extent or multiple, unknown, or previous primary malignancies. No trial was open at the time of presentation for 33 of the off-study patients, and 14 patients specifically declined participation in the hyperfractionated study because of logistic concerns. It should be noted that, although our initial phase III study was restricted to patients with resectable disease,3 it soon became apparent that the definition of resectable versus unresectable was, for us, subjective and largely irrelevant. We no longer use these terms in our eligibility requirements and, instead, consider this chemoradiotherapeutic approach in all appropriate patients with locoregionally advanced disease, irrespective of technical resectability. Indeed, our phase II hyperfractionated trial was designed for patients with advanced locoregional tumors, many of whom were not resectable at presentation.15 The clinical characteristics of these 222 patients and their tumors are listed in Table 1. Patients were predominately white males. Fifty-two percent of patients had primary tumor sites in the oropharynx. The 13 patients with oral cavity tumors had advanced lesions that were not easily amenable to surgical extirpation without major deformity or dysfunction. Patients ranged in age from 14 to 77 years, with a median age of 58 years. There were seven stage II patients (3.2%; who would have required a laryngectomy for surgical control), 36 stage III patients (16.2%), and 179 stage IV patients (80.6%). No significant differences were noted between the on-study and the off-study patients for any of these characteristics except for stage, which was statistically less advanced in patients treated off study (P = .013).
Tumor and lymph node distribution is presented in Table 2 and is broken down by whether patients were treated on or off study. Among the N2 patients, 24 had N2a disease, 38 had N2b disease, and 45 had N2c disease. Patients treated off study had significantly earlier tumor (P = .005) and earlier nodal (P = .007) stages than the on-study patients. The six patients with unknown or multiple primary sites are not included in Table 2.
Radiation therapy was administered once daily in 133 patients (59.9%) and twice daily in 89 patients (40.1%). Off-study patients were more likely to be treated once daily than patients treated on trial (P < .001). All but nine of these patients (4.1%) received both courses of concurrent chemotherapy. Toxicity from this chemotherapy and radiation therapy regimen was formidable and has been previously described in detail.3,14,15 One hundred seventy-four of these patients (78.4%) required a feeding tube for nutritional support. There was only one toxic death during treatment, which occurred in a patient who developed a pulmonary embolism. This patient cohort has now been observed for a median of 73 months (range, 18 to 185 months). There has been no disease recurrence in 166 patients (74.8%), and 122 patients (55.0%) are alive. Death resulted from the index head and neck cancer in 46 patients (20.7%), from a second primary malignancy in 23 patients (10.4%), and from an unrelated medical problem while clinically cancer free in 31 patients (14.0%). The 5-year projected freedom from recurrence rate is 74.0% (Fig 2), and the 5-year projected overall survival rate is 65.7% (Fig 3). No statistically meaningful difference can be identified in survival or freedom from recurrence when analyzed by primary site, tumor stage, nodal stage, overall stage, tumor differentiation, or radiation therapy administration schedule. However, the projected 5-year survival rate was significantly better in the off-study patients compared with on-study patients (73.1% v 58.9%, respectively; P = .02) and in patients with a performance status of 0 compared with greater than 0 (70.2% v 57.8%, respectively; P = .01). It should be pointed out that none of the seven patients with stage II disease have developed recurrent cancer.
The development of a second primary malignancy was not considered as an event in calculating the freedom from recurrence, and a distinct subsequent malignancy was felt to have occurred in 35 of the 222 patients. However, it is recognized that the distinction between a second primary malignancy and a recurrence or an isolated metastasis can, at times, be subtle, particularly because the second malignancy arose in the upper aerodigestive tract in 28 (80%) of these 35 patients. These patients are the subject of a separate report.17
Local Control
Local control was also assessed by calculating the overall survival with organ preservation (Fig 4). Both death and local failure (before any surgical salvage) were considered events for this calculation. Table 3 lists the 3- and 5-year projected overall survival rates with organ preservation, which were better in patients treated off-study and in patients with a performance status of 0 compared with greater than 0 (5-year estimate, 66.8% v 54.0%, respectively; P = .008). Overall survival rates with organ preservation were not predicted by tumor differentiation, nodal status, overall stage, radiation therapy schedule, or primary site. Overall survival with organ preservation was also more likely in patients with earlier tumor stage (5-year estimates for T1, T2, T3, and T4: 87.0%, 66.4%, 60.3%, and 55.2%, respectively; P = .043).
If primary site resection was required, it proved to be highly successful. The overall local control rate (including patients undergoing primary site resection) was 92.4% at both 3 and 5 years. Local control could not be established or maintained in only 16 of the 222 patients.
Regional Control Regional recurrence later developed in 18 patients (in seven despite the planned neck dissection and in 11 who had not undergone initial neck surgery). Regional recurrence was isolated in seven of these patients, but local recurrence had also developed in six patients, and distant recurrence had also developed in five patients. Regional control is an end point that considers any regional recurrence after initial regional management as an event and censors patients who die without regional recurrence. The 3- and 5-year projected regional control rate is 92.4% (Table 3) and could not be predicted by tumor stage, overall stage, primary site, tumor differentiation, performance status, or radiation therapy administration schedule. Not surprisingly, regional control was better for patients with N0-1 disease versus N2-3 disease at presentation (5-year estimates, 97.1% v 90.0%, respectively; P = .041) and for patients treated off study. As can be seen from Figure 5, among the 149 N2-3 patients, regional control at 5 years was significantly inferior in the 49 patients not undergoing neck surgery compared with the 100 patients who did undergo neck surgery (82.0% v 93.9%, respectively; P = .028). Salvage neck dissection did not prove to be successful often. Only one of the seven patients with isolated regional recurrence and only two of the six patients with both local and regional recurrence achieved successful regional control after surgery.
Distant Control The control of distant metastases as the site of first recurrence was analyzed by calculating the distant metastatic control rate, a function in which the event of interest is distant disease recurrence. Patients dying with distant control or experiencing local or regional relapse with distant control were censored in this calculation. Distant metastases developed in 29 (13.1%) of the 222 patients. All but one patient (who underwent a pulmonary metastatectomy) have died. The 3- and 5-year projected distant metastatic control rates are listed in Table 3. Distant disease control did not correlate with tumor stage, nodal stage, overall stage, performance status, treatment off study, or radiotherapy schedule. However, distant disease control did correlate with primary site, with 5-year projected distant metastatic disease control rates for patients with primary sites in the oral cavity, oropharynx, larynx, and hypopharynx of 92.3%, 90.4%, 84.4%, and 70.6%, respectively (P = .038). Distant metastatic disease control also correlated with tumor differentiation. The 5-year distant metastatic disease control rate for patients with moderately to well-differentiated tumors was 88.5%, but it was only 78.8% for patients with poorly differentiated tumors (P = .045). Using a multivariable Cox proportional hazards analysis, it was apparent that both hypopharyngeal primary site and poorly differentiated histology were independent predictors for the development of distant metastases (Table 4).
When both local control without surgery and distant control are plotted on the same graph, one can see a reversal of the usual pattern of failure for this disease (Fig 6). Local persistence or recurrence after chemoradiotherapy alone is a less common cause for treatment failure than distant metastases in this patient cohort.
This long-term follow-up analysis confirms the durability of results previously reported from our institution and suggests that late relapse is infrequent after multiagent concurrent chemoradiotherapy. With a 5-year overall survival rate of 65.7% and a 5-year survival rate with organ preservation of 62.2%, we now consider almost all patients with locoregionally confined squamous cell head and neck cancer to be potentially curable without the need for primary site resection. However, this observation must be tempered by the scarcity of data regarding the long-term functional outcomes of patients treated in this fashion. Although the on-study and off-study patient cohorts differed in both their clinical characteristics and outcomes, these differences reflected the eligibility criteria of the clinical trial open at the time of patient presentation. Since 1995, we have adopted concurrent chemoradiotherapy as a standard of care for patients with stage III to IV disease. With the demonstration of benefit from altered fractionation radiation therapy schedules,20,21 our recent investigative interest has focused on the use of hyperfractionated radiation in conjunction with chemotherapy. However, this approach has generally been restricted to patients with more advanced disease. It is not surprising that our off-study patients had earlier-staged tumors and were more likely to experience better outcomes. They were also more likely to have been irradiated once daily. Therefore, it is also not surprising that the patients treated with the more aggressive hyperfractionated regimens, who had more advanced tumors in general, did not experience the expected improved outcomes. However, it must be recognized that this patient cohort did not include patients presenting with extensive bone or cartilage involvement. In general, definitive chemoradiotherapy was also not considered appropriate for patients with extensive organ destruction at the time of diagnosis. Such patients are unlikely to experience organ-function preservation after chemoradiotherapy and are often better managed with an initial surgical approach. For example, it is difficult to justify an attempt at laryngeal preservation in a patient with a destroyed larynx at presentation, particularly if organ-preservation therapy may result in compromised deglutition. Our continued attention to appropriate patient selection reflects concern about both acute and late morbidity from this treatment regimen, and we have previously presented data reviewing several aspects of this problem.22-25 Close surgical follow-up both during and after definitive chemoradiotherapy is extremely important. Active and aggressive surgical evaluation is necessary to identify patients with early local recurrence. Our ability to achieve a local control rate of 92.4% after surgical salvage therapy attests to the importance of this ongoing surgical involvement. Similarly, the importance of the planned neck dissection must be stressed. The neck remains difficult to adequately evaluate after chemoradiotherapy. Neck nodes may disappear clinically and yet contain residual microscopic tumor. Fibrosis and edema after chemoradiotherapy make clinical examination difficult. Our results18,19 and results from other centers26,27 continue to suggest a role for planned neck dissection in patients with advanced neck node involvement at diagnosis. The impact of positron emission tomography scanning on our ability to evaluate neck node disease after chemoradiotherapy requires further study. The acute toxicity of this and other multiagent chemoradiotherapy regimens is significant.3-6,14,15 Aggressive supportive care by an experienced management team is critical. Our patients were vigorously supported nutritionally, and feeding tubes were required in most patients. As we have previously reported, 8% and 6% of patients remained dependent on feeding tubes at 12 and 24 months, respectively.24 However, at 24 months, 91% of our patients were eating a normal or near-normal diet. Delayed feeding tube placement (after 24 months) was required in only two patients (1%). The importance of pain control, early antibiotic therapy for neutropenic fever, and dental, mouth, and skin hygiene cannot be overstated. It must also be recognized that the Cleveland Clinic Foundation is a tertiary referral center and that patients often travel significant distances for the specialized care provided at this institution. This patient population may not be typical of patients with squamous cell head and neck cancer in general. It is quite likely that patients treated at our institution represent patients with a better socioeconomic status or lesser degrees of comorbidity and, therefore, a better prognosis. An analysis by the University of Chicago group indicating that the greater distances traveled for treatment of their disease were associated with better survival would support this impression.28 Furthermore, our patient population is quite heterogeneous and includes patients with both resectable and far-advanced locoregional tumors, who were treated both on and off clinical trial. The commonality of their treatment and the encouraging overall results justify consolidating this experience for this report. As others have noted, the patterns of failure for patients with squamous cell head and neck cancer have changed.29,30 Historically, local and/or regional failure have been the major problems in disease control. However, locoregional control after chemoradiotherapy is excellent, and distant metastases have now emerged as the most common cause of treatment failure. This suggests the need to pursue better systemic treatments. Although our results are encouraging, they represent the work of a single treatment center and do not demonstrate superiority of this treatment regimen over single-agent cisplatin chemoradiotherapy regimens. Similarly, concurrent chemoradiotherapy has not been tested directly against initial surgery-based approaches. We still consider surgery to be an important part of patient management, and it is our first choice for patients with readily resectable oral cavity tumors or extensive laryngeal or other neoplasms with bone or cartilage involvement. Nonetheless, these results do suggest that significant progress has been made in the management of this disease. Directions for future investigation should include attempts to reduce the incidence of distant metastases. The lack of correlation between distant metastases and initial disease extent (tumor, node, and stage) was striking and suggests a need to identify better clinical or molecular predictors for this event. The use of induction chemotherapy followed by concurrent chemoradiotherapy and the role of targeted treatments also require further study. Having achieved better disease control, reducing both acute and late treatment-related morbidity becomes a critical issue in the management of these patients. Careful measurements of both quality of life and specific functional outcomes are now a part of most large ongoing clinical trials. Ideally, we would hope to better identify those patients who will not benefit from chemoradiotherapy and who should first undergo surgical resection. Similarly, it is important that we identify better predictors of regional control so that neck dissection can be avoided in patients achieving disease control in the neck after chemoradiotherapy alone. Concurrent multiagent chemoradiotherapy can result in organ preservation and cure in the majority of patients with locoregionally advanced, nonmetastatic squamous cell head and neck cancer. Toxicity is formidable but manageable with an experienced clinical team, and close surgical follow-up remains critical. Distant metastatic disease is the most common cause of treatment failure in this series.
The authors indicated no potential conflicts of interest.
Presented in part at the 6th International Conference on Head and Neck Cancer, Washington, DC, August 7-11, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Forastiere A, Koch W, Trotti A, et al: Head and neck cancer. N Engl J Med 345:1890-1900, 2001 2. Cohen EEW, Lingen MW, Vokes EE: The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 22:1743-1752, 2004 3. Adelstein DJ, Saxton JP, Lavertu P, et al: A phase II randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: Preliminary results. Head Neck 19:567-575, 1997[CrossRef][Medline] 4. 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 338:1798-1804, 1998 5. 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 22:69-76, 2004 6. Staar S, Rudat V, Stuetzer H, et al: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy: Results of a multicentric randomized German trial in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 50:1161-1171, 2001[CrossRef][Medline] 7. 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. Lancet 355:949-955, 2000[Medline] 8. El-Sayed S, Nelson N: Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 14:838-847, 1996 9. Al-Sarraf M, LeBlanc M, Shanker Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-1317, 1998 10. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003 11. 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 21:92-98, 2003 12. 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 350:1945-1952, 2004 13. 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 350:1937-1944, 2004 14. Lavertu P, Adelstein DJ, Saxton JP, et al: Aggressive concurrent chemoradiotherapy for squamous cell head and neck cancer: A 8-year single-institution experience. Arch Otolaryngol Head Neck Surg 125:142-148, 1999 15. 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 Oncol 20:1405-1410, 2002 16. American Joint Committee on Cancer: Manual for Staging of Cancer (eds 3, 4, 5). Philadelphia, PA, J.B. Lippincott Co, 1988, 1992, 1997 17. Tso E, Adelstein DJ, Rybicki LA, et al: Is the second primary malignancy an important competing cause of death in patients with squamous cell head and neck cancer? J Clin Oncol 22:492, 2004 (suppl, abstr 5516) 18. Lavertu P, Adelstein DJ, Saxton JP, et al: Management of the neck in a randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer. Head Neck 19:559-566, 1997[CrossRef][Medline] 19. McHam SA, Adelstein DJ, Rybicki LA, et al: Who merits a neck dissection after definitive chemoradiotherapy for N2–N3 squamous cell head and neck cancer? Head Neck 25:791-798, 2003[CrossRef][Medline] 20. Ang KK: Altered fractionation trials in head and neck cancer. Semin Radiat Oncol 8:230-236, 1998[CrossRef][Medline] 21. 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 48:7-16, 2000[CrossRef][Medline] 22. Mekhail TM, Adelstein DJ, Rybicki LA, et al: Enteral nutrition during the treatment of head and neck carcinoma. Cancer 91:1785-1790, 2001[Medline] 23. Mercado G, Adelstein DJ, Saxton JP, et al: Hypothyroidism: A frequent event after radiotherapy and after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer 92:2892-2897, 2001[CrossRef][Medline] 24. Akst LM, Chan J, Elson P, et al: Functional outcomes following chemoradiotherapy for head and neck cancer. Otolaryngol Head Neck Surg 131:950-957, 2004[Medline] 25. Lee WT, Akst LM, Adelstein DJ, et al: Risk factors for hypopharyngeal/upper esophageal stricture formation after concurrent chemoradiation. Presented at the 6th International Conference on Head and Neck Cancer, Washington, DC, August 7-11, 2004 26. Stenson KM, Haraf DJ, Pelzer H, et al: The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: The feasibility of selective neck dissection. Arch Otolaryngol Head Neck Surg 126:950-956, 2000 27. Brizel DM, Prosnitz RG, Hunter S, et al: Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 58:1418-1423, 2004[CrossRef][Medline] 28. Lamont EB, Hayreh D, Pickett KE, et al: Is patient travel distance associated with survival on phase II clinical trials in oncology? J Natl Cancer Inst 95:1370-1375, 2003 29. Vokes EE, Kies MS, Haraf DJ, et al: Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 18:1652-1661, 2000 30. Machtay M, Rosenthal DI, Hershock D, et al: Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: A University of Pennsylvania phase II trial. J Clin Oncol 20:3964-3971, 2002 Submitted February 16, 2005; accepted November 9, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
