The use of radiotherapy and concurrent chemotherapy has been explored in the management of squamous cell head and neck cancer for more than 3 decades. Even the earliest phase II and phase III studies, which used conventional radiotherapy and single-agent chemotherapy with drugs such as fluorouracil, bleomycin, and cisplatin, suggested a survival benefit from this approach. Validation of concurrent chemoradiotherapy as a community standard occurred in 1996, with the initial report from INT 0099, a randomized trial comparing radiotherapy alone with concurrent radiation and single-agent cisplatin, followed by adjuvant fluorouracil and cisplatin in patients with advanced nasopharyngeal cancer (1Al-Sarraf M. LeBlanc M. Shankar Giri P.G. et al.Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099.J Clin Oncol. 1998; 16: 1310-1317Crossref PubMed Scopus (1826) Google Scholar). This study, subsequently published in 1998, demonstrated a highly significant progression-free and overall survival advantage for patients treated with the combined-modality regimen, and this regimen was rapidly accepted as a standard of care for advanced nasopharyngeal cancer.Also in 1998 came a report from a large meta-analysis of updated, individual data assessing the role of chemotherapy in squamous cell head and neck cancer (2Pignon J.P. 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. 2000; 355: 949-955Abstract Full Text Full Text PDF PubMed Scopus (2202) Google Scholar). Patients from randomized trials conducted between 1965 and 1993 were included. This analysis, subsequently published in 2000, reviewed results from 63 separate trials involving 10,741 patients, comparing locoregional treatment with or without chemotherapy. Although no overall survival benefit was seen for treatment schedules using either induction or adjuvant chemotherapy, a highly significant survival benefit was identified for concomitant chemotherapy and radiation. A hazard ratio of 0.81 (95% Confidence Interval (CI), 0.76–0.88) with a p value of <0.0001 and an 8% 5-year survival benefit was observed, even from these older studies. Although oropharynx cancer often predominated in these clinical trials, they were, in general, not site specific. Nonetheless, this meta-analysis further justified the use of concurrent chemoradiotherapy as a standard nonoperative treatment for this disease.Results from a North American Intergroup trial of chemoradiotherapy in patients with unresectable head-and-neck tumors were first presented in 2000 and were published in 2003 (3Adelstein D.J. Li Y. Adams G.L. 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: 92-98Crossref PubMed Scopus (1347) Google Scholar). This study compared radiotherapy alone with radiotherapy and single-agent cisplatin and a third arm using a split course of radiotherapy and concurrent combination fluorouracil and cisplatin. As seen in nasopharynx cancer, the concurrent chemoradiotherapy arm using single-agent cisplatin proved superior to radiotherapy alone, with a projected 3-year survival improvement from 23% to 37% and a median survival improvement from 12.6 to 19.1 months (p = 0.014). The third treatment arm, which used a split course of radiotherapy, did not prove to be statistically different from the other two arms, an observation attributed to the scheduled break in radiotherapy delivery on this arm of the trial. This Intergroup study firmly established concurrent chemoradiotherapy with single-agent cisplatin as a treatment standard for unresectable head and neck cancer. Although it was not a site-specific study, primary tumors in the oropharynx predominated in the study population.During this same period, several other smaller single- and multi-institution trials were also published, comparing various combinations of concurrent chemotherapy and radiotherapy with radiotherapy alone as definitive treatment for this disease. In general, they were also not site-specific studies. The results, however, were very consistent. The addition of concurrent chemotherapy to radiotherapy reproducibly improved both survival and locoregional control.In 2001 and 2002, results were first made available from two large and very similar multi-institutional trials from the North American Intergroup/Radiation Therapy Oncology Group (RTOG) (4Cooper J.S. Pajak T.F. Forastiere A.A. et al.Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.N Engl J Med. 2004; 350: 1937-1944Crossref PubMed Scopus (2331) Google Scholar) and from the European Organization for Research and Treatment of Cancer (EORTC) (5Bernier 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: 1945-1952Crossref PubMed Scopus (2253) Google Scholar), comparing postoperative radiotherapy with postoperative radiation and concurrent single-agent cisplatin in high-risk patients after surgical resection. Both of these trials were published in 2004 and reported similar results. The addition of concurrent cisplatin to postoperative radiation improved both the disease-free survival and locoregional control. Overall survival was statistically better after chemoradiotherapy in the EORTC study, which had the longer reported follow-up. Although a trend toward overall survival prolongation after chemoradiotherapy was observed in the Intergroup/RTOG study, it did not reach statistical significance.Thus, over the past decade, a strong consensus has emerged, from multiple large, multi-institutional phase III trials, in support of the concept that radiation and concurrent platin-based chemotherapy is superior to radiotherapy alone and is a standard of care in the management of nasopharyngeal cancer and in the primary management of head-and-neck cancer in patients undergoing definitive nonoperative therapy, particularly for unresectable disease. Concurrent chemotherapy and radiation has also become a treatment standard for high-risk patients in the postoperative setting.Although site-specific standards have been established for the use of chemoradiotherapy in nasopharyngeal cancer and in larynx cancer, there have been relatively few site-specific studies conducted in North America for other head-and-neck subsites, such as hypopharynx or oropharynx. Three oropharynx-specific studies have been published from Europe, however, and all report a consistent benefit (Table 1) (6Calais 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 Inst. 1999; 91: 2081-2086Crossref PubMed Scopus (956) Google Scholar, 7Staar 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. 2001; 50: 1161-1171Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar, 8Bensadoun R.J. 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: 983-994Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar).Table 1Phase III randomized trials comparing radiotherapy with concurrent chemoradiotherapy in squamous cell oropharynx cancerFirst author (reference)YearNo. of eligible patientsChemotherapyRadiation (Gy)Survival: radiation vs. chemoradiationpCalais 6Calais 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 Inst. 1999; 91: 2081-2086Crossref PubMed Scopus (956) Google Scholar1999222CpF7031% vs. 51% (3 y)0.02Staar 7Staar 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. 2001; 50: 1161-1171Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar2001178∗Planned subset analysis.CpF69.9†Altered fractionation radiation.57% vs. 68% (1 y)0.05Bensadoun 8Bensadoun R.J. 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: 983-994Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar2006123∗Planned subset analysis.PF80.4†Altered fractionation radiation.22% vs. 41% (2 y)0.04Abbreviations: Cp = carboplatin; F = fluorouracil; P = cisplatin.∗ Planned subset analysis.† Altered fractionation radiation. Open table in a new tab Although the results from these three studies vary considerably, this variability can be accounted for by differences in patient entry criteria. The impact from the addition of concurrent chemotherapy is apparent in all trials, and the adoption of this approach as a treatment standard is supported by both site-specific and non–site-specific evidence.It should be pointed out, however, that no statement can be made about the superiority of concurrent chemoradiotherapy when compared with primary surgical therapy. Decisions about whether an operative or nonoperative approach will be taken for a head and neck cancer often depend on the expected functional deficits resulting from the intervention and on local expertise. Recent trends in the management of oropharynx cancer have favored definitive radiotherapy-based treatment, given the significant functional deficits often resulting from surgical resection of large base-of-tongue or tonsillar primary lesions. Whether the overall survival and treatment-related morbidity of these radiation-based approaches is equivalent to that achieved after surgery and postoperative therapy is unknown. It remains an important question requiring resolution, particularly for those oropharynx cancer patients with smaller primary tumors.Although the results from multiple trials of concurrent chemoradiotherapy have been highly reproducible and have allowed the establishment of evidence-based treatment standards for this disease, several questions have emerged. These questions form the focus of much of the current research agenda in the treatment of this disease (Table 2).Table 2Concurrent chemoradiotherapy in head and neck cancer: unanswered questions1. Can we identify those patients most likely to benefit from this treatment approach?2. Is single-agent cisplatin the optimal concurrent chemotherapy regimen?3. With better locoregional control, is there a role for the reintroduction of induction chemotherapy in an effort to decrease distant metastases?4. How do we integrate targeted therapies into these concurrent chemoradiotherapy programs?5. How can we reduce and manage both the acute and the consequential late toxicities of concurrent chemoradiotherapy? Open table in a new tab Most of the clinical trials using chemoradiotherapy have been performed in patients with advanced Stage III or IV disease. The first question of concern is whether this kind of aggressive and toxic treatment is necessary, or even justifiable, in all patients with advanced disease. Are there clinical or biologic markers that might help us identify those most likely to benefit from this approach and those who might be better served with other treatment?A second question is whether single-agent cisplatin represents the optimal concurrent chemotherapeutic choice. Although the Intergroup nasopharynx study (1Al-Sarraf M. LeBlanc M. Shankar Giri P.G. et al.Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099.J Clin Oncol. 1998; 16: 1310-1317Crossref PubMed Scopus (1826) Google Scholar), the Intergroup unresectable study (3Adelstein D.J. Li Y. Adams G.L. 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: 92-98Crossref PubMed Scopus (1347) Google Scholar), the two postoperative adjuvant trials (4Cooper J.S. Pajak T.F. Forastiere A.A. et al.Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.N Engl J Med. 2004; 350: 1937-1944Crossref PubMed Scopus (2331) Google Scholar, 5Bernier 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: 1945-1952Crossref PubMed Scopus (2253) Google Scholar), and even RTOG 91-11, the Intergroup larynx preservation study (9Forastiere A.A. Goepfert H. Maor M. et al.Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer.N Engl J Med. 2003; 349: 2091-2098Crossref PubMed Scopus (2389) Google Scholar), used concurrent single-agent cisplatin, it is rare in medical oncology for single-agent chemotherapy to be the most effective regimen. Many other studies have been reported, including the three site-specific oropharynx cancer trials that have combined a platin with fluorouracil or with other agents. Further investigation of this question is in order in an effort to optimize the impact of chemotherapy, particularly on distant metastases.This question of distant metastases is, in fact, emerging as a larger problem. With effective concurrent chemoradiotherapy and the resulting improvement in locoregional control, distant metastases have become a more common cause for treatment failure. Extensive previous testing of sequential induction chemotherapy regimens followed by definitive management has failed to demonstrate an improvement in overall survival. An observation frequently made in studies of this approach, however, was that distant metastases were reduced. The question has therefore been raised as to whether there is a role for the reintroduction of induction chemotherapy before definitive concurrent chemoradiotherapy, in an effort to reduce this problem of distant metastases. Several Phase III trials are now underway attempting to address this question. Recent work has also suggested that the three-drug combination of cisplatin, fluorouracil, and a taxane is superior to the well-studied cisplatin and fluorouracil doublet, and this three-drug combination has been chosen as the induction regimen for these newer randomized studies.Targeted therapies have generated excitement in the management of many of the solid tumors, including squamous cell head-and-neck cancer. Several agents targeting the epidermal growth factor receptor have been demonstrated to have activity in patients with relapsed or refractory disease. A randomized trial reported in 2006 explored the use of definitive radiation and concurrent cetuximab (a monoclonal antibody directed against the epidermal growth factor receptor), compared with radiotherapy alone (10Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4120) Google Scholar). A clear progression-free and overall survival benefit was observed from the addition of the cetuximab. A major question for future investigation is how best to incorporate this, or other targeted agents, into multi-modality treatment programs that build on the success achieved with concurrent chemoradiotherapy.Finally, it is well recognized that these concurrent chemoradiotherapy schedules produce significant toxicity, far in excess of that observed from single-modality chemotherapy or radiotherapy alone. Supportive care measures have greatly improved, however, and have allowed the administration of these difficult treatment regimens. Efforts to reduce the significant short-term toxicity and, more importantly, ameliorate the consequential late effects and functional impairments resulting from these approaches, are critical to further improving this treatment. The use of radiotherapy and concurrent chemotherapy has been explored in the management of squamous cell head and neck cancer for more than 3 decades. Even the earliest phase II and phase III studies, which used conventional radiotherapy and single-agent chemotherapy with drugs such as fluorouracil, bleomycin, and cisplatin, suggested a survival benefit from this approach. Validation of concurrent chemoradiotherapy as a community standard occurred in 1996, with the initial report from INT 0099, a randomized trial comparing radiotherapy alone with concurrent radiation and single-agent cisplatin, followed by adjuvant fluorouracil and cisplatin in patients with advanced nasopharyngeal cancer (1Al-Sarraf M. LeBlanc M. Shankar Giri P.G. et al.Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099.J Clin Oncol. 1998; 16: 1310-1317Crossref PubMed Scopus (1826) Google Scholar). This study, subsequently published in 1998, demonstrated a highly significant progression-free and overall survival advantage for patients treated with the combined-modality regimen, and this regimen was rapidly accepted as a standard of care for advanced nasopharyngeal cancer. Also in 1998 came a report from a large meta-analysis of updated, individual data assessing the role of chemotherapy in squamous cell head and neck cancer (2Pignon J.P. 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. 2000; 355: 949-955Abstract Full Text Full Text PDF PubMed Scopus (2202) Google Scholar). Patients from randomized trials conducted between 1965 and 1993 were included. This analysis, subsequently published in 2000, reviewed results from 63 separate trials involving 10,741 patients, comparing locoregional treatment with or without chemotherapy. Although no overall survival benefit was seen for treatment schedules using either induction or adjuvant chemotherapy, a highly significant survival benefit was identified for concomitant chemotherapy and radiation. A hazard ratio of 0.81 (95% Confidence Interval (CI), 0.76–0.88) with a p value of <0.0001 and an 8% 5-year survival benefit was observed, even from these older studies. Although oropharynx cancer often predominated in these clinical trials, they were, in general, not site specific. Nonetheless, this meta-analysis further justified the use of concurrent chemoradiotherapy as a standard nonoperative treatment for this disease. Results from a North American Intergroup trial of chemoradiotherapy in patients with unresectable head-and-neck tumors were first presented in 2000 and were published in 2003 (3Adelstein D.J. Li Y. Adams G.L. 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: 92-98Crossref PubMed Scopus (1347) Google Scholar). This study compared radiotherapy alone with radiotherapy and single-agent cisplatin and a third arm using a split course of radiotherapy and concurrent combination fluorouracil and cisplatin. As seen in nasopharynx cancer, the concurrent chemoradiotherapy arm using single-agent cisplatin proved superior to radiotherapy alone, with a projected 3-year survival improvement from 23% to 37% and a median survival improvement from 12.6 to 19.1 months (p = 0.014). The third treatment arm, which used a split course of radiotherapy, did not prove to be statistically different from the other two arms, an observation attributed to the scheduled break in radiotherapy delivery on this arm of the trial. This Intergroup study firmly established concurrent chemoradiotherapy with single-agent cisplatin as a treatment standard for unresectable head and neck cancer. Although it was not a site-specific study, primary tumors in the oropharynx predominated in the study population. During this same period, several other smaller single- and multi-institution trials were also published, comparing various combinations of concurrent chemotherapy and radiotherapy with radiotherapy alone as definitive treatment for this disease. In general, they were also not site-specific studies. The results, however, were very consistent. The addition of concurrent chemotherapy to radiotherapy reproducibly improved both survival and locoregional control. In 2001 and 2002, results were first made available from two large and very similar multi-institutional trials from the North American Intergroup/Radiation Therapy Oncology Group (RTOG) (4Cooper J.S. Pajak T.F. Forastiere A.A. et al.Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.N Engl J Med. 2004; 350: 1937-1944Crossref PubMed Scopus (2331) Google Scholar) and from the European Organization for Research and Treatment of Cancer (EORTC) (5Bernier 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: 1945-1952Crossref PubMed Scopus (2253) Google Scholar), comparing postoperative radiotherapy with postoperative radiation and concurrent single-agent cisplatin in high-risk patients after surgical resection. Both of these trials were published in 2004 and reported similar results. The addition of concurrent cisplatin to postoperative radiation improved both the disease-free survival and locoregional control. Overall survival was statistically better after chemoradiotherapy in the EORTC study, which had the longer reported follow-up. Although a trend toward overall survival prolongation after chemoradiotherapy was observed in the Intergroup/RTOG study, it did not reach statistical significance. Thus, over the past decade, a strong consensus has emerged, from multiple large, multi-institutional phase III trials, in support of the concept that radiation and concurrent platin-based chemotherapy is superior to radiotherapy alone and is a standard of care in the management of nasopharyngeal cancer and in the primary management of head-and-neck cancer in patients undergoing definitive nonoperative therapy, particularly for unresectable disease. Concurrent chemotherapy and radiation has also become a treatment standard for high-risk patients in the postoperative setting. Although site-specific standards have been established for the use of chemoradiotherapy in nasopharyngeal cancer and in larynx cancer, there have been relatively few site-specific studies conducted in North America for other head-and-neck subsites, such as hypopharynx or oropharynx. Three oropharynx-specific studies have been published from Europe, however, and all report a consistent benefit (Table 1) (6Calais 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 Inst. 1999; 91: 2081-2086Crossref PubMed Scopus (956) Google Scholar, 7Staar 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. 2001; 50: 1161-1171Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar, 8Bensadoun R.J. 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: 983-994Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). Abbreviations: Cp = carboplatin; F = fluorouracil; P = cisplatin. Although the results from these three studies vary considerably, this variability can be accounted for by differences in patient entry criteria. The impact from the addition of concurrent chemotherapy is apparent in all trials, and the adoption of this approach as a treatment standard is supported by both site-specific and non–site-specific evidence. It should be pointed out, however, that no statement can be made about the superiority of concurrent chemoradiotherapy when compared with primary surgical therapy. Decisions about whether an operative or nonoperative approach will be taken for a head and neck cancer often depend on the expected functional deficits resulting from the intervention and on local expertise. Recent trends in the management of oropharynx cancer have favored definitive radiotherapy-based treatment, given the significant functional deficits often resulting from surgical resection of large base-of-tongue or tonsillar primary lesions. Whether the overall survival and treatment-related morbidity of these radiation-based approaches is equivalent to that achieved after surgery and postoperative therapy is unknown. It remains an important question requiring resolution, particularly for those oropharynx cancer patients with smaller primary tumors. Although the results from multiple trials of concurrent chemoradiotherapy have been highly reproducible and have allowed the establishment of evidence-based treatment standards for this disease, several questions have emerged. These questions form the focus of much of the current research agenda in the treatment of this disease (Table 2). Most of the clinical trials using chemoradiotherapy have been performed in patients with advanced Stage III or IV disease. The first question of concern is whether this kind of aggressive and toxic treatment is necessary, or even justifiable, in all patients with advanced disease. Are there clinical or biologic markers that might help us identify those most likely to benefit from this approach and those who might be better served with other treatment? A second question is whether single-agent cisplatin represents the optimal concurrent chemotherapeutic choice. Although the Intergroup nasopharynx study (1Al-Sarraf M. LeBlanc M. Shankar Giri P.G. et al.Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099.J Clin Oncol. 1998; 16: 1310-1317Crossref PubMed Scopus (1826) Google Scholar), the Intergroup unresectable study (3Adelstein D.J. Li Y. Adams G.L. 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: 92-98Crossref PubMed Scopus (1347) Google Scholar), the two postoperative adjuvant trials (4Cooper J.S. Pajak T.F. Forastiere A.A. et al.Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.N Engl J Med. 2004; 350: 1937-1944Crossref PubMed Scopus (2331) Google Scholar, 5Bernier 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: 1945-1952Crossref PubMed Scopus (2253) Google Scholar), and even RTOG 91-11, the Intergroup larynx preservation study (9Forastiere A.A. Goepfert H. Maor M. et al.Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer.N Engl J Med. 2003; 349: 2091-2098Crossref PubMed Scopus (2389) Google Scholar), used concurrent single-agent cisplatin, it is rare in medical oncology for single-agent chemotherapy to be the most effective regimen. Many other studies have been reported, including the three site-specific oropharynx cancer trials that have combined a platin with fluorouracil or with other agents. Further investigation of this question is in order in an effort to optimize the impact of chemotherapy, particularly on distant metastases. This question of distant metastases is, in fact, emerging as a larger problem. With effective concurrent chemoradiotherapy and the resulting improvement in locoregional control, distant metastases have become a more common cause for treatment failure. Extensive previous testing of sequential induction chemotherapy regimens followed by definitive management has failed to demonstrate an improvement in overall survival. An observation frequently made in studies of this approach, however, was that distant metastases were reduced. The question has therefore been raised as to whether there is a role for the reintroduction of induction chemotherapy before definitive concurrent chemoradiotherapy, in an effort to reduce this problem of distant metastases. Several Phase III trials are now underway attempting to address this question. Recent work has also suggested that the three-drug combination of cisplatin, fluorouracil, and a taxane is superior to the well-studied cisplatin and fluorouracil doublet, and this three-drug combination has been chosen as the induction regimen for these newer randomized studies. Targeted therapies have generated excitement in the management of many of the solid tumors, including squamous cell head-and-neck cancer. Several agents targeting the epidermal growth factor receptor have been demonstrated to have activity in patients with relapsed or refractory disease. A randomized trial reported in 2006 explored the use of definitive radiation and concurrent cetuximab (a monoclonal antibody directed against the epidermal growth factor receptor), compared with radiotherapy alone (10Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4120) Google Scholar). A clear progression-free and overall survival benefit was observed from the addition of the cetuximab. A major question for future investigation is how best to incorporate this, or other targeted agents, into multi-modality treatment programs that build on the success achieved with concurrent chemoradiotherapy. Finally, it is well recognized that these concurrent chemoradiotherapy schedules produce significant toxicity, far in excess of that observed from single-modality chemotherapy or radiotherapy alone. Supportive care measures have greatly improved, however, and have allowed the administration of these difficult treatment regimens. Efforts to reduce the significant short-term toxicity and, more importantly, ameliorate the consequential late effects and functional impairments resulting from these approaches, are critical to further improving this treatment.
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Nov 23, 2023
Juanita Crook 
Open Access