• 2/27/2006
  • East Lansing, MI
  • Barbara A. Conley
  • Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1023-1025

Treatment of advanced squamous cell cancers of the head and neck (HNSCC) can be a frustrating endeavor. Early diagnosis may be missed by delay on the part of patients or their physicians and dentists. Patients are often elderly and have multiple medical or social comorbidities. HNSCC is an interdisciplinary disease, with optimum management requiring the input of the medical, radiation, and surgical oncologist, as well as pathologist, dentist, speech pathologist, social worker, and a dedicated home caregiver. The necessary specialists for optimum management may not be present near the patient’s home, necessitating ad hoc clinical teams or further delay and dislocation of the patient and caregiver for an extended treatment period.

Numerous phase II and phase III studies have been performed with the hope of improving survival and preserving organ function in locally advanced disease. We now know that survival is improved by radiation administered concurrent with chemotherapy, but there are added toxicities.1 We also know that radiation with chemotherapy can result in survival that approximates the survival obtained by radical surgery followed by radiation therapy, especially if surgical salvage is performed at early signs of residual or recurrent disease.2,3 We know less about what the optimal radiation regimen or chemotherapy regimen should be for an individual patient.

Currently, standard therapy for locally advanced HNSCC could be radiation administered daily, twice daily, or in a concomitant boost regimen, with or without intensity-modulated radiation therapy, together with a platinum-based chemotherapy. When complete response is obtained, a planned neck dissection is often performed in those patients whose disease was at least N2 at presentation. If complete response is not obtained, resection of the primary and/or regional nodes is performed as is feasible. Standard care could also be surgery, followed by radiation therapy with or without concurrent chemotherapy. These modalities generally result in a 5-year survival rate of 20% to 65%, depending on stage and primary site. The choice of treatment is often dictated by the primary site, patient preferences (eg, organ preservation), and the experience of the treatment team.

Survival has slightly improved over that seen before 1990.4 Complete response and local control are generally high with combined-modality treatments. However, chemoradiotherapy is associated with severe acute toxicities, with approximately 80% of patients requiring a feeding tube during treatment. Late toxicities, such as loss of salivary function and soft tissue fibrosis, can lead to difficulty in speaking and eating. Over half of these patients are permanently disabled from work.5 Our goals must include not only improved survival but also reduction in morbidity.

The term unresectable is somewhat subjective and depends on the experiences of the treatment team, as noted in the article published in this issue by Adelstein et al.6 This review of the clinical experience of this consistent multidisciplinary team also notes the following: (1) some patients, notably those with oral cavity tumors, organ destruction, or bony involvement, are not considered for chemoradiotherapy therapy and are managed preferentially by surgery; (2) there was only one toxic death among 222 patients, although hospitalization was frequently required for hydration, antiemetics, and other supportive care; (3) local control, overall survival, and organ preservation could not be predicted by nodal status, stage, or primary site; (4) recurrence was more commonly distant than locoregional and correlated with hypopharyngeal primary site and poorly differentiated histology; and (5) 5-year projected survival rate was 65.7%, with a regional control rate of 92.4%. These data can be compared with a report from Brockstein et al7 of a series of trials carried out by this Chicago-based consortium. They noted that T and N stage independently predicted locoregional recurrence and overall survival, respectively, for patients treated with a regimen of concurrent chemoradiotherapy. In their series, the treating institution was also a significant factor for locoregional failure. Primary site was not investigated as a potentially significant prognostic factor. Overall 5-year survival rate was 47%. Hitt et al8 have published a phase III multicenter trial comparing induction regimens of cisplatin and fluorouracil with or without paclitaxel followed by chemoradiotherapy in responders and have found that the triple chemotherapy resulted in higher complete response rates but only improved overall survival in the group with unresectable disease.

As mentioned in the article by Adelstein et al6 in this issue, there may be selection bias in a referral center, with patients referred only if they have exceptional performance status. Note that in this report, the 5-year projected survival rate is 65.7%, whereas in the chemoradiotherapy arm of the intergroup trial comparing standard radiation and two schedules of concurrent chemoradiotherapy in patients with unresectable HNSCC, the 3-year projected survival rate for the best arm, cisplatin concurrent with radiation, is 37%.9 In the multicenter study by Hitt et al,8 the projected 5-year survival rate of the best arm is 45% to 50%.

Adelstein et al6 found that stage alone is not a predictor for efficacy of combined-modality treatment. As in other malignancies, analysis of the molecular characteristics of HNSCC has been undertaken to search for better prognostic and/or predictive factors, as well as for new therapeutic targets.

Epidermal growth factor receptor (EGFR) is overexpressed in the majority of HNSCC, and its expression has been noted as a prognostic factor for response in both radiation and chemoradiotherapy. Pivot et al10 found that lower EGFR levels predicted better disease-free interval in patients with laryngeal and hypopharyngeal cancers treated with induction chemotherapy followed by radiation. Hitt et al11 reported similar findings in their study of induction chemotherapy followed by chemoradiotherapy. Ang et al,12,13 using tissue samples from a phase III Radiation Therapy Oncology Group trial of radiation alone, noted that EGFR expression was a significant adverse prognostic factor for locoregional control and survival for patients treated with radiation. Recently, lower EGFR expression seemed to be predictive for response to cetuximab in relapsed HNSCC.14 Given these data and the favorable data on toxicity with the combination of cetuximab with radiation or chemotherapy,14-17 proceeding with a combination of radiation, chemotherapy, and cetuximab is a logical next step. However, Pfister et al18 have reported in this issue that cetuximab combined with cisplatin concurrent with concomitant boost radiation was too toxic to recommend at this time. There is some doubt that the two grade 5 toxicities and three other serious adverse effects seen were a result of the treatment. There was one fatal pneumonia, one bacteremia (in a patient with a port), one myocardial infarction, one atrial fibrillation, and one death from unknown cause among the 22 enrolled patients. Although a death rate of two of 22 patients is clearly of concern, the decision to stop the trial was difficult because any of these events could have occurred despite the chemoradiotherapy treatment. A phase I trial was not performed for this combination, but with the typical dose-escalation schema in a small number of patients (three to five per cohort), these events may not have been discerned. Serum concentrations of cetuximab had no correlation with toxicity. Cisplatin has been reported not to impact the pharmacokinetics of cetuximab.19 Although serum concentrations of cisplatin were not measured, the reported toxicities were not typical for cisplatin. Unfortunately, a safe and convenient method to assess impact of drug(s) or radiation on potential targets does not presently exist. For further elucidation, we await results from other trials of cetuximab with chemoradiotherapy.

To minimize toxicity and improve efficacy in HNSCC, we need to redouble our efforts to find appropriate predictive and prognostic features that can be used to choose and modify the treatment given. With more than 80% of patients experiencing severe toxicity with current regimens, as well as enduring long-term effects from treatment, relapse, or metastasis, we clearly need to investigate agents directed to biologic targets of this disease and to enter patients onto trials on the basis of molecular or other characteristics that optimize the chance for success.

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