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EDITORIALS |
From the Division of Otolaryngology, Southern Illinois University, Springfield, Illinois.
Correspondence: Address correspondence to: K. Thomas Robbins, MD, Division of Otolaryngology, Southern Illinois University, PO Box 19638, Springfield, IL 62794-9638; Fax: 217-565-0253; E-mail: ktrgew{at}aol.com
In the treatment of advanced head and neck cancer, the chemotherapy era began more than three decades ago. The trends or phases throughout this era can be characterized by what agents, combinations of agents and modalities (surgery, radiotherapy, and chemotherapy), and sequencing of the modalities have been explored. Always with the hope of finding a better regimen to improve survival and preserve organ function, the ongoing chemotherapy era represents a time of intense interest and investigations for this disease. As part of this wave, Loré and colleagues1 have pursued the pathway of sequential chemosurgery. In this issue they report on the experience spanning 20 years during which patients with locally advanced squamous cell carcinoma of the head and neck underwent sequential chemosurgery. Although the overarching goal was to improve survival, the strategy also presented an opportunity to avoid postoperative radiotherapy in many patients. At initial presentation, all patients had disease that could have been treated by primary surgery. Following the induction chemotherapy consisting of cisplatin/bleomycin (regimen A, early phase) or cisplatin/5-flurouracil (regimen B, later phase), all patients had surgery irrespective of the degree of response to induction chemotherapy. Testing the efficacy of this approach and determining if chemotherapy could be substituted for radiotherapy was a worthwhile endeavor.
Based on the assumption that survival is the most important outcome for a therapeutic trial, the results are impressive. With a median follow-up of 7.6 years, the 5-year absolute survival rate for the total group of 82 patients was a respectable 60%. For the subset receiving the contemporary regimen of cisplatin/5-fluorouracil, the 5-year survival rate was 77%. Only 23% of patients required postoperative radiotherapy. This included six patients within 6 weeks of resection for protocol-specific indications based on the 1979 National Institutes of Health guidelines and 12 patients at an interval exceeding 6 weeks to treat recurrent disease. Based on the premise that all patients enlisted for the protocol would have required postoperative radiotherapy had they undergone primary surgery, it is suggestive from this data that induction chemotherapy may serve as an effective substitute in this setting. An earlier randomized trial comparing sequential chemosurgery to primary surgery failed to show any survival advantage for chemosurgery.2 However, the chemotherapy regimens tested at that time were suboptimal compared with contemporary standards. Furthermore, the goal of substituting chemotherapy for radiotherapy was not a goal of earlier studies. Although not part of the data presented, one may also speculate that the 63 patients who were spared radiation had less posttreatment problems related to radiation-induced fibrosis and xerostomia. However, comparative studies would be necessary to determine if the toxicity associated with ionizing radiation is more harmful than chemotherapy-related toxicity.
Acutely aware of the likelihood for residual subclinical disease among major responders treated with induction chemotherapy, the authors believed it was necessary to perform "uncompromised" oncologic resections for all patients. With the exception of a single patient, all were subsequently found to have histological disease in the resected specimen and thus the policy appeared to be a wise one. However, it would be interesting to know if the geographical pattern of the residual microscopic disease associated with complete responders was unpredictable or whether it was confined to the epicenter. The latter would support a lesser surgical resection. Common perception is that the location of residual disease is unpredictable for solid tumor treated with induction chemotherapy. Following the induction chemotherapy phase, there were several trends or phases each focusing on unique combinations, sequences, or end points. These included the organ preservation trials,3 therapeutic concurrent chemoradiation,4 adjuvant chemotherapy,5 and induction concurrent chemoradiation.6 Theoretically, the latter combination is a more potent cytoreduction approach since the two modalities are highly synergistic when used simultaneously. The major drawback to induction concurrent chemoradiation is the higher rate of acute and chronic toxicity, particularly if the total dose of radiation is in the therapeutic range. To minimize this, protocols have been developed which employ a reduced total dose of radiation as part of the concurrent therapy.7,8
The disadvantage of the Loré approach for treating locally advanced head and neck cancer with sequential chemosurgery is the necessity for all patients to undergo a major oncologic resection. In many cases, it is likely that organ function was compromised. However, as the authors correctly point out, the alternative approach using nonsurgical modalities for the purpose of preserving major organs has no guarantee that organ dysfunction will be avoided. Although this partly may be attributable to the residual scar of the sterilized tumor, a significant component is related to the chronic effects of chemoradiation such as xerostomia and fibrosis. By avoiding postoperative radiation in 75% of patients, Loré et al. were able to provide an effective therapy without these side effects. As a surgeon, it is particularly appealing to operate on tissue that has not been previously treated with radiation and to manage patients in follow-up who do not suffer from severe xerostomia. However, it is also important to pursue new protocols incorporating nonsurgical modalities designed to spare the surrounding normal tissue. In this context, conformal radiotherapy may prove to be beneficial. A second important strategy is to understand the functional results of existing treatment regimens and to identify subsets of patients at greater risk for developing dysfunction. By selecting patients who are more likely to do well, it is possible to minimize the subset of surviving patients who have poor functional outcomes. We have previously reported that patients with laryngeal fixation from advanced cancer combined with a history of chronic pulmonary disease have only a 50% chance of retaining a functional organ after successful sterilization of their disease with concurrent intra-arterial cisplatin and concurrent radiotherapy.9
The survival rate for the subset of patients who required postoperative radiotherapy was not described specifically in the Loré report. From Tables 5 and 6, one might assume their survival was worse just as others have demonstrated lower survival rates for patients having partial responses following nonsurgical protocols that incorporate induction chemotherapy. One may argue that induction treatment essentially serves as a biologic marker to help separate the poor prognostic group from the good. Currently, it is a major challenge to treat effectively the poor prognostic group with more intensive regimens.
Loré et al. must be commended for their long-term commitment to a trial exploiting the potential benefits of induction chemotherapy. Certainly, the ability to avoid postoperative radiotherapy in the majority of patients is a worthwhile achievement albeit at the cost of organ sacrifice in some patients. While newer drug combinations such as paclitaxel/cisplatin may be tested in the same sequence, either with surgery or radiotherapy, it is unlikely that induction chemotherapy will stand alone as a modality making a substantial difference. Although the alternative of concurrent chemoradiation is therapeutically more potent, it is also more toxic. Other potential gains are possible with existing modalities and agents using novel sequencing or combinations. The piloting of triple modality therapy using modified quantities of the three modalities is an attractive approach. While modest gains may be possible with such strategies, the reality is that head and neck cancer is a tough nut to crack. Clinicians will continue to struggle to make progress because this disease is heterogeneous, advanced at presentation, and associated with a tremendous amount of comorbidity and a high incidence of secondary cancers. True success for improved survival and preservation of function awaits more effective agents and modalities. Until then, we will continue to explore the many pathways in what has turned out to be a complex maze.
Received for publication May 12, 2003. Accepted for publication May 20, 2003.
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