Originally published as JCO Early Release 10.1200/JCO.2008.19.0868 on October 20 2008

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Reirradiation and Concurrent Chemotherapy After Salvage Surgery: Pay Now or Pay Later

Stuart J. Wong

Department of Medicine, Medical College of Wisconsin, Milwaukee, WI

Sharon Spencer

Department of Radiation Oncology, University of Alabama, Birmingham, AL

Reirradiation with concurrent chemotherapy (CT/Re-RT) is now firmly established as a feasible treatment for selected patients with unresectable, locoregional recurrent head and neck cancer in a previously irradiated field. Several groups have reported their retrospective experiences with Re-RT and suggested feasibility and survival benefit of this approach.^1-5 Prospective clinical trials have validated these findings, indicating that long-term survival is achievable in a subset of this poor-prognosis patient population. Two consecutive Radiation Therapy Oncology Group (RTOG) Re-RT trials have been completed. RTOG 96-10 (concurrent hydroxyurea/fluorouracil/Re-RT) and RTOG 99-11 (concurrent cisplatin/paclitaxel/Re-RT) demonstrated 2-year survival rates of 15.2% and 25.9%, respectively.^6-8 The suggestion of a step-wise improvement in survival from these two trials is encouraging. However, many questions remain unanswered regarding the optimal delivery of Re-RT and the best CT agents, as well as more elementary questions regarding which patients derive benefit from CT/Re-RT.

Patients with locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (HNSCC) who are able to undergo salvage surgery have a better prognosis than do those patients with unresectable disease.^9-11 However, even if a complete salvage resection can be achieved, these patients remain at high risk for subsequent relapse and death resulting from disease.^9-12 In the present issue of Journal of Clinical Oncology, Janot et al¹³ from the Groupe d’Etude des Tumeurs de la Tête et du Cou/Groupe d’Oncologie Radiothérapie Tête Et Cou report the results of a phase III study of post operative CT/Re-RT compared with observation in patients who have undergone salvage surgery for local and regional recurrent HNSCC.

This study demonstrated an improvement in locoregional disease control as well as an improvement in disease-free survival, the primary end point of the study. These observations provide strong evidence that CT/Re-RT is effective in killing microscopic residual disease after salvage resection. But if CT/Re-RT is effective, then why was an overall survival advantage not observed? First, the CT regimen used in this study may have been suboptimal. It is possible to speculate that a more effective CT/Re-RT regimen, such as that used in RTOG 99-11, may have elicited a greater magnitude of benefit and may have translated into an overall survival advantage. Second, the study was not powered for this end point. Even if it were positive, a much larger trial would be necessary to confirm this. Moreover, it is probable that use of salvage CT/Re-RT in patients randomly assigned to the observation arm diminished the ability to detect an overall survival advantage associated with the use of postoperative CT/Re-RT in the experimental arm. Of the 65 patients randomly assigned to the observation arm, 32 patients (49%) later experienced treatment failure in a local or regional site. Sixteen patients (25%) were treated with CT/Re-RT. Taken in this light, this study can be viewed as a comparison of immediate postoperative CT/Re-RT with delayed CT/Re-RT for local or regional relapse. Some patients who undergo salvage surgery are destined to experience treatment failure again in a locoregional site, whether because of molecular genetic factors or because of the presence of microscopic residual disease. Is it better to give patients immediate postoperative CT/Re-RT or to wait until failure and then treat with CT/Re-RT—pay now versus pay later? Arguments can be made for either case. The likelihood of achieving prolonged disease-free survival might be improved if tumor cells are sterilized at the time of early microscopic disease rather than treating bulkier disease at the time of gross failure when tumors are prone to hypoxia and to poor tissue penetration of CT.¹⁴ However, some patients may be cured with salvage surgery alone; postoperative CT/Re-RT may subject these patients to significant unnecessary toxicity, including death. Treatment-related deaths occurred in five patients (8%) in this trial, similar to that reported in other CT/Re-RT studies.^3,5-7

What conclusions can we draw from this study and how should we use these data to make recommendations for our patients? One conclusion that we can firmly draw from this study is that CT/Re-RT works, adding to the general body of literature demonstrating the efficacy of CT/Re-RT. It also underscores the need for additional studies of CT/Re-RT to further our understanding of how best to administer CT/Re-RT, who should get it, and when it should be given.

RTOG and Groupe d’Oncologie Radiothêrapie Tête Et Cou have both attempted phase III studies to compare CT/Re-RT with CT alone for previously irradiated, locoregional recurrent, unresectable HNSCC. Both studies were closed early because of poor accrual. It is likely that this question will never be resolved. It is necessary, therefore, that the next generation of CT/Re-RT studies move forward to test whether integrating new agents and new radiation techniques enhance efficacy or reduce toxicity. Improving the therapeutic index of CT/Re-RT may make the decision to deliver immediate postoperative CT/Re-RT a more palatable option. Examining new treatment sequences may also be helpful in resolving issues regarding the optimal timing of CT/Re-RT.

A sequential regimen of induction CT followed by salvage surgery followed by CT/Re-RT has been piloted and has a number of theoretical advantages.¹⁵ First, patients who receive salvage surgery, with or without postoperative CT/Re-RT, are at high risk for distant metastasis. In the Janot et al study,¹³ isolated distant metastases were observed in 10 patients (15%) in the RT arm and two patients (3%) in the observation arm. The dose and schedule of CT used in Re-RT regimens, such as used in the study by Janot et al, are likely to act primarily by eliciting a radiosensitizing effect more so than a systemic effect. Full-dose CT may decrease the incidence of distant failure in this group. Second, some patients with HNSCC have disease that is particularly aggressive and refractory to multimodality therapy. Induction CT may be used as a predictor of response to subsequent CT/Re-RT. Patients who experience treatment failure with induction CT may not be well served by undergoing CT/Re-RT, and alternative approaches may be preferable. This paradigm has been examined by other groups in the setting of definitive therapy for locally advanced HNSCC.^16,17 A stronger argument can be made for use of this induction treatment algorithm in the recurrent, previously irradiated patient population because their tumors are more likely to be populated with resistant clonagens.

In summary, the rate of locoregional failure is unacceptably high in previously irradiated patients who have undergone salvage surgery (50% in this trial); therefore, CT/Re-RT after salvage surgery is justifiable. However, close observation with delayed CT/Re-RT for locoregional relapse is also reasonable. Treatment-related toxicity, particularly death, remains a major deterrent and should be the starting point for any consent discussion regarding immediate postoperative CT/Re-RT. Such therapy is best performed in the setting of a clinical trial.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Manuscript writing: Stuart J. Wong, Sharon Spencer

Final approval of manuscript: Stuart J. Wong, Sharon Spencer

NOTES

published online ahead of print at www.jco.org on October 20, 2008

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