Clinical Investigation
Volume, Dose, and Fractionation Considerations for IMRT-based Reirradiation in Head and Neck Cancer: A Multi-institution Analysis

Presented in oral form at the 58th American Society for Radiation Oncology Annual Meeting, September 25-28, 2016, Boston, Massachusetts.
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Purpose

Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity.

Methods and Materials

Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints.

Results

From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates.

Conclusions

Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity.

Introduction

Although the development of recurrence or second primary (RSP) squamous carcinoma in the head and neck after a previous course of radiation therapy (RT) is relatively uncommon, this clinical scenario occurs frequently enough to form the basis of ≥3 prospective clinical trials testing the efficacy of reirradiation 1, 2, 3. In general, these trials prescribed radiation in altered schedules (eg, 1.5 Gy twice daily, given every other week) to a dose of 60 Gy and targeted gross disease (or the resection bed) with a 2-cm margin and no elective (uninvolved) volume. Although these approaches are understandable given the first forays into reirradiation with 2-dimensional or 3-dimensional techniques in the prospective setting, these fractionation schemes and doses are not often used in the current era, especially for gross disease.

With the adoption of conformal RT techniques such as intensity-modulated RT (IMRT) and volumetric-modulated arc therapy, the therapeutic ratio of reirradiation might have changed, facilitating higher doses and minimizing the incidence and severity of acute or late toxicities (4). Additionally, evidence from the initial definitive RT setting has cast doubt on the utility of accelerated fractionation with concurrent systemic therapy 5, 6. Furthermore, given the high risk of failure at the treated site, the benefit of elective nodal treatment remains an open question (7). Therefore, we performed a multi-institution study of patients with RSP squamous cell carcinoma in the head and neck who had undergone reirradiation with IMRT techniques (re-IMRT) to investigate these questions of treatment volume, dose, and fractionation.

Section snippets

Materials and Methods

After institutional review board and legal approval, 9 institutions agreed to participate and formed the multi-institution reirradiation (MIRI) consortium. Eight centers contributed to the present analysis: Memorial Sloan-Kettering Cancer Center (New York, New York), Moffitt Cancer Center (Tampa, Florida), the Josephine Ford Cancer Institute at Henry Ford Health System (Detroit, Michigan), the University of Louisville (Louisville, Kentucky), University Hospitals Case Medical Center (Cleveland,

Patients

In this updated analysis, a total of 505 patients from the 8 participating institutions met the inclusion criteria. The patient, disease, and treatment characteristics of the study population are listed in Table 1. For surviving patients (n = 176), the median follow-up was 21.5 months (range 0-128.1). The initial approach to the RSP tumor consisted of surgery in 49.2%. Fractionation of re-IMRT was once daily for 79.6%. The target volume included elective treatment to the unilateral neck in

Discussion

In the accompanying analyses from this multi-institution collaboration, we have devised a prognostic grouping to aid with patient counseling and treatment selection of conventionally delivered RT or stereotactic RT 9, 10. We focused on the details that could affect the volume and prescription of re-IMRT.

In the reirradiation scenario, in which disease is presumed to be inherently radioresistant and normal organs at risk might have already received tolerance doses, the benefit of elective nodal

Conclusion

The routine use of elective neck irradiation or hyperfractionation during re-IMRT does not appear beneficial. For patients undergoing definitive re-IMRT, doses of ≥66 Gy appear to be relatively safe and might improve outcomes, especially for high-performing patients or those with a prolonged natural history such as HPV-associated RSP oropharynx cancer. For patients receiving postoperative re-IMRT in the absence of gross disease, doses of 50 to 66 Gy appear adequate.

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Conflict of interest: J. Bonner has a consulting role with Merck Serma, Eli Lilly, Bristol-Meyers Squibb, and Cell-Sci, all outside the submitted work. J. Caudell has a consulting role with EMD Serano outside the submitted work. N. Lee is on the advisory board for Merck, Pfizer, and Vertex, all outside the submitted work. M. Machtay has received honoraria and has consulting and advisory roles with Stemnion and Abbvie, all outside the submitted work. N. Riaz has received honoraria from Medimmunue outside the submitted work. F. Siddiqui has received honoraria and has a speaker and travel relationship with Varian Medical Systems, American College of Radiology, Med Dos advisory board, and Wayne State University, all outside the submitted work.

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