Intraoperative radiation therapy in the multimodality approach to upper aerodigestive tract cancer

The cure rate of operable lung cancer and locally advanced head and neck cancer remains suboptimal, with a limited rate of local control despite improvements in the surgical removal of primary tumors and in methods for mediastinal lymph node dissection, in particular. The efficacy of adjuvant therapy, such as EBRT, has improved, and the immediate efficacy of new chemotherapeutic drugs is increasingly significant, although local recurrences remain frequent. Locoregional failure is not uncommon in upper aerodigestive tract cancers. Factors limiting radiocurability for locally advanced (stage III) lung cancer include mediastinal intolerance of irradiation (high risk of mediastinal fibrosis, which increases exponentially when levels of much more than 50 Gy are administered to the whole mediastinum) and the very high radiosensitivity of the healthy lung, which can develop fibrosis with relatively small or moderate doses starting at 18 to 20 Gy, and even more frequently when larger volumes are irradiated. Head and neck neoplasms are less difficult sites in which to administer doses of up to 70 Gy of external beam radiotherapy initially, but, like locoregionally recurrent lung cancers, they are not easily reirradiated with tumoricidal doses of EBRT. For these reasons, IORT seems to be a good option for increasing local control, because areas of residual microscopic disease may be irradiated using IOERT approaches without affecting critical organs to the same extent. In addition, careful patient selection is paramount. Combined modality treatment regimens incorporating IORT may benefit patients with locally advanced disease. The ability of IORT to sterilize microscopic residual disease can enhance the "completeness" of resection and thus, theoretically, improve local control. Although distant disease dissemination remains by far the overriding issue, as newer effective agents emerge, local failure will continue to be a problem. Preliminary studies have demonstrated that IORT can be administered to patients who have locally advanced NSCLC and head and neck cancer, in the context of aggressive combined modality therapy, and is generally well tolerated. Long-term efficacy and benefit can only be determined in the setting of carefully designed clinical trials. (See the article by Thomas and Merrick elsewhere in this issue for further discussion of this topic.) Several relatively small, single-institution pilot studies exploring the utility and benefit of IORT for locally advanced upper aerodigestive tract cancers have been conducted. Clear conclusions have been difficult to determine because of the mixing of disease stages, varying degrees and completeness of surgical resection, varying radiation doses, different schemas, and other factors. Yet, given the major morbidity and mortality associated with locally recurrent lung cancer, methods of improving local control need to be pursued and refined. Encouraging preliminary data suggest that IOERT can be safely administered and may benefit local control. Based on several centers' expertise in the combined modality treatment of locally advanced lung cancer and familiarity with IORT, the UCSF Thoracic Oncology Program has proposed a multicenter phase 2 study incorporating IORT in a combined multimodality treatment schema for patients who have completely resected locally advanced stage IIIA and IIIB NSCLC (nonpleural effusion, non-N3) (Fig. 1). It is hoped that this study will commence in the upcoming year.