Faculty Bibliography

Locoregional recurrence remains a major obstacle to achieving cure of locally advanced head and neck cancers despite maximal resection and postoperative external beam radiation therapy (EBRT). Locoregional failure occurs in 30% to 40% of high-risk resected head and neck cancer patients after standard postoperative EBRT. In an effort to overcome this problem, a number of strategies have been designed to enhance the effectiveness of radiation including concurrent postoperative chemoradiation, accelerated radiation schedules, incorporation of targeted biologic therapies, and improved radiation delivery techniques such as intensity modulated radiation and high-dose rate (HDR) intraoperative radiation therapy. Intraoperative radiation therapy (IORT) represents an important approach to improve outcome in head and neck cancer patients treated with definitive surgery. High-dose rate IORT is defined as the delivery of a single, large dose of radiation at the time of surgery when the tumor bed is exposed. In conjunction with EBRT, HDR-IORT offers several advantages including: (1) conformal delivery of a large dose of radiation while the tumor bed is precisely defined, minimizing the risk of a geographic miss; (2) potential for subsequent dose reduction of EBRT; (3) shortening overall treatment time; and (4) dose-escalation. Because mucositis represents the dose-limiting acute toxicity and xerostomia ranks as the most common long-term quality-of-life complaint, a reduction of the EBRT dose may provide an important benefit in reducing toxicity, especially when combined with the radioprotectant amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD). The purpose of this article is to review the rationale for integrating HDR-IORT with a reduced dose of postoperative EBRT combined with amifostine to improve locoregional control and quality of life outcomes in advanced-stage resected head and neck cancer patients.

Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO(2) levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratumoral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ultimately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for "low" should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO(2) thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly requires further evaluation. Nonetheless, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival.

Intraoperative irradiation (IORT) refers to the delivery of a single high dose of radiation therapy at the time of surgery when the tumor bed can be precisely defined and adjacent normal tissue maximally protected. It can be effectively delivered using either electrons (IOERT) or photons produced from a high-dose-rate gamma emitting radioisotope (HDR-IORT) and has been explored primarily for locally advanced or recurrent tumors at high risk for local failure despite extensive resection and full dose external beam radiation. With coordinated multidisciplinary interaction, IORT can be integrated in a combined-modality setting without undue additional toxicity. The purpose of this review will be to summarize the growing HDR-IORT experience in the treatment of various cancers, to compare its efficacy and toxicity vis a vis the IOERT data, and to discuss future trials as well as new areas of potential application.

The mainstay of treatment for rectal cancer over the past 100 years has been surgical resection. However, for the majority of rectal cancers treated conventionally by resection alone, locoregional recurrence is the major mode of failure. Over the past several decades, significant progress has been made in developing effective adjuvant regimens. In the United States, postoperative chemoradiation is standard treatment for T3 or node-positive patients. However, preoperative radiation with or without chemotherapy decreases local recurrence, increases sphincter preservation, and may improve survival. The purpose of this article is to review the role of adjuvant therapy in resectable rectal cancers and to update the status of ongoing randomized trials.

PURPOSE: Retroperitoneal sarcomas represent a formidable challenge to the treating oncologist due to their location, large size, and poor prognosis. The purpose of this study was to determine if the addition of high-dose-rate intraoperative radiation therapy (HDR-IORT) to surgery and external beam radiotherapy (EBRT) would improve the outcome in these patients. METHODS AND MATERIALS: Thirty-two patients with retroperitoneal soft tissue sarcoma were prospectively treated according to a protocol that included maximal tumor resection, HDR-IORT, and postoperative EBRT when feasible. Twelve patients presented with primary and 20 with locally recurrent disease. The tumors were high-grade in 20 patients and low-grade in 12 patients. Complete gross resection was achieved in 30 patients. HDR-IORT was given to a dose of 12-15 Gy. Additional EBRT was given to 78% of patients to a dose of 45-50.4 Gy. The two patients with gross residual disease received an additional I-125 permanent implant to a median peripheral dose of 140-160 Gy. The median follow-up was 33 months (range 1-77 mo). RESULTS: The 5-year actuarial local control rate for the whole group was 62%. For patients with primary disease, the local control rate was 74% compared to 54% in patients with recurrent disease (p = 0.4). The overall 5-year distant metastasis-free survival rate was 82%. In patients with high-grade tumors the rate was 70% vs. 100% in those with low-grade tumors. This difference was statistically significant, p = 0.05. The 5-year disease-free and overall survival rates were 55% and 45%, respectively. The most common type of post-treatment complication was gastrointestinal obstruction (18%) followed by fistula formation (9%), peripheral neuropathy (6%), hydronephrosis (3%), and wound complication (3%). CONCLUSIONS: We are encouraged by the favorable local control rate and the acceptable morbidity with this new technique applied to a challenging patient population.

Intra-operative radiation therapy (IORT) can benefit patients with pelvic tumors by delivering a high dose of radiation with precise delineation of tumor bed and maximal protection of surrounding normal tissues. The IORT experience has been particularly promising for locally advanced primary or recurrent rectal cancers in which a gross total resection is achieved. However, its potential benefit must be weighed against added toxicity. The main dose-limiting toxicity of pelvic IORT is peripheral neuropathy and ureteral stenosis. We will review the techniques for optimal IORT delivery, the results of the major studies investigating IORT treatment of rectal cancer, and the pelvic complications associated with combining surgery and IORT. A team of surgeons and radiation oncologists providing close multidisciplinary coordination is essential to integrate IORT with combined modality regimens in a safe and effective manner.

Purpose. The purpose is to review the natural history, the clinicopathological prognostic factors, and the role of adjuvant radiation therapy with particular attention to the limited but favorable experience with IORT.Methods. Retroperitoneal sarcomas present a continuing therapeutic challenge to the oncologist. In contrast to sarcomas of the extremity and superficial trunk in which complete resection plus radiation therapy results in excellent local control, sarcomas of the retroperitoneum are difficult to resect and even if completely resected, demonstrate high rates of local relapse, the primary pattern of failure. Due to the proximity of normal organs, the delivery of therapeutic doses of adjuvant external beam radiation therapy is problematic.To deliver adequate doses (>60 Gy) of external beam to most patients would result in unacceptable toxicity. The therapeutic dilemma is unfortunate and better strategies are needed. One attractive approach has been to incorporate intraoperative radiation therapy (IORT) with maximal resection and external beam radiation. Results and Discussion. A number of institutions have explored this approach with encouraging preliminary results.

Several altered fractionation schemes have evolved to exploit different aspects of head and neck cancer growth kinetics and normal tissue repair. Hyperfractionation schedules exploit the differential repair abilities of tumor and normal tissue, whereas accelerated fractionation regimens minimize the time of tumor repopulation. Significant clinical data have accumulated that indicate an improvement between 15% and 20% in locoregional control from altered fractionation. Preliminary analysis of a randomized Radiation Therapy Oncology Group trial testing four fractionation schemes confirms the benefit of one altered fractionation approach. Several promising concurrent chemoradiation treatments involving altered fractionation have been reported. Future trials will determine whether the addition of chemotherapy to altered fractionation schemes is warranted in light of the factor of added toxicity.