Optimal treatment for salivary gland tumors

Abstract

Salivary gland tumors are relatively rare when compared to other malignancies of the head and neck region. They are a histologically diverse group of tumors, generally slow growing with long doubling times, and they demonstrate a propensity for late local/regional and distant recurrences. Because of their slow growing nature, patients afflicted with these tumors often have prolonged survivals, even in the presence of distant metastatic disease (usually lung). Treatment has traditionally been either surgery alone, or surgery plus postoperative radiation therapy in the setting of potentially residual postoperative microscopic disease. Low LET radiation therapy, given with standard fractionation, has met with only limited success in the setting of gross postoperative residual, or unresectable disease (7). These suboptimal results led to the conclusion that salivary gland tumors are relatively radioresistant, and led to clinical trials with high LET radiations such as fast neutrons and high LET charged particles. The case for high LET radiation therapy is strong in this tumor system. Tumors with low growth fractions and long doubling times are predicted to be more sensitive to high LET than to low LET radiations. Reduced variation in radiosensitivity throughout the cell cycle predicts that slowly growing tumors with slowly cycling cells, such as salivary gland cancers, would be advantageously treated with high LET radiations. Batterman er al. published pioneering work clinically defining the RBE of fast neutrons for various human malignancies (1). One of the highest RBE’s of neutrons was found in adenoid cystic carcinomas (8.0 with fractionated neutron therapy), which indicates an inherent radiosensitivity of this tumor to high LET radiation. More importantly, the RBE for adenoid cystic carcinomas is substantially higher than that for normal mesenchymal tissues. Treating an adenoid cystic carcinoma with 2000 neutron cGy would be approximately equivalent to 16,000 photon cGy in its tumor effect, but equivalent to only 60004600 photon cGy in its effect on normal tissues. This differential effect gives rise to a therapeutic gain factor of approximately 250%, and is thought to be the underlying reason for the success of high LET radiations in salivary gland malignancies. Clinical trials have confirmed these predictions. In excess of 300 patients have been treated for locally advanced, unresectable salivary gland tumors with fast neutrons (6). Patients have been treated with both neutrons alone and mixed beam irradiation over both short (4 weeks) and long (8 weeks) overall treatment times. Patients have been treated with physics-laboratory-based and hospitalbased neutron generators of both high and low energy. The results have been remarkably consistent (3, 4, 6). These studies have demonstrated long-term local/regional tumor control rates of approximately 67% compared to average long-term local/regional tumor control rates of approximately 25% for standard fractionated, low LET radiations (6). The normal tissue complication rates have been marginally higher with low energy, fixed beam neutron generators but have been equivalent to megavoltage photons when high energy and/or isocentric hospital-based neutron generators were employed (3, 4, 5). Subsequently, a prospective, cooperative, randomized clinical trial sponsored jointly by the MRC and RTOG directly compared fast neutrons with megavoltage photons for patients with locally advanced, unresectable salivary gland tumors (5). This study demonstrated a long-term local/regional tumor control rate of 67% for neutrons versus 17% for photons @ < 0.005) in this group of patients with advanced tumors (up to 16 cm in maximum dimension). The normal tissue toxicities were not statistically significantly different between the two groups. Drs. Wang and Goodman present the results of a retrospective review of accelerated, hyperfractionated, low LET radiation for malignant salivary gland tumors in this journal. The rationale for accelerated fractionation with photons is less compelling than is the rationale for high LET radiations in this tumor system. Accelerated fractionation schemes are usually advocated for fast growing tumors with rapidly cycling cells to minimize the potential for repopulation. They are not generally advocated for slowly growing tumors such as salivary gland malignancies, and, in fact, may be disadvantageous in this setting. Nonethe-