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Michigan Oncology Journal Summer 2001
Improving Efficacy of Irradiation for Head and Neck Cancer
Avraham Eisbruch, M.D.
Radiation (RT) has historically been the standard therapy for advanced, non-resectable head and neck cancer. In addition, some patients with advanced resectable tumors who would suffer significant functional deficit following surgery, may benefit from a nonsurgical approach that includes irradiation (reviewed elsewhere in this issue of the Journal). Patients with locally advanced tumors who receive RT alone have a five-year survival rate of less than 25% and most treatment failures occur locally or regionally, within the irradiated fields. In recent years, several strategies have evolved in an effort to improve the efficacy of radiation. These strategies include changes in the radiation fractionation schemes and the addition of chemotherapy or radiosensitizers to radiation.
Altered Fractionation Schemes
Changes in the radiation fractionation schemes have several different aims. In a typical standard RT course, a daily dose of 2.0 Gray (Gy, a unit representing energy absorbed in tissue) is delivered to the tumor, five days a week, for a total of 70 Gy over seven weeks. This treatment course enables recovery of the non-involved irradiated tissue and is associated with a small risk of long-term complications.
A strategy that relies on a better capability of the noninvolved tissue compared with the tumor to repair damage from small radiation fractions is called hyperfractionation. In common hyperfractionation schemes, two fractions (typically 1.1-1.25 Gy each) are delivered twice daily. A higher than standard total dose, up to 80 Gy, can be delivered without increasing permanent complication rates, and tumor control can be expected to improve. Another altered fractionation scheme called accelerated fractionation strives to deliver all the radiation dose quickly, over five to six weeks, to counteract accelerated repopulation of tumor stem cells that have not been inactivated during the early phase of therapy.
The results of a large multi-institutional, randomized study assessing the efficacy of altered fractionated RT compared with standard RT for locally advanced head and neck cancer has recently been published (1). Both accelerated and hyperfractionated RT were found to increase local-regional tumor control, by approximately 5 to 6%, and a trend toward improved disease free survival (but not overall survival) was found. While acute toxicity (mainly mucositis) was more severe in the altered fractionation scheme, no difference was found among the regimens in late, permanent complication rates.
Radiation and Chemotherapy
Chemotherapy has been combined with RT in an attempt to improve patients' outcome. The most promising approach is the administration of chemotherapy concurrent with RT, taking advantage of the radiation sensitizing effects of certain chemotherapeutic agents. Several randomized studies have shown improved outcome when RT was combined with concurrent cytotoxic agents, compared with RT alone (2, 3). Many of these studies reported an increased toxicity of the combined treatments, notably hematological and mucosal toxicities, which limited the ability to deliver full doses of radiation or the chemotherapeutic agents. The optimal drugs, doses and schedules of concurrent chemotherapy and RT for head and neck cancer are not yet known.
Taking advantage of both altered fractionation and concurrent chemotherapy would be the next logical step. A randomized study of hyperfractionated RT concurrent with chemotherapy (cisplatin and 5-FU) compared with hyperfractionated RT alone was reported by Brizel et al (4). The rates of local-regional tumor control at two years were 70% in the combined modality arm and 44% in the RT alone arm (p=0.01); the rates of relapse-free survival were 61% and 41%, respectively (p=0.07); and overall survival rate was 55% and 34%, respectively (p=0.07). The rate of acute mucositis was similar between the two arms (patients in the RT and chemotherapy arm received a slightly lower RT dose compared with the RT alone arm, and a treatment break of one week was inserted mid-course to reduce mucositis).
It can be argued that more aggressive treatment regimens may achieve even better therapeutic results, at the expense of more severe acute reactions. Severe acute mucositis has emerged as the most important factor limiting the intensity of combined modality therapy for head and neck cancer. An increased rate of severe acute mucositis is apparent as more aggressive chemotherapy is being delivered concurrent with RT. Grade 4 mucositis was reported in 12% of patients receiving a standard course of RT concurrent with cisplatin (2), compared with 30% in patients receiving similar RT concurrent with cisplatin and 5-FU (3). In both studies, the rate of severe mucositis in patients randomized to receive radiation alone was less than 5% and a significant benefit in disease-free survival was observed in the combined modality arms compared with RT alone.
Aggressive regimens may increase cure without worsening long-term complication rates or affecting survivors' long-term quality of life if feeding during chemo-RT can be accomplished by a gastric feeding tube and mucositis is reversible. Vokes et al., have treated patients with a sequential regimen of radiation concurrent with an intensive chemotherapy regimen consisting of cisplatin, 5-FU and hydroxyurea (5). Severe mucositis required a gastric feeding tube in almost all patients, and late-functional problems, including dysphagia, were prevalent. A high local-regional control rate was achieved (92% at three years), but the authors concluded that the regimen was too toxic and that more tolerable radiation and chemotherapy combinations should be evaluated.
Selective Tumor Radiosensitization
Severe acute mucositis may progress to late fibrosis causing severe dysphagia as a consequential effect, due to a severe depletion of stem cells that precludes complete healing of the mucosa and the submucosal tissue. In order to improve the therapeutic index of radiation and chemotherapy, strategies that selectively increase tumor response compared with mucosal toxicity should be developed. Examples of such strategies include the selective administration of chemotherapy to the tumor, and the use of radiosensitizers that have a specific affinity to tumors compared with the normal tissue. Robbins et al., have reported their extensive experience with targeted, intraarterial infusion of high-dose cisplatin (150 mg/m2/week) concurrent with irradiation for head and neck cancer (6). The infusion is performed through a catheter placed angiographically to selectively encompass only the dominant blood supply of the tumor. Intravenous thiosulfate is then injected to neutralize systemic cisplatin. The two-year local-regional disease control rate was 73%. Acute mucositis was prevalent, but only 12% of the patients required long-term gastric tube feeding.
The use of specific tumor characteristics to sensitize tumor cells to radiation may increase the therapeutic index. Notable current efforts in this regard are trials of radiation concurrent with Tirapazamine. This drug is toxic to hypoxic cells and its administration concurrent with radiation predominantly causes tumor cell radiosensitization (7). Another novel approach to selective radiation sensitization is the administration of antibodies to the Epidermal Growth Factor receptor (EGFR). Many squamous cell head and neck cancers overexpress this receptor, having a higher receptor density compared with the normal mucosa. Pre-clinical studies of radiation concurrent with antibodies to the EGF receptor in head and neck cancer showed enhanced tumor cell kill compared with RT alone, and early results of clinical trials using this strategy suggest that the toxicity of this approach is limited (8).
At the University of Michigan, a phase I trial of radiation concurrent with weekly low-dose gemcitabine for non-resectable head and neck cancer was performed, following pre-clinical findings that this chemotherapeutic drug is a potent radiosensitizer at sub-cytotoxic concentrations. We have found a high rate of complete tumor regression, but the rate of severe acute mucositis and late pharyngeal fibrosis was also high, and the regimen's therapeutic index was judged to be low (9). Based on this experience and on new data suggesting a better therapeutic index for twice weekly gemcitabine infusion, the regimen was modified. Gemcitabine is now delivered twice weekly during the last phase of radiation, when only the gross tumor is being irradiated. This study is now open for accrual of patients with non-resectable head and neck cancer. For more information, contact Avraham Eisbruch, M.D., at (734) 936-9337.
3. Adelstein DJ, Saxton JP, Lavertu P, et al. A phase III randomized study comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer. Head Neck. 1997;19:567-575.
9.Eisbruch A, Shewach D, Bradford C, et al. Radiation concurrent with gemcitabine for locally advanced head and neck cancer: A phase I study and intracellular drug incorporation study. J Clin Oncol. (in press).