International Journal of Radiation Oncology*Biology*Physics
Clinical investigationEffects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non–small-cell lung cancer: report of a randomized comparative trial☆
Introduction
Although concurrent chemotherapy and radiotherapy (RT) have been shown to improve survival in patients with inoperable non–small-cell lung cancer (NSCLC) who have favorable pretreatment characteristics, this comes at the price of increased toxicity. For example, although preliminary experience with intravenous cisplatin and oral etoposide plus hyperfractionated thoracic RT at a single institution suggested the treatment improved the survival time, the rate of acute toxicity, especially severe odynophagia, was great (1). Although a reduction in the dose of etoposide permitted this regimen to be studied in a cooperative group setting 2, 3, the toxicity still posed a serious problem. Severe esophageal reactions occurred in 38% of patients, a rate significantly greater than that in patients receiving RT without concurrent chemotherapy (4). Likewise, Langer et al. (5) reported that concurrent cisplatin, etoposide, and hyperfractionated RT caused severe esophagitis in 60% of patients ≥70 years old and 42% of patients <70 years of age in Radiation Therapy Oncology Group (RTOG) protocol 9410. At our institution, this combination of twice-daily RT and concurrent cisplatin/etoposide resulted in a favorable long-term outcome (26%, 5-year survival rate) that was among the best reported for patients with these advanced tumors, but it too came at a price of an increased incidence of Grade 3 or 4 esophagitis (6). It is, therefore, particularly important to reduce the incidence and severity of the acute toxicities of these more effective treatment regimens.
Efforts to develop pharmacologic agents that protect normal tissues from the effects of radiation are long-standing. One very promising radioprotector that has emerged from these efforts is amifostine, an organic thiophosphate developed by the United States Army (WR [Walter Reed]-2721) in the post–World War II era to protect against the possible effects of radioactive fallout. The active metabolite (WR-1065) is a free thiol that is thought to provide an alternative target for reactive species from alkylating agents that would otherwise target DNA. The free thiol is also believed to scavenge the free radicals released during the interaction of ionizing radiation and water. With regard to its tissue selectivity, amifostine has been shown to protect both the salivary glands from the damaging effects of RT (7) and the kidneys from the nephrotoxic effects of cisplatin (8). Nonetheless, amifostine's ability to protect normal tissue is not well understood, and the dosage required to reduce specific toxicities has not been established (9). However, it appears to protect normal tissues, including the esophagus, lung, kidney, liver, bone marrow, immune system, skin, colon, small bowel, salivary glands, oral mucosa, and testes, from radiation damage; the brain and spinal cord, however, were not protected. In addition, no evidence has shown that it caused tumors to be spared the effects of RT or chemotherapy. Also in its favor, amifostine has been shown to protect normal tissues against the toxic effects of several classes of cytotoxic agents, including the alkylating and organo-platinum agents, anthracyclines, and taxanes (10). In a preclinical investigation (11), amifostine protected the jejunal mucosa of mice against the damage inflicted by combined cisplatin-RT. All these qualities, therefore, indicate amifostine's potentially broad applicability as a cytoprotective agent. Amifostine is already approved for use as a radioprotector in the United States as the result of an international multi-institutional Phase III comparative trial that showed a significant reduction in the severity of acute and late xerostomia in patients given intravenous amifostine before each fraction of RT (7).
On the basis of these findings, it was thus hypothesized that amifostine might reduce the major toxic effects of concurrent chemotherapy and RT on critical organs in patients with lung cancer (in particular the esophagus and lungs). This might, in turn, allow the two therapies to be intensified, which might increase tumor control and survival. We, therefore, conducted a prospective, randomized, comparative study of concurrent cisplatin-based chemotherapy and RT with and without amifostine (Ethyol, MedImmune, Gaithersburg, MD) at the University of Texas M. D. Anderson Cancer Center to test this hypothesis in patients with inoperable NSCLC. An additional consideration in the study was that the degree of protection would have to be enough to justify the side effects of amifostine and the logistical problems associated with its intravenous administration before treatment during the several weeks of RT. To minimize the risk of side effects, amifostine was given only twice each week. However, to achieve maximal cytoprotection, it was given before chemotherapy and RT whenever both modalities were used.
Section snippets
Patient selection
Patients with NSCLC registered at M. D. Anderson Cancer Center participated in this study. The Surveillance Committee, which is the institutional review board of M. D. Anderson, reviewed and approved the study. Patients were eligible if they had histologically or cytologically confirmed Stage II (medically inoperable) or Stage IIIA-IIIB squamous cell carcinoma, adenocarcinoma, large cell carcinoma, or NSCLC, not otherwise specified (12). The pretreatment evaluation included a complete medical
Results
Between November 1998 and January 2001, 64 patients with inoperable Stage II or Stage III NSCLC were enrolled in this trial; 2 of these patients were subsequently found to be ineligible. The remaining 62 eligible patients were randomly assigned to one of the two treatment arms (Arm 1, chemoradiotherapy without amifostine; Arm 2, chemoradiotherapy with amifostine). The pretreatment characteristics of prognostic significance were distributed equally between the two treatment groups (Table 2). In
Discussion
We observed a statistically significant reduction in the severity of dysphagia in the patients who received amifostine compared with those who did not (Fig. 2). Pain on swallowing (odynophagia) is the most disabling component of dysphagia and can profoundly interfere with the patient's ability to maintain caloric intake or even adequate hydration, necessitating the use of narcotics for pain control or the placement of a PEG tube if the pain is particularly severe.
Clearly, a degree of
References (25)
- et al.
A pilot trial of hyperfractionated thoracic radiation therapy with concurrent cisplatin and oral etoposide for locally advanced inoperable non-small-cell lung cancerA 5-year follow-up report
Int J Radiat Oncol Biol Phys
(1998) - et al.
Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancerRadiation Therapy Oncology Group (RTOG) 9204
Int J Radiat Oncol Biol Phys
(1997) - et al.
Do elderly patients (pt) with locally advanced non-small cell lung cancer (NSCLC) benefit from combined modality therapy? A secondary analysis of RTOG 94-10
Int J Radiat Oncol Biol Phys
(2001) - et al.
Twice daily irradiation increases locoregional control in patients with medically inoperable or surgically unresectable stage II-IIIB non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
(2002) - et al.
Chemical radioprotectionA critical review of amifostine as a cytoprotector in radiotherapy
Semin Radiat Oncol
(2003) - et al.
Randomized phase III trial of radiation treatment ± amifostine in patients with advanced-stage lung cancer
Int J Radiat Oncol Biol Phys
(2001) A phase III randomized evaluation of amifostine in stage IIIA/IIIB non-small cell lung cancer patients receiving concurrent carboplatin, paclitaxel, and radiation therapy followed by gemcitabine and cisplatin intensificationPreliminary findings
Semin Oncol
(2002)- et al.
Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
(2003) - et al.
Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small cell lung cancerRadiation Therapy Oncology Group protocol 91-06
J Clin Oncol
(1996) - et al.
Impact of adding concurrent chemotherapy to hyperfractionated radiotherapy for locally advanced non-small cell lung cancer (NSCLC)Comparison of RTOG 83-11 and RTOG 91-06
Am J Clin Oncol
(1997)
Phase III randomized trial of amifostine as a radioprotector in head and neck cancer
J Clin Oncol
Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicitiesResults of a randomized control trial in patients with advanced ovarian cancer
J Clin Oncol
Cited by (151)
Taste disorders in disease
2022, Flavor: From Food to Behaviors, Wellbeing and Health, Second EditionRadiation Modifiers
2019, Hematology/Oncology Clinics of North AmericaCancer of the Lung: Non-Small Cell Lung Cancer and Small Cell Lung Cancer
2019, Abeloff’s Clinical OncologyOral Assessment and Management of the Patient with Head and Neck Cancer
2018, Oral and Maxillofacial Surgery Clinics of North America
- ☆
Supported in part by Grants CA6294 and CA16672 from the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, and by MedImmune, Inc., Gaithersburg, MD.