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© 2003 American Society for Clinical Oncology Randomized Double-Blind Trial of Combined Modality Treatment With or Without Amifostine in Unresectable Stage III Non–Small-Cell Lung Cancer
From the National Cancer Centre, Singapore. Address reprint requests to Swan Swan Leong, MD, Department of Medical Oncology, National Cancer Centre, 11 Hospital Dr, Singapore 169610; email: dmolss{at}nccs.com.sg.
Purpose: Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non–small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy. Patients and Methods: Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity. Results: There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of -27% (95% confidence limit = -50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms. Conclusion: Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.
THE CURRENT acceptable management strategy of stage III non–small-cell lung cancer (NSCLC) is combined modality treatment. Although the best mode of combination treatment has yet to be established, and the need for surgery largely still is a debatable issue, combining chemotherapy and radiotherapy has shown promising results in various phase III trials.1–3 The most widely used chemotherapy regimens in combination with radiotherapy have been platinum-based or taxane-based regimens.1–12 Survival results have improved with combined-modality treatment,1–3 but chemoradiotherapy, especially when given concurrently, has been associated with significant toxicities. The predominant toxicity in many studies was esophagitis, the incidence and severity of which was largely dependent on chemotherapeutic agents used, as well as on the radiotherapy schedule used. Cisplatin-based regimens were generally associated with a lower incidence of esophagitis, with significant esophagitis occurring in 3% to 13% of patients.4–8 For treatment protocols using paclitaxel, esophagitis rates of 37% to 70% have been reported.9–12 The incidence was also notably higher with hyperfractionated accelerated radiotherapy schedules.12,13 Paclitaxel, with or without carboplatin, was frequently given concurrently with radiotherapy in the treatment of stage III NSCLC, with reported response rates of between 52% and 86%.11,12,14 The main toxicity of the paclitaxel and carboplatin combination, when given in full doses, is marrow toxicity, affecting mainly the neutrophils. Langer et al15 documented 57% grade 3 to 4 neutropenia after the first cycle of paclitaxel and carboplatin used in the treatment of advanced NSCLC. In other similar studies, grade 3 to 4 neutropenia rates of 47% to 59%16,17 have been reported. Another well-recognized toxicity with paclitaxel is neurotoxicity, especially when the drug is given as a short infusion. Paclitaxel induces peripheral neuropathy, which is characterized mainly by sensory symptoms, such as numbness and paresthesia in a glove-and-stocking distribution,18,19 although motor and autonomic dysfunction may also occur. The primary pathology of paclitaxel peripheral neurotoxicity is thought to be a neuronopathy or axonopathy. The incidence of developing grade 2 and 3 neuropathy with 3-hour paclitaxel infusions was reported to be 25% to 57% in various studies,20–23 with grade 3 neuropathy occurring in about 10% of patients.17 Amifostine is an organic thiophosphate, originally developed to protect cells against radiation injury in the event of a nuclear war.24 It has been shown to protect normal tissue selectively against both radiation25 and a variety of chemotherapeutic agents.26–29 It is converted by alkaline phosphatase to free thiol WR-1065, which then exerts its protective action by scavenging free radicals and by donating hydrogen ions for DNA repair. There is a preferential uptake of amifostine and a higher rate of conversion to WR-1065 in normal cells than in tumor tissue probably because of the greater activity of membrane-bound alkaline phosphatase and higher pH of normal cells, and hence, selective protection is achieved.24,30,31 The potential clinical impact of amifostine in reducing the toxicities of chemotherapy was well demonstrated by studies conducted by Kemp26 and Mollman.27 In both studies, there was a significant reduction in neurologic toxicity when patients receiving cisplatin were pretreated with amifostine. In the study reported by Kemp, there was also a reduction in hematologic and renal toxicities. In a separate study, Glover et al28 demonstrated that pretreatment with amifostine reduced the hematologic toxicity of cyclophosphamide. On the basis of preclinical and clinical studies that indicated protection against the toxicities of paclitaxel29,32 and carboplatin,33,34 we initiated a randomized double-blind trial to determine the role of amifostine in the setting of using induction paclitaxel plus carboplatin followed by concurrent radiotherapy and weekly paclitaxel in the treatment of stage III NSCLC. The objective of the study was to assess the efficacy of amifostine in reducing myelosuppression, neurotoxicity, and esophagitis associated with the treatment regimen.
Eligibility Criteria Patients with a histologically or cytologically proven diagnosis of NSCLC were eligible for the study. Only patients with stage IIIA disease (if deemed unresectable on medical grounds) and stage IIIB disease (excluding malignant pleural effusion)35 were accepted. Patients had to be at least 18 years old, with good performance status, no prior symptoms of peripheral neuropathy, and no other severe comorbid conditions. Patients should not have had other malignancies in the previous 5 years, and adequate hematologic, renal, and hepatic functions were required. All of the patients who entered the study were fully informed about the nature and purpose of the study and gave written informed consent. The local ethics committee approved the protocol.
Pretreatment Evaluation
Neurophysiologic Studies
Study Design The study was a single-institution, randomized, double-blind trial. All patients were registered and randomly assigned to one of two treatment arms (A and B), using random permuted blocks of size 4.38 There was equal allocation between the two treatment arms. Treatment was initiated within 7 days of random assignment to a treatment arm. Both patients and treating physicians (as well as nurses instituting the chemotherapy) were blinded to the test treatment. The pharmacists, who were not directly involved in patient care, were given the randomization results and prepared the amifostine or placebo solution (100 mL of clear infusion fluid for each of the treatment arms) accordingly.
Patients enrolled were scheduled to receive two cycles of induction chemotherapy consisting of paclitaxel and carboplatin on days 1 and 22. All patients who had response to the induction chemotherapy or had stable disease on CT scan went on to receive concurrent chemoradiotherapy. Concurrent chemoradiotherapy was started on week 7 combining weekly doses of paclitaxel and standard once-daily radiotherapy for 6 to 7 weeks. In arm A, patients received amifostine before each dose of paclitaxel and carboplatin. In arm B, patients received placebo before each dose of paclitaxel and carboplatin (Fig 1
Chemotherapy Induction chemotherapy consisted of two cycles of combination chemotherapy given on days 1 and 22. Patients were given paclitaxel 175 mg/m2 via a 3-hour intravenous (IV) infusion followed (30 minutes after completion) by carboplatin dosed to a target area under the time-concentration curve (AUC) of 6, as determined by the Calvert formula.39 Creatinine clearance was estimated for each patient, using the creatinine level and the Cockroft-Gault formula.40 All patients received dexamethasone 20 mg orally at 12 and 6 hours before the chemotherapy and cimetidine 300 mg IV, diphenhydramine 50 mg IV, and granisetron 3 mg IV at 30 minutes before paclitaxel infusion. Patients in treatment arm A also received two dosages of amifostine at 740 mg/m2, given 30 minutes before paclitaxel and 30 minutes before carboplatin, as a 15-minute infusion. Patients in arm B received two dosages of placebo, given similarly. During concurrent chemoradiotherapy, paclitaxel 60 mg/m2 was given once a week (on days 43, 50, 57, 64, 71, and 78) as a 1-hour infusion. Premedication and pretreatment with amifostine or placebo were similar to that of induction treatment. All patients were treated while in a supine position throughout the administration of chemotherapy and premedication, and were prehydrated with 500 mL of normal saline before the start of treatment. These measures were instituted as prophylaxis against any significant hypotensive episodes.
Radiotherapy
Toxicity and Response Evaluation Response to treatment was assessed after the two cycles of induction chemotherapy, using CT scan. Patients who had complete response (CR), partial response (PR), or stable disease could proceed to receive chemoradiotherapy. Response to the entire treatment was evaluated by CT scan 8 weeks after the completion of chemoradiotherapy.
Statistical Analysis Overall survival and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method,42 and the comparisons between the two treatment procedures were carried out using the log-rank test.43 Statistical analyses were generated using SPSS Base 8.0 for Windows (SPSS Inc, Chicago, IL). All analyses were performed according to intent-to-treat procedures, with the exception of the evaluation of treatment toxicities. Differences in neurophysiologic parameters between groups A and B were also calculated, using the independent samples t test from SPSS Base 8.0 for Windows.
Patient Characteristics The trial opened in August 1997 and was closed to accrual in February 2000. Sixty patients met the eligibility criteria and were accrued into the study; 30 patients were randomly assigned to each treatment arm. The median follow-up duration (from date of accrual until last follow-up or death) was 14 months. Patient characteristics are listed in Table 1  . Treatment arms were balanced with respect to most characteristics; however, there were fewer patients in arm B than in arm A with squamous cell carcinoma (seven v 14 patients, respectively).
The median age was 65 years (range, 33 to 77 years). There were 48 men and 12 women. Forty-four of 60 patients (73%) had stage IIIB disease and 16 of 60 patients (27%) had stage IIIA disease. The cell type was squamous cell carcinoma in 21 patients (35%), large cell in 15 patients (25%), adenocarcinoma in 15 patients (25%), and not specified in nine patients (15%).
Treatment Received
Of the 48 patients treated with chemoradiotherapy, 47 patients (98%) received at least 50 Gy. One patient died during the fifth week of treatment from pulmonary embolism after receiving only 44 Gy of radiotherapy. Thirty-eight patients (79%) received all six doses of weekly paclitaxel (Table 3 ). Eight patients required interruption of weekly chemotherapy because of toxicities. One patient refused the last two doses of paclitaxel. The patient who died from pulmonary embolism did not complete treatment.
Toxicity The objective of the study was to evaluate the role of amifostine in reducing the toxicities of treatment in this combined-modality regimen. Only the 48 patients (21 patients from arm A and 27 patients from arm B) who received induction chemotherapy and concurrent chemoradiotherapy were assessable for toxicities of treatment.
Toxicities were graded using National Cancer Institute common toxicity criteria. Radiation-induced toxicity of esophagitis was graded using the Radiation Therapy Oncology Group criteria (Table 4
Hematologic toxicity was not statistically different between the two arms. Grade 3 or 4 neutropenia occurred in 11 patients (52%) in arm A and in 12 patients (44%) in arm B. The difference was 8% (95% CL = -19%, 34%). Mild anemia was seen equally, with grade 3 anemia occurring in only one patient from each arm. Thrombocytopenia was also mild and there was no documentation of grade 3 or 4 toxicities.
According to clinical evaluation, five patients (24%) from arm A and 10 patients (37%) from arm B developed grade 2 or 3 neuropathy (sensory and/or motor; difference of -13%; 95% CL = -36%, 13%). Objective evaluation of neurotoxicity was made using neurophysiologic studies performed before treatment and 2 weeks after completion of chemoradiotherapy. Overall, the 72 neurophysiologic parameters before and after treatment showed worsening in both treatment groups, but there was no statistical difference between the groups (Fig 2
Other toxicities were similar in both treatment arms. Most patients had pronounced alopecia, and five patients (24%) in arm A and seven patients (26%) in arm B had grade 3 fatigue. Nausea and vomiting were generally tolerable and could readily be controlled with medication; however, nausea and vomiting were severe in one patient from each treatment arm.
Side effects reported during the infusion of amifostine or placebo were also analyzed. The predominant side effect observed during infusion of amifostine was hypotension, defined here as a decreases in systolic blood pressure of
There were four treatment-related deaths, all of which occurred during the induction chemotherapy phase. One patient from arm A died from acute pulmonary edema, which developed on day 2 after the first cycle of chemotherapy. Another patient from arm A developed a perforated duodenal ulcer on day 4; the ulcer was surgically repaired, but the patient died of neutropenic sepsis in the postoperative period. Two patients from arm B died within 14 days of the first cycle of chemotherapy; the deaths were considered treatment related. Other serious adverse events included massive hemoptysis during the induction phase in two patients; one of the patients survived after arterial embolization and continued treatment, whereas the other patient died. One patient died from pulmonary embolism during the fifth week of concurrent chemoradiotherapy treatment.
Response and Survival
Overall survival curves for the two treatment arms are shown in Fig 3A . Median survival times of patients in arm A and B were 12.5 and 14.5 months, respectively. There was a reduction in risk of death in arm A, compared with arm B (hazard ratio [HR], 0.84; 95% CI, 0.46 to 1.52; P = .56). This result was not materially altered after adjusting for disease stage (HR, 0.86; 95% CI, 0.47 to 1.58; P = .64).
PFS curves comparing the two treatment arms are shown in Fig 3B  . The median time to disease progression in arms A and B were 9.0 and 13 months, respectively. No significant difference in PFS was noted (HR, 0.81; 95% CI, 0.44 to 1.51; P = .50).
In an effort to improve the therapeutic index of combined-modality treatment in the management of locally advanced NSCLC, this study was designed to explore the role of amifostine in reducing both the toxicities of chemotherapy and the escalated toxicities of chemoradiotherapy. The results of this double-blind, placebo-controlled trial showed that pretreatment with amifostine before each dose of paclitaxel during concurrent chemoradiotherapy reduced the incidence of severe esophagitis of grade 2 or higher. The results are consistent with recent data reported by Komaki et al44 and Werner-Wasik et al.45 The difference in incidence of severe esophagitis of 43% in amifostine-treated patients versus 70% in the control group, however, failed to reach statistical significance. This was probably because patient numbers were too small to detect the degree of difference shown in the study; as stated earlier, the study was designed to detect a reduction in severe esophageal toxicity from 40% to 10%. Another plausible reason for the lack of statistical significance may be that amifostine was not administered frequently enough during radiotherapy. In this study, amifostine (or placebo) was given only once a week (before each dose of chemotherapy) because the aim was to reduce the radiosensitization effect. This model was similar to that used in a study of patients with head and neck cancer.46 Because amifostine has also been shown to reduce esophagitis in patients treated with radiotherapy alone,47 protection against esophagitis might be greater if it was administered twice weekly44,45 or more frequently,47,48 before each fraction of radiotherapy. With regard to myeloprotection and protection against neurotoxicity, we have been unable to show a significant reduction in severe toxicities. Myelosuppression and neurotoxicity are toxicities associated mainly with the combination paclitaxel and carboplatin given during the induction phase. In a study by Gelmon et al,49 breast cancer patients given one dose of amifostine before a 3-hour paclitaxel infusion similarly did not experience less neurotoxicity or myelosuppression, compared with patients who did not receive amifostine. Why the results of preclinical studies29 have not been borne out in our study may again be because the study was not powered to detect small differences or because amifostine just did not reduce paclitaxel-induced neurotoxicity and myelosuppression. Another postulation is that perhaps this was a flaw in the study design itself. Kemp et al26 showed that amifostine was effective protection against myelotoxicity and neurotoxicity in ovarian cancer patients treated with a combination of cyclophosphamide and cisplatin. The difference between the Kemp study and our study was, of course, the use of different chemotherapy agents. In addition, the infusion times for chemotherapy were shorter: 20 and 30 minutes for cyclophosphamide and cisplatin, respectively. In animal models, WR-1065, the major metabolite responsible for cytoprotection, was found in normal cells within 15 minutes of IV injection of amifostine into mice and it remained there for up to 60 minutes.50 It is possible that with paclitaxel being infused over 3 hours and carboplatin being infused over another hour, one dose of amifostine before the administration of each chemotherapy agent may not be sufficient to bring about meaningful cytoprotection. Larger studies have been performed that may be able to shed more light on the use of amifostine together with the paclitaxel and carboplatin combination.32 Future studies, with perhaps a change in the strategy of amifostine administration, using multiple doses during paclitaxel and carboplatin34 infusion, may be required.
Supported in part by Schering Plough, which also provided the amifostine.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20 mmHg from the baseline value. Of the 30 patients who were given amifostine, 21 patients (70%) experienced at least one episode of reduction in systolic blood pressure, as defined. This occurred most commonly toward the end of the amifostine infusion. In most affected patients, the episode(s) was transient and the blood pressure recovered within 5 to 10 minutes of completing the amifostine. In three patients however, an interruption of amifostine treatment was required, and additional normal saline had to be infused. Two of the patients were able to complete the amifostine infusion after corrective measures. In the third patient, the hypotensive episode, which occurred during the first cycle of induction chemotherapy, was associated with severe dizziness and vomiting, such that the second dose of amifostine had to be omitted. Only nine patients (30%; P = .002) in the placebo group had a hypotensive episode, and all episodes were transient and required no intervention. Other side effects that occurred significantly more in the amifostine arm than in the placebo arm were vomiting, sneezing, dizziness, chills, and hiccups (Table 5
