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Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non–small-cell lung cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 57, No. 2, pp. 402– 408, 2003 Copyright © 2003 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter
doi:10.1016/S0360-3016(03)00590-X
CLINICAL INVESTIGATION
Lung
EFFECT OF AMIFOSTINE ON TOXICITIES ASSOCIATED WITH RADIOCHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED NON–SMALL-CELL LUNG CANCER DOSIA ANTONADOU, M.D.,* NIKOLAS THROUVALAS, M.D.,* ARIS PETRIDIS, M.D.,* NICOLAS BOLANOS, M.D.,† ALEXANDROS SAGRIOTIS, M.SC.,* AND MARIA SYNODINOU, M.D.* Departments of *Radiation Oncology and †Thoracic Surgery, Metaxa Cancer Hospital, Piraeus, Greece Purpose: Radiochemotherapy (RCT) is an effective treatment for locally advanced non–small-cell lung cancer (NSCLC), but can be limited by acute and late toxicities (esophagitis, pneumonitis, and myelosuppression). This trial investigated whether pretreatment with amifostine, a radioprotector, could reduce the incidence of radiochemotherapy-induced acute and late toxicities. Methods and Materials: Between October 1997 and August 1999, 73 patients with previously untreated Stage IIIa–IIIb NSCLC were randomized to treatment with RCT alone (n ⴝ 36) or RCT plus amifostine (300 mg/m2 daily i.v. infusion, n ⴝ 37). RCT consisted of either paclitaxel (60 mg/m2) or carboplatin (AUC 2) once weekly during a 5- to 6-week course of conventional radiotherapy given as 2 Gy/5 days/week to a total dose of 55 to 60 Gy. Blood cell counts were measured weekly; esophagitis and acute lung toxicity were evaluated during the treatment course. Treatment efficacy was assessed following World Health Organization criteria for response. Late lung toxicity was assessed at 3 and 6 months after RCT and was graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria. Results: A total of 68 patients were evaluable for toxicity analysis (RCT group, n ⴝ 32; RCT ⴙ amifostine, n ⴝ 36). There was no significant difference between treatment arms in patient baseline characteristics. The incidence of Grade >3 esophagitis during RCT was significantly lower for patients receiving amifostine than for patients receiving RCT alone (38.9% vs. 84.4%%, p < 0.001). Furthermore, the incidence of Grade >3 acute pulmonary toxicity was significantly reduced in patients treated with RCT plus amifostine compared to patients who received RCT alone (19.4% vs. 56.3%, p ⴝ 0.002). At 3 months after RCT, patients treated with amifostine had a significantly lower incidence of pneumonitis than patients who received RCT alone (p ⴝ 0.009). Combined response rates (complete plus partial responses) were 82.2% in the RCT group and 88.8% in the RCT plus amifostine group (p ⴝ 0.498). Conclusion: Amifostine is effective in reducing the incidence of both acute and late toxicities associated with RCT in patients with locally advanced NSCLC without compromising antitumor efficacy. © 2003 Elsevier Inc. Radiochemotherapy, Non–small-cell lung cancer, Amifostine, Toxicity, Cytoprotectant.
INTRODUCTION Lung cancer is the leading cause of cancer-related mortality for both men and women (1). Approximately 75% to 85% of all lung neoplasms are non–small-cell lung cancer (NSCLC), and as many as 40% of all NSCLC patients present with locally advanced and/or unresectable disease (2). Although thoracic radiotherapy (RT) has been the traditional treatment strategy, numerous clinical studies have demonstrated that the addition of a chemotherapeutic regimen to RT results in an improvement in survival rates and median survival times for patients with NSCLC (3– 6). Thus, combined modality radiochemotherapy (RCT) has emerged as the primary treatment option for locally advanced NSCLC (7, 8).
Earlier clinical trials of combined-modality treatments for NSCLC evaluated sequential (induction) chemotherapy followed by fractionated RT. Although clinical outcomes have improved with sequential chemotherapy plus RT compared with RT alone, long-term survival remains poor in patients with locally advanced disease (9, 10). Thus, concurrent RCT regimens have also been studied. Concurrent RCT offers several advantages over sequential chemotherapy followed by radiotherapy, and, in addition, radiosensitization during RT may improve locoregional tumor control (11). Randomized trials have demonstrated that concurrent RCT results in increased time to disease progression (12, 13) and improved survival (14) compared with sequential chemotherapy plus RT.
Reprint requests to: Dosia Antonadou, M.D., Radiation Oncologist, Metaxa Cancer Hospital, 51 Botasi Street, 185 37, Piraeus, Greece. Tel: (301) 428-4444; Fax: (301) 801-0647; E-mail:
[email protected] Received Nov 11, 2002, and in revised form Apr 21, 2003. Accepted for publication Apr 23, 2003. 402
Radiochemotherapy ⫾ amifostine in non–small-cell lung cancer
Platinum compounds and taxanes are two classes of chemotherapeutic agents that have been evaluated in combination with thoracic RT. Recent meta-analyses of randomized clinical trials have demonstrated a statistically significant survival benefit for advanced-stage NSCLC patients receiving cisplatinum-based chemotherapy combined with RT compared with RT alone (15, 16). Carboplatin, a less toxic cisplatin analog, has activity in NSCLC that is comparable to the parent compound (17). Jeremic et al. (4) demonstrated that daily carboplatin plus etoposide combined with hyperfractionated RT results in improved median survival time (22 months vs. 14 months) and 4-year survival rates (23% vs. 9%, p ⫽ 0.021) compared with hyperfractionated RT alone. Paclitaxel has antitumor activity when used as a single agent in the treatment of NSCLC (18) and has also been shown to be a potent radiosensitizer (19). In a Phase II trial in which paclitaxel (60 mg/m2) was administered once per week with daily RT in patients with Stage III NSCLC, an overall response rate of 86% and a median survival time of 20 months were reported (20). More recent studies have evaluated combinations of paclitaxel and carboplatin administered concurrently with RT (21–24). However, toxicities associated with combined modality RCT are of great concern, because they may be doselimiting or have a negative impact on patient quality of life. These toxicities may necessitate interruptions in planned radiation treatment, which may subsequently influence local control and possibly patient survival. Toxicities associated with RCT regimens for NSCLC include acute esophagitis and acute and late lung toxicity, which are related primarily to radiation-induced toxicity that occurs in normal tissues of the respiratory system and nearby anatomic structures. The clinical question of whether pneumonitis progresses into fibrosis remains under investigation (25). The current standard is that pneumonitis might lead to fibrosis after a dose of 30 Gy. In theory, the chemotherapeutic component of RCT regimens may have inherent pulmonary toxicity or produce additional adverse effects such as myelosuppression, nephrotoxicity, neurotoxicity, and alopecia. However, the doses of chemotherapeutic agents administered concurrently with RT are low and generally do not produce additional side effects, with the exception of myelosuppression. Several studies have demonstrated increased incidences of esophagitis and pneumonitis with combined modality RCT regimens for the treatment of lung cancer (5, 26, 27). Such toxicity concerns have led to an increased interest in cytoprotective agents that are capable of preserving normal tissues without compromising antitumor efficacy (2, 28). Amifostine is the first broad-spectrum cytoprotectant approved for clinical use in many countries (29). Amifostine is an organic thio-phosphate molecule that is an analog of cysteamine. Amifostine itself is not biologically active, but is dephosphorylated by membrane-bound alkaline phosphatase to yield its active free-thiol metabolite, WR-1065. WR-1065 provides cytoprotection primarily by two mech-
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anisms: It acts as a scavenger of oxygen free radicals induced by ionizing radiation, and it serves as an alternative target to nucleic acids for the reactive molecules of alkylating or platinum drugs (2, 29, 30). The objective of this randomized study was to investigate whether pretreatment with amifostine could safely reduce the incidence of esophagitis and acute and late lung toxicities during conventional thoracic radiation combined with weekly paclitaxel or carboplatin administration in patients with locally advanced (Stage III) NSCLC. METHODS Study design This was a Phase II randomized study. All patients underwent radiation treatment and were randomly allocated to receive weekly paclitaxel or carboplatin with or without amifostine pretreatment. Baseline evaluations were performed before initiation of treatment and included a complete medical history; physical examination; determination of Eastern Cooperative Oncology Group (ECOG) performance status; full blood counts; biochemistry profile; cardiovascular examination; and thorax, abdomen, and brain computed tomography (CT) scans. All patients underwent bronchoscopic biopsy or fine-needle aspiration cytology before study entry. The primary end points of the study were as follows: (1) evaluation of the incidence of Grade 3 or higher esophagitis and acute lung toxicity, and (2) evaluation of the clinical outcome following World Health Organization criteria for response. The secondary end points were (1) evaluation of the incidence of pneumonitis and/or fibrosis, and (2) evaluation of hematologic toxicity. Eligibility criteria All patients (ⱖ18 years of age) had histologically or cytologically proven NSCLC and ECOG performance status of ⱕ2. The disease was confined to the primary site of the lung and/or regional lymph nodes. Patients with Stage IIIa or IIIb NSCLC were eligible. Life expectancy of ⬎6 months was required. Patients were ineligible if they had pleural effusion, weight loss of ⬎10%, and if they had received prior radiotherapy or chemotherapy, or had distant metastases. All patients were required to give written informed consent. Radiotherapy The patients underwent conventional RT with a 12-MV photon beam. The target volume included the primary site plus a 2-cm margin and mediastinal and ipsilateral hilar lymph nodes. Planning was CT scan assisted, and corrections were made for tissue inhomogeneities. The dose of 52 Gy was prescribed to the isodose line encompassing the target volume. The total dose to the primary tumor site ranged between 55 to 60 Gy and was given using anterior and posterior opposed parallel fields, and an oblique field whenever possible. The daily dose was 2 Gy for 5 days per
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week. A complementary (boost) dose was administered to the primary site and ranged from 5 to 7 Gy. The spinal cord was protected at 45 Gy. On the days of chemotherapy, RT was given 30 to 60 min after completion of chemotherapy and 15 min after the infusion of amifostine. Chemotherapy Patients were randomized to receive paclitaxel (60 mg/ m2) or carboplatin (AUC 2) as a radiosensitizer once per week. If myelosuppression occurred (defined as an absolute neutrophil count of ⬍1.3 ⫻ 109/L and/or platelet count ⱕ100 ⫻ 109/L), the next course of chemotherapy was postponed for 1 week. Before paclitaxel, all patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Amifostine Amifostine (300 mg/m2) was administered by i.v. infusion over 10 min daily 15 min before RT and before carboplatin or paclitaxel infusion on chemotherapy days. An antiemetic agent was given before the amifostine infusion. Blood pressure was measured before the infusion, during the entire infusion, and immediately after the procedure. Attention was given to the antihypertensive medication of the patients, and whenever systolic blood pressure was ⱕ100 mm Hg, patients received i.v. hydration with 500 mL normal saline. Toxicity Acute and late toxicities were graded 0 to 4 according to Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria, with the exception of fibrosis. All patients were monitored once per week during treatment, and the clinical symptoms of RCTinduced toxicities were evaluated by two independent clinicians taking into consideration also the patient’s selfassessment. Patients were initially seen at 15 days and monthly for the first 3 months after RCT, then at 3-month intervals. Whenever the study population presented clinical symptoms of lung toxicity during the follow-up period, the patient was further evaluated with CT scan, which offers more accurate information concerning the presence of pneumonitis. The radiographic findings (chest X-rays or thoracic CT scans) were centrally reviewed. Radiologic changes were inferred from diffuse haze, and a ground glass opacification confined within the radiation field indicated the appearance of pneumonitis. The presence of fibrosis, whenever present, was assessed by a thoracic CT scan at 6 months after RCT. Clinical outcome Response to radiochemotherapy was assessed according to World Health Organization criteria based on CT scan 2 months after completion of treatment and was confirmed 1 month later. The evaluation of response was necessary in this trial to exclude any adverse effect of amifostine admin-
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istration on treatment efficacy. A more detailed analysis of treatment efficacy will be described separately. Statistical analyses Based on our previous experience, the expected number of patients with esophagitis and/or lung toxicity has been estimated (29). Sample size was calculated based on the comparison of esophagitis and lung toxicity during RCT between subjects receiving amifostine with RCT and the RCT-alone group. Based on a two-sided test of significance and a random assignment to one of the two treatment arms in a 1:1 ratio, at the 5% significance level with a power of 80%, a sample size of 72 evaluable patients was sufficient to allow for the detection of a difference of 40% esophagitis ⱖ Grade 3 (20% lung toxicity) in the amifostine and RCT group and of 80% esophagitis (50% lung toxicity) in the RCT-alone group. According to the “intention-to-treat” principle, all patients who passed through the randomization phase in the study were evaluated. The baseline demographic characteristics of treatment groups, stratified according to the presence or absence of amifostine treatment, were tested for differences using an analysis of variance for age and Pearson’s exact two-sided test for gender and disease stage. Pearson’s exact test was used also to compare the number of patients with acute toxicities (ⱖ Grade 3) during treatment and the incidence of pneumonitis (ⱖ Grade 3) and fibrosis post-RCT. A p value of 0.05 or less was interpreted as statistically significant; p values were not adjusted. All computations were carried out using SPSS and StatXact software systems. RESULTS Patient characteristics Between October 1997 and August 1999, 73 patients were randomized. One patient was not treated, because he did not fulfill inclusion/exclusion criteria. Of the 72 subjects treated, 2 patients withdrew their consent, and 2 patients were lost to follow-up. All 4 patients were enrolled in the carboplatin arm, but the reasons for discontinuation were not relevant to the investigational drug. In total, 68 patients were analyzed in an intention-to-treat analysis; 36 received RCT plus amifostine (paclitaxel, n ⫽ 19, and carboplatin, n ⫽ 17) whereas 32 patients were treated with RCT alone (paclitaxel, n ⫽ 17, and carboplatin, n ⫽ 15). The demographics and baseline characteristics of the patients are summarized in Table 1. The two treatment groups were evenly balanced, and there were no significant differences between groups with respect to patient age, gender, or disease stage. All patients had NSCLC; 3 patients in each group had Stage IIIa disease, and 29 and 33 patients had Stage IIIb disease in the RCT-alone and RCT plus amifostine groups, respectively. The majority of patients had a good ECOG performance status at baseline, and there was a minimum weight loss during the previous 3 months. The radiation treatment characteristics were evenly bal-
Radiochemotherapy ⫾ amifostine in non–small-cell lung cancer
Table 1. Patient demographics and baseline characteristics
Patients: n Age: mean (SD) Gender: n (%) Female Male NSCLC stage: n (%) IIIa IIIb ECOG status: n (%) 0 1 3 Weight loss: n (%) None ⬍10%
RCT
RCT ⫹ amifostine
32 61.9 (11.4)
36 62.2 (7.9)
28 (87.5) 4 (12.5)
34 (94.4) 2 (5.6)
3 (9.4) 29 (90.6)
3 (8.3) 33 (92.7)
1 (3.1) 28 (87.5) 3 (9.4)
2 (5.6) 32 (88.9) 2 (5.6)
0.753
27 (84.4) 5 (15.6)
29 (80.6) 7 (19.4)
0.925
p value 0.952 0.410 1.00
Abbreviations: RCT ⫽ radiochemotherapy; SD ⫽ standard deviation; NSCLC ⫽ non–small-cell lung cancer.
anced with respect to total dose delivered for both treatment groups and treatment duration (Table 2). Patients in both groups did not receive any supportive medication routinely during RCT treatment. Acute toxicity All patients were monitored once per week during treatment and every 4 weeks thereafter for at least 3 months or until toxicities resolved. Although the RCT protocols using either paclitaxel or carboplatin were relatively well tolerated in the study population, the addition of amifostine pretreatment produced significant reductions in the incidence of acute toxicities associated with RCT. The incidence of (Grade ⱖ3) esophagitis during RCT was significantly lower for patients treated with RCT and amifostine than for patients treated with RCT alone (38.9% vs. 84.4%, p ⬍ 0.001). Furthermore, the incidence of (Grade ⱖ3) acute pulmonary toxicity experienced by the patients receiving amifostine was significantly reduced compared to the acute lung toxicity experienced by patients treated with RCT alone (19.4% vs. 56.3%, p ⫽ 0.002). Because different findings were observed in the group of patients either with paclitaxel or carboplatin, a subgroup analysis was conTable 2. Radiation treatment characteristics
Patients: n Radiation dose Total (Gy) SD Treatment duration Mean (days) SD
RCT
RCT ⫹ amifostine
32
36
57.5 44.0
58.3 53.6
0.604
36.5 7.5
37.2 8.0
0.523
p value
Abbreviations: RCT ⫽ radiochemotherapy; SD ⫽ standard deviation.
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ducted. The incidence of esophagitis (Grade ⱖ3) during RCT was significantly lower for patients receiving amifostine and paclitaxel than for patients receiving paclitaxel alone (47% vs. 88%, p ⫽ 0.014) and for patients receiving amifostine and carboplatin than for patients given carboplatin alone (29% vs. 80%, p ⫽ 0.006). The incidence of acute pulmonary toxicity (Grade ⱖ3) during RCT was significantly reduced in patients receiving amifostine plus paclitaxel compared with patients treated with paclitaxel alone (21% vs. 59%, p ⫽ 0.039). In addition, the reduction in acute pulmonary toxicity observed in patients treated with amifostine plus carboplatin compared with patients receiving carboplatin alone (18% vs. 53%, p ⫽ 0.062) approached statistical significance (Fig. 1). The incidences of neutropenia and thrombocytopenia were lower in patients pretreated with amifostine during RCT; in the carboplatin treatment arm, this difference showed a trend toward statistical significance in favor of amifostine (p ⫽ 0.075). In the paclitaxel group at 2 months posttreatment, Grade ⱖ3 esophagitis was present in 9/16 patients in the control group (without amifostine), but in only 2/16 patients in the paclitaxel plus amifostine group. The incidence of esophagitis reached statistical significance (p ⫽ 0.023). In the carboplatin group, no patients experienced symptoms of esophagitis at 15 days post-RCT. Amifostine administration was well tolerated. Only 3 of the 36 patients treated with amifostine experienced nausea and vomiting during more than 5 infusions, and 8 patients had transient hypotension during the administration. No patients discontinued amifostine pretreatment. Late toxicity During the follow-up period after completion of RCT, patients were stratified into two groups based on whether they had received amifostine during RCT, independent of paclitaxel or carboplatin chemotherapy (Table 3). At 3 months, 60 patients were evaluable for late toxicity. In 8 patients, the evaluation of toxicity was not possible for the following reasons: Two patients in the RCT plus amifostine group were lost to follow-up, and 1 patient died; in the RCT group, 3 patients were lost to follow-up, and 2 patients died. At 6 months, 52 patients completed the follow-up visits, and deaths in both groups accounted for most of the patients lost to follow-up. At the 3-month follow-up, a significantly reduced incidence of pneumonitis was observed in the amifostine pretreatment group compared with patients who received no pretreatment (30.3% vs. 66.7%, p ⫽ 0.009). The incidence of fibrosis also was lower in the amifostine pretreatment group at the 6-month follow-up (28.6% vs. 50.0%, p ⫽ 0.156); however, this finding did not reach statistical significance. Clinical outcome All patients enrolled in this study were evaluable for response at 2 months post– combined treatment. Table 4 summarizes the response rates. The combined response
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Fig. 1. Incidence of acute toxicities during radiochemotherapy ⫾ amifostine. Acute toxicities were defined as ⱖ Grade 3 for esophagitis and pulmonary toxicities, and absolute neutrophil count ⬍1.3 ⫻ 109/L and platelets ⬍100 ⫻ 109/L for neutropenia and thrombocytopenia, respectively. (a) The incidence of acute toxicities with RT plus paclitaxel. (b) The incidence of acute toxicities with RT plus carboplatin. Values on the bars indicate the number of patients in each group that experienced the toxicity.
rates (complete plus partial responses) were 82.2% in the RCT group and 88.8% in the RCT plus amifostine group (p ⫽ 0.498 for patient distribution across clinical outcomes). DISCUSSION Although the optimal therapeutic regimen has yet to be defined, combined modality RCT represents the current standard of treatment for selected patients with locally advanced unresectable NSCLC (31). Radiation may be delivered as conventional external beam thoracic RT, hyperfractionated RT, or hyperfractionated accelerated RT. In general, chemotherapy administered concurrently rather than sequentially with RT is associated with improved clinical outcomes. However, toxicities associated with RCT regimens can be dose-limiting, resulting in treatment interruptions. In addition, patient quality of life is an important therapeutic consideration, because treatment-related toxicities may negate modest survival benefits conferred by aggressive treatment regimens. Esophagitis and lung toxicities are the most common acute toxicities associated with RT for NSCLC. Pneumonitis, which is characterized primarily by cough and dyspnea, Table 3. Incidence of late pulmonary toxicities after radiochemotherapy RCT 3-month follow-up Patients: n Pneumonitis: n (%) 6-month follow-up Patients: n Fibrosis: n (%)
27 18 (66.7) 24 12 (50)
RCT ⫹ amifostine 33 10 (30.3) 28 8 (28.6)
Abbreviation: RCT ⫽ radiochemotherapy.
usually occurs between 2 and 3 months after radiation (32). With the exception of myelosuppression, the addition of chemotherapeutic agents (at relatively low doses) to RT generally does not result in a change in the pattern of toxicities that is observed, although the incidence and severity may increase (33). For example, in the Phase I study by Choy et al. (34), the maximum tolerated dose of paclitaxel administered weekly with concurrent RT (60 Gy) in patients with locally advanced NSCLC was 60 mg/m2, and the dose-limiting toxicity was esophagitis. In three subsequent Phase II studies of paclitaxel at this dose, the most common acute toxicity again was esophagitis, with reported incidences of 17% to 26% using Radiation Therapy Oncology Group criteria (33). Although there are relatively few studies of carboplatin used as a single agent with RT, information regarding toxicities can be gleaned from studies of combination chemotherapeutic regimens that include this agent. For example, in the study of Jeremic et al. (4), bronchopulmonary and esophageal toxicities were the most common acute and late toxicities in NSCLC patients treated with hyperfractionated RT plus carboplatin and etoposide. Numerous clinical trials have evaluated combination carboplatin/paclitaxel regimens administered concurrently with RT. In a recent Phase II study of weekly paclitaxel (50 mg/m2) plus carboplatin (AUC 2) with concurrent hyperfractionated RT, esophagitis Table 4. Clinical responses to RCT according to WHO criteria RCT
RCT ⫹ amifostine
32 5 (15.6) 21 (65.6) 4 (12.5) 2 (6.2)
36 12 (33.3) 20 (55.5) 3 (8.3) 1 (2.7)
p value
0.009 0.156
Patients: n Complete response: n (%) Partial response: n (%) Stable disease: n (%) Progressive disease: n (%)
Abbreviation: RCT ⫽ radiochemotherapy.
p value
0.498
Radiochemotherapy ⫾ amifostine in non–small-cell lung cancer
was the most common toxicity, and esophagitis ⱖ Grade 3 occurred in 26% of patients (24). In a Phase II trial that evaluated hyperfractionated RT with concurrent weekly carboplatin (AUC 1.5), but that divided the paclitaxel dose (30 mg/m2 twice weekly), esophagitis (38%) and neutropenia (12%) were the most frequent Grade 3 or 4 toxicities observed during the RCT phase of the study (22). Reduction of esophageal and lung toxicities during RCT may reduce the need for treatment interruptions and increase patient quality of life (2). In this regard, the potential therapeutic role of cytoprotective agents such as amifostine has drawn considerable interest. Several clinical studies have been performed to evaluate the effects of amifostine in patients undergoing treatment for NSCLC. Betticher et al. (35) reported significant reductions in the duration of thrombocytopenia (13.5 days vs. 21 days, p ⫽ 0.004) and the need for hospitalization (0/20 vs. 6/25 patient courses, p ⫽ 0.006) with carboplatin plus amifostine treatment than with carboplatin treatment alone. Response rates and median survival times were similar in both treatment arms (35). Tannehill et al. (36) evaluated 26 patients with Stage III NSCLC who received amifostine before induction chemotherapy with cisplatin and vinblastine followed by largefield thoracic radiation. Given that no cases of Grade 3 or 4 esophagitis or nephrotoxicity were observed and that the objective response rate was 60%, the authors concluded that amifostine reduced cisplatin-related and radiation-induced toxicities without impairing the response to treatment (36). Komaki et al. (37) evaluated 60 patients with inoperable Stage II or III NSCLC treated with concurrent radiochemotherapy. Both groups received oral etoposide and cisplatin, together with twice-daily radiation therapy (1.2 fractions, 5 days per week) to a total dose of 69.6 Gy. Patients in the study group received 500 mg of amifostine twice weekly before chemoradiation. Morphine intake to reduce severe odynophagia was significantly lower in the amifostine group, 7.4% vs. 31% in the control group (p ⫽ 0.03). Furthermore, acute pneumonitis was significantly lower in the amifostine group, 3.7%, than in the RCT-alone group, 23% (p ⫽ 0.037). The authors concluded that amifostine reduced RCT-related toxicities without compromising treatment efficacy. The lower incidence of toxicity observed in the study by Komaki et al. (37), compared to the incidence of acute toxicity in our study, is probably because of a more selected patient sample, as well as the chemotherapeutic agents and chemotherapy schedule applied in her study. Morphine intake is another approach in the evaluation of
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esophagitis. In her study, a statistically significant difference in the incidence of RCT-induced toxicities was observed, although amifostine was administered twice a week before chemoradiation. The results from the randomized Phase II study presented herein further demonstrate that the addition of amifostine to an RCT regimen (conventional thoracic radiation combined with concurrent weekly paclitaxel or carboplatin treatment) reduces the incidence of treatment-related toxicities without compromising antitumor efficacy. For all acute toxicities assessed during treatment (esophagitis, pulmonary toxicity, neutropenia, thrombocytopenia), the incidences were lower in treatment groups receiving amifostine. The high incidence of esophagitis presented in our study was probably the result of the selection of the patients entered in this trial. Patients with lung cancer are usually in bad health and have harmful habits such as smoking that they continue during treatment, so the lung tissue and the esophageal mucosa are heavily compromised. The majority of the patients entered in our study were Stage IIIb patients, so the probability of lymph node involvement in the mediastinum was high, and we were obliged to use a large radiation field, which, combined with the weekly administration of carboplatin or paclitaxel, enhanced the acute toxicities. These differences were statistically significant in favor of amifostine for acute esophagitis in both the paclitaxel and carboplatin arms, and for acute pulmonary toxicity in the paclitaxel arm. The results for acute pulmonary toxicity and thrombocytopenia approached statistical significance in favor of amifostine in the carboplatin arm. With respect to late toxicities after the 5- to 6-week treatment duration, the addition of amifostine significantly reduced the incidence of pneumonitis at 3 months after RCT in all evaluable patients. There was also a reduction in fibrosis at the 6-month post-RCT evaluation in patients who had received amifostine; however, this result did not achieve statistical significance. Nonetheless, it should be noted that the number of patients in this Phase II study was relatively small, so larger Phase III studies are warranted. In summary, combined modality RCT plays an important role in the treatment of NSCLC. With the recognition that treatment-related toxicities can compromise therapy outcome and quality of life, the reduction of these toxicities becomes essential. The addition of amifostine allowed patients to complete the scheduled treatment without interruptions and without the major side effects that might compromise treatment efficacy.
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in stage III non-small-cell lung cancer: Seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210–1215. Werner-Wasik M, Scott C, Cox JD, et al. Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): Identification of five groups with different survival. Int J Radiat Oncol Biol Phys 2000;48:1475– 1482. Choi NC, Carey RW, Daly W, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer. J Clin Oncol 1997;15:712–722. Belani CP. Incorporation of paclitaxel and carboplatin in combined-modality therapy for locally advanced non-small cell lung cancer. Semin Oncol 1999;26(1 Suppl. 2):44–54. Choy H, MacRae R. The current state of paclitaxel and radiation in the combined-modality therapy of non-small cell lung cancer. Semin Oncol 2001;28(Suppl. 14):17–22. Gaspar LE. Optimizing chemoradiation therapy approaches to unresectable stage III non–small cell lung cancer. Curr Opin Oncol 2001;13:110–115. Vokes EE, Green MR. Current strategies for locoregionally advanced unresectable non-small cell lung cancer. Semin Oncol 1999;26(5 Suppl 15):40–43. Curran WJ, Scott C, Langer C, et al. Phase III comparison of sequential versus concurrent chemoradiation for patients with unresected stage III non-small cell lung cancer (NSCLC): Initial report of Radiation Therapy Oncology Group (RTOG) 9410 (Abstr.). Proc Am Soc Clin Oncol 2000;19:1891a. Komaki R, Seriferheld W, Curran W, et al. Sequential versus concurrent chemotherapy and radiation therapy for inoperable non-small cell lung cancer (NSCLC): Analysis of failures in a phase III study (RTOG 9410) (Abstr.). Int J Radiat Oncol Biol Phys 2000;48:5. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999; 17:2692–2699. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 1995;311:899–909. Pignon JP, Stewart LA. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb non-small cell lung cancer: A metaanalysis. Cancer 1996;77:2413–2414. Gordon GS, Vokes EE. Chemoradiation for locally advanced, unresectable NSCLC. New standard of care, emerging strategies. Oncology (Huntingt) 1999;13:1075–1088. Murphy WK, Fossella FV, Winn RJ, et al. Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst 1993;85:384–388. Choy H, Browne MJ. Paclitaxel as a radiation sensitizer in non-small cell lung cancer. Semin Oncol 1995;22(3 Suppl. 6):70–74. Choy H, Safran H, Akerley W, et al. Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Clin Cancer Res 1998;4: 1931–1936. Belani CP. Combined modality therapy for unresectable stage III non-small cell lung cancer: New chemotherapy combinations. Chest 2000;117(4 Suppl. 1):127S–132S.
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22. Lau D, Leigh B, Gandara D, et al. Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/paclitaxel consolidation for stage III non-small-cell lung cancer: A California Cancer Consortium phase II trial. J Clin Oncol 2001;19:442–447. 23. Ratanatharathorn V, Lorvidhaya V, Maoleekoonpairoj S, et al. Phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer. Lung Cancer 2001;31:257–265. 24. Choy H, Devore RF III, Hande KR, et al. A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study). Int J Radiat Oncol Biol Phys 2000;47:931–937. 25. Do¨ rr W, Baumann M, Herrmann T. Radiation-induced lung damage: A challenge for radiation biology, experimental and clinical radiotherapy. Int J Radiat Biol 2000;76:443–446. 26. Lee JS, Scott C, Komaki R, et al. Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: Radiation Therapy Oncology Group protocol 91– 06. J Clin Oncol 1996;14:1055– 1064. 27. Frasci G, Comella P, Scoppa G, et al. Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: A phase I study. J Clin Oncol 1997;15:1409–1417. 28. Castiglione F, Porcile G, Gridelli C. The potential role of amifostine in the treatment of non small cell lung cancer. Lung Cancer 2000;29:57–66. 29. Antonadou D, Coliarakis N, Synodinou M, et al. Randomized phase III of radiation treatment ⫾ amifostine in patients with advanced-stage lung cancer. Int J Radiat Biol 2001;51:915– 922. 30. Capizzi RL, Oster W. Chemoprotective and radioprotective effects of amifostine: An update of clinical trials. Int J Hematol 2000;72:425–435. 31. American Society of Clinical Oncology. Practice guidelines for the treatment of unresectable non-small cell lung cancer. J Clin Oncol 1997;15:2996–3018. 32. Roach M, Gandara DR, You HS, et al. Radiation pneumonitis following combined modality therapy for lung cancer: Analysis of prognostic factors. J Clin Oncol 1995;13:2606–2612. 33. Choy H, LaPorte K, Knill-Selby E, et al. Esophagitis in combined modality therapy for locally advanced non-small cell lung cancer. Semin Radiat Oncol 1999;9(2 Suppl. 1):90– 96. 34. Choy H, Akerley W, Safran H, et al. Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer. J Clin Oncol 1994;12: 2682–2686. 35. Betticher DC, Anderson H, Ranson M, et al. Carboplatin combined with amifostine, a bone marrow protectant, in the treatment of non-small-cell lung cancer: A randomised phase II study. Br J Cancer 1995;72:1551–1555. 36. Tannehill SP, Mehta MP, Larson M, et al. Effect of amifostine on toxicities associated with sequential chemotherapy and radiation therapy for unresectable non-small-cell lung cancer: Results of a phase II trial. J Clin Oncol 1997;15:2850–2857. 37. Komaki R, Lee JS, Kaplan B, et al. Randomized phase III study of chemoradiation with or without amifostine for patients with favorable performance status inoperable stage II-III non-small cell lung cancer: Preliminary results. Semin Radiat Oncol 2002;12(Suppl. 1):46–49.
doi:10.1016/S0360-3016(03)00590-X
CLINICAL INVESTIGATION
Lung
EFFECT OF AMIFOSTINE ON TOXICITIES ASSOCIATED WITH RADIOCHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED NON–SMALL-CELL LUNG CANCER DOSIA ANTONADOU, M.D.,* NIKOLAS THROUVALAS, M.D.,* ARIS PETRIDIS, M.D.,* NICOLAS BOLANOS, M.D.,† ALEXANDROS SAGRIOTIS, M.SC.,* AND MARIA SYNODINOU, M.D.* Departments of *Radiation Oncology and †Thoracic Surgery, Metaxa Cancer Hospital, Piraeus, Greece Purpose: Radiochemotherapy (RCT) is an effective treatment for locally advanced non–small-cell lung cancer (NSCLC), but can be limited by acute and late toxicities (esophagitis, pneumonitis, and myelosuppression). This trial investigated whether pretreatment with amifostine, a radioprotector, could reduce the incidence of radiochemotherapy-induced acute and late toxicities. Methods and Materials: Between October 1997 and August 1999, 73 patients with previously untreated Stage IIIa–IIIb NSCLC were randomized to treatment with RCT alone (n ⴝ 36) or RCT plus amifostine (300 mg/m2 daily i.v. infusion, n ⴝ 37). RCT consisted of either paclitaxel (60 mg/m2) or carboplatin (AUC 2) once weekly during a 5- to 6-week course of conventional radiotherapy given as 2 Gy/5 days/week to a total dose of 55 to 60 Gy. Blood cell counts were measured weekly; esophagitis and acute lung toxicity were evaluated during the treatment course. Treatment efficacy was assessed following World Health Organization criteria for response. Late lung toxicity was assessed at 3 and 6 months after RCT and was graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria. Results: A total of 68 patients were evaluable for toxicity analysis (RCT group, n ⴝ 32; RCT ⴙ amifostine, n ⴝ 36). There was no significant difference between treatment arms in patient baseline characteristics. The incidence of Grade >3 esophagitis during RCT was significantly lower for patients receiving amifostine than for patients receiving RCT alone (38.9% vs. 84.4%%, p < 0.001). Furthermore, the incidence of Grade >3 acute pulmonary toxicity was significantly reduced in patients treated with RCT plus amifostine compared to patients who received RCT alone (19.4% vs. 56.3%, p ⴝ 0.002). At 3 months after RCT, patients treated with amifostine had a significantly lower incidence of pneumonitis than patients who received RCT alone (p ⴝ 0.009). Combined response rates (complete plus partial responses) were 82.2% in the RCT group and 88.8% in the RCT plus amifostine group (p ⴝ 0.498). Conclusion: Amifostine is effective in reducing the incidence of both acute and late toxicities associated with RCT in patients with locally advanced NSCLC without compromising antitumor efficacy. © 2003 Elsevier Inc. Radiochemotherapy, Non–small-cell lung cancer, Amifostine, Toxicity, Cytoprotectant.
INTRODUCTION Lung cancer is the leading cause of cancer-related mortality for both men and women (1). Approximately 75% to 85% of all lung neoplasms are non–small-cell lung cancer (NSCLC), and as many as 40% of all NSCLC patients present with locally advanced and/or unresectable disease (2). Although thoracic radiotherapy (RT) has been the traditional treatment strategy, numerous clinical studies have demonstrated that the addition of a chemotherapeutic regimen to RT results in an improvement in survival rates and median survival times for patients with NSCLC (3– 6). Thus, combined modality radiochemotherapy (RCT) has emerged as the primary treatment option for locally advanced NSCLC (7, 8).
Earlier clinical trials of combined-modality treatments for NSCLC evaluated sequential (induction) chemotherapy followed by fractionated RT. Although clinical outcomes have improved with sequential chemotherapy plus RT compared with RT alone, long-term survival remains poor in patients with locally advanced disease (9, 10). Thus, concurrent RCT regimens have also been studied. Concurrent RCT offers several advantages over sequential chemotherapy followed by radiotherapy, and, in addition, radiosensitization during RT may improve locoregional tumor control (11). Randomized trials have demonstrated that concurrent RCT results in increased time to disease progression (12, 13) and improved survival (14) compared with sequential chemotherapy plus RT.
Reprint requests to: Dosia Antonadou, M.D., Radiation Oncologist, Metaxa Cancer Hospital, 51 Botasi Street, 185 37, Piraeus, Greece. Tel: (301) 428-4444; Fax: (301) 801-0647; E-mail:
[email protected] Received Nov 11, 2002, and in revised form Apr 21, 2003. Accepted for publication Apr 23, 2003. 402
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Platinum compounds and taxanes are two classes of chemotherapeutic agents that have been evaluated in combination with thoracic RT. Recent meta-analyses of randomized clinical trials have demonstrated a statistically significant survival benefit for advanced-stage NSCLC patients receiving cisplatinum-based chemotherapy combined with RT compared with RT alone (15, 16). Carboplatin, a less toxic cisplatin analog, has activity in NSCLC that is comparable to the parent compound (17). Jeremic et al. (4) demonstrated that daily carboplatin plus etoposide combined with hyperfractionated RT results in improved median survival time (22 months vs. 14 months) and 4-year survival rates (23% vs. 9%, p ⫽ 0.021) compared with hyperfractionated RT alone. Paclitaxel has antitumor activity when used as a single agent in the treatment of NSCLC (18) and has also been shown to be a potent radiosensitizer (19). In a Phase II trial in which paclitaxel (60 mg/m2) was administered once per week with daily RT in patients with Stage III NSCLC, an overall response rate of 86% and a median survival time of 20 months were reported (20). More recent studies have evaluated combinations of paclitaxel and carboplatin administered concurrently with RT (21–24). However, toxicities associated with combined modality RCT are of great concern, because they may be doselimiting or have a negative impact on patient quality of life. These toxicities may necessitate interruptions in planned radiation treatment, which may subsequently influence local control and possibly patient survival. Toxicities associated with RCT regimens for NSCLC include acute esophagitis and acute and late lung toxicity, which are related primarily to radiation-induced toxicity that occurs in normal tissues of the respiratory system and nearby anatomic structures. The clinical question of whether pneumonitis progresses into fibrosis remains under investigation (25). The current standard is that pneumonitis might lead to fibrosis after a dose of 30 Gy. In theory, the chemotherapeutic component of RCT regimens may have inherent pulmonary toxicity or produce additional adverse effects such as myelosuppression, nephrotoxicity, neurotoxicity, and alopecia. However, the doses of chemotherapeutic agents administered concurrently with RT are low and generally do not produce additional side effects, with the exception of myelosuppression. Several studies have demonstrated increased incidences of esophagitis and pneumonitis with combined modality RCT regimens for the treatment of lung cancer (5, 26, 27). Such toxicity concerns have led to an increased interest in cytoprotective agents that are capable of preserving normal tissues without compromising antitumor efficacy (2, 28). Amifostine is the first broad-spectrum cytoprotectant approved for clinical use in many countries (29). Amifostine is an organic thio-phosphate molecule that is an analog of cysteamine. Amifostine itself is not biologically active, but is dephosphorylated by membrane-bound alkaline phosphatase to yield its active free-thiol metabolite, WR-1065. WR-1065 provides cytoprotection primarily by two mech-
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anisms: It acts as a scavenger of oxygen free radicals induced by ionizing radiation, and it serves as an alternative target to nucleic acids for the reactive molecules of alkylating or platinum drugs (2, 29, 30). The objective of this randomized study was to investigate whether pretreatment with amifostine could safely reduce the incidence of esophagitis and acute and late lung toxicities during conventional thoracic radiation combined with weekly paclitaxel or carboplatin administration in patients with locally advanced (Stage III) NSCLC. METHODS Study design This was a Phase II randomized study. All patients underwent radiation treatment and were randomly allocated to receive weekly paclitaxel or carboplatin with or without amifostine pretreatment. Baseline evaluations were performed before initiation of treatment and included a complete medical history; physical examination; determination of Eastern Cooperative Oncology Group (ECOG) performance status; full blood counts; biochemistry profile; cardiovascular examination; and thorax, abdomen, and brain computed tomography (CT) scans. All patients underwent bronchoscopic biopsy or fine-needle aspiration cytology before study entry. The primary end points of the study were as follows: (1) evaluation of the incidence of Grade 3 or higher esophagitis and acute lung toxicity, and (2) evaluation of the clinical outcome following World Health Organization criteria for response. The secondary end points were (1) evaluation of the incidence of pneumonitis and/or fibrosis, and (2) evaluation of hematologic toxicity. Eligibility criteria All patients (ⱖ18 years of age) had histologically or cytologically proven NSCLC and ECOG performance status of ⱕ2. The disease was confined to the primary site of the lung and/or regional lymph nodes. Patients with Stage IIIa or IIIb NSCLC were eligible. Life expectancy of ⬎6 months was required. Patients were ineligible if they had pleural effusion, weight loss of ⬎10%, and if they had received prior radiotherapy or chemotherapy, or had distant metastases. All patients were required to give written informed consent. Radiotherapy The patients underwent conventional RT with a 12-MV photon beam. The target volume included the primary site plus a 2-cm margin and mediastinal and ipsilateral hilar lymph nodes. Planning was CT scan assisted, and corrections were made for tissue inhomogeneities. The dose of 52 Gy was prescribed to the isodose line encompassing the target volume. The total dose to the primary tumor site ranged between 55 to 60 Gy and was given using anterior and posterior opposed parallel fields, and an oblique field whenever possible. The daily dose was 2 Gy for 5 days per
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week. A complementary (boost) dose was administered to the primary site and ranged from 5 to 7 Gy. The spinal cord was protected at 45 Gy. On the days of chemotherapy, RT was given 30 to 60 min after completion of chemotherapy and 15 min after the infusion of amifostine. Chemotherapy Patients were randomized to receive paclitaxel (60 mg/ m2) or carboplatin (AUC 2) as a radiosensitizer once per week. If myelosuppression occurred (defined as an absolute neutrophil count of ⬍1.3 ⫻ 109/L and/or platelet count ⱕ100 ⫻ 109/L), the next course of chemotherapy was postponed for 1 week. Before paclitaxel, all patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Amifostine Amifostine (300 mg/m2) was administered by i.v. infusion over 10 min daily 15 min before RT and before carboplatin or paclitaxel infusion on chemotherapy days. An antiemetic agent was given before the amifostine infusion. Blood pressure was measured before the infusion, during the entire infusion, and immediately after the procedure. Attention was given to the antihypertensive medication of the patients, and whenever systolic blood pressure was ⱕ100 mm Hg, patients received i.v. hydration with 500 mL normal saline. Toxicity Acute and late toxicities were graded 0 to 4 according to Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria, with the exception of fibrosis. All patients were monitored once per week during treatment, and the clinical symptoms of RCTinduced toxicities were evaluated by two independent clinicians taking into consideration also the patient’s selfassessment. Patients were initially seen at 15 days and monthly for the first 3 months after RCT, then at 3-month intervals. Whenever the study population presented clinical symptoms of lung toxicity during the follow-up period, the patient was further evaluated with CT scan, which offers more accurate information concerning the presence of pneumonitis. The radiographic findings (chest X-rays or thoracic CT scans) were centrally reviewed. Radiologic changes were inferred from diffuse haze, and a ground glass opacification confined within the radiation field indicated the appearance of pneumonitis. The presence of fibrosis, whenever present, was assessed by a thoracic CT scan at 6 months after RCT. Clinical outcome Response to radiochemotherapy was assessed according to World Health Organization criteria based on CT scan 2 months after completion of treatment and was confirmed 1 month later. The evaluation of response was necessary in this trial to exclude any adverse effect of amifostine admin-
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istration on treatment efficacy. A more detailed analysis of treatment efficacy will be described separately. Statistical analyses Based on our previous experience, the expected number of patients with esophagitis and/or lung toxicity has been estimated (29). Sample size was calculated based on the comparison of esophagitis and lung toxicity during RCT between subjects receiving amifostine with RCT and the RCT-alone group. Based on a two-sided test of significance and a random assignment to one of the two treatment arms in a 1:1 ratio, at the 5% significance level with a power of 80%, a sample size of 72 evaluable patients was sufficient to allow for the detection of a difference of 40% esophagitis ⱖ Grade 3 (20% lung toxicity) in the amifostine and RCT group and of 80% esophagitis (50% lung toxicity) in the RCT-alone group. According to the “intention-to-treat” principle, all patients who passed through the randomization phase in the study were evaluated. The baseline demographic characteristics of treatment groups, stratified according to the presence or absence of amifostine treatment, were tested for differences using an analysis of variance for age and Pearson’s exact two-sided test for gender and disease stage. Pearson’s exact test was used also to compare the number of patients with acute toxicities (ⱖ Grade 3) during treatment and the incidence of pneumonitis (ⱖ Grade 3) and fibrosis post-RCT. A p value of 0.05 or less was interpreted as statistically significant; p values were not adjusted. All computations were carried out using SPSS and StatXact software systems. RESULTS Patient characteristics Between October 1997 and August 1999, 73 patients were randomized. One patient was not treated, because he did not fulfill inclusion/exclusion criteria. Of the 72 subjects treated, 2 patients withdrew their consent, and 2 patients were lost to follow-up. All 4 patients were enrolled in the carboplatin arm, but the reasons for discontinuation were not relevant to the investigational drug. In total, 68 patients were analyzed in an intention-to-treat analysis; 36 received RCT plus amifostine (paclitaxel, n ⫽ 19, and carboplatin, n ⫽ 17) whereas 32 patients were treated with RCT alone (paclitaxel, n ⫽ 17, and carboplatin, n ⫽ 15). The demographics and baseline characteristics of the patients are summarized in Table 1. The two treatment groups were evenly balanced, and there were no significant differences between groups with respect to patient age, gender, or disease stage. All patients had NSCLC; 3 patients in each group had Stage IIIa disease, and 29 and 33 patients had Stage IIIb disease in the RCT-alone and RCT plus amifostine groups, respectively. The majority of patients had a good ECOG performance status at baseline, and there was a minimum weight loss during the previous 3 months. The radiation treatment characteristics were evenly bal-
Radiochemotherapy ⫾ amifostine in non–small-cell lung cancer
Table 1. Patient demographics and baseline characteristics
Patients: n Age: mean (SD) Gender: n (%) Female Male NSCLC stage: n (%) IIIa IIIb ECOG status: n (%) 0 1 3 Weight loss: n (%) None ⬍10%
RCT
RCT ⫹ amifostine
32 61.9 (11.4)
36 62.2 (7.9)
28 (87.5) 4 (12.5)
34 (94.4) 2 (5.6)
3 (9.4) 29 (90.6)
3 (8.3) 33 (92.7)
1 (3.1) 28 (87.5) 3 (9.4)
2 (5.6) 32 (88.9) 2 (5.6)
0.753
27 (84.4) 5 (15.6)
29 (80.6) 7 (19.4)
0.925
p value 0.952 0.410 1.00
Abbreviations: RCT ⫽ radiochemotherapy; SD ⫽ standard deviation; NSCLC ⫽ non–small-cell lung cancer.
anced with respect to total dose delivered for both treatment groups and treatment duration (Table 2). Patients in both groups did not receive any supportive medication routinely during RCT treatment. Acute toxicity All patients were monitored once per week during treatment and every 4 weeks thereafter for at least 3 months or until toxicities resolved. Although the RCT protocols using either paclitaxel or carboplatin were relatively well tolerated in the study population, the addition of amifostine pretreatment produced significant reductions in the incidence of acute toxicities associated with RCT. The incidence of (Grade ⱖ3) esophagitis during RCT was significantly lower for patients treated with RCT and amifostine than for patients treated with RCT alone (38.9% vs. 84.4%, p ⬍ 0.001). Furthermore, the incidence of (Grade ⱖ3) acute pulmonary toxicity experienced by the patients receiving amifostine was significantly reduced compared to the acute lung toxicity experienced by patients treated with RCT alone (19.4% vs. 56.3%, p ⫽ 0.002). Because different findings were observed in the group of patients either with paclitaxel or carboplatin, a subgroup analysis was conTable 2. Radiation treatment characteristics
Patients: n Radiation dose Total (Gy) SD Treatment duration Mean (days) SD
RCT
RCT ⫹ amifostine
32
36
57.5 44.0
58.3 53.6
0.604
36.5 7.5
37.2 8.0
0.523
p value
Abbreviations: RCT ⫽ radiochemotherapy; SD ⫽ standard deviation.
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ducted. The incidence of esophagitis (Grade ⱖ3) during RCT was significantly lower for patients receiving amifostine and paclitaxel than for patients receiving paclitaxel alone (47% vs. 88%, p ⫽ 0.014) and for patients receiving amifostine and carboplatin than for patients given carboplatin alone (29% vs. 80%, p ⫽ 0.006). The incidence of acute pulmonary toxicity (Grade ⱖ3) during RCT was significantly reduced in patients receiving amifostine plus paclitaxel compared with patients treated with paclitaxel alone (21% vs. 59%, p ⫽ 0.039). In addition, the reduction in acute pulmonary toxicity observed in patients treated with amifostine plus carboplatin compared with patients receiving carboplatin alone (18% vs. 53%, p ⫽ 0.062) approached statistical significance (Fig. 1). The incidences of neutropenia and thrombocytopenia were lower in patients pretreated with amifostine during RCT; in the carboplatin treatment arm, this difference showed a trend toward statistical significance in favor of amifostine (p ⫽ 0.075). In the paclitaxel group at 2 months posttreatment, Grade ⱖ3 esophagitis was present in 9/16 patients in the control group (without amifostine), but in only 2/16 patients in the paclitaxel plus amifostine group. The incidence of esophagitis reached statistical significance (p ⫽ 0.023). In the carboplatin group, no patients experienced symptoms of esophagitis at 15 days post-RCT. Amifostine administration was well tolerated. Only 3 of the 36 patients treated with amifostine experienced nausea and vomiting during more than 5 infusions, and 8 patients had transient hypotension during the administration. No patients discontinued amifostine pretreatment. Late toxicity During the follow-up period after completion of RCT, patients were stratified into two groups based on whether they had received amifostine during RCT, independent of paclitaxel or carboplatin chemotherapy (Table 3). At 3 months, 60 patients were evaluable for late toxicity. In 8 patients, the evaluation of toxicity was not possible for the following reasons: Two patients in the RCT plus amifostine group were lost to follow-up, and 1 patient died; in the RCT group, 3 patients were lost to follow-up, and 2 patients died. At 6 months, 52 patients completed the follow-up visits, and deaths in both groups accounted for most of the patients lost to follow-up. At the 3-month follow-up, a significantly reduced incidence of pneumonitis was observed in the amifostine pretreatment group compared with patients who received no pretreatment (30.3% vs. 66.7%, p ⫽ 0.009). The incidence of fibrosis also was lower in the amifostine pretreatment group at the 6-month follow-up (28.6% vs. 50.0%, p ⫽ 0.156); however, this finding did not reach statistical significance. Clinical outcome All patients enrolled in this study were evaluable for response at 2 months post– combined treatment. Table 4 summarizes the response rates. The combined response
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Fig. 1. Incidence of acute toxicities during radiochemotherapy ⫾ amifostine. Acute toxicities were defined as ⱖ Grade 3 for esophagitis and pulmonary toxicities, and absolute neutrophil count ⬍1.3 ⫻ 109/L and platelets ⬍100 ⫻ 109/L for neutropenia and thrombocytopenia, respectively. (a) The incidence of acute toxicities with RT plus paclitaxel. (b) The incidence of acute toxicities with RT plus carboplatin. Values on the bars indicate the number of patients in each group that experienced the toxicity.
rates (complete plus partial responses) were 82.2% in the RCT group and 88.8% in the RCT plus amifostine group (p ⫽ 0.498 for patient distribution across clinical outcomes). DISCUSSION Although the optimal therapeutic regimen has yet to be defined, combined modality RCT represents the current standard of treatment for selected patients with locally advanced unresectable NSCLC (31). Radiation may be delivered as conventional external beam thoracic RT, hyperfractionated RT, or hyperfractionated accelerated RT. In general, chemotherapy administered concurrently rather than sequentially with RT is associated with improved clinical outcomes. However, toxicities associated with RCT regimens can be dose-limiting, resulting in treatment interruptions. In addition, patient quality of life is an important therapeutic consideration, because treatment-related toxicities may negate modest survival benefits conferred by aggressive treatment regimens. Esophagitis and lung toxicities are the most common acute toxicities associated with RT for NSCLC. Pneumonitis, which is characterized primarily by cough and dyspnea, Table 3. Incidence of late pulmonary toxicities after radiochemotherapy RCT 3-month follow-up Patients: n Pneumonitis: n (%) 6-month follow-up Patients: n Fibrosis: n (%)
27 18 (66.7) 24 12 (50)
RCT ⫹ amifostine 33 10 (30.3) 28 8 (28.6)
Abbreviation: RCT ⫽ radiochemotherapy.
usually occurs between 2 and 3 months after radiation (32). With the exception of myelosuppression, the addition of chemotherapeutic agents (at relatively low doses) to RT generally does not result in a change in the pattern of toxicities that is observed, although the incidence and severity may increase (33). For example, in the Phase I study by Choy et al. (34), the maximum tolerated dose of paclitaxel administered weekly with concurrent RT (60 Gy) in patients with locally advanced NSCLC was 60 mg/m2, and the dose-limiting toxicity was esophagitis. In three subsequent Phase II studies of paclitaxel at this dose, the most common acute toxicity again was esophagitis, with reported incidences of 17% to 26% using Radiation Therapy Oncology Group criteria (33). Although there are relatively few studies of carboplatin used as a single agent with RT, information regarding toxicities can be gleaned from studies of combination chemotherapeutic regimens that include this agent. For example, in the study of Jeremic et al. (4), bronchopulmonary and esophageal toxicities were the most common acute and late toxicities in NSCLC patients treated with hyperfractionated RT plus carboplatin and etoposide. Numerous clinical trials have evaluated combination carboplatin/paclitaxel regimens administered concurrently with RT. In a recent Phase II study of weekly paclitaxel (50 mg/m2) plus carboplatin (AUC 2) with concurrent hyperfractionated RT, esophagitis Table 4. Clinical responses to RCT according to WHO criteria RCT
RCT ⫹ amifostine
32 5 (15.6) 21 (65.6) 4 (12.5) 2 (6.2)
36 12 (33.3) 20 (55.5) 3 (8.3) 1 (2.7)
p value
0.009 0.156
Patients: n Complete response: n (%) Partial response: n (%) Stable disease: n (%) Progressive disease: n (%)
Abbreviation: RCT ⫽ radiochemotherapy.
p value
0.498
Radiochemotherapy ⫾ amifostine in non–small-cell lung cancer
was the most common toxicity, and esophagitis ⱖ Grade 3 occurred in 26% of patients (24). In a Phase II trial that evaluated hyperfractionated RT with concurrent weekly carboplatin (AUC 1.5), but that divided the paclitaxel dose (30 mg/m2 twice weekly), esophagitis (38%) and neutropenia (12%) were the most frequent Grade 3 or 4 toxicities observed during the RCT phase of the study (22). Reduction of esophageal and lung toxicities during RCT may reduce the need for treatment interruptions and increase patient quality of life (2). In this regard, the potential therapeutic role of cytoprotective agents such as amifostine has drawn considerable interest. Several clinical studies have been performed to evaluate the effects of amifostine in patients undergoing treatment for NSCLC. Betticher et al. (35) reported significant reductions in the duration of thrombocytopenia (13.5 days vs. 21 days, p ⫽ 0.004) and the need for hospitalization (0/20 vs. 6/25 patient courses, p ⫽ 0.006) with carboplatin plus amifostine treatment than with carboplatin treatment alone. Response rates and median survival times were similar in both treatment arms (35). Tannehill et al. (36) evaluated 26 patients with Stage III NSCLC who received amifostine before induction chemotherapy with cisplatin and vinblastine followed by largefield thoracic radiation. Given that no cases of Grade 3 or 4 esophagitis or nephrotoxicity were observed and that the objective response rate was 60%, the authors concluded that amifostine reduced cisplatin-related and radiation-induced toxicities without impairing the response to treatment (36). Komaki et al. (37) evaluated 60 patients with inoperable Stage II or III NSCLC treated with concurrent radiochemotherapy. Both groups received oral etoposide and cisplatin, together with twice-daily radiation therapy (1.2 fractions, 5 days per week) to a total dose of 69.6 Gy. Patients in the study group received 500 mg of amifostine twice weekly before chemoradiation. Morphine intake to reduce severe odynophagia was significantly lower in the amifostine group, 7.4% vs. 31% in the control group (p ⫽ 0.03). Furthermore, acute pneumonitis was significantly lower in the amifostine group, 3.7%, than in the RCT-alone group, 23% (p ⫽ 0.037). The authors concluded that amifostine reduced RCT-related toxicities without compromising treatment efficacy. The lower incidence of toxicity observed in the study by Komaki et al. (37), compared to the incidence of acute toxicity in our study, is probably because of a more selected patient sample, as well as the chemotherapeutic agents and chemotherapy schedule applied in her study. Morphine intake is another approach in the evaluation of
● D. ANTONADOU et al.
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esophagitis. In her study, a statistically significant difference in the incidence of RCT-induced toxicities was observed, although amifostine was administered twice a week before chemoradiation. The results from the randomized Phase II study presented herein further demonstrate that the addition of amifostine to an RCT regimen (conventional thoracic radiation combined with concurrent weekly paclitaxel or carboplatin treatment) reduces the incidence of treatment-related toxicities without compromising antitumor efficacy. For all acute toxicities assessed during treatment (esophagitis, pulmonary toxicity, neutropenia, thrombocytopenia), the incidences were lower in treatment groups receiving amifostine. The high incidence of esophagitis presented in our study was probably the result of the selection of the patients entered in this trial. Patients with lung cancer are usually in bad health and have harmful habits such as smoking that they continue during treatment, so the lung tissue and the esophageal mucosa are heavily compromised. The majority of the patients entered in our study were Stage IIIb patients, so the probability of lymph node involvement in the mediastinum was high, and we were obliged to use a large radiation field, which, combined with the weekly administration of carboplatin or paclitaxel, enhanced the acute toxicities. These differences were statistically significant in favor of amifostine for acute esophagitis in both the paclitaxel and carboplatin arms, and for acute pulmonary toxicity in the paclitaxel arm. The results for acute pulmonary toxicity and thrombocytopenia approached statistical significance in favor of amifostine in the carboplatin arm. With respect to late toxicities after the 5- to 6-week treatment duration, the addition of amifostine significantly reduced the incidence of pneumonitis at 3 months after RCT in all evaluable patients. There was also a reduction in fibrosis at the 6-month post-RCT evaluation in patients who had received amifostine; however, this result did not achieve statistical significance. Nonetheless, it should be noted that the number of patients in this Phase II study was relatively small, so larger Phase III studies are warranted. In summary, combined modality RCT plays an important role in the treatment of NSCLC. With the recognition that treatment-related toxicities can compromise therapy outcome and quality of life, the reduction of these toxicities becomes essential. The addition of amifostine allowed patients to complete the scheduled treatment without interruptions and without the major side effects that might compromise treatment efficacy.
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