Combined chemoradiotherapy in the treatment of locally advanced non-small cell lung cancer

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1 Journal of BUON 7: 47-51, Zerbinis Medical Publications. Printed in Greece ORIGINAL ARTICLE Combined chemoradiotherapy in the treatment of locally advanced non-small cell lung cancer S. Isaković-Vidović, L. Radosević-Jelić, N. Borojević Department of Radiotherapy, Institute of Oncology and Radiology of Serbia, Beograd, Yugoslavia Summary Purpose: To evaluate prospectively the combination of radiotherapy with low doses of carboplatin given as radiosensitizer in patients with locally advanced non-small cell lung cancer (NSCLC). Patients and methods: Patients enrolled in this trial were randomly allocated in two groups. The study group consisted of 67 patients with stage IIIA/B NSCLC who were treated initially with a tumor dose (TD) of 30 Gy in 10 fractions, 5 fractions per weeks, in 2 weeks. Carboplatin was administered simultaneously as radiosensitizer at a dose of 20 mg/m 2 i.v. bolus just prior to each radiotherapy fraction. After a 2-week rest an additional 25 Gy were given in 10 fractions, with carboplatin as previously described. The total tumor dose (TTD) was 55 Gy (30+25 Gy) in 20 fractions in 6 weeks and the total dose of carboplatin was 600 mg. The study group was compared with a control group of 70 NSCLC patients who were treated with radical conventional radiotherapy (60 Gy in 30 fractions, 2 Gy per fraction, 5 fractions per week). Results: Haematological toxicity and oesophagitis were statistically more often seen in the study group. There was no statistically significant difference in the response rate between the 2 groups (53.7% versus 62.8%). The 2-year survival was 27% in the study group and 33% in the control group (p >0.05). Conclusion: The results showed no response and survival benefit of concomitant chemoradiotherapy compared with conventional radiotherapy. We believe that further prospective, multicenter trials are required to evaluate the concurrent combination of new cytotoxic agents used as radiosensitizers with conventional radiotherapy or radiotherapy with different fractionation schedules and high-technology equipment which enables the application of higher tumor doses. Key words: carboplatin, chemoradiotherapy, non-small cell lung cancer, radiosensitizer Introduction Radiopotentiators or radiosensitizers are modifiers of response to radiotherapy. Numerous cytotoxic drugs were shown to act as modifiers of response to radiation, Received ; Accepted Author and address for correspondence: Dr Suzana Isaković-Vidović Institute of Oncology and Radiology of Serbia Pasterova 14 Beograd Yugoslavia Tel: Fax: isakovic@ncrc.ac.yu including platinum compounds. Preclinical studies have shown that there are several mechanisms to enhance radiation effectiveness. Theoretically there are 4 mechanisms of interaction between radiotherapy and chemotherapy: 1. spatial cooperation; 2. independent cytotoxic effect; 3. protection of normal tissues; and 4. additive or synergistic antitumor activity. Such a concomitant antitumor activity is most effective in the treatment of locally advanced tumors and is mostly applied in clinical practice [1-3]. The activity of such modalities could be as follows: activity of cytotoxic metabolites in radioresistant hypoxic cells (e.g. mitomycin C); activity in S-phase of the cell cycle which is less radiosensitive (e.g. 5-fluorouracil); inhibition of the repair process following sublethal or potentially lethal radiation damage of DNA (e.g. platinum compounds); and inhibition of the radiation damage repair process, cell cycle synchronization, etc. [4-7].

2 48 The aim of applying radiopotentiation in our study was initiated by the fact that patients with locally advanced NSCLC are at high risk of relapse, due to the high rate of failure in local disease control and the existence of systemic micrometastases. Nowadays, the treatment of locally advanced NSCLC cancer is an important clinical problem, as it was in the past two decades, as there has been no significant survival improvement with the use of conventional, radical radiotherapy with or without chemotherapy. According to the results found in the relevant literature the 2-year overall survival ranges between 15 to 25% (all stages included) [8], while the 5-year survival following external beam radiotherapy with conventional fractionation is 5-10 % [9]. As the local disease control was associated with the overall treatment results, several multicentric, randomized clinical studies have been carried out to test new radiotherapy approaches, with or without radiopotentiation. Published data showed improvement in local response and 2-year survival, with an acceptable rate of acute and late toxicity [10,11]. Based on these data we compared prospectively the efficacy of conventional radical radiotherapy to concomitant chemoradiotherapy using low doses of carboplatin as radiosensitizer in NSCLC patients. Patients and methods This was a prospective randomized 2-arm study. Eligibility criteria included all of the following: histological verification of NSCLC; locally advanced primary tumor without distant metastases (T1-4, N0-3, M0, stage IIIA and B); Karnofsky performance status (PS) ³70; age 70 years; weight loss within the last 3 months < 15%; creatinine clearance ³70 ml/min; haemoglobin ³10 g/l; no serious medical illness; adequate cardiac and liver functions. All patients gave informed consent after adequate discussion with their attending physician. The patients included in the study group were treated with radical radiotherapy potentiated by low doses of carboplatin. Patients were firstly treated with 30 Gy TD in 10 fractions, 5 fractions per week, in 2 weeks time. Carboplatin 20 mg/m 2 given by a short i.v. infusion was administered as radiosensitizer prior to each radiotherapy fraction. After a 2-week pause, an additional radiotherapy course of 25 Gy was given in the same way, for a total tumor dose (TTD) of 55 Gy in 20 fractions during 6 weeks. The total dose of carboplatin was 600 mg. The patients in the control group were treated with radical radiotherapy using conventional fractionation (60 Gy in 30 fractions, 2 Gy per fraction, 5 fractions per week). All patients were treated with the same linear accelerator with 10 MeV energy of X rays. External beam irradiation was delivered using a locoregional technique consisting of 2 opposite parallel fields (front/back), which included the site of the primary tumor and the mediastinum, up to a tolerant dose of 45 Gy for the spinal cord. Then radiotherapy continued through corrected fields which were either front/back or opposite lateral fields, up to the planned radical radiotherapy doses. Pretreatment evaluation for all patients included clinical examination and haematological, biochemical, radiographic, ultrasonographic, and endoscopic investigations. Computerized tomography and magnetic resonance imaging of the chest were carried out in individual cases. During treatment, acute toxicity was recorded. Haematological toxicity (haemoglobin, white blood cell (WBC) count and platelet count) and nephrotoxicity (creatinine clearance) were graded using the WHO criteria [12]. Acute radiation sequelae (oesophagitis) were evaluated according to the LENT-SOMA scale [13]. Response to treatment was evaluated 6 weeks after the end of therapy. Response was assessed by chest radiography. In individual cases bronchoscopy was carried out as well. After treatment, the patients were followed every 2 months during the first year, every 3 months during the second year, and every 6 months thereafter. The probability of survival was calculated by the Kaplan-Meyer method, and the significance of differences by the log-rank test [14]. Results Sixty-seven patients entered the study group and 70 the control group. The vast majority of them were males (Table 1). The average age in the study group was 56.12±7.30 years (range years), while in the control group it was 56.74±7.48 years (range years). Table 1 shows the patient demographics. Table 1. Patient demographics Study group (n=67) Control group (n=70) Sex male 62 (92.5) 64 (91.4) female 5 (7.5) 6 (8.6) Age (years) median (range) 56 (40-67) 57 (41-72) (20.9) 14 (20.0) (41.8) 26 (37.2) (35.8) 29 (41.4) (1.5) 1 (1.4)

3 49 Most of the patients had stage IIIA disease. Squamous cell carcinoma of the lung was diagnosed in all of them with grade 1 in more than 50% of the cases. Statistically significant haematological toxicity was recorded more often in the study group (haemoglobin level p=0.004; WBC count p=0.001; platelet count p=0.001, Table 2). In the same group more than 30% of the patients showed grade 1 and 2 nephrotoxicity (p=0.001) which was transient and did not cause significant compromise of the renal function. Oesophagitis was statistically more often seen in the control group (p=0.004, Table 2). Response to treatment is shown in Table 3. The response rate (CR+PR) in the study and control groups was 53.7% and 62.8%, respectively (p=0.233). Table 2. Acute toxicity Acute toxicity Study group Control group p value (grade) (n=67) (n=70) Anaemia* 1 8 (11.9) 1 (1.5) 2 2 (3.0) 0 (0.0) 3 2 (3.0) 0 (0.0) 4 0 (0.0) 1 (1.5) Leucopenia* 1 11 (16.4) 1 (1.4) 2 5 (7.5) 1 (1.4) 3 2 (3.0) 0 (0.0) Thrombocytopenia* 1 5 (7.5) 0 (0.0) 2 1 (1.5) 0 (0.0) 3 1 (1.5) 0 (0.0) Creatinine clearance* 1 21 (31.3) 0 (0.0) 2 1 (1.5) 0 (0.0) 3 0 (0.0) 0 (0.0) Oesophagitis** 1 14 (20.9) 5 (7.1) 2 16 (23.9) 8 (11.4) 3 7 (10.4) 5 (7.1) 4 0 (0.0) 1 (1.5) *WHO grading; **LENT-SOMA grading The mean follow-up period in the study group was 17 months, while in the control group it was 15 months. Table 4 analyses the treatment long-term outcome. Sixteen (24%) patients in the study group and 15 (21.5%) in the control group were alive by the end of the follow-up period (p > 0.64). In the study group, no evidence of disease was recorded in 7.5% of the patients, in local relapse in 50.8%, distant metastases in 13.5% and both local relapse and distant metastases in 14.9%. In the control group, the corresponding numbers were 8.6%, 42.8%, 10% and 17.2%. There was no statistically significant difference in local, systemic, both local/systemic and total relapse rate between the two groups (Table 4). The cumulative probability of 2-year survival in the study group was 27%, while it was 33% in the control group (Figure 1). Table 4. Patients outcome at the last follow-up according to the response to therapy Study group Control group p value (n=67) (n=70) Status Alive NED* 5 (7.5) 6 (8.6) 0.61 local relapse 5 (7.5) 4 (5.7) 0.82 distant metastasis 4 (6.0) 3 (4.3) 0.51 local relapse and 2 (3.0) 2 (2.9) 0.53 distant metastasis Total 16 (24.0) 15 (21.5) 0.64 Dead local relapse 29 (43.3) 26 (37.1) 0.81 distant metastasis 5 (7.5) 4 (5.7) 0.81 local relapse and 8 (11.9) 10 (14.3) 0.48 distant metastasis other causes 1 (1.4) 0 (0.0) 0.60 Total 43 (64.1) 40 (57.1) 0.40 Lost to follow-up 8 (11.9) 15 (21.4) 0.10 * no evidence of disease Table 3. Response according to treatment group Response Study group Control group p value (n=67) (n=70) Complete response 6 (8.9) 8 (11.4) Partial response 30 (44.8) 36 (51.4) Stable disease 28 (41.8) 25 (35.7) Progressive disease 3 (4.5) 1 (1.5) Complete + 36 (53.7) 44 (62.8) partial response Figure 1. Two-year overall survival in the study and control groups.

4 50 Discussion In this study, acute complications were recorded during and immediately after the treatment completion. Haemoglobin was within normal limits in 82.2% of the patients in the study group and 97% in the control group. In both groups anaemia was mostly of grade 1. Grade 1-3 leucopenia was recorded in 26.9% of patients in the study group and grade 1-2 in 2.8% in the control group (p=0.001). Thrombocytopenia was the rarest acute haematological toxicity recorded. None of the patients in the control group developed thrombocytopenia, while grade 1-3 thrombocytopenia was seen in 10.5% of patients in the study group (p=0.001). A statistically significant higher total haematological toxicity was recorded in the study group, most probably due to the use of carboplatin [15,16]. Nephrotoxicity was evaluated on the basis of creatinine clearance. In the study group treated with radiotherapy and carboplatin 67.2% of the patients had values within normal range while the rest had decreased creatinine clearance of grade 1 (31.3%) and 2 (1.5%). No nephrotoxicity was recorded in the control group. This difference was statistically significant (p=0.001). Schaake-Koning et al. reported nephrotoxicity in a small number of patients (3/26 patients), due to the direct effect of platinum compounds on the renal function [10]. Trovo et al. reported nephrotoxicity of grade 1 in 8/94 patients, and grade 3 in 1/94 patients [11]. In the relevant literature all authors agree that the toxicity of chemotherapy with low doses of drugs given as radiosensitizers is generally acceptable. Despite the fact that the side-effects of these two therapeutic modalities do not overlap, it is rather difficult to be given concurrently in clinical practice [16]. Oesophagitis as an acute complication was recorded in 55.2% of the patients in the study group and in 27.1% in the control group. This difference was statistically significant (p=0.004). Oesophagitis was mostly of grade 1 and 2. In the Shaake-Koning et al. study, 50% of the patients who received combined therapy developed oesophagitis, with only one patient developing grade 4 oesophagitis. In the control group treated with standard radiotherapy, this complication was present in approximately 30% of the patients [10]. In our study the overall response rate (CR+PR) in the control and the study group was 62.8% and 53.7%, respectively (p >0.05). Trovo et al. reported objective responses to the combined treatment in 54.3% of the patients, and a complete regression in 16.6% of the cases [11]. Byhardt et al. have summarized the results of 5 trials from the Radiation Therapy Oncology Group, where they compared the efficacy of a sequential chemoradiotherapy (conventional radiotherapy, 60 Gy in 6 weeks), to a concomitant chemoradiotherapy (conventional chemoradiotherapy, 60 Gy in 6 weeks), and a concomitant hyperfractionated radiotherapy (hyperfractionated radiotherapy, 69.6 Gy in 6 weeks), with the use of cisplatin in patients with inoperable stage II-III A and B NSCLC. The response rate in the first group was 63%, in the second 77%, and in the third 79% [17]. Atagi et al. presented the results of a concomitant radiotherapy (50-60 Gy, 2 Gy/day, 5 fractions/week) and chemotherapy with low doses of carboplatin (30 mg/m 2 ), administered on days 1-5. Thirty-eight patients with inoperable NSCLC of stages IIIA and IIIB were included. Complete regression was achieved in 1/38 patients and partial regression in 18/ 38, for an overall response rate of 50% [18]. During follow-up in the study group local relapse was recorded in 50.7% of the patients, distant metastases in 23.4% and both in 14.9%. In the control group, the corresponding numbers were 42.9%, 10% and 17.1%. In the Schaake-Koning et al. study, patients who received combined therapy showed an overall relapse rate of 75% (local relapse in 24%, distant metastases in 22% and both of them in 29% of the patients) [10]. In a similar trial, Trovo et al. reported recurrent disease in 59/94 of patients (23 local relapses, 4 local relapses and distant metastases, and 32 distant metastases) [11]. According to Emami and Perez, the rate of failure in patients with unresectable NSCLC treated with radical radiotherapy using conventional fractionation was 62% for local relapse, 22% for local relapse and distant metastases, and 41% for isolated distant metastases [9]. The 1-year survival for the study group was 47.5±6.5%, the 2-year survival 27.1±5.8%, the mean survival time 30±5 months, and the median survival time 12±1 months. In the control group the corresponding numbers were 55.5±6.2%, 33.1±6.3%, 37±4, and 16±3. No statistically significant difference was found between the two groups in the 2-year survival (p=0.063). The Schaake-Koning et al. study included 331 patients with inoperable non-small cell lung cancer, divided into 3 groups. The first and the second were treated with radiotherapy only (the first-3gy 10 fractions; the second 2Gy 10 fractions), while the third group received cisplatin, 30 mg/m 2 per week, or 6 mg/m 2 per day, just prior to the radiation. Statistically significant differences (p=0.009) were found in the 1- year survival (54% versus 46%), in the 2-year survival (26% versus 13%), and in the 3-year survival (16% versus 2%) [19]. In a nonrandomized study Soresi et al. evaluated low doses of weekly cisplatin during radical

5 51 radiotherapy for the treatment of locally advanced lung cancer. The median survival time was 9 months [20]. Ball et al. compared the combination of carboplatin plus radiotherapy, conventional or accelerated, with radiotherapy alone and found that the longest survival was achieved in patients treated with carboplatin and standard radiotherapy [21]. In our study the applied therapeutic modalities showed an acceptable toxicity. Haematological toxicity, nephrotoxicity and eosophagitis were considerably higher in the study group. The overall response rate, the median survival time, and the 1 and 2-year survival were similar in both groups. 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