Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 2, Num. 2, 2006, pp. 47-51

Journal of Cancer Research and Therapeutics, Vol. 2, No. 2, April-June, 2006, pp. 47-51

Original Article

A prospective and randomized study of radiotherapy, sequential chemotherapy radiotherapy and concomitant chemo therapy-radiotherapy in unresectable non small cell carcinoma of the lung

Dasgupta Anirban, Dasgupta Chandan, Basu Siddhartha, Majumdar Anup

Department of Radiotherapy, Institute of Post Graduate Medical Education and Research, Kolkata
Correspondence Address:16, Ramdhan Bose Road, Sonarpur, Kolkata-700 149, www.anirbandasgupta2000@yahoo.co.in

Code Number: cr06011

Abstract

Keywords: Non small cell lung cancer, neoadjuvant, concurrent response, disease free survival, metastasis, acute toxicities.

Introduction

Lung Cancer is one of the most commonly occurring malignancy and the leading cause of cancer related death, worldwide. Non-small cell Lung Cancer (NSCLC) constitutes about more than 80% of all lung cancer cases. Historically, surgery has provided the best chance of cure in resectable (NSCLC). But only 15% of NSCLC patients present with localized disease, the rest have either lymph node metastasis (25%) or distant metastasis (65%), at the time of diagnosis.[1] In early stage (Stage I & II), when the disease has not extended beyond the bronchopulmonary lymph nodes, a complete excision is almost always possible. Whereas in advanced stage (Stage III), the treatment often produced dismal results, in spite of much progression in the field of multimodality therapy. Involvement of bronchopulmonary nodes [N ₁ ] in large primary (T3 disease) makes survival poor, even after complete excision (Five year survival rate is 20%). When mediastinal lymph nodes are involved [N ₂ disease on wards], survival is even poorer in any stage of primary tumour, with surgery alone.[2] Therefore combined modality treatments have been tried in advanced stages [N ₂ disease onwards] of NSCLC, with an expectation of some survival advantage.

Surgery, radiotherapy and chemotherapy have been used in varying combinations, in advanced NSCLC. Only radiation of 6000 cGy in conventional fractionation, has shown a two year survival rate of 5-10%.[3] Addition of Cisplatin- based chemotherapy with radiation, shows a 24% improvement in the two year survival rate. Concomitant chemo-radiotherapy also documented an improvement of survival with a five year survival rate of 16%.[4]

With these results in back ground, a Phase III randomized trial was designed at our institution, in order to evaluate different combination regimens of Radiotherapy and Chemotherapy, in unresectable NSCLC.

Materials and Methods

In this randomized trial, a total of 103 patients were randomized to three treatment groups -A, B and C. In group A, patients received Radiotherapy alone. In group B, patients were treated by sequential chemotherapy and radiotherapy. In group C, patients received concurrent radiotherapy and chemotherapy. All patients had measurable or evaluable disease and were diagnosed to have uncresectable NSCLC. Inclusion criteria were, patients up to 75 yrs at diagnosis, Karnofsky′s performance status (KPS) ≥60, absence of distant metastasis, no prior therapy for cancer and no hematological, cardiac, renal, or liver function abnormalities contraindicating combined modality therapy. Prior to therapy, all patients were informed about the randomization and had given written informed consent to participate in the study. The characteristics of the patients in the three randomized groups are seen in [Table - 1].

The distribution of patients prior to therapy, regarding age, stage, and performance status, is near homogenous in the three randomized groups.

Treatment
In all the treatment groups, radiotherapy was delivered by Cobalt 60 teletherapy unit. In group A, patients were treated with radiotherapy alone, the dose of radiation was 6500cGy 30 fraction, over six weeks. In group B, patients were treated with sequential chemotherapy. They received three cycles of Neoadjuvant chemotherapy, with Inj. Cisplatinum 80 mg/m ² intravenously on Day one and Inj. Etoposide 120 mg/m ² intravenously, from day one to day three, followed by local radiation of 6000cGy in 30 fractions, over six weeks. Radiotherapy was started 3-4 weeks after the third cycle of chemotherapy. After completion of radiation, three more cycles of chemotherapy were given, using the same drugs and regimen. In group C, patients were treated with concomitant chemo-radiotherapy. They received Radiation of 5000cGy in 25 fractions over five weeks, along with concurrent chemotherapy using Inj. Cisplatinum 20 mg/m ² intravenously, from day one to day fiv and Inj. Etopside 50 mg/m ² intravenously, from day one to day five. The same schedule was repeated after three weeks, from day 22 to day 26. Day one chemotherapy was started from the first day of radiation. After completion of concurrent chemo-radiotherapy, two more cycles of chemotherapy were given, using the same drugs and regimen, at a three week interval.

After completion of treatment, the patients were assessed clinically and radiologically for treatment response and for evidence of any tumour progression. Then, they were followed up at one month interval, during the first year. Thereafter, follow up examinations were performed at three months interval. Patients who failed to show response with therapy, were given salvage treatment, either with alternative chemotherapy or radiation, as and when needed.

Statistical analysis
All patients were randomized to either radical radiotherapy alone, or sequential chemo-radiotherapy, or concurrent chemo-radiotherapy. Only those patients who completed the full course of treatment were subjected to a complete statistical analysis, to document response rate, overall survival, disease free survival and time to tumor progression. Thus, a total of 103 patients were analysed. The results of the three treatment groups were compared by Chi-square test and log rank test, to identify any significant differences among them.

Results

Treatment tolerance and toxicity

Acute toxicity
They were primarily cutaneous, oropharyngeal, upper gastrointestinal (upper GI) and also haemotological. All patients developed grade I cutaenous toxicity during treatment. But grade III toxicity was observed more with the addition of chemotherapy (Group B and C), in comparison to radiotherapy alone (Group A). They improved with conservative management. Similarly, enhanced mucosal, upper G.I and heamatological toxicities, were observed in patients who received a combination of chemotherapy and radiotherapy. When patients of group B i.e. sequential chemo-radiotherapy (CT→ RT) and group C i.e., concurrent chemo-radiotherapy (CT and RT) were compared, acute toxicities were found to be more pronounced in the concomitant treatment group. Acute radiation reactions did not interrupt radiation treatment in group A, but radiotherapy was interrupted in four patients (11%) in group B and in six patients (17%) in group C. But in none of the patients, were chemotherapy drug doses altered or modified or delayed, in combination treatment groups. A summary of acute toxicities is shown in [Table - 2].

Initial treatment response
The initial treatment response as determined at the time of first follow-up examination i.e. four weeks after completion of therapy, is shown in [Table - 3].

The results showed a statistically significant advantage in terms of overall survival, for those patients who were treated with CT → RT in group B ( P < 0.05), as well as those who were treated with CT+RT in group C ( P < 0.03), in comparison to patients who received only radiation in group A. But there was no statistically significant difference in terms of overall survival, between group B & C ( P < 0.52).

Follow-up
The follow-up period was calculated after completion of total planned treatment. Mean follow up duration was two years. Patients status at one year and at two year follow-up, are shown in [Table - 4][Table - 5], respectively.

Survival: Survival was calculated from the date on which patients were registered in the cancer OPD, to death, or last follow up available. [Table - 5] showed that 19(59.4%) out of 32 patients in group A, 20(57%) out of 35 patients in group B and 24(66.6%) out of 36 patients in group C, survived after two years of follow up. Comparison of survival by log rank test showed P values of 0.3, 0.47 and 0.57 among the three groups A, B, & C respectively, which were not statistically significant.

Distant Metastasis: During the two years follow up period, 20 patients (62.5%) in group A, 17 patients (48.6%) in group B and 16 patients (44.4%) in group C, developed distant metastasis. Brain was found to be the commonest site of distant metastasis. Metastasis in the non- regional lymph nodes, either in cervical group, or in the retroperitoneal group, were the second most common site. Distribution of site wise metastasis is shown in [Table - 6].

Time to tumor progression: Time to tumor progression in group A was 16 months (ranging from 5-20 months). In group B, it was 21 months and in group C it was also 21 months, (ranging from 8 m-22 m). The again clearly indicates, that addition of chemotherapy improves disease free survival.

Discussion

Therapeutic approach in unresectable NSCLC is widely discussed and a debatable problem. The optimum treatment modality, the intention of treatment and toxicity management, are major issues in the physicians′ mind.

Radiation alone, as a treatment modality, was in vogue for a long time. In the RTOG 73-01 study, which had a defining role in effective dose prescription, showed that 6000cGy in conventional fractionation was effective in this disease status. Complete Response (CR) was seen in 25% of patients and with lower doses, CR was recorded as 10-20%. But survival did not improve with higher radiation dose.[3] Further improvement was achieved by means of hyper fractionate radiation therapy schedule and by three dimensional treatment planning, which enabled us to deliver a further higher dose of radiation. Dose escalation from 6000cGy to 6900cGy improved two year survival from 16 to 20% and dose escalation up to 7400cGy by three dimensional treatment planning, enhanced two year survival to 37%.[5] Subsequently, (CHART) Continuous Hyperfractionated Accelerated Radiotherapy showed a two year survival of 34%.[6],[7] Benefits of combined modality therapy, were also observed in different trials. CALGB 8433 study conclusively proved the advantage of addition of chemotherapy to radiotherapy, where they showed doubling of five year survival rate, from 7% in radiation alone group, to 17% in combined modality group.[8] The same trial also observed a median survival of 11 months in the RT alone group and that of 14 months, in the combination therapy group.[8] Trovo et al also documented similar results, with improvement in the five year survival by 16%, by addition of chemotherapy to radiotherapy. Johnson et al showed a reduced rate of distant metastasis by combination therapy, with median survival of 11 month.[10] Le Chevalier et al showed almost identical results.[11] A meta-analysis by Marino et al , showed that Cisplatin- based chemotherapy is associated with a 24% reduction in chance of metastasis, as compared to radiation alone.[4]

Concurrent use of chemotherapy with radiotherapy, probably increases their individual effectivity, as one mode may sensitize tumour cell to other one. Many randomized trials[12],[13],[14],[15],[16],[17],[18],[19],[20] compared concurrent chemordiotherapy with sequential chemordiotherapy and radiotherapy alone, where few of them showed a statistically significant survival rate and others did not. Schakke-konning et al showed that concomitant chemoradiotherapy using Cisplatin, is associated with a three year survival rate of 16%, in comparison to that of 2% in the only radiation arm.[12] Reboul F et al observed that concurrent use of three weekly Cisplatinum, along with radiotherapy, had an overall response rate of 84% and a two year survival rate of 42%.[20]

In the present trial, sequential chemo-radiotherapy and concomitant chemo-radiotherapy showed overall response rates of 65.7 and 66.7%, respectively, which is modest when compared with Lechavalier et al , where sequential regimen showed a response rate of over 84%. One year follow up in the present trial, also showed a poor local control in all the three groups, 18.8% in group A, 20% in group B and 25% in group C, whereas Schakke - Konning et al[12] showed a three years actuarial local control rate of 53%. Previous studies by Le chavalier et al[11] and Marino et al ,[14] documented that addition of chemotherapy to radiotherapy, could reduce the chance of metastasis by 24%. In this study, we have observed that 62.5% of patients in group A, 48.6% in group B and 44.4% in group C, developed metastasis during a two year follow up. There was about 14-18% reduction in the rate of metastasis, when chemotherapy was added to radiation, which is near similar to previous experiences.

However, impact on survival remains below significant level. The only three arm study which showed a significant survival advantage, was that of Schakke-Konning et al . The improved survival of that study was attributed to improved local control. The present trial failed to show any significant effect on long term local control of disease. Poor local control might be an explanation of lower survival in our study.

We conclude, that addition of chemotherapy to radiation in the treatment of unresectable NSCLC, significantly improves the initial response and thereby quality of life. Toxicities were more frequent in the combination regimen, but they were manageable. Although our study failed to show any significant survival advantage among the treatment groups, two years follow up observations show that concomitant chemo- radiotherapy has better long term control of disease, lesser chance of distant metastasis and a marginal impact on survival.

References

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