Peri-Operative Chemo-Radio-Therapy Versus Radiotherapy Alone in NSC-Lung Cancer

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1 Med. J. Cairo Univ., Vol. 82, No. 1, March: 7-11, Peri-Operative Chemo-Radio-Therapy Versus Radiotherapy Alone in NSC-Lung Cancer HAMDY ELAYOUTY, M.D.*; EHAB HASSANIN, M.D.**; AHMED BA. ZAEB, M.D.** and SAYED LABIB, M.D.*** The Departments of Chest Surgery*, Oncology** & Chest Diseases Unit***, Suez Canal University, Ismailia and Department of Oncology, Hadramout University, Al-Mukalla, Yemen** Abstract Background: In patients with unresectable non-small cell lung cancer, a short course of cisplatin and vinblastine prior to radiation significantly improves median survival and doubles the number of long-term survivors, as compared with radiation therapy alone. A randomized prospective study using radiotherapy with or without concomitant chemotherapy in patients who have undergone resection as well as initial chemotherapy for those with marginally resectable disease. The goals are to assess the feasibility and reproducibility of the combined regimen and to evaluate its ability to improve local control and survival. Methods: Forty two patients (30 men, 12 women) had stage II or IIIA disease. Their median age was 54 years (range 33-63years). All had experienced no significant weight loss. Group A (21 patients): Patients with marginally resectable disease received two cycles of chemotherapy pre-operatively and a maximum of four cycles post-operatively. Patients with initially resectable tumors received four cycles postoperatively. Radiation therapy was begun on day 1 or 2 concomitantly with chemotherapy. Group B (21 patients) received radiotherapy alone. Results: During chemo-radiotherapy two patients developed toxicity and were shifted to group B. Eighteen out of 19 remained alive at the end of chemoradio-therapy and recorded median survival of 51.3 months compared with 16 out of 23 in group B who had median survival of 42.9 months (p=0.001). Conclusion: Concomitant chemo-radio-therapy is feasible and reproducible as adjuvant treatment in non small-cell lung cancer. Key Words: Chemotherapy Radiotherapy Concomitant chem.-radiotherapy Bronchogenic carcinoma Cisplatin Etoposide. Correspondence to: Dr. Hamdy D. Elayouty, Department of Chest Surgery, Suez Canal University Hospitals, Ismailia, Egypt, h.dosoky@yahoo.com Introduction MOST patients with non small-cell lung cancer have advanced disease at the time of initial treatment and only one third of patients are candidates for curative lung resection. Treatment of advanced lung cancer has evolved from trials of postoperative adjuvant radiotherapy to postoperative chemotherapy to induction chemotherapy and induction chemo-radiotherapy [1]. In recent years, there has been increasing evidence that the use of concomitant chemotherapy and radiotherapy is feasible in the treatment of non-small cell lung cancer. Recently, it has been shown that even in patients with unresectable stage III, a short course of cisplatin and vinblastine prior to radiation significantly improves median survival and doubles the number of long-term survivors, as compared with radiation therapy alone [2]. Current study represents the results of a randomized prospective pilot study using conventional radiation therapy with or without concomitant cisplatin and etoposide as an adjuvant treatment in patients who had undergone resection as well as initial therapy for those with marginally resectable disease. Cisplatin is a well-known and extensively studied radiation sensitizer. The combination of cisplatin and etoposide has clear synergistic effects against a variety of human tumors and can produce a response rate of 30-40% in patients with non-small cell lung cancer [3]. The Eastern Cooperative Oncology Group reported that patients randomized to this combination had a modest but significantly higher survival over patients treated with the other drug regimens [4]. 7

2 8 Peri-Operative Chemo-Radio-Therapy Versus Radiotherapy Objectives: The goals are to assess the feasibility and toxicity of the combined chemo.-radiotherapy regimen and to evaluate its ability to improve local control and survival. Patients and Methods This randomized prospective pilot study included 42 patients (30 men, 12 women) participated in this study. We received these patients at the Departments of Chest medicine and thoracic Surgery, Suez Canal University, Ben Sena Teaching Hospital-Yemen and King Fahd Central Hospital, Jazan, KSA. This study continued from 1 stmarch 2006 to 3 1 st March Follow-up continued for sixty months. Consent from patients and ethics committee were obtained. All had experienced neither significant decrease of appetite nor weight loss. Staging evaluation included medical history and full clinical examination, chest X-ray, CT-scan of the chest, upper abdomen and brain, bronchoscopy and bone scan. Invasive staging of mediastinal lymph nodes was performed as indicated by CT-scan. We used mediastinoscopy or mediastinotomy for this target. All had histological diagnosis of non-small cell lung cancer. Their median age is 54 (range: years). All patients had stage II or IIIA disease. Patients were randomized to receive radiation or chemo-radiation therapy. Patients with marginally resectable disease were randomized to receive radiation or chemoradiation before possible surgery, they received two cycles of chemotherapy pre-operatively and a maximum of four cycles post-operatively. Patients with initially resectable tumors received four cycles postoperatively. Radiation therapy was begun on day 1 or 2 concomitantly with chemotherapy. Two patients discontinued chemotherapy and were added to group B. Initially Group A, included 21 patients After this shift, they became reduced to 19 patients. Group B: Became 23 patients who received radiotherapy without chemotherapy. Patient characteristics are listed in (Table 1). All patients underwent pulmonary resection and had complete lymph node dissection performed guided by computerized tomography of chest and results of mediastinoscopy. Chemotherapy, when given, consisted of cisplatin 60mg/m. Square on day 1 and etoposide 100 mg/ m square in day 1,2 and 3 repeated at day intervals, based on recovery of white blood count to a minimum of 4,000/C mm and platelet count of 100,000/C mm. Preventive use of G-CSF (granulocyte colony-stimulating factor) or GM- CSF (granulocyte macrophage colony-stimulating factor) was applied according to the guide lines described by the American Society of Clinical Oncology. Updated guidelines for anti-emetics in oncology were applied [5]. Radiation therapy was given to both groups of patients A and B, on day 1 or 2. Treatment consisted of thirty-three 180 cgy fractions (total dose, 5940 cgy) for patients receiving radiation only in group B. For those in group A, undergoing concomitant chemo-radio-therapy 30 fractions were given (5400 cgy total). Treatment was withheld if white blood cell counts were lower than 2000/C mm or platelet levels were below 50,000/C mm. Individualized treatment planning employs lead shielding tailored to shape the field and limit the radiation exposure of normal tissues. Often the radiation is delivered from two or three different positions. Conformal three-dimensional treatment planning permits the delivery of calculated doses of radiation to the target mass without increasing complications in the transit volume. Despite the small numbers, the two groups were well matched for age, histological type and stage of tumor. Statistical analysis: The sample size was calculated according to the usual equation. We used the mean, the percentage and the median values. SPSS program was used to apply bivariate analysis for correlation between method of treatment and survival on one side and modality of treatment and toxicity on the other side. Results The toxicity of chemotherapy was acceptable, early discontinuation was required in 2 patients due to an anaphylactoid reaction, candida esophagitis, cardiac arrhythmia and patient refusal. Temporary discontinuation was necessary for fungal sinusitis in a diabetic patient who later completed therapy. Esophagitis and radiation pneumonitis required steroid therapy. Eighteen out of 19 patients who received cisplatin and etoposide plus radiation were alive by the end of the therapy. They recorded median survival rate of 51.3 months. Those who received adjuvant radiation, 16 of 23 patients were alive by the end of therapy. One patient developed constrictive pericarditis and early pericardectomy was done. Two patients developed recurrent, rapidly

3 Hamdy Elayouty, et al. 9 accumulating pericardial effusion. Thoracoscopic pericardial window was performed for each one. One developed Radiation pneumonitis. 1.0 Servival Functions Sta = Dead Median survival rate for this group was 42.9 months. The difference in survival between group A and group B is statistically significant. (p=0.001). The rate of toxicity was generally low but more among patients who had chemo.-radiotherapy; the difference is statistically insignificant. Table (1): Patients characteristics. Concomitant chemo-radiation (group A) Group (B) Radiation (group B) Final Number of patients Median age Histological types: Adenocarcinoma Squamous cell 6 7 Large cell 1 2 Stage: II (T2 N1M0) 5 5 IIIA (T1N2M0) 3 4 (T2N2M0) 4 5 (T3N0M0) 5 6 (T3N1M0) 1 2 (T3N2M0) 1 1 Pulmonary resection: Lobectomy 7 9 Bilobectomy 6 8 pneumonectomy 4 4 Wedge resection (biopsy alone) 2 2 Table (2): The results of chemo-radio-therapy in group (A) versus radiotherapy in group (B). Patients Group (A) Notes No No. after toxicity of chemotherapy Survivors at the endof therapy Notes Mortality 1 7% 7 33% during therapy Median survival Higher 51.3 months Toxicity of therapy Lower 42.9 months. Discontinued 1 Constrictive chemo.: pericarditis 2 Anaphylactoid 2 Pericardial reaction, candida effusion esophagitis, cardiac arrhythmia. 1 Recovered bone 1 Pneumonitis. marrow depression and continued chemo. Cun Servival Res Treat Chemoradiotherapy Ragiotherapy Chemoradiotherapy-censored Ragiotherapy-censored Res stands for duration of response = Symptom free inter-val, blue line represents survival rate for chemoradiotherapy-group and green line represents survival among radiotherapy group of patients. Fig. (1): Kaplan-Meier Curves (as derived from the statistical program). Discussion Lung cancer remains the most common cause of death by malignancy in both men and women. Two thirds of the cases are resectable at presentation but resection is not curable in most of the cases. The diversity of molecular abnormalities in nonsmall cell lung cancer may partly contribute to variable results of therapy [6]. Also, adjustments in dosage of chemotherapeutic agents or changes in radiotherapy planning could reduce toxicity and improve results [7]. Radiation therapy (Teletherapy) is a component of curative therapy for a number of diseases, including breast cancer, Hodgkin s disease, head and neck cancer, prostate cancer and gynecological cancers. Radiation therapy can also, palliate disease symptoms in a variety of settings: Relief of bone pain from metastatic disease, control of brain metastasis, reversal of spinal cord compression and superior vena cava obstruction, shrinkage of painful masses, and opening of threatened airways [8]. Acute toxicities include skin erythema and ulceration and bone marrow toxicity. These were alleviate among our patients by interruption of treatment. Chronic toxicities included pericardial effusions, chronic constrictive pericarditis and lung fibrosis interfering with efficiency of cardiac and pulmonary functions. They are preventable in most

4 10 Peri-Operative Chemo-Radio-Therapy Versus Radiotherapy ofthe cases by proper planning of the radiotherapy. Recurrent rapidly accumulating pericardial effusion indicated pericardial window in two cases. Cisplatin was discovered fortuitously by observing that bacteria present in electrolysis solutions could not divide. Only the cisdiamine configuration is active as an antitumor agent. Cisplatin requires administration with adequate hydration, including forced dieresis with mannitol to minimize renal damage.in conventional doses, hearing loss is likely to develop in 50% of patients. Etoposide is one of the antitumor antibiotics. This drug causes G2arrest, reflecting the action of a DNA damage checkpoints. Clinical effects include myelosuppresion, nausea and transient hypotension related to the speed of administration [8]. Indications for the clinical use of G-CSF or GM-CSF are both preventive and therapeutic. According to the Amirican Society of Clinical Oncology [9] preventive uses include: 1- With the 1st cycle of chemotherapy (primary CSF administration). - If the probability of febrile neutropenia is >20%. - If a patient was presenting with neutropenia or active infection. - Age is above 65 treated for lymphoma or other tumors with curative intent. - Poor performance status after extensive prior chemotherapy. - Dose dense therapy. 2- With subsequent cycles if febrile neutropenia has previously occurred. Anemia associated with chemotherapy can be managed by transfusion of pcked RBCs. Transfusion is not undertaken until the hemoglobin falls to <80gm/L (8gm/dL). Current randomized prospective pilot study was designed to explore the feasibility of developing a regimen for delivering concomitant chemoradiation using moderate dosage cisplatin on day 1 plus etoposide on days 1,2 and 3 in day cycles with a goal of 4 cycles of treatment. There are several theoretical reasons why a simultaneous approach would be advantageous. First, a situation where there are local recurrence and systematic metastasis, there is the early delivery of each treatment modality-each with its independent activity. In the post-operative sitting, each treatment can be initiated within 6 weeks of surgery. This eliminates the concern that chem.-therapy admin- istered before radiation might produce an unwelcome delay that could compromise local control or even produce resistance of the tumor cell to radiation. On the other hand, one of the arguments in favor of induction or neo-adjuvant chemotherapy is that initial radiation may alter tumor blood flow or decrease patient tolerance or sensitivity to chemotherapy [11]. Second, the toxicity profiles of the two modalities are sufficiently different to allow high doses of each in order not to compromise the effects of either. The toxicity of radiation is for the most part limited to the mediastinum, esophagus and lungs. The side effects of chemotherapy often involve the bone marrow, the kidney and liver. Finally, cisplatin and radiation have synergistic cytotoxicity. Cisplatin can generate free radicals that will enhance radiation and can inhibit repair of the damage caused by radiation, specially damage induced on DNA, RNA and protein cross-links. Enhanced survival with concomitant chemo-radiotherapy has been shown for patients treated in randomized studies for renal, pancreatic, colorectal, small cell lung, head and neck and cancer cervix. This is presumed to be due to improving local and systemic control, a decrease in radio-resistance and elimination of sites of early metastasis [11]. Caution is required in drawing any conclusions regarding survival given the small size of our group of patients. Conclusions: Concomitant cisplatin, etoposide and radiation therapy is feasible as adjuvant treatment in nonsmall cell lung cancer. Further studies on larger patients populations are highly recommended. References 1- DALY B.: Late results of pneumonectomy. Chest Surgery Clinics of North America, 5: , BYFIELDI, STANTON W. and SHARP T.: Phase I-II study of 120-hour infused 5- FU and split course radiation therapy in localized NSCLC. Cancer Treat. Rep., 67: , KLENTERSKY I.: Therapy with cisplatin and etoposide for non-small cell lungcancer. Chest, 89: , RUCHDESCHEL I., FINKELISTEIN D. and ETINGER D.: A randomized trial of the four most active regimens for metastatic non-small cell lung cancer. J. Clin. Oncol., 4: 14-22, American Society of Clinical Oncology: Update of recommendations for the use ofwhite blood cells growth factors. An evidence-based clinical practice guidelines. J. Clinic. Oncol., 24: , SACCO P., MAIONE P., ROSSI A., BARESCHIENO M., PALAZZOI G. and GRIDELLI C.: Combination of radio-

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