Concurrent Chemoradiation of Patients with Inoperable

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1 Med. J. Cairo Univ., VoL 81, No. 2, March: 29-34, Concurrent Chemoradiation of Patients with Inoperable Non-Metastatic Pancreatic Cancer MOHAMED S. ELZAHI, M.Sc.; MOHAMED M. ELAWADI, M.D.; IBRAHIM A. AWAD, M.D. and HANAN A. WAHBA, M.D. The Departments of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Mansoura University Abstract Background: Inoperable non-metastatic pancreatic cancer is a great challenge because the median survival is generally less than 1 year and the impact of standard therapies is so limited. All patients should be considered for protocol-based therapy. The aim of this study is to determine the tolerability and efficacy of Gemcitabine concurrent with 3D conformal radiotherapy for locally advanced, unresectable, non-metastatic pancreatic cancer. Methods: Thirty three patients received the following protocol in 3 phases; induction phase: Weekly Gemcitabine at a dose of 1,000 mg/m2 over 30 minutes infusion for 7 weeks, chemoradiotherapy phase: Gemcitabine 600 mg/m2 weekly for 5 weeks concurrent with 3 dimensional (3D) conformal radiotherapy for a total dose of 50.4 Gy in 28 fractions in 5.5 weeks, 5 days per week, and maintenance phase: Gemcitabine at a dose of 1,000 mg/m2 weekly for 3 weeks with 1 week rest between 2 cycles. Results: Forty eight patients with locally advanced unresectable pancreatic cancer were enrolled; only 33 patients completed the treatment protocol. After a median follow-up period of 20 months 15 patients were alive. The median progression free survival (PFS) was 15 months; the median overall survival was 19 months. The estimated 12 months, 18 months and 24 months survival was 79%, 42%, and 18% respectively. Grade III toxicity were reported in 37.5% of patients with no grade VI toxicity, vomiting were the most common toxicity (32.5%) followed by fatigue (21.5%). Conclusions: Gemcitabine concurrent with 3D conformal radiotherapy is active, well tolerated and associated with encouraging survival in patients with locally advanced pancreatic cancer. Key Words: 3D conformal radiotherapy - Locally advanced pancreatic cancer - Gemcitabine. Introduction ALTHOUGH pancreatic cancer accounts for only 2% of all cancer diagnosis, it is the fourth-leading Correspondence to: Dr. Mohamed S. Elzahi, The Departments of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Mansoura University cause of cancer death and one of the most difficult malignancies to manage. Because of the usually late onset of symptoms, only 10%-15% of patients present with resectable disease, whereas the remaining 85%-90% present with locally advanced unresectable or metastatic disease in. Inoperable pancreatic cancer is a great challenge that oncologists frequently encounter. Because the median survival in patients with locally advanced disease is generally less than 1 year, the goals of treatment are to palliate symptoms and prolong life [2]. Since the impact of standard therapies is so limited, all patients with locally advanced pancreatic cancer should be considered for protocol-based therapy. Patients with locally advanced disease are usually eligible for clinical trials evaluating systemic therapy alone as well as trials evaluating novel chemoradiation regimens. Some clinical trials have established that the concurrent use of chemotherapy with radiotherapy can improve the median survival compared to radiation alone and to chemotherapy alone [3]. Because gemcitabine is superior to other agents in patients with advanced pancreatic cancer, the substitution of Gemcitabine with concurrent radiotherapy has been evaluated in several trials which demonstrated encourage results as regards efficacy and tolerability [4]. Aim of the study: To determine the tolerability and efficacy of Gemcitabine concurrent with 3D conformal radiotherapy for locally advanced, unresctable, non-metastatic pancreatic cancer. Patients and Methods This prospective study included 33 patients with locally advanced pancreatic cancer who at- 29

2 30 Concurrent Chemoradiation of Pancreatic Cancer tended to Clinical Oncology and Nuclear Medicine Department, Mansoura University Hospital in the period from September 2009 to Mars 2012 inclusive. Eligibility criteria: - Age not less than 20 years and not more than 70 years. - ECOG performance status from Locally advanced unrespectable non-metastatic pancreatic cancer with no lymph node involvement. - Diagnosis is confirmed histologically or radiologically by triphasic CT or (MRI) with elevated tumor marker CA Adequate hematological, hepatic and renal function. - No prior anti- cancer treatment. - No other malignancy. Pretreatment evaluation: All patients were evaluated by: Accurate full personal, present, and past history; full clinical examination including evaluation of performance status, general and locoregional examination. Laboratory investigations included complete blood picture, renal function, hepatic function, serum CA19-9 and CEA. Radiological investigations included base line triphasic CT or MRI abdomen and pelvis and radiological investigations to exclude metastasis included chest X-ray (or CT chest if there is suspicious lesion) and bone scan if indicated. Treatment protocol: All patients were planned to receive the following protocol in 3 phases; induction phase: Weekly Gemcitabine at a dose of 1,000 mg/m2 over 30 minutes infusion for 7 weeks, chemoradiotherapy phase: Gemcitabine 600 mg/m2 over 30 minutes infusion, at least 1 hour before the radiotherapy, weekly for 5 weeks concurrent with radiotherapy for a total dose of 50.4 Gy in 28 fractions in 5.5 weeks, 5 days per week, using 3D conformal radiotherapy, and maintenance phase: After completion of chemoradiotherapy in the form of 2 cycles of Gemcitabine at a dose of 1,000 mg/m2 over 30 minutes infusion weekly for 3 weeks with 1 week rest between 2 cycles. Radiotherapy was delivered by 3D conformal radiotherapy modality. CT-based treatment planning (with a contrast enhanced CT scan using 5mm slices) was required for all patients. Planning was done using 3D Precise Treatment Planning System version Optimization of 3DCRT plan was confirmed with cumulative dose volume histogram (DVH). Clinical target volum (CTV) was cover by 95% of isodose curves, inhomogenicity ranged from 95% to 105%, and doses to organs at risk were limited to their tolerances. 3D CRT was delivered by high energy linear accelerator (Elekta, Precise Treatment System TM), Version 5, with 6 MEV photon energy. Post treatment evaluation was done at least 1 month after the end of chemoradiotherapy phase using triphasic CT (or MRI) and tumor markers CA19-9 and CEA. Patients were followed-up every month by clinical examination, complete lab, tumor markers and evaluation of toxic effects, every 3 months by CT or MRI for 1 year then every 6 months for the second year then annually. Statistical analysis: Drug and radiotherapy related toxicities were graded using the NCI-CTC (version 2.0) [5]. Response was assessed by the RECIST criteria [6]. Progression free survival (PFS) was calculated as the interval between the start of treatment and the earliest event of disease progression. Overall survival (OAS) was calculated as the interval between the diagnosis and last follow-up or death of the patient. The Kaplan-Meier product limit method was used to estimate PFS and OAS. Statistical analyses were performed using SPSS 2004 (version 16) [7]. Results Patient characteristics: Patient characteristics are summarized in (Table 1). Forty eight patients were eligible to start the study, (66%) male and (33%) female with a median age 52years. Fifteen patients (30%) were presented with ECOG 0, 17 patients (37%) with ECOG 1, and 16 patients (33%) with ECOG 2. The most common site of the tumor was the head (72%). Nearly 95% of the histologically assessed cases were proved to be adenocarcinoma and 66% of them were grade II. Only 40% of all cases had elevated tumor marker CA19.9 (more than 37 u/l) at the time of diagnosis. Prevalence of symptoms: Almost all patients were presented with more than one symptom. In general, the most common presenting symptoms were pain (66%), jaundice (48%), and vomiting (36%).

3 Mohamed S. Elzahi, et al 31 Toxicity: The induction phase of the study was well tolerated for most of patients, only 3 patients developed grade III vomiting and diarrhea without improvement on supportive treatment and they did not complete the induction phase and were excluded from the study. Patients were evaluated for adverse events during chemoradiotherapy (Table 3). Four patients out of 37 (11%) did not complete phase II of the protocol; 2 patients (5.5%) developed gastro-intestinal bleeding and another 2 patients (5.5%) developed marked deterioration of general condition with grade 3 vomiting and diarrhea. Thirty three patients completed the phase. Five patients (13.5%) developed grade I toxicity, 20 patients (54%) developed grade II toxicity, 14 patients (37.5%) developed grade III toxicity and no one developed grade VI toxicity. The most common toxicity was vomiting (32.5%) followed by fatigue (21.5%). Only 3 patients (8%) needed to stop the treatment due to grade III vomiting and diarrhea (1 patient for 1 week and 2 patients for 2 weeks), they received supportive treatment and then continued their therapy. In the other 30 patients, adverse effects were tolerable. About 80% of these toxicities started to appear after the 3rd week of therapy. As regards phase III of the study, it was well tolerated with no remarkable toxicity. Response rate: All 33 patients were assessed radiologically and by tumor markers CA19-9 and CEA 1 month after ending phase II. Radiologically; 2 patients (6%) had complete response (CR), 6 patients (18%) had partial response (PR), 22 patients (67%) had stable disease (SD) and 3 patients (9%) had progressive disease (PD) (two patients developed liver metastasis and 1 patient developed liver and lung metastasis) (Table 4). As regards CA19-9, only 12 patients out of the thirty three patients had elevated levels before starting the protocol. Six patients (50%) had achieved 50% reduction relative to the baseline value, 4 patients (33%) had stabilization (<50% reduction to <25% increase) and 2 patients (17%) had progression (>30% increase) [3]. Survival: After a median follow-up period of about 20 months (range months) and at the time of analysis 15 patients were alive. The median PFS time for patients in this study was 15 months (95% CI, months) (Fig. 1). The median overall survival time was 19 months (95% CI, months). The estimated 12 months, 18 months and 24 months survival was 79%, 42%, and 18% respectively (Fig. 2). It was noticed that the liver was the main site of relapse (95%), followed by abdominal lymph nodes and peritoneum (20%), then the lung (15%), and bone (5%). Table (1): Patient characteristics. Characteristic Number (total) Percentage Sex Male 32 (48) 66 Female 16 (48) 34 Age (48) 60 Median 52y >60 19 (48) 40 Range (34-70) ECOG 0 15 (48) 30 P.S 1 17 (48) (48) 33 Site of Tumor Head 35 (48) 72 Body 11 (48) 23 Tail 2 (48) 5 Pathology Adenocarcinoma 39 (41) 95 Others 2 (41) 5 Tumor Grade I 10 (41) 24 II 27 (41) 66 HI 4 (41) 10 Marker 37U/L 29 (48) 60 (CA19.9) >37U/L 19 (48) 40 Comorbidities D.M 8 (48) 16 HTN 6 (48) 12 Table (2): Prevalence of symptoms. Symptoms Number (total) Percentage Pain 32 (48) 66 Jaundice 23 (48) 48 Vomiting 17 (48) 36 Weight loss 15 (48) 31 Anorexia 11 (48) 23 Nausea 8 (48) 17 Table (3): Toxicity of chemoradiation. Toxicity G1 G2 G3 N % N % N % Vomiting Fatigue Diarrhea Anorexia Nausea Stomatitis Dyspepsia N.B: No patients developed G VI toxicities.

4 32 Concurrent Chemoradiation of Pancreatic Cancer Table (4): Response rate (radiological). CR PR SD PD 1.0 _ cd E rn g ,1,?:, 0.6 rn g Number Percentage 2 (33) 6 6 (33) (33) 67 3 (33) 9 Survival Function PFS Fig. (1): PFS. ' Survival Function + Censored ' Li, Survival Function 25: ' Survival Function + Censored OAS Fig. (2): OAS. Discussion The optimal treatment of locally advanced pancreatic cancer is still a matter of controversy. Few studies have demonstrated median survival durations longer than 12 months [4]. Our study aimed to assess the efficacy and tolerability of concurrent use of Gemcitabine and 3D conformal radiotherapy for those patients with locally advanced inoperable non- metastatic pancreatic cancer who showed a response or at least a non progressive course after an induction phase of weekly Gemcitabine. The results of our study were better than the results of a retrospective study done by Iciarashi et al., [8] on 18 patient with locally advanced pancreatic cancer utilizing Gemcitabine adminis- tered twice weekly at a dose of 40mg/m2 concurrent with total dose of Gy delivered using Gy daily fractions. Regarding response rate, there was 5% complete response, 22% partial responses, 50% stable diseases and 23% progressive disease. The median survival was 15.0 months and the overall 1-year survival rate was 60%, while the median progression-free survival was 8.0 month. The higher dose of Gemcitabine given concurrently with radiation may explain the better results in our study. Shibuya et al., [9] has studied a dose of 250 mg/m2 of Gemcitabine weekly given with a total dose of 54Gy was delivered in 30 fractions of 1.8Gy/d on 21 patients. Radiological partial response was observed in 23%, stable disease was noted in 52% and progressive disease was in 25%. The 1-year survival rate was 74% and the median survival time was 16.6 months. Again the higher dose of Gemcitabine with radiation in our study may explain the better results. Gemcitabine was studied also concomitant with radiotherapy by Cardenes et al., Rol on 28 patients. Patients received GEM 600mg/m2 IV weekly, with concurrent RT (50.4Gy in 28 fractions, 1.8Gy/d, 5 days per week) (the same as our study). The median follow-up was 10 months (20 months in our study) for all enrolled patients. Six patients (21%) had a radiologic partial response, 16 patients (57%) had stable disease, 5 patients (18%) had progressive disease, and 1 patient (4%) had an unevaluable response at last follow-up. Median time to progression was 6 months. Median survival time was 10.3 months. The 1- and 2-year actuarial survival rates were 30% and 11%. The results were disappointing as regards median survival and TTP. Compared to our study, and although the researchers of the previous study used the same dose of Gemctabine concurrent with the radiation, they did not consider the induction phase before the concurrent chemoradiotherapy phase and this may explain the weak results of the that study. In the same time, it gives an idea about the benefit of starting with the induction phase aiming to exclude the non responsive and metastatic cases before the chemoradiation phase which is reflected on the end result of the study as regards the OAS and PFS. This concept is confirmed by Gillmore et al., [iii who compared induction chemotherapy followed by chemoradiotherapy versus chemradiotherapy from the start. A multi-centre retrospective analysis of 48 patients with biopsy-proven LAPC treated with CRT from the start (n 24) or starting with induction chemotherapy (n 24) in four regional

5 Mohamed S. Elzahi, et al 33 oncology centers in the UK between March 2000 and October The disease control rate was 73.4% vs 81.3%. The median overall survival was 13 vs 17 months. The same idea is supported in a published nonrandomized series of 181 patients who were treated with Gemcitabine-based chemotherapy for 3 months, and those with stable disease (128 patients) were treated with CRT or chemotherapy alone. The median survival time was significantly longer in patients receiving CRT (15 months versus 11.7 months). This shows a probable benefit of CRT in patients who have achieved stable disease with induction chemotherapy [12]. As regards the toxicity assessment of our study, and compared to other studies used chemotherapy alone for treatment of locally advanced pancreatic cancer, the benefit of adding radiation to chemotherapy came at the cost of increased gastrointestinal toxicity as confirmed by Loehrer et al., [4] who compared gemcitabine alone to gemcitabine with radiation. Grade III gastrointestinal toxicity was 23% and 38% respectively. Grade III toxicity were 37.5 in our study. But in comparison to other studies of chemoradiation using other agents than gemcitabine, our protocol seems to be safer and less toxic. Oberic et al., [13] studies 5 FU and docetaxel with radiation on 40 patients. Twelve patients (60%) experienced grade 3-4 toxicities during CRT treatment. The most relevant severe toxicity involved the gastrointestinal tract in 34 patients (85%) including vomiting (35%). Also, Saif et al., [14] studies capicitabine concurrent with radiation on 82 patients. Sixty-six (80%) experienced grade III or greater toxicity. There were three deaths reported related to treatment. Some studies explored the addition of another agent to Gemcitabine with radiotherapy. Seventy eight patients received radiation therapy (50.4Gy) with concurrent infusional 5FU (200mg/m2 5 days/week) and weekly gemcitabine (200mg/m2). After a 3-week break, patients received weekly gemcitabine at 1000mg/m2 for 3 of 4 weeks, for 4 cycles. The median survival of the 78 eligible patients was 12.2 months, the estimated one-year survival was 51%, and the median TTP was 10 months [15]. In another study done by Arnolelli et al. [15], Sixteen Patients with non-metastatic, locally advanced pancreatic cancer were treated in a dose escalation study with gemcitabine (0-300mg/ m2/week) given concurrently with cetuximab (400mg/m2 loading dose, 250mg/m2 weekly main- tenance dose) and irradiation (50.4Gy). The most frequent Grade 3 toxicity was thrombocytopenia 73% and hyperkalemia 68%. The most Grade 4 toxicity was perforated duodenum (3 patients 19%) and pulmonary embolism (2 patients 12.5%). The overall survival was 10.5 months. These studies suggest that addition of other agents to gemcitabine during the radiotherapy leads to more toxicity to the patients with no benefit or even worse results as regards the response, median survival and PFS. Conclusions: Concurrent chemoraiotherapy using gemcitabine and 3D conformal radiotherapy with initial and subsequent systemic gemcitabine is tolerable, feasible, and effective, and offers good local control for a substantial proportion of patients with locally advanced pancreatic disease. This protocol showed a significantly better progression free survival, overall survival and a comparable toxicity profile in comparison with other regimens. However, further studies with larger numbers of patients are needed to confirm our finding. References 1- CARDENES H.R., CHIOREAN E.G., DEWITT J., et al.: Locally advanced pancreatic cancer: Current therapeutic approach. Oncologist. 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6 34 Concurrent Chemoradiation of Pancreatic Cancer 10- CARDENES H.R., MOORE A.M., JOHNSON C.S., et al.: A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: A Hoosier Oncology Group study. J. Clin. Oncol. Oct., 34 (5): 460-5, GILLMORE R., LAURENCE V., RAOUF S., et al.: Chemoradiotherapy with or without induction chemotherapy for locally advanced pancreatic cancer: A UK multiinstitutional experience. Clin Oncol (R Coll Radiol). Sep; 22 (7): Epub 2010 Jun., 1, HUGUET F., ANDRE T., HAMMEL P., et al.: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J. Clin. Oncol. Jan., 20, 25 (3): , OBERIC L., VIRET F., BAEY C., et al.: Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: A FN- CLCC-ACCORD/0201 randomized phase II trial's preplanned analysis and case report of a 5.5-year disease- free survival. Radiat Oncol. Sep., 26, 6: 124. doi: / X-6-124, SAIF M.W., BLACK G., ROY S., et al.: Phase II study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: Up-regulation of thymidine phosphorylase.cancer J. Jul-Aug., 13 (4): , MAMON H.J., NIEDZWIECKI D., HOLLIS D., et al.: A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma: Cancer and Leukemia Group B (CAL- GB) Cancer. Jun., 15; 117 (12): doi: /cncr Epub 2010 Dec., 23, ARNOLETTI J.P., FROLOV A., ELOUBEIDI M., et al.: A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer. Cancer. Chemother. Pharmacol. Apr., 67 (4): Epub 2010 Jun 30, 2011.