|Year : 2014 | Volume
| Issue : 2 | Page : 176-179
Role of neoadjuvant concurrent chemoradiation in locally advanced unresectable pancreatic cancer: A feasibility study at tertiary care centre
R Kapoor1, D Khosla1, R Gupta2, A Bahl1, AK Shukla1, SC Sharma1
1 Department of Radiotherapy and Oncology, Regional Cancer Centre, Chandigarh, Haryana and Punjab, India
2 Department of Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, Haryana and Punjab, India
|Date of Web Publication||7-Aug-2014|
Department of Radiotherapy and Oncology, Regional Cancer Centre, Chandigarh, Haryana and Punjab
Source of Support: None, Conflict of Interest: None
Background: Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease. The objective of the present study was to assess the effect of neoadjuvant chemoradiation therapy (NACRT) on tumor response, down staging and resection, toxicity and any survival advantage. Materials and Methods: A prospective pilot study was carried out from January 2009 to June 2011 in which 15 patients of locally advanced unresectable pancreatic cancer were included. All patients were treated with NACRT protocol with oral Capecitabine and 3D conformal radiotherapy (3DCRT) of 30 Gy in 10 fractions. The patients were restaged 3 to 4 weeks after the completion of NACRT and explored for resection. Results: Out of 15 patients, fourteen were evaluable. Four patients underwent surgery, 5 had partial response but remained unresectable, 2 patients had stable disease and 3 had progressive disease. Most of the toxicities were slight and were in grade 1 to 2. None of the patients developed grade 3 or 4 gastrointestinal or hematological toxicity. The median survival was 15 months for resected patients and 8.6 months for unresected patients, respectively. The 2 year actuarial overall survival was 34.6%. Conclusion: All patients with locally unresectable pancreatic cancer should be offered chemoradiation therapy, in hopes of down staging the tumor for possible resection and achieving higher survival.
Keywords: Capecitabine, neoadjuvant chemoradiation, pancreatic cancer, toxicity, unresectable
|How to cite this article:|
Kapoor R, Khosla D, Gupta R, Bahl A, Shukla A K, Sharma S C. Role of neoadjuvant concurrent chemoradiation in locally advanced unresectable pancreatic cancer: A feasibility study at tertiary care centre. Indian J Cancer 2014;51:176-9
|How to cite this URL:|
Kapoor R, Khosla D, Gupta R, Bahl A, Shukla A K, Sharma S C. Role of neoadjuvant concurrent chemoradiation in locally advanced unresectable pancreatic cancer: A feasibility study at tertiary care centre. Indian J Cancer [serial online] 2014 [cited 2019 Aug 24];51:176-9. Available from: http://www.indianjcancer.com/text.asp?2014/51/2/176/138295
| » Introduction|| |
Pancreatic cancer is accompanied by an unacceptably high mortality. It is associated with an extremely poor prognosis, reflected by a median survival of 5-8 months and a 5-year survival probability of less than 5% when all stages are combined. , At present, the only chance for cure and prolonged survival is surgical resection with macroscopic tumor clearance. However, only approximately 10-20% of patients are considered candidates for curative resection.  Among patients with resectable disease, median, 3-year, and 5-year survival is approximately 25 months, 35%, and 20%, respectively with multimodality treatment. , These survival data are from series with large numbers of patients, and are probably appropriate benchmarks against which to measure further trials.
In a substantial number of patients (approximately 30-40%) the disease is considered "locally advanced" at the time of diagnosis. The definition of locally advanced disease is unresectability and the absence of distant metastasis. This group of patients has been intensively discussed during the last years and neoadjuvant therapies have been proposed to achieve better local tumor control or tumor down-staging with a subsequent potentially resectable tumor. Current guidelines generally consider encasement/involvement of the superior mesenteric artery/celiac trunk as signs of unresectability,  portal vein/superior mesenteric vein involvement has been more critically discussed  and categories such as "borderline resectable" have been introduced.  Furthermore, all criteria depend heavily on the experience and technical expertise of the involved radiologists, gastroenterologists, and surgeons. The relatively high percentage of pancreatic carcinoma patients presenting with non-metastatic but "locally advanced" disease as well as the large number of microscopic incomplete resections should provide a strong rationale for a neoadjuvant approach. 
Here we examine the current feasibility and efficacy of neoadjuvant chemoradiation therapy (NACRT) for patients with locally advanced pancreatic cancer.
| » Materials and Methods|| |
Fifteen patients of locally advanced histologically proven adenocarcinoma of pancreas were enrolled in this prospective study from January 2009 to June 2011. Patients were considered eligible for the study if they had: Cytologic or histologic proof of adenocarcinoma of pancreas; locally advanced, unresectable, non-metastatic disease; baseline Karnofsky performance status (KPS) of ≥70; adequate bone marrow reserve (white blood cell count >3,000 μL, platelet count >100,000 μL, hemoglobin >9 gm/dL, hematocrit >27%; adequate renal function; adequate hepatic function (a serum aspartate aminotransferase (AST) level <2 times upper normal limit (UNL); a serum alanine aminotransferase (ALT) level <2 times UNL; total bilirubin levels of less than 2.0 mg/dL). Patients were excluded if there was history of prior chemotherapy or radiotherapy; serious concomitant systemic disorders i.e., significant cardiac or pulmonary morbidity. All pathologically confirmed cases presenting with obstructive jaundice, first underwent biliary stenting or surgical biliary decompression. A two week period was allowed after biliary decompression for return of liver functions to acceptable level before treatment was started. All patients signed a written informed consent prior to participation in the study. Ethical clearance for the conduction of the study was obtained from the institutional ethics committee prior to the inception of the study.
| » Treatment Protocol|| |
All patients received oral Capecitabine 1000 mg/m 2 daily in three divided doses, 5 days per week, coinciding with radiation therapy administration. Therapy continued for the entire duration of radiation therapy. Hemogram, renal function tests and liver function tests were monitored weekly during the therapy.
All patients underwent planning CT receiving intravenous contrast as well as oral contrast with 2.5 mm slices in Light Speed VFX-16 CT simulator (GE Medical Systems, Waukesha, WI, USA). Planning was done on Eclipse treatment planning Varian Medical system version 8.6 (Varian Medical Systems, Palo Alto, CA, USA). The gross tumor volume (GTV) was contoured on axial images. Two clinical target volumes were entered for each patient- CTV tumor and CTV nodal. CTV tumor consisted of the gross tumor volume. In those with unresected pancreatic head malignancies, the CTV also included the duodenal bulb. CTV nodal consisted of the draining lymph node basin. This included the lymph nodes in the porta hepatis, celiac axis, superior mesenteric and retroperitoneal areas. The volume extended laterally (toward the splenic hilum) 1.5 cm beyond the target volume to partially include the superior and inferior pancreatic nodes. Both CTV's were combined to make total CTV. The radiation dose was prescribed to a planning target volume (PTV), which was generated by expanding the total CTV by 1 cm. Normal structures were also contoured, including kidneys, liver, spinal cord, and non-target GI tissue, which encompassed the small bowel and stomach outside the target. Dose constraints were specified for kidneys, liver and spinal cord as mentioned in [Table 1]. A 3 or 4 field 3DCRT plan was generated for each patient [Figure 1]. Dose of 30 Gy in 10 fractions over two weeks was prescribed to PTV.
|Figure 1: Example target volume coverage with 3D CRT (3 field arrangement) in a patient with pancreatic cancer|
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Assessment of initial response by NACRT was based on CT scans that were obtained 3 weeks after completion of NACRT. Response to NACRT was defined as follows: Complete response (CR), complete disappearance at all sites and no new lesions; partial response (PR), decrease of 30% in the sum of the single largest diameters of all measurable lesions; progressive disease (PD), an increase in the sum of the single largest diameters by 20%; stable disease (SD), neither PR nor PD criteria met. Resectability criteria included: Absence of extra pancreatic metastasis; patent superior mesenteric - portal vein axis; no direct tumor extension to celiac axis or superior mesenteric axis. Surgical resection was to be performed 4 to 5 weeks after NACRT completion. For resected patients, radical surgery was performed with an extended lymph node dissection. If tumor progression was evident, additional treatment with chemotherapeutic regimens was determined on an individual basis.
Patients were evaluated on a weekly basis. Toxicity experienced by the patients was evaluated using the Common Terminology Criteria for adverse events version 3.0 (CTCAE v 3.0) systems developed by NCI.  All patients were followed until either recurrence or death. One patient was lost to follow-up. Survival and disease control parameters were calculated using Kaplan- Meier actuarial analysis. Overall survival (OS) was defined as the time from pathologic diagnosis until death or the last date of contact.
| » Results|| |
The patients and tumor characteristics are listed in [Table 2]. Median age was 63.4 years (range of 48-72). All patients had Karnofsky performance status of >70. All patients in our study had some degree of pain requiring analgesic support. Nine patients were started on step-2 and six on step-3 analgesics. After NACRT, pain was improved in all patients. Accordingly, analgesic consumption was stopped for 12 patients. None of the patients required step-3 analgesics after NACRT.
All except one who absconded after NACRT were re-evaluated with a CT scan for surgery. Four patients underwent surgery, 5 had partial response but remained unresectable, 2 patients had stable disease and 3 had progressive disease. Out of four who underwent surgery, 3 were given adjuvant chemotherapy and one was kept on follow-up. The pattern of failure after NACRT in unresectable patients was: Liver metastasis in 5; peritoneal metastasis in 4 and peritoneum and lung in 1 patient respectively.
Median follow-up was 7.5 months (range 4-24 months). The 1 year overall survival was 59.8% (95% confidence interval [CI], 22.6%-72.4%). The median survival was 15 months for resected patients. Patients with unresected tumors after NACRT had median survival of 8.6 months (95% CI, 5.6-9.8%).
Treatment was tolerated well. Most of the toxicities were slight and were in grade 1 to 2. Acute toxicity is summarized in [Table 3]. As shown, there were no treatment-related deaths or Grade 3 or Grade 4 toxicity. Four patients had Grade 1/2 anemia but it predated this course of treatment. Three had grade 1-2 diarrhea, 6 had grade 1-2 nausea and 3 had grade 1-2 vomiting. None of the patients developed grade 3 or 4 gastrointestinal or hematological toxicity.
|Table 3: Acute treatment - related toxicity in 15 patients with locally advanced pancreatic cancer treated with NACRT|
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| » Discussion|| |
Locally advanced pancreatic cancer describes pancreatic cancer without evidence of distant metastasis but unresectable situation because of tumor encasement of major vessel structures such as celiac and superior mesenteric arteries or adherence to the portal vein. Because surgical resection of the primary tumor remains the only potentially curative treatment for pancreatic cancer, NACRT has been investigated in locally advanced pancreatic cancer to down-stage locoregional disease to facilitate surgical resection.
There is a paucity of data regarding the use of neoadjuvant chemoradiation in clearly unresectable, non-metastatic pancreatic cancer. In one of the first studies, Jessup et al. reported the results of 16 patients who were treated with 5FU and 45 Gy radiotherapy. Disappointingly, only 12.5% (two patients) underwent surgery. However, these patients were disease free 20 and 22.5 months later. Wilkowski et al.  described the use of gemcitabine (300 mg/m 2 ) and 5-FU along with EBRT (45 Gy) in patients with primary inoperable pancreatic cancer that occasionally led to resection, but close examination of inclusion criteria demonstrate that many patients who underwent resection may have more appropriately been labeled borderline resectable.
We intend to use rapid fractionation radiotherapy (30 Gy over 2 weeks) in our protocol as its safety has been documented by Spitz et al.  Moreover, it helps to significantly shorten the duration of treatment. A high dose per fraction was considered as it may produce down staging in otherwise moderately sensitive pancreatic cancer.
In a retrospectively study conducted by Snady et al.,  a group of patients who were treated with neoadjuvant therapy was compared to a group who underwent surgery alone. In the neoadjuvant setting, the patients received 5FU/streptozotocin/cisplatin and EBRT with 54 Gy followed by selective surgical resection (n = 68). The results of this study showed an advantage for patients receiving neoadjuvant therapy and subsequent surgery. Finally, 20 patients (29%) in the neoadjuvant group underwent resection. Therefore, the investigators demonstrated the feasibility of the regimen and an improvement of survival. One of the main criticisms of this study is that there was no objective, uniform classification for resectable or locally advanced disease.
Ammori et al.  conducted a study that enrolled 67 patients with borderline and locally advanced tumors. These patients received neoadjuvant therapy with gemcitabine in combination with radiation therapy. Ultimately, nine of these 67 patients underwent surgical resection. The median survival time of the patients whose tumors had been resected was 17.6 months, and the survival time of the remaining 58 unresected patients was 11.9 months. This study showed at least a small positive effect of using neoadjuvant therapy.
In a meta-analysis that compared 111 studies in the period from 1980 to 2009 retrospectively and prospectively, no significant difference with respect to the overall survival was found. Considered were neoadjuvant chemoradiation, radiotherapy, or chemotherapy, followed by re-staging, and surgical exploration or resection. The group with resectable findings following treated with resection, showed similar survival rates compared to the resected patients who received adjuvant therapy. So no clear advantage referring to neoadjuvant therapy was found. However, it was shown that one third of patients with initial locally advanced findings had an analogical survival rate after neoadjuvant therapy and resection in comparison to patients with initial resectable tumors.  Thus, neoadjuvant therapy can allow some patients with unresectable or borderline resectable disease to achieve resection with negative pathologic margins. The median survival has not been shown to improve significantly.
Morganti et al.  conducted a systematic review of resectability and survival after concurrent chemoradiation in primarily unresectable pancreatic cancer. Thirteen studies with a total of 510 patients met selection criteria. The review concluded that, after neoadjuvant radiochemotherapy, radical surgery should be considered in patients with primarily unresectable locally advanced pancreatic cancer, since complete tumor removal was achieved in almost a quarter of patients, a third of whom survived for more than three years. Due to potential limitations, mainly arising from the analysis, the conclusions should be treated with caution. Prospective high-quality trials are required for patients with locally advanced unresectable pancreatic cancer to determine whether this provides sustained benefits and to identify the best approach to down staging tumors for resection.
It is proved that infusion 5 FU gives better response then bolus 5 FU and also this method of drug delivery by protracted infusion produces less toxicity of 5 FU. An abundance of preclinical data suggests that Capecitabine is at least as good a radiosensitizer as 5-FU. Capecitabine is an oral prodrug of 5-FU. The pharmacokinetics of capecitabine mimic that of continuous infusion 5-FU, the concurrent administration of which has been shown to result in superior disease-free survival and overall survival compared with bolus 5-FU.  Laboratory experiments have demonstrated that the synergy between radiation and capecitabine is superior to that observed with 5-FU.  Over-expression of cytidine deaminase and, more importantly, thymidine phosphorylase in tumor cells is the key to capecitabine tumor-selectivity.  This effect can be attributed to higher 5-FU levels in tumor cells and induction of tumor over-expression of thymidine phosphorylase by radiation.  Tumor- to-healthy-tissue and tumor-to-plasma concentration ratios of 3.2 and 21.4, respectively, have been reported.  Therefore, 5-FU levels achieved in tumor cells are higher and levels in surrounding normal-tissues are lower than those attained by bolus injection. Furthermore, radiation upregulates thymidine phosphorylase levels in tumor cells, further enhancing tumor selectivity.  This improved therapeutic index, along with the more favorable pharmacokinetics (approximating that of protracted intravenous infusion of 5-FU), make Capecitabine a particularly appealing agent to use in conjunction with radiotherapy. In addition, the use of Capecitabine is particularly appealing in this setting because it is absorbed as an inert drug, therefore producing little direct toxicity in the gastrointestinal tract and can be safely prescribed orally.
Our current study, the first being reported from India, is a prospective study of locally advanced pancreatic cancer treated with NACRT. The limitations of our study are small number of patients and short follow-up. However, the combination of conformal radiotherapy with tumor-selective radiosensitization resulted in a well-tolerated regimen. Four out of 15 patients underwent surgery after NACRT. Thus, neoadjuvant therapy can allow some patients with unresectable disease to achieve resection. These results may need further confirmation by larger multi-institutional and randomized clinical trials.
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[Table 1], [Table 2], [Table 3]