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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 3  |  Page : 519-525
 

Compliance and outcomes of concurrent Chemo-radiation in patients with peri-ampullary cancer undergoing curative resections


1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
4 Department of GI Surgery, All India Institute of Medical Sciences, New Delhi, India
5 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication24-May-2018

Correspondence Address:
Dr. Sushmita Pathy
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_358_17

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 » Abstract 


OBJECTIVES: We aimed to study the compliance and treatment outcome of patients who received adjuvant treatment following curative resection for periampullary cancers periampullary cancers. MATERIALS AND METHODS: Institute medical records of PAC treated during 2007–2014 were retrieved. Demographics, treatment, and outcome in patients who were intended to receive adjuvant chemoradiation after curative resection were analyzed. Patients received first cycle chemotherapy with 5-fluorouracil folinic acid/capecitabine, followed by external radiotherapy 45 Gy/25 fractions/5 weeks and second and third cycle concurrent chemotherapy. Fourth and fifth cycle chemotherapy were administered after radiotherapy). Various prognostic factors, disease-free survival (DFS), and overall survival (OS) were evaluated. RESULTS: Sixty-five patients were evaluated. Median age was 50 years. 96.9% patients completed the intended course of radiation and overall adherence to chemotherapy was 86.2%. Median follow-up and DFS were 20 and 29.64 months, respectively (range: 1.9–97.3 months). Estimated 1-, 2-, 5-year DFS was 77.8%, 59.3%, and 37.6%, respectively. One-year estimated OS was 92.7%. Median DFS for node-negative and node-positive patients was 88.6 and 24.33 months (P = 0.06). Grade ≥III hematological toxicity was 20%. CONCLUSION: Positive node indicated a trend toward poor survival. The study highlights high compliance to multimodal management of PAC with acceptable toxicity in and out of clinical trial setting in a tertiary cancer center in India.


Keywords: Adjuvant radiotherapy, compliance, periampullary carcinoma


How to cite this article:
Pathy S, Mallick S, Sharma A, Shukla NK, Sahni P, Pal S, S Deo SV, Mohanti BK, Upadhyay AD. Compliance and outcomes of concurrent Chemo-radiation in patients with peri-ampullary cancer undergoing curative resections. Indian J Cancer 2017;54:519-25

How to cite this URL:
Pathy S, Mallick S, Sharma A, Shukla NK, Sahni P, Pal S, S Deo SV, Mohanti BK, Upadhyay AD. Compliance and outcomes of concurrent Chemo-radiation in patients with peri-ampullary cancer undergoing curative resections. Indian J Cancer [serial online] 2017 [cited 2019 Dec 16];54:519-25. Available from: http://www.indianjcancer.com/text.asp?2017/54/3/519/233151





 » Introduction Top


Periampullary carcinoma (PAC) consists of pancreatic head, ampulla of vater, distal common bile duct, and duodenal cancer. It constitutes 3%–4% of gastrointestinal (GI) tract malignancies.[1] Surgical resection is the primary treatment of choice and is the only curative intervention in early stage. Despite radical resection, 5-year survival rates are only 10%–11% and treatment outcome with surgery alone is dismal.[2],[3] The pattern of failure of periampullary tumors is primarily locoregional and distant metastasis is rarely seen in the absence of locoregional recurrence.[4],[5],[6] Therefore, a treatment with chemoradiation aiming to improve locoregional control may also translate to improved survival. The gastrointestinal tumor study group randomized patients of pancreatic head cancers to observation or adjuvant chemoradiation after surgery. The survival benefit of adjuvant radiotherapy and 5-fluorouracil (5-FU) after surgery was investigated. However, the benefit was small compared to observation alone after surgery. The study reported a median survival of 19.0 months for the observation group and 24.5 months in the treatment group. The 2-year survival rates were also comparable (63% vs. 67%) and there was no reduction in locoregional rates in the two groups.[7] The European Study Group for Pancreatic Cancer (ESPAC-1) trial evaluated the effect of adjuvant therapy on survival of pancreatic cancer and reported poor results with chemoradiotherapy. However, the study had several limitations and was criticized for its radiation dose, schedule, and poor design. The results should therefore be interpreted with caution.[8]

In the absence of clear guidance in regard to adjuvant therapy, patients with resected ampullary cancers often receive concurrent chemoradiation based on results from resected pancreas and biliary cancers.[9]

Several studies evaluated the outcome of adjuvant therapy and impact of tumor location, histological features as prognosticator and concluded that pancreatic location and perineural invasion (PNI) significantly affect survival regardless of histology.[10],[11],[12] However, most of the studies evaluating the role of adjuvant chemoradiation were retrospective and underpowered to make a definite conclusion. There has been considerable variability in various centers and lack of uniform histopathological examinations; detection of the epicenter of resected PAC is observed as an important outcome in clinical outcome.[13]

Based on these reports, a modified protocol in line with intergroup trial on stomach cancer, we adopted a uniform policy of delivering adjuvant chemoradiotherapy after curative resection in periampullary cancers in our center. Lack of prospective studies and paucity of Indian data encouraged us to analyze our data on PAC and identify the association of various prognostic factors for tumor response and the pattern of failure in patients who were treated with curative surgery and adjuvant treatment. The current study evaluates compliance and treatment outcome for patients who received adjuvant treatment following curative resection for periampullary cancers in our center.


 » Materials and Methods Top


Patient characteristics

This is a retrospective study. Medical records of all patients who underwent curative resection and adjuvant treatment during 2007–2014 were reviewed. A total of 168 periampullary carcinoma patients were registered in GI cancer clinic at our center during the study period. During the study period, 65 patients fulfilling the inclusion criteria were evaluable who were investigated and treated according to our institute protocol during 2007–2014. Patients who received palliative treatment were excluded from the study [Figure 1]. Data regarding demographic characteristics, clinical details, stage, histopathology, treatment outcome, and recurrence of all patients of PAC who received adjuvant treatment after curative surgery was analyzed. The study was carried after obtaining ethical approval from the Institute Ethics Board (IEC/NP-07/09.01.2015).
Figure 1: Consort diagram depicting the inflow of patients with periampullary cancer and selection of cases for the present analysis

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Evaluation

The patients were jointly evaluated by a multidisciplinary team comprising a surgical oncologist, radiation oncologist, and medical oncologist. The detailed evaluation included a detailed history, physical evaluation, complete blood count, liver and renal function tests, computed tomography (CT) imaging of the abdomen and pelvis, and X-ray/CT of thorax were performed to assess the extent of disease. In patients who presented for ≥12 weeks after surgery, repeat postoperative imaging was carried out to rule out locoregional recurrence. Positron emission tomography-CT was performed only for doubtful lymph nodes in CT.

The postoperative histopathology was reviewed to ascertain the location, T-stage, N-stage, the grade of tumor, lymph vascular invasion, margin status, and adequacy of node dissection. Information was collected on additional patient characteristics and prognostic factors including age (<50 vs. ≥50 years), histology (WDACC vs. MDACC vs. PDACC), tumor location (pancreas, duodenum, ampulla), pancreatic versus nonpancreatic location, number of nodes dissected (≤ 5 vs. >5), number of nodes positive (0 vs ≥1 node), serum albumin ≤ 4.1 and > 4.1 gm/dl. Staging was made as per the American Joint Committee on Cancer staging system (7th edition) based on the available clinical and radiological findings. Compliance to treatment of patients was defined by their ability to complete the intended course of treatment that was planned at the beginning by the team. Patients with incomplete clinical details and who did not receive any form of treatment were excluded from the analysis.

Surgical protocol

All patients who were medically fit and had operable disease were subjected to a standard Whipple's pancreaticoduodenectomy procedure. During later part of the study, some patients had pylorus preserving pancreaticoduodenectomy. Regional lymphadenectomy was performed in all patients and pancreaticojejunostomy or pancreaticogastrostomy was performed depending on surgeon's preference. A feeding jejunostomy was performed in all the patients and oral feeding started between 4th and 10th postoperative days depending on postoperative recovery.

Adjuvant chemoradiotherapy

Adjuvant therapy for periampullary carcinoma was delivered within 4–8 weeks of surgery, with a modified protocol in line with intergroup trial (INT-0116) on stomach cancer.[14] External beam radiotherapy consisted of Linac-based three-dimensional (3D) conformal radiotherapy (Elekta Medical Systems Crawley, UK) and was planned to the tumor bed and regional lymph nodes. Patients were planned for one cycle chemotherapy followed by external beam radiotherapy. A dose of 45 Gy in 25 fractions in 5 weeks was delivered. Chemotherapy was administered concurrently along with radiotherapy followed by two more cycles after completion of radiotherapy. Patients treated after 2010 received capecitabine 825 mg/m 2 twice daily, in place of fluorouracil during the concurrent phase. Before 2010, 5-FU 425 mg/m 2 and leucovorin 20 mg/m 2 D1-5 were administered. Only three patients received gemcitabine 200 mg/m 2 weekly during radiotherapy followed by 6 cycles of adjuvant gemcitabine (1.2 g/m 2 D1, D8) and carboplatin (AUC5 on D1) at 3 weeks interval. The dose of chemotherapy drugs was reduced by 25% in the presence of Grade III of higher toxicity.

Radiation therapy

All patients underwent CT simulation in Brilliance Big Bore CT Simulator (Phillips Medical System Cleveland, OH, USA). The images were transferred to ECLIPSE (Varian Medical Systems, Palo Alto, CA version 6.5) treatment planning system. The target volume constituted of periampullary tumor bed (clinical target volume [CTV] primary) and regional lymph node stations including portal, celiac, superior mesenteric, and proximal aortocaval lymph node region (CTV node). All patients received standard dose of 45 Gy in 25 fractions over 5 weeks using 3D conformal techniques (Varian Medical System, Palo Alto, California, USA).

Evaluation of treatment response

Patients were monitored during chemoradiotherapy/radiotherapy weekly with hematological investigations and clinical examination for acute treatment-related morbidities. The grading of acute and late toxicity was carried out using common terminology and criteria for adverse events version 4.0 and radiation therapy and oncology group late morbidity scoring criteria, respectively.

Statistical analysis

Descriptive statistics was used for describing demographic and clinical characteristics. Impact of prognostic factors on outcome was computed using Fisher's exact test. Disease-free survival (DFS) was calculated from date of surgery to the date of documented disease progression. Overall survival (OS) was calculated from date of diagnosis to death (due to any cause). DFS was estimated by the Kaplan–Meier method. To assess the effect of patient characteristics and prognostic factors on DFS, hazard ratio and their 95% confidence intervals (CIs) were obtained using Cox proportional hazard regression analysis. P ≤ 0.05 was considered statistically significant. Statistical analysis was carried out using the STATA version 11.2 (StataCorp. 2009. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP.).


 » Results Top


Patient characteristics

Of 4423 patients registered in GI clinic in the study period, 168 cases were diagnosed as PAC, which makes only 3.8% of the total burden in our clinic. The demographics and treatment characteristics are summarized [Table 1]. During the study period, 65 patients fulfilled the inclusion criteria and received adjuvant radiotherapy with or without chemotherapy. The remaining patients had metastatic disease, insufficient clinical details, or did not receive any form of treatment. The median age of the cohort was 50 years (range: 22–72 years). The male:female ratio was 2:1. The subsite distribution was discerned with the available information in imaging, intraoperative finding, and histology specimen. Duodenal cancer (n = 17), ampullary cancer (n = 32), and pancreatic head (n = 16). Common symptoms among the cohort were jaundice (n = 47) and abdominal pain (n = 19). Median duration of symptom was 2 months (range: 1–12 months). The majority of them was addicted to alcohol and had T3 node-positive disease. The patient and tumor characteristics are detailed in [Table 1].
Table 1: Summarizes patient characteristics

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Treatment

All patients underwent Whipple's pancreaticoduodenectomy or its modified surgical approach as described earlier. The median number of lymph node dissected was 7 (range: 0–37); extracapsular spread was noted in 4 cases (6.1%). Thirty-two patients had node-positive disease and three patients had positive margins. All 65 patients, except two received radiation to a dose of 45 Gy in 25 fractions over 5 weeks. Radiation was withheld at 34 Gy because of poor tolerance. Concurrent chemotherapy was administered in 60 patients and was deferred in 5 patients due to poor performance status. Concurrent fluorouracil folinic acid (FUFA) was administered in 37 patients. The institute protocol was modified to capecitabine-based chemotherapy from 2011; therefore, 22 (33.8%) patients received concurrent capecitabine and 21 patients received adjuvant capecitabine.

Toxicity

Hematological toxicity (≥Grade III) was observed in 13 patients (20%). Common adverse effect were neutropenia and leukopenia. Only one patient developed febrile neutropenia. Four patients developed ≥Grade III nonhematological toxicity. None of the patients needed discontinuation of therapy. The treatment details, toxicity, and recurrence have been summarized in [Table 2].
Table 2: Summarizes patient treatment details, toxicity (Grade III or higher)

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Compliance to treatment

Radiation therapy was completed in 63 patients. Five patients did not receive concurrent chemotherapy. Only one patient did not receive any form of adjuvant treatment. Four patients defaulted for adjuvant chemotherapy and one patient did not receive radiotherapy. Overall adherence to treatment was 86%.

Survival analysis

The median follow-up duration was 20 months (range: 1.9–97.3 months). Median DFS was 29.64 months [Figure 2] (95% CI: 20.79–not reached [NR]), median OS was NR. The estimated 1-, 2-, 5-year DFS was 77.8%, 59.3%, and 37.6%, respectively. One-year estimated OS was 92.7%.
Figure 2: Kaplan–Meier graph depicting disease-free survival

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Univariate analysis demonstrated significantly improved survival in node-negative patients (median DFS 88.6 months [95% CI: 20.79–NR] versus 24.33 [95% CI: 13.38–51.18] months) with a trend toward statistical significance (P = 0.06) [Figure 3]. Prognostic variables including age (<50 vs. >50), gender (male vs. female), postoperative stage, number of nodes, grade of tumor, and baseline serum albumin did not confer statistical significance [Table 3]. Patients receiving FUFA-based chemotherapy had comparable outcome with patients receiving capecitabine-based chemotherapy (P = 0.11).
Figure 3: Kaplan–Meier graph depicting survival in node positive and node negative cases

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Table 3: Impact of prognostic variables and the survival at 12, 24, and 60 months

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Pattern of failure and salvage treatment

At median follow-up of 20 months, 29 patients developed tumor recurrence. Systemic failure was most common (n = 19) with isolated liver metastasis in 11 patients. Locoregional recurrence was observed in 4 patients. The details of pattern of recurrence have been summarized in [Table 4].
Table 4: Pattern of Recurrence

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Salvage treatment with chemotherapy was possible only in 11 cases with combination of gemcitabine and oxaliplatin. Two patients received palliative radiation to the supraclavicular node and painful bony metastasis.


 » Discussion Top


The present study was intended to evaluate compliance, treatment response, and pattern of failure in periampullary carcinoma undergoing curative resection and adjuvant chemoradiation. Periampullary carcinoma constitutes a small proportion of GI malignancies worldwide. This has also been highlighted in the current study as PAC patients made up only 4% of all GI cancers in the multidisciplinary clinic at our center. About one-third (38.7%) patients were found suitable for curative surgery and adjuvant therapy which reflects late presentation of PAC. Adherence to treatment was excellent and majority of patients completed the intended therapy.

Kim et al. studied the outcome of adjuvant chemoradiotherapy for periampullary adenocarcinoma and the impact of tumor location as a prognosticator and concluded that pancreatic location and nodal involvement are adverse prognostic factor affecting survival. However, our study has shown a trend toward statistical significance for nodal involvement (P = 0.06).[11]

Lee et al. assessed the impact of histologic type and PNI on recurrence and survival in ampullary carcinoma and confirmed that PNI significantly affects survival irrespective of histology.[12] The present study did not reveal such correlation. This could be attributed to small sample size. The most common subsite was ampulla (32 patients) followed by second part duodenum (17 patients). This finding is in line with a similar Indian study.[15]

Adjuvant treatment of periampullary carcinoma varies widely from chemotherapy to chemoradiotherapy across different institutes with little agreement to the optimum regimen.[10],[11],[16],[17],[18] Adjuvant therapy is often decided by the predominant pattern of disease recurrence. The pattern of failure in PAC is dominated by regional failure followed by systemic failure.[4],[5],[6] Our study reported only 6 patients with locoregional failure and 19 patients had distant failure. The median and 5-year DFS in our study were 29.6 months and 37.6%, respectively. This observation concurred with other studies which reported similar outcome.[7],[16]

Invasion of pancreas and tumor size has been identified as important factor predicting locoregional failure whereas lymph node positivity predicts systemic failure. Lymph node metastasis and PNI may be useful to strategize risk-oriented adjuvant therapy. The present study highlights similar finding.[4],[19]

Inadequate surgical lymphadenectomy or histological examination in the resected specimen may under-stage patients. Therefore, evaluation of lymph node ratio (number of positive nodes/number of examined nodes) is valuable. Several studies have reported that lymph ratio is an independent prognostic factor after resection of periampullary carcinoma.[20],[21],[22] However, the current report lymph node ratio did not appear as a prognostic factor for tumor response. The addition of radiotherapy could have reduced the incidence of locoregional failure, thus decreasing the significance of node positivity on DFS.

Majority received 5-FU/capecitabine-based chemotherapy (85%) as concurrent chemotherapy. The regimen was well tolerated with no treatment-related mortality and nearly 20% developed Grade III or higher hematological/GI toxicity. Overall adherence to adjuvant treatment was observed as 85%. The modified regimen with capecitabine was well tolerated and reduced in patient burden and also cost of cancer care. Few patients did not receive chemotherapy concurrently with radiotherapy due to poor performance status at presentation. Although adjuvant chemotherapy has shown survival benefit in pancreatic cancer, there has been no randomized trial for periampullary adenocarcinomas. The ESPAC-3 trial evaluated the role of adjuvant chemotherapy (5-FU or gemcitabine) on survival following resection.[23] The study supported the use of adjuvant chemotherapy to improve survival in patients with periampullary cancers. In the current study lack of randomization to compare with observation/chemotherapy alone, it is difficult to make a definite conclusion.

Nonpancreatic periampullary cancer has a more favorable outcome compared to pancreatic cancer. The study reported did not observe such a finding.[24],[25]

The outcome of patients with recurrent disease is dismal and locoregional failure is mostly not salvageable for cure. The cost of treatment is prohibitive in a resource-constrained setting in developing countries. Social background, family support, and distances to treatment center play a decisive role for posttreatment follow-up. Therefore, adjuvant chemoradiation can be considered in such patients for improved locoregional control. Adherence to the planned treatment in majority of patients and low local recurrence with the combined modality approach in an unselected patient population outside a clinical trial can be considered as strength of the data.


 » Conclusion Top


The impact of adjuvant chemoradiation in PAC undergoing curative resection is not clearly established. However, this study found support for adjuvant chemoradiation for effective locoregional control in patients with periampullary cancers following curative resection. The present study also highlights high compliance to multimodal management of periampullary carcinoma with acceptable toxicity in and out of clinical trial setting in a tertiary cancer center in India. With the limitation of small underpowered studies, clinical heterogeneity, poor trial design, poor patient selection, and lack of prospective Indian data in literature, a prospective multicenter randomized study from Indian subcontinent may be useful.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Kim K, Chie EK, Jang JY, Kim SW, Han SW, Oh DY, et al. Prognostic significance of tumour location after adjuvant chemoradiotherapy for periampullary adenocarcinoma. Clin Transl Oncol 2012;14:391-5.  Back to cited text no. 11
    
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Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs. observation on survival in patients with resected periampullary adenocarcinoma: The ESPAC-3 periampullary cancer randomized trial. JAMA 2012;308:147-56.  Back to cited text no. 23
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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