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Influence of adjuvant therapy on pattern of failure and survival in curatively resected gallbladder carcinoma


1 Department of Radiotherapy and Radiation Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Radiotherapy, Apex Cancer Institute, Apex Hospital, Varanasi, Uttar Pradesh, India
3 Department of Radiation Oncology, Tata Memorial Centre, Kolkata, West Bengal, India
4 Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Submission02-Aug-2019
Date of Decision20-Aug-2019
Date of Acceptance23-Aug-2019
Date of Web Publication28-Oct-2020

Correspondence Address:
Neha Gupta,
Apex Cancer Institute, Apex Hospital, Varanasi, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_550_19

 > Abstract 


Purpose: The study was done to evaluate the role of adjuvant therapy in curatively resected Stage II and III gallbladder carcinoma (GBC).
Materials and Methods: This was a retrospective analysis of patients of GBC registered between 2008 and 2017 in outpatient department of a tertiary cancer hospital in India. Patients who had any of the following adjuvant treatment after radical surgery: (a) external beam radiotherapy (RT) alone, (b) chemotherapy (CT) alone, and (c) RT with CT (CRT) were considered for the study.
Results: A total of fifty patients could meet the selection criteria. It was seen that seven patients were treated with RT, 20 with CT, and 23 with CRT. Median follow-up for patients who were alive was 26.7 months. Nineteen patients had locoregional failure while eight had distant failure. Patients treated with CRT had a significantly better mean overall survival compared to those treated with RT or CT (44.0 months, 12.5 months, and 15.1 months, respectively; P = 0.003). Similarly, mean disease-free survival was superior in CRT arm compared to RT and CT arms (43.6 months, 9.6 months, and 12.4 months, respectively; P = 0.002).
Conclusions: Adjuvant CRT had better survival outcome compared to patients treated with either RT or CT with Stage II and III disease after curative cholecystectomy.

Keywords: Adjuvant chemotherapy, adjuvant radiotherapy, cholecystectomy, combined modality therapy, gallbladder cancer



How to cite this URL:
Choudhary S, Gupta N, Verma CP, Das A, Aggarwal LM, Tewari M, Mandal A, Asthana AK. Influence of adjuvant therapy on pattern of failure and survival in curatively resected gallbladder carcinoma. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 2]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299459




 > Introduction Top


Gallbladder cancer is a disease with dismal prognosis that affects thousands of people annually. The 2004 National Comprehensive Cancer Network does not recommend adjuvant treatment for Stage I disease. Patients who present with metastatic disease are usually offered best supportive care or palliative chemotherapy (CT). Most of the retrospective series addressing adjuvant therapy have small sample size and are heterogenous due to the inclusion of the following: (a) patients with both complete and incomplete surgery with residual disease, (b) Stage II and III are mixed with Stage I/IV diseases, and (c) gallbladder carcinoma (GBC) included with other intrahepatic and extrahepatic cholangiocarcinoma. Therefore, it is very difficult to draw any meaningful conclusion from these trials.

It is very difficult to have prospective studies for Stage II and III GBC for two reasons: (1) GBC is very rare and (2) GBC usually presents in advanced stage. Therefore, we could do a retrospective study where only Stage II and III GBC patients were included so as to evaluate the effect of adjuvant treatment.


 > Materials and Methods Top


Patients of GBC registered in our radiotherapy (RT) outpatient department between 2008 and 2017 were considered for this study. The record files of these patients were thoroughly studied for patient, disease, and treatment characteristics. Patients who fulfilled the selection criteria as mentioned below were included in the study.

  • Histopathologically proven gallbladder cancer
  • Curative cholecystectomy
  • Stage II and III GBC
  • Completed any of the below adjuvant treatment:


  1. External beam RT (EBRT) alone to a dose of 40–54 Gy/4–6 weeks
  2. CT alone: 5–6 cycles
  3. EBRT and CT combined.


Patients were treated with telecobalt or linear accelerator with conventional/three-dimensional conformal RT technique (3DCRT) or intensity-modulated RT (IMRT). Patients were treated with conventional fractionation schedule. Tumor bed with draining regional lymph nodes were included in the treatment voulme. Radical dose of 40 Gy–54 Gy in 20–30 fractions were prescribed. Two anterolateral wedge pair fields were used when the patients were treated on telecobalt unit. Multiple fields were used with 3DCRT and IMRT techniques.

CT was given 3 weeks after completion of adjuvant RT. Gemcitabine and cisplatin were used in combination as 3 weekly regimes. The patients were planned for six cycles of CT.

Statistical analysis was done using SPSS Inc, (Chicago, USA). The primary endpoints were overall survival (OS) and disease-free survival (DFS). DFS and OS were estimated by the Kaplan–Meier method and differences between curves tested by the Log-rank test. All endpoints were measured from the date of registration, and patients dying of any cause (or lost to follow-up (FU) were considered as events for both the end points of DFS and OS.

Since this was a retrospective study, permission of the ethical committee and consent of the patients were not deemed necessary.


 > Results Top


A total of 50 patients were found who could fulfill all the selection criteria. Majority of the population cohort was female (84%). The median age was 55 years (range 24–73 years). All except two patients had adenocarcinoma. Stage II and III had almost equal distribution.

All the patients had cholecystectomy with no gross residual disease at the primary site. Lymph node dissection was not done in thirty patients. Lymphovascular invasion (LVI) was not reported in half of the patients. Perineural invasion (PNI) was unknown in 58% of population. Resection margin was negative in about two-third of cohort.

Seven patients had received RT alone, twenty patients were treated with CT alone while remaining 23 patients were treated with CRT. Median dose of RT was 45 Gy and median RT duration was 34.5 days. Gemcitabine with cisplatin regimen was given to 43 patients, and they had received 5–6 cycles at 3 weeks' interval.

Overall FU duration for entire population was 14.4 months. Median FU for patients who were alive was 26.7 months. The status of the patients at the time of analysis is mentioned in [Table 1]. The pattern of disease failure and survival outcome based on the treatment group is mentioned in [Table 2]. There was no difference in OS and DFS between RT and CT arms (P = 0.561 and 0.942) [Figure 1]. However, the difference in OS and DFS between CRT and RT or CT was significant (P = 0.003 and 0.002) [Figure 2]. We compared the demographic profile of the patients in these three treatment arms and found that they were comparable in all the aspects except the grade of the tumor [Table 3].
Table 1: Status of patients on last follow-up

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Table 2: Pattern of failure and disease outcome

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Figure 1: Overall survival based on treatment arm

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Figure 2: Disease-free survival based on treatment arm

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Table 3: Demographic profile of patients

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Univariate analysis was done to find the factors which could have affected the survival. It was tested for age, stage of the disease, LVI, PNI, and resection margin. None of these factors were found to have significant impact on survival outcome [Table 4].
Table 4: Univariate analysis

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Most of the patients had completed RT in the intended duration of treatment. CT toxicities were usually confined to nausea and vomiting. CT dose modification was deemed necessary in few patients because of hematological toxicities. No major complication was recorded in any of these patients. There was no difference in late toxicities among the three treatment groups.


 > Discussion Top


Gallbladder cancer is known to fail both at locoregional sites as well as distant regions. Therefore, it is reasonable to combine treatment modalities so as to reduce both locoregional and distant failure. Both locoregional and distant failure were less in patients who were treated with CRT than those compared to patients treated with only one modality. The results of our study have shown that combination of RT and CT gave us better survival outcome compared to single modality treatment with comparable toxicity.

Kim had studied the pattern of failure in 70 patients of GBC who had undergone curative-intent cholecystectomy.[1] About 80% of these patients had pathological T2 and beyond disease. None of these patients had adjuvant RT while about a quarter of patients were treated with adjuvant CT. Median FU period was 29 months. A total of 41 patients had disease failure. Locoregional recurrence as any component of first failure was seen in 29 patients (41.4%), with isolated locoregional recurrence in 13 (18.6%). Distant metastasis with or without concomitant locoregional recurrence was found in 28 patients (40%). Twelve patients had isolated distant failure. Based on the initial pattern of failure, the author suggested adjuvant RT after curative cholecystectomy for GBC with pT2 or beyond.

Meta-analysis of ten retrospective observational studies was done by Ma et al. to determine the impact of adjuvant treatment on OS in GBC patients.[2] They observed that there was a no significant survival benefit with adjuvant treatment compared with surgery alone. However, sensitive analysis showed that adjuvant CT improved OS significantly (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.22–0.80). HR for RT and chemo-RT was 0.64 and 0.65, respectively. Patients with either R1 resection or lymph node-positive disease or Stage II and beyond benefitted the most.

Takada et al. in a Phase III multicentric prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma had compared surgery alone with surgery followed by adjuvant CT (5FU and Mitomycin C). They had reported that the 5-year survival rate in GBC patients was significantly better in the adjuvant CT group. The authors had noted that adjuvant treatment was not effective for Stage I GBC.[3]

Wang et al. had developed a prediction model for estimating the survival benefit of adjuvant RT for GBC.[4] They did a multivariate regression analysis using data from 4,180 patients with resected GBC diagnosed between 1988 and 2003 from the surveillance, epidemiology, and end results (SEER) database. The authors reported that adjuvant RT produced a survival benefit in node-positive or >T2 disease. Based on the above evidences, we had excluded Stage I disease from our study.

Kim et al. had done a systematic review and meta-analysis of 14 retrospective studies which had compared adjuvant chemo-RT with surgery alone in GBC patients.[5] Despite more patients with unfavorable characteristics in the adjuvant arm, OS and DFS of these patients were significantly better compared to patients in the other group. Exploratory analyses clearly demonstrated a survival advantage for patients with R1 resection and lymph node-positive disease.

Wang et al. had developed a nomogram for predicting the benefit of adjuvant chemo-RT for resected GBC.[6] The authors had worked on the SEER database between 1995 and 2005. A total of 1137 GBC patients could fit into their selection criteria. The model they developed predicts that certain subsets of patients with at least T2 or N1 disease have a survival advantage when treated with adjuvant chemo-RT compared to CT alone.

Kasumova et al. had analyzed the data National Cancer Database 2004–2014.[7] GBC patients who had surgical resection and were pT2/T3 were selected. A total of 6825 patients were selected for analysis, of which 2168 patients had received adjuvant CT or CRT. Patients who were treated with both RT and CT had survival advantage over those who had received CT alone, irrespective of extent of cholecystectomy (P = 0.0001).

Mitin et al. had retrospectively evaluated the survival outcome of adjuvant treatment in 5029 patients of GBC taken from National Cancer Data Base 2005–2013.[8] The authors reported that adjuvant chemo-RT improved survival in all categories except T1No and in patients with negative margin. The 3-year unadjusted all-cause survival rates were 38.7% (95% CI = 36.5–40.8), 43.0% (95% CI = 38.4–47.5), 28.6% (95% CI = 23.3–34.1), and 36.5% (95% CI = 27.2–45.8) among patients who had surgery alone, adjuvant chemo-RT, adjuvant CT, and adjuvant RT, respectively. The 3-year OS in our study was 38% and 17% for chemo-RT and CT groups, respectively. It is important to note that about 20% patient populations in the study by Mitin et al. had Stage I disease which resulted in superior survival outcome compared to that of ours.

Tran Cao et al. had done a retrospective analysis to evaluate the role of surgery and adjuvant therapy in lymph node-positive cancers of the gallbladder (n = 1335) and intrahepatic bile ducts (n = 1009). The median OS of patients in the nonoperative, surgery, and surgery plus adjuvant treatment group was 11.6, 13.3, and 19.6 months, respectively, for those with GBC (P < 0.001). On subset analysis, it was noted that adjuvant therapy that included RT was associated with a lower risk of death relative to surgery alone for patients with GBC, but adjuvant CT alone was not.[9]

A retrospective was study done by Kresl et al. where 21 consecutive patients of GBC Stage I-IV were treated with adjuvant RT and concurrent 5-FU. Patients with complete resection had a favorable survival outcome compared those to those with microscopic and residual disease after surgery.[10] Unlike our study, this trial had included GBC with all stages that had complete resection as well as gross residual disease.

Gold et al. had evaluated the role of EBRT with concurrent 5-FU for gallbladder cancer after complete resection in 73 patients of Stage I and II. Only 25 patients had received adjuvant therapy.[11] The median OS for patients who had received adjuvant chemo-RT and surgery alone was 4.8 years and 4.2 years, respectively (P = 0.56).

Czito et al. had shared a 23-year experience of treating Stage III and IV patients of gallbladder with adjuvant EBRT with concurrent 5-FU. Of these 22 patients, 20 had undergone simple cholecystectomy while the remaining two had radical surgery. The authors suggested the use of adjuvant RT with radiosensitizing agent to improve the survival outcome in GBC.[12]

Mantripragada et al. had analyzed patients with T2–3 or node positive, nonmetastatic GBC using National Cancer Data base between 2004 and 2011. Adjuvant CT was administered to 28.8% of 4775 patients and upfront concurrent chemo-RT to 13.5%. Patients with T3 or node-positive tumors who were treated with upfront adjuvant chemo-RT had a modest early survival advantage.[13]

Our study has several limitations. The most important caveat of this study is its retrospective nature resulting in selection bias. Extended cholecystectomy was done in limited number of patients. Many of the histopathology findings were missing in several patients. Toxicities of treatment modalities were not documented meticulously.


 > Conclusions Top


Our study supports the use of adjuvant RT combined with CT instead of CT alone or RT alone for patients of GBC of Stage II and III after curative surgery.

Randomized controlled trial may be conducted prospectively to compare single modality treatment (RT or CT alone) with combined treatment (RT with CT) after curative surgery for GBC so as to strengthen the results of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Kim TG. Patterns of initial failure after resection for gallbladder cancer: Implications for adjuvant radiotherapy. Radiat Oncol J 2017;35:359-67.  Back to cited text no. 1
    
2.
Ma N, Cheng H, Qin B, Zhong R, Wang B. Adjuvant therapy in the treatment of gallbladder cancer: A meta-analysis. BMC Cancer 2015;15:615.  Back to cited text no. 2
    
3.
Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002;95:1685-95.  Back to cited text no. 3
    
4.
Wang SJ, Fuller CD, Kim JS, Sittig DF, Thomas CR Jr., Ravdin PM, et al. Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin Oncol 2008;26:2112-7.  Back to cited text no. 4
    
5.
Kim BH, Kwon J, Chie EK, Kim K, Kim YH, Seo DW, et al. Adjuvant chemoradiotherapy is associated with improved survival for patients with resected gallbladder carcinoma: A systematic review and meta-analysis. Ann Surg Oncol 2018;25:255-64.  Back to cited text no. 5
    
6.
Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol 2011;29:4627-32.  Back to cited text no. 6
    
7.
Kasumova GG, Tabatabaie O, Najarian RM, Callery MP, Ng SC, Bullock AJ, et al. Surgical management of gallbladder cancer: Simple versus extended cholecystectomy and the role of adjuvant therapy. Ann Surg 2017;266:625-31.  Back to cited text no. 7
    
8.
Mitin T, Enestvedt K, Jemal A, Sineshaw HM. Limited use of adjuvant therapy in patients with resected gallbladder cancer despite a strong association with survival. J Natl Cancer Inst 2017;109:1-9.  Back to cited text no. 8
    
9.
Tran Cao HS, Zhang Q, Sada YH, Chai C, Curley SA, Massarweh NN, et al. The role of surgery and adjuvant therapy in lymph node-positive cancers of the gallbladder and intrahepatic bile ducts. Cancer 2018;124:74-83.  Back to cited text no. 9
    
10.
Kresl JJ, Schild SE, Henning GT, Gunderson LL, Donohue J, Pitot H, et al. Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys 2002;52:167-75.  Back to cited text no. 10
    
11.
Gold DG, Miller RC, Haddock MG, Gunderson LL, Quevedo F, Donohue JH, et al. Adjuvant therapy for gallbladder carcinoma: The mayo clinic experience. Int J Radiat Oncol Biol Phys 2009;75:150-5.  Back to cited text no. 11
    
12.
Czito BG, Hurwitz HI, Clough RW, Tyler DS, Morse MA, Clary BM, et al. Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: A 23-year experience. Int J Radiat Oncol Biol Phys 2005;62:1030-4.  Back to cited text no. 12
    
13.
Mantripragada KC, Hamid F, Shafqat H, Olszewski AJ. Adjuvant therapy for resected gallbladder cancer: Analysis of the national cancer data base. J Natl Cancer Inst 2017;109:1-8.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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



 

 
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