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Chemotherapy or chemotherapy followed by consolidation chemoradiation in postoperative (simple cholecystectomy) gall bladder cancer with residual disease, unsuitable for revision surgery? Risk stratification and outcomes


1 Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission18-Jul-2021
Date of Decision27-Oct-2021
Date of Acceptance29-Oct-2021
Date of Web Publication03-May-2022

Correspondence Address:
Md Nawed Alam,
Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_1161_21

 > Abstract 


Background: Revision surgery (RS) is the standard of care for gallbladder cancer (GBC) after simple cholecystectomy (SC). Often these patients are unsuitable for RS due to late referral or unresectable disease. Do such patients benefit with chemotherapy (CT) alone or dual-modality (CT followed by consolidation chemoradiotherapy [CTRT])? In the absence of any guidelines, we reviewed our data with CT or CTRT to inform us regarding adequate therapy.
Materials and Methods: Patients of GBC post-SC referred to us (January 2008 to December 2016) were risk-stratified into three categories based on a diagnostic CT scan: No residual disease (NRD), limited volume residual disease (LR1: Residual/recurrent disease in GB bed with or without N1 nodal station involvement), advanced residual disease (LR2: Residual/recurrent disease involving GB bed with N2 nodal station involvement) and treated with CT or CT followed by CTRT. Response to therapy (RECIST), overall survival (OS), and adverse prognostic factors affecting OS were evaluated.
Results: Out of 176 patients, 87were nonmetastatic (NRD = 17, LR1 = 33 and LR 2 = 37). 31 received CT, 49 CTRT and 8 defaulted. At a median follow up of 21 months, the median OS with CT versus consolidation CTRT was not reached in NRD (P = 0.57), 19 months versus 27 months in LR1 (P = 0.003) and 14 months versus 18 months in LR 2 (P = 0.29), respectively. On univariate analysis, residual disease burden, type of treatment (CT vs. CTRT), N stage, and response to treatment were found statistically significant.
Conclusion: Our data suggest that CT followed by CTRT improves outcomes in patients with limited volume disease.

Keywords: Chemo-radiotherapy, chemotherapy, gallbladder, simple cholecystectomy



How to cite this URL:
Alam MN, Agrawal S, Rastogi N, Saxena R. Chemotherapy or chemotherapy followed by consolidation chemoradiation in postoperative (simple cholecystectomy) gall bladder cancer with residual disease, unsuitable for revision surgery? Risk stratification and outcomes. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=344706




 > Introduction Top


Gallbladder carcinoma (GBC) is the fifth most common malignancy of the gastrointestinal tract.[1] GBC has been associated with a uniformly poor prognosis due to its highly aggressive behavior, with only 10%–30% of the patients presenting with resectable disease.[2] Better understanding of the biology of the disease, its pattern of dissemination, better diagnostic tools, and more aggressive therapy has resulted in some improvement in survival in the last decade.[3] Extended cholecystectomy is the standard treatment for patients presenting with resectable disease. Unfortunately, a large number of the patients undergo simple cholecystectomy (SC), especially those operated at peripheral centers, or those who are incidentally detected as GBC after SC. On re-staging, the following scenarios emerge– (a) no residual disease (NRD), (b) residual disease in GB bed, (c) lymph nodes, or (d) metastatic disease. Revision surgery (RS) is the standard of care for such patients but may not be possible in all because of the following reasons– (i) encasement of major vessels by residual disease, (ii) delayed presentation (>3 months after SC), or (iii) socio-medical reasons. It is unclear whether these patients should be offered chemotherapy (CT) alone, chemo-radiotherapy (CTRT) or CT followed by consolidation CTRT.

In the absence of any clear management guidelines for the aforementioned clinical presentations, we offered 6 cycles CT, or 4 cycles of CT followed by consolidation CTRT. Having treated the different presentations as defined and stated, the purpose of this analysis is to evaluate the efficacy of the three modalities in the patient presentations as stated, with a view to defining management protocols for future management of these complex cases. We audited patients of GBC post-SC with loco-regional residual disease.


 > Materials and Methods Top


We reviewed data of a prospectively maintained database of GBC (registered in Radiotherapy outpatient department of a Regional Cancer Centre, between January 2008 to December 2016) who underwent SC by community surgeons (peripheral centers) and thereafter referred to us after a histopathological diagnosis of GBC. On restaging with CECT abdomen, they were un-resectable due to the presence of residual disease either in GB bed or loco-regional lymph-nodes. Evidence of residual disease in GB bed on CECT abdomen was assigned T3 and involvement of adjacent structures as T4. For the purpose of this analysis, risk stratification was done based on presence or absence of residual disease burden (AJCC 7th edition) into three categories: NRD, limited volume residual disease (LR 1: Residual/recurrent disease in GB bed with or without N1 nodal station involvement), advanced residual disease [LR 2: Residual/recurrent disease involving GB bed with N2 nodal station involvement, [Figure 1]]. In the absence of any guidelines for this subset of patients, patients either received 6 cycles of combination CT (cisplatin and gemcitabine combination) or 3-4 cycles of the same CT followed by consolidation concurrent CTRT.[4] Concurrent Capecitabine was administered @1250 mg/m2 on RT days) along with RT to a dose of 50-54 Gy to GB bed, adjacent liver infiltration and peri-choledochal, peri-portal, hepatoduodenal, common hepatic artery, coeliac, superior mesenteric and para-aortic lymph nodes (up to L2 vertebral level). RT was administered by the 3D-Conformal radiotherapy technique. Only those patients who received full course of CT or CT followed by Consolidation CTRT were analyzed, those with frank metastatic disease were excluded for the purpose of this analysis. Response assessment to CT was based on RECIST criteria into CR, PR, SD, and PD (based on CECT abdomen). Only those who did not progress on CT received consolidation CTRT. After completion of treatment (CT or CTRT) patients were followed up 3 monthly with a CT scan abdomen to evaluate response to chemoradiation. Side-effects to treatment were recorded according to ctc v 3.
Figure 1: Definition of risk categories

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Our aim was to evaluate the benefit of adding CTRT to CT in terms of overall survival (OS). OS and univariate analysis of prognostic factors affecting OS was analyzed by the Kaplan–Meier method (SPSS-20, IBM SPSS Statistics, RRID: SCR_019096). A P < 0.05 was considered statistically significant. Multivariate analysis using Cox regression was used to evaluate the significant prognostic factors. The study was approved by the institutional ethics committee.


 > Results Top


Out of 176 patients of GBC registered after SC, 89 were metastatic and 87 were non-metastatic. All underwent SC by community surgeons and only 20% were suitable for RS (but patients refused to undergo RS). The rest either reported 3 months after SC or were unresectable due to residual disease burden. Data on the approach of SC (laparoscopic or open) or per-operative findings were not mentioned in the referral letter of all patients. Postoperative histopathology reports or blocks for a central review were not available in all patients, hence the T stage was designated as Tx in 20% of patients. N staging are reported based on enlarged lymph nodes on CECT reports. The median age at presentation was 51 years (interquartile range: 45–60 years) and there were 14 males and 73 females. Majority were T2 (44%) or T3 (28%) and N0 (13%), N1 (14%) or N2 (73%). Based on risk categorization, 17 (20%) had NRD, 33 (38%) had LR1 and 37 (47%) had LR 2. The consort diagram for the patient subsets registered during this period is given in [Figure 2]. Patient and treatment characteristics are mentioned in [Table 1]. Out of 87 patients, 80 received treatment with radical intent and rest (n = 7) did not turn up for any treatment after taking advice in our institute. Side-effects of therapy (hematological and gastrointestinal) were limited to grade 2 toxicity in 10% of patients only. The median follow-up was 21 months (2–129 months) and 30% of patients were lost to follow-up. The median OS of all patients was 20 months [Figure 3].
Table 1: Patient and treatment characteristics

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Figure 2: Consort diagram of various patient subsets

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Figure 3: Overall survival for all patients

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On univariate analysis, residual disease burden, type of treatment (CT vs. CTRT), N stage and response to treatment were found statistically significant, while factors such as age, sex, presence of comorbidity, BMI, and performance status were not significant [Table 2]. The median OS of NRD was not reached versus 19 months for LR1 and 13 months for LR2 (P ≤ 0.001). There was no significant difference in median OS of patients with NRD or LR 2 based on type of treatment (CT vs. CT followed by CTRT), while in LR1, consolidation CTRT yielded a significantly better OS (27 months vs. 19 months, P = 0.003). Based on response to treatment, those with CR had significantly better OS than those with PR, SD, PD (NR vs. 17 months vs. 16 months versus 7 months, P ≤ 0.001). A multivariate analysis of significant factors on univariate, revealed residual disease burden (hazard ratio [HR] 2.97 [95% confidence interval (CI) 1.8–4.8], P = 0.00) and response to therapy (HR 1.5 [95% CI 1.2–1.8], P = 0.00) as significant factors [Table 3] and [Figure 4]a and [Figure 4]b].
Table 2: Univariate significant parameters affecting overall survival

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Table 3: Multivariate analysis of factors affecting overall survival

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Figure 4: Kaplan–Meier survival curve of significant factors affecting overall survival. (a) Overall survival according to residual disease burden. (b) Overall survival according to response to treatment

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 > Discussion Top


Radical surgery is considered as the only definitive treatment for nonmetastatic GBC with pathological stages beyond T1a. SC is considered adequate for tumors limited to the lamina propria [T1a] only. There is 10% incidence of residual disease in the liver gallbladder fossa, as well as a 10%–20% incidence of lymph node metastases that are discovered on repeat surgery, and incidence of finding the residual disease at any site depends on the pathological T stage of the tumor. This incidence can be as high as 37.5% in T1 tumors, 56.7% in T2 tumors, and 77.3% in T3 tumors. Thus, for patients diagnosed as Incidental GBC (presenting within 3 months of SC) and tumors going beyond lamina propria (> than T1a), RS is the standard of care.[5],[6] The loco-regional recurrence rate without RS may range from 20% to 50%. Preventing this high rate of loco-regional recurrence provides a survival benefit, as re-resection has been reported to result in better OS in patients with T1b, T2, and T3 disease.[7] It has been observed that there is no difference in survival between patients undergoing initially extended resection versus SC followed by re-resection.[8],[9]

In a National cancer database report, three-quarters (78.9%) of patients with GBC were diagnosed incidentally. Patients were found significantly less likely to undergo extended (39.7%) versus simple (83.8%) cholecystectomy for their T2 and T3 disease. Furthermore, patients treated at academic facilities are nearly twice as likely to undergo extended resection versus those treated at nonacademic centers (9.5% vs. 4.5%, respectively).[10] Our data highlights the challenges faced in an academic center, for patients of GBC referred by community surgeons after SC. We found inadequacy in reporting of histopathology, i.e., lack T status in 20% of patients, and lack of grading and other high-risk features like lymphovascular invasion and perineural invasion. Hence, categorization of these patients into incidental or missed GBC was not possible. Late reporting to oncologists after a diagnosis of GBC was another challenge leading to unsuitability for RS and a high incidence of recurrent metastatic disease at the time of presentation. Our data reveal that 47% of patients reported after 3 months of SC, when RS is not the norm and 80% of patients were unsuitable for RS due to the presence of residual disease. An interval of 4–8 weeks between SC and RS has been found to yield superior survival as compared to late surgery.[11]

Because of the relatively high risk of metastatic disease in this disease, some investigators have suggested that restaging with [18 F] -fluoro-deoxy-glucose positron emission tomography (PET) is useful in the evaluation of patients with GBC reporting after SC. In this study, patients of incidental GBC were subjected to PET-computed tomography (CT) for re-staging before RS. Those with no uptake had less residual disease than those with uptake (23% vs. 52%). pT1b patients did not have residual disease in liver wedge irrespective of PET status.[12] In our patients, PET-CT could not be advised due to its high cost and lack of national health insurance policy for stakeholders.

Our data included patients with predominantly T2 (42%) and T3 (27%) patients. Though the median survival difference was not statistically significant among the different T groups, it was numerically different, i.e., 29 months versus 24 months versus 20 months versus 40 months versus 13 months for T1, T2, T3, T4, Tx respectively. The higher survival in T4 patients can be explained by the small number of such patients (n = 4) in our series. 5-year survivals have been reported to range from 70% to 80% for T2 disease and 30%–45% with T3 disease for patients without residual disease managed with re-resection as compared with 19%–41% following SC alone.[13] In our series, the estimated 5 years OS was 50%, 33%, 32%, 20% with T1, T2, T3, T4 disease with residual disease managed with CT/consolidation CTRT. This information is hypothesis generating. Can efforts to reinforce treatment with chemo-radiation in responders offer survival advantage equivalent to surgical series? Similar observations of survival advantage with consolidation chemoradiation and its equivalence with surgical series, have also been reported by Kasumuvo.[10]

The nodal burden was also prognostic for OS in our series. The median OS difference was statistically significant, i.e., NR versus 28 months versus 15 months versus 20 months for N0, N1, N2, Nx, respectively (P = 0.005). Dixon reported 5-year survival of 63% with RS in T3N0 patients while our estimated 5-year survival was 72% with CT/Consolidation CTRT in N0 patients unsuitable for RS.[14] Similarly, the reported 5-year OS was 24% with RS in T4N0, T1-4N1 patients while our estimated 5-year survival was 45% with CT/Consolidation CTRT in N1 patients and 16% in N2 patients.

The effect of type of adjuvant therapy was also prognostic for OS in our series. The median OS was NR with either CT or consolidation CTRT in patients with NRD,19 months with CT, and 27 months with consolidation CTRT in LR1. Similar observations of survival advantage with consolidation chemo-radiation have also been reported by Kasumovo on the data from the National Cancer Database of 6825 patients.[10] Among these 88.8% of patients underwent SC, and 31% of patients received CT. 48% of patients who received adjuvant CT also received adjuvant RT. The median OS of patients who received CT was 12 months and with CTRT was 25 months. These observations indicate the effectiveness of chemo-radiation in a subgroup of patients who report late after surgery without metastatic disease. Efforts should be made to sift out these patients in the clinic, to offer a survival advantage to them.

We also found that responders to CT had better outcomes. The median OS in those who achieved CR (37.5%) was NR, while it was 16-17 months for PR (38.7%) and SD (6%) and 9 months for those who progress on therapy. In a large database of 500 patients of GBC (including 20% patients with incidental GBC), neoadjuvant CT/CTRT was offered in 20% of patients and some patients of SC underwent RS after neoadjuvant therapy, but the survivals are not reported separately for SC subset.[15] In view of the impressive CR rates with neoadjuvant therapy in our series, perhaps subjecting them to RS after neoadjuvant therapy might be curative. Our data also highlight that the standard CT regime of cisplatin and gemcitabine is effective in patients with residual disease after SC, as 70% of patients received this regime. We did not attempt to segregate the response based on the type of CT because of small patient numbers.

GBC risk prediction score predicts recurrence in patients of GBC based on T stage and grade of tumor.[16] Risk stratification proposed by us is based on residual burden after SC (as evaluated by CECT abdomen) and it suggests that there is the scope of de-escalation of therapy in NRD and escalation of therapy in LR1. It allows judicious use of resources (RT) in patients with LR1 (rather than any patient with residual disease) in countries with limited resources. Since the outcome of patients with NRD is similar with CT or consolidation CTRT, we should offer single modality therapy to limit toxicity. Patients with LR 2 did not benefit with the addition of consolidation CTRT, so it should be avoided in this subset of patients. Risk stratification based on response to therapy also selects a population who survive long. Perhaps re-resection should be offered in responders and outcomes there-of should be evaluated prospectively, as currently being evaluated by Engineer et al. in phase III randomized controlled trial (POLCAGB) to see the role of preoperative CTRT in unresectable/borderline resectable/residual disease in postcholecystectomy patients as well.[17] Similarly, another randomized study (the AIO/CALGP/ACO-GAIN-trial) is ongoing, which will investigate preoperative CT followed by re-resection for unresectable biliary tumors or incidental GBC who have undergone SC with or without residual disease and will hopefully answer many questions.[18] Selection of therapy according to risk categorization based on disease burden has not been reported before. To prospectively validate the approach proposed by us, histopathology reporting of all cholecystectomy samples and early referral of all GBC to oncology facilities should be made mandatory in countries where this disease presents in endemic proportions.

The limitation of this study is the small sample size, which can be explained by the high incidence of metastatic disease in this subset of patients (50%).


 > Conclusion Top


Our data suggest that single modality therapy yields good outcomes in SC with NRD. CT followed by consolidation CTRT improves outcomes in limited volume residual disease (LR1). In advanced residual disease (LR2) there is no benefit with consolidation CTRT. Responders to CT have better outcomes with consolidation CTRT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Duffy A, Capanu M, Abou-Alfa GK, Huitzil D, Jarnagin W, Fong Y, et al. Gallbladder cancer (GBC): 10-year experience at memorial sloan-kettering cancer centre (MSKCC). J Surg Oncol 2008;98:485-9.  Back to cited text no. 8
    
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Foster JM, Hoshi H, Gibbs JF, Iyer R, Javle M, Chu Q, et al. Gallbladder cancer: Defining the indications for primary radical resection and radical re-resection. Ann Surg Oncol 2007;14:833-40.  Back to cited text no. 9
    
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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. 10
    
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Ethun CG, Postlewait LM, Le N, Pawlik TM, Buettner S, Poultsides G, et al. Association of optimal time interval to re-resection for incidental gallbladder cancer with overall survival: A multi-institution analysis from the us extrahepatic biliary malignancy consortium. JAMA Surg 2017;152:143-9.  Back to cited text no. 11
    
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Goel M, Tamhankar A, Rangarajan V, Patkar S, Ramadwar M, Shrikhande SV. Role of pet CT scan in redefining treatment of incidental gall bladder carcinoma. J Surg Oncol 2016;113:652-8.  Back to cited text no. 12
    
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Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: Comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 2000;232:557-69.  Back to cited text no. 13
    
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Dixon E, Vollmer CM Jr., Sahajpal A, Cattral M, Grant D, Doig C, et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: A 12-year study at a North American center. Ann Surg 2005;241:385-94.  Back to cited text no. 14
    
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Patkar S, Ostwal V, Ramaswamy A, Engineer R, Chopra S, Shetty N, et al. Emerging role of multimodality treatment in gall bladder cancer: Outcomes following 510 consecutive resections in a tertiary referral center. J Surg Oncol 2018;117:372-9.  Back to cited text no. 15
    
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Mochizuki T, Abe T, Amano H, Hanada K, Hattori M, Kobayashi T, et al. Efficacy of the gallbladder cancer predictive risk score based on pathological findings: A propensity score-matched analysis. Ann Surg Oncol 2018;25:1699-708.  Back to cited text no. 16
    
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Engineer R, Patkar S, Lewis SC, Sharma AD, Shetty N, Ostwal V, et al. A Phase III randomised clinical trial of perioperative therapy (neoadjuvant chemotherapy versus chemoradiotherapy) in locally advanced gallbladder cancers (polcagb): Study Protocol. BMJ Open 2019;9:e028147.  Back to cited text no. 17
    
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Goetze TO, Bechstein WO, Bankstahl US, Keck T, Königsrainer A, Lang SA, et al. Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC) – a phase III study of the german registry of incidental gallbladder carcinoma platform (GR) – The AIO/CALGP/ACO- GAIN-trial. BMC Cancer 2020;20:122.  Back to cited text no. 18
    


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