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Radiotherapy for Locally Advanced Unresectable Gallbladder Cancer-A Way Forward: Comparative Study of Chemotherapy Versus Chemoradiotherapy

Most studies include both ), contemporary data in this regard seems more encouraging with retrospective analysis of two Abstract Background: For non-metastatic locally advanced gallbladder cancer (LAGBC) which remain unresectable and nonmetastatic after chemotherapy, there is no consensus on whether to continue chemotherapy or add local radiotherapy for improving outcomes. Materials and Methods: Forty-five patients of surgically unresectable non-metastatic LAGBC were analysed. Twenty patients did not receive radiotherapy (No RT cohort) and received only chemotherapy, while 25 patients received RT (RT cohort) with conformal techniques along with concurrent gemcitabine based chemotherapy. No RT and RT cohorts were compared for disease related outcomes and toxicities. Results: Conclusion:


Introduction
Gallbladder Cancers (GBC) are rare but highly aggressive tumours of the extrahepatic biliary tree. As per GLOBOCAN 2018, the worldwide age standardized incidence and mortality (per 1,00,000) for GBC are 2.3 and 1.7, respectively [1]. Approximately 50-60% of the nonmetastatic GBC present at a locally advanced stage (T3/T4 or N+). The median survival for locally advanced gall bladder cancer (LAGBC) in multiple series ranges from 6-16 months with a 2 year survival of < 20% [2,3]. These patients generally receive chemotherapy or chemoradiation followed by an assessment for surgery if optimal response. For patients who receive chemotherapy, and do not achieve optimal downstaging to undergo R0 resection and continue to be nonmetastatic, there is no consensus, whether they should receive further chemotherapy alone or local radiotherapy (RT) should be added with an aim to achieve better local control and prolong survival. The role of RT has remained a matter of debate for LAGBC, with multiple older series failing to demonstrate any potential benefit of RT in LAGBC [4][5][6]. Most of these studies include both gall bladder cancers and extrahepatic bile duct cancers together and have utilized conventional RT techniques. However, with the emergence of newer RT techniques (IMRT, IGRT etc.), contemporary data in this regard seems more encouraging with retrospective analysis of two 334 population database (SEER and NCDB) showing survival benefit with addition of RT to chemotherapy in unresectable localized disease [7,8]. We performed a retrospective comparative analysis to ascertain the benefit of giving local RT in these unresectable LAGBC at our institute.

Materials and Methods
This study is a retrospective analysis of patients of LAGBC patients treated between March 2013 to December 2018 at a single tertiary cancer institute. Institutional Review Board (IRB) approval was obtained for the study (IEC no: 900653).

Inclusion and Exclusion Criteria
All cases of non-metastatic LAGBC who had received neoadjuvant chemotherapy (NACT) as per predefined protocol were considered.
Patients who were deemed as unresectable in Multidisciplinary Tumor Board (MDT) after NACT due to local factors like hilar infiltration, non-communicating hilar block, complete encasement of one or more major vessels at porta, involvement of D2 requiring Whipple's procedure or extensive liver infiltration, were considered for the study. Few patients who were deemed as "unlikely to ever come up for curative resection" in MDT due to extensive local factors were not offered NACT and were considered for definitive chemoradiotherapy (CTRT). Exclusion criteria were patients who were treated with palliative intent RT (8Gy/ 1 fraction, 20Gy/ 5 fractions or 30Gy/ 10 fractions) for symptomatic relief, patients who did not complete the planned RT schedule and patients in whom no follow up data was available. The patients were classified into two cohorts: patients who received only chemotherapy (No RT cohort) vs patients received a fractionated course of local radiotherapy (RT cohort). As per institutional protocol, patients with spread to regional nodes including coeliac nodes were also treated with RT and hence were considered for analysis. The two cohorts were matched as per age, sex, comorbidities, T and N stage.

Treatment
All patients selected either received few more cycles of chemotherapy or received local radiotherapy followed by chemotherapy as per the decision of the MDT. If the patient had obstructive jaundice, drainage procedure with ERCP or PTBD was performed and self-expanding metal stents placed allowing bilirubin to normalize before the start of the treatment. The chemotherapy regimen used at our institute was either a combination of gemcitabine and cisplatin or gemcitabine and oxaliplatin and has been described in detail in previous publications from our institute [9][10][11]. Response to therapy was assessed in MDT with a Contrast Enhanced Computerized Tomography (CECT)/ Positron Emission Tomography-Computerized Tomography (PET-CT) as per RECIST 1.1 criteria and Carbohydrate Antigen-19.9 (CA-19.9) levels [12].

Radiotherapy
Patients were simulated using a planning contrast enhanced CT scan. Clinical Target Volume primary and node (CTVp and CTVn) delineation was done as per existing institutional practice already published earlier [10]. The dose prescription to PTVp (Primary) and PTVn (nodes) was 45-50Gy at 1.8-2 Gy per fraction respectively. A dose of 52-57Gy as simultaneous integrated boost (SIB) was given to gross tumor volume (GTV) primary and node (GTVp and GTVn respectively) if feasible. Organs at risk (OARs) were delineated as per standard guidelines [13]. The desired dose volume constraints for target and OARs are given in table 1. Weekly concurrent chemotherapy as gemcitabine (300 mg/ mt 2 ) was given to all patients.Treatment planning was with Intensity Modulated Radiotherapy Techniques (IMRT) or related techniques (Helical tomotherapy, Volumetric Modulated Arc Therapy). Treatment verification (Image Guided Radio Therapy) was done by KV-CBCT or MVCT. Further chemotherapy with palliative intent was continued as per MDT discussion.

Follow-up/ Toxicity
Patients were followed up post completion of CTRT or chemotherapy at an interval of 2-3 months with CECT/ PET-CT and CA-19.9 for response. Patients were advised for subsequent follow ups after completion of all treatment were at 3-4 monthly interval with subsequent imaging at 6 monthly interval or for rising CA-19.9/ suspected clinical progression. Acute and late radiation toxicity was scored using Radiation therapy Oncology Group (RTOG) morbidity schema [14].

Statistics
The primary end point of the study was progression free  The median RT dose to the CTV was 50Gy while the median tumor dose was 52Gy. Median RT duration was 36 days (range 32-50 days) with a median of 6 (range 2-7) cycles of concurrent chemotherapy.

Toxicity
The acute RT toxicities (skin and GI) are shown in Table 4. Only 1 patient had a grade 3 diarrhoea at RT completion which was managed conservatively. Additionally, 4 (16%) patients had grade 3 haematological toxicity (neutropenia).Severe late toxicity (≥ grade 2) was seen in 2 patients (1 duodenal stricture and 1 diarrhoea).
Two patients had pneumobilia.  The severe late toxicity of CTRT (≤ RTOG grade 3) remained low in our series. We ascribe this to our meticulous treatment protocol especially with regards to the delineation of the duodenum by an experienced gastrointestinal radiation oncologist and limiting of doses to the duodenum (19). A meticulous image guidance protocol may also have a role in limiting the late GI toxicity in the current series.
We agree that superior outcomes in CTRT cohort may be due to a selection bias with patients having no progression on chemotherapy being selected for RT (table 4). Nevertheless, the lesser incidence of locoregional failures as well as encouraging disease related outcomes in the CTRT cohort demonstrate that RT should be incorporated into the treatment protocol whenever feasible. Since 8 (18%) patients progressed (4 locally and 4 local with distant metastasis) after few cycles of chemotherapy would they have benefitted with upfront CTRT is matter o f speculation. Further randomized studies are required to determine the optimal sequencing of treatment that is chemotherapy followed by CTRT or upfront CTRT followed by chemotherapy.
The current the study is subject to the drawbacks of a retrospective analysis. The number of patients in each cohort are limited owing to the paucity of non-metastatic and unresectable LAGBC. The time duration for response assessment post NACT was not standardized across the cohort with patients receiving a variable number of chemotherapy cycles before assessment for radiotherapy and some patients (n=6) receiving CTRT upfront (depending on the volume of the disease). Also, the criteria for continuing with chemotherapy or giving chemoradiation was not very well defined. However, as mentioned above the treatment protocol was chosen in a multidisciplinary tumor board comprising of dedicated biliary tract surgeons and radiologists, radiation oncologists, and medical oncologists specializing in gastrointestinal cancers. We believe this to be one of the most important factors for our relatively better outcomes in these cancers.
In conclusion, patients with unresectable GBC who have responded to chemotherapy can be considered for CTRT as definitive local treatment.