Dealing with unresectable and metastatic Gall Bladder Cancer

Dealing with Unresectable &
Metastatic GBC
DR. AMIT SEHRAWAT
ASSISTANT PROFESSOR
DEPARTMENT OF MEDICAL ONCOLOGY HAEMATOLOGY
ALL INDIA INSTITUTE OF MEDUCAL SCIENCES, RISHIKESH

OUTLINE
Disease Burden
Introduction
Management of Obstructive jaundice
Management of Locally Advanced Disease
Palliative Systemic Therapy
Immuno-Oncology and Targeted therapy
Guidelines
Conclusion
Feb 13, 2021 Dr. Amit Sehrawat 2

GLOBOCAN 2020

ICMR,PBCR-2014

STAGEWISE DISTRIBUTION OF GBC
PATIENTS: INDIA
Singh et al. J Gastrointest Cancer. 2018
MORE PATIENTS REQUIRE PALLIATIVE TREATMENTS THAN CURATIVE

THE STAGE DISTRIBUTION: ROW
• T1 – 11 percent
(61 percent peritoneal [T2a] and 39 percent hepatic [T2b])
Shindoh J et al. Ann Surg. 2015
(Japan, US, Europe)
QUITE CONTRAST TO THAT OF THE INDIAN SCENARIO

OUTLINE
Disease Burden
Introduction
Guidelines
Conclusion

INTRODUCTION:
 Surgery is the only potentially curative modality
 But only minority eligible for curative-intent surgery
 Vast Majority present with advanced metastatic disease
 For most treatment intent is palliative in nature

GOALS OF PALLIATION IN GBC
• Symptomatic relief
Pain relief
jaundice management
bowel obstruction
improving survival
• Pain Management- Medical therapy, Radiotherapy, Nerve block
• Biliary drainage- percutaneous or endoscopic
• Percutaneous approaches are generally preferred/practical

SURVIVAL IN INDIA
 About 75% metastatic at presentation
 GBC is reported the most common cause of malignant obstructive jaundice in
North India
 < 15% Early stages at presentation
 Overall resectability rate less than 20%
 Estimated 1-year survival for stages II, IIIA, IIIB, IVA, and IVB was 100, 76, 47.4,
26, and 10.6%,
Dubey et al, 2018,OJI
Sk Singh, 2018, J Gastrointest Cancer

WHY PAUCITY OF EVIDENCE?
• Indian Subcontinent / Latin American Disease
• Western trials: of Hepatobiliary Cancers, GBC just a subset
• Different disease than west?
• Advanced presentation in majority
• Most data retrospective , fewer RCTs

OUTLINE
Disease Burden
Introduction
Guidelines
Conclusion

MANAGEMENT OF OBSTRUCTIVE JAUNDICE
 presenting feature in 30 to 60 percent
 Direct tumour infiltration most common cause
 S/o disseminated disease hence relative contraindication to radical resection
 Stenting via an endoscopic or percutaneous approach
 30 percent of the liver parenchyma drainage - may be sufficient to alleviate
symptoms like pruritus

 Successful drainage was more with PTBD (89 versus 41 percent),
 early cholangitis was a more with endoscopic stenting (48 versus 11 percent).
 Rates of stent occlusion (32 versus 39 percent)
 mOS (60 days in both groups) were not significantly different.
 Success rate with endoscopic drainage in this study (41 percent) was much lower
 PTBD- External assembly, worse quality of life
Saluja et al. Clin Gastroenterol Hepatol. 2008
PTBD VS INTERNAL STENTING

METALLIC VS PLASTIC STENTS
 lack of definite consensus on the relative merits of plastic vs. metal stents and
single vs. multiple stents
 Superiority of metal stenting over plastic shown in cholangiocarcinoma has
been shown
 existing evidence does not support the superiority of metal stents over plastic
stent in unresectable GBC
 plastic stents should be preferred over metal stents especially when cost-
effectiveness and limited survival
AK Jha, 2020, Annals of Gastroenterology

OUTLINE
Disease Burden
Introduction
Guidelines
Conclusion

MANAGEMENT OF LA DISEASE
 Obstructive jaundice with LA disease- NACT is one of the options
 Poor Quality of data, mostly extrapolated, retrospective, single institute
 RT + CT commonly used especially if symptomatic disease
 RT alone not enough
 Despite uncertainty as to benefit, CTRT is an acceptable commonly practiced
choice
NCCN 2021
Jarnagin et al. Cancer. 2003

 NCCN: fluoropyrimidine-based CTRT or palliative chemotherapy
 ESMO: chemotherapy; RT may be considered after first-line chemotherapy
 Clinical trial participation to be encouraged
 Small number of patients may be deemed operable after NACT/RT or NACT
 Recent systemic review s/o insufficient data to support the routine use of NACT
or NACRT in advanced GBC
 Decision needs to be individualized, NACT/RT not SOC for all
 Important tool to study disease biology and to avoid futile surgery
Hakeem et al. 2019, Eur J Surg Oncol
•.

INDIAN EXPERIENCE:
 37 Indian patients with locally advanced GBC post NACT
 17 patients who were able to undergo (46%) R0 resection
 significantly better overall survival — median not reached versus 9.5 months
 Progression free survival of 25.8 versus 5.6 months respectively
Sirohi B, 2015, Future Onco

OUTLINE
Disease Burden
Introduction
Guidelines
Conclusion

PALLIATIVE SYSTEMIC THERAPY
• Only modest survival benefit
• Based on small series and consist of a heterogeneous population
• only limited data evaluating the impact of treatment on survival
• Response rates 10-60 %

FIRST LINE CHEMOTHERAPY OPTIONS
 Optimal regimen not defined
 Patient specific issues crucial in decision making
 PS, Jaundice, Cholangitis, nutrition, co-morbidities
 Good performance status and no or minimal hyperbilirubinemia
 Gemcitabine + Cisplatin
 Gemcitabine + Capecitabine
 Gemcitabine + Oxaliplatin
 Gemcitabine plus S-1

GEMCITABINE+ CISPLATIN
 SOC option, especially without hyperbilirubinemia
 Landmark UK ABC-02 trial
 410 patients with locally advanced or metastatic HBCs
 mOS was 11.7 months cisplatin-gemcitabine (214) Vs 8.1 months in the
gemcitabine group (206)
 but limited quality data on Gem+Cis vs Gem+ other combinations
 insufficient to prove whether or not a gemcitabine-containing combination is
better
Valle et al. N Engl J Med. 2010.

UK-ABC-02

GEMCITABINE PLUS S-1
 S-1 is an oral fluoropyrimidine
 Tegafur +Gimeracil +Oteracil
 Japanese phase III FUGA-BT trial
 354 patients with chemotherapy-naive recurrent or unresectable HBC
 Gemcitabine plus S-1 was non-inferior
 mOS: 15.1 versus 13.4 months, hazard ratio 0.95, 95% CI 0.78-1.15
 Better toxicity Profile
 Not available in India
Mizusawa, 2016, Jpn J Clin Oncol

GEMCITABINE PLUS CAPECITABINE
 associated with higher response rates than gemcitabine plus FU
 study of 75 patients (27 with GBC)
 22 objective responses (three complete)
 median progression-free and overall survival durations were 6.2 and 12.7
months
 Two smaller phase II trials reported 14-16 months OS
 Atleast two trials including one SWOG reported no significant OS benefit with
the combination
Riechelmann RP Cancer 2007

GEMCITABINE PLUS OXALIPLATIN
• One of the most promising alternative to Gem+Cis
• 36% RR in a phase II study reported on 31 previously untreated patients, mOS
14.3 months
• Phase III non-inferiority trial directly comparing GEMOX versus CAPOX in 222
• 27 percent GBC
• 26% ORR with GEMOX Vs 16% with CAPOX
• mOS 10.4 versus 10.6 months
Sharma et al, 2010, JCO

Sharma et al, 2010, JCO

GEMCITABINE PLUS CARBOPLATIN
 carboplatin for cisplatin reduces the severity of non-hematologic toxicity
 37 percent, and there were four complete responders
 mOS 11 months
 marked inter-individual variability in the hematologic tolerance
 3 or 4 thrombocytopenia rates of 38-31%

NON-GEMCITABINE-BASED REGIMENS
 Better suited for persistent hyperbilirubinemia despite stenting
 However variable response rates ( 0-30%), mOS around 6months
 Longer infusion regimes have recently shown better outcomes

FOLFOX/CAPOX
 CAPOX active regimen, more than 60% disease control rates in a German study
 mOS 12.8 Months
 Korean non-inferiority study by Kim et al XELOX ( 114) vs GEMOX (108)
 XELOX showed significant non-inferiority to GEMOX in terms of 6-month PFS rate
 mPFS 5.3 mo Vs 5.8 mo, 6 month PFS 44.5%
Nehls et al. 2008, Br J Cancer
Kim at al, 2019, Annals of Oncology

SECOND-LINE CHEMOTHERAPY:
 Limited prospective studies, Based on still weaker evidence
 Regimen based on first line chemotherapy use and tolerance
 Indian experience with FOLFOX/CAPOX…modest survival benefits
 ABC-06 mFOLFOX in 162 patients post Gem+Cis, 34 GBC, median 6mo OS 61 vs
36%
 Irinotecan based options can be explored
 BSC appropriate for poor PS
Lamarca et al, 2019, JCO

ATYPICAL HISTOLOGY
• Adeno-squamous or squamous cell GBCs: typically managed similarly
• advanced small cell carcinoma of the gallbladder- poor prognosis
• median OS of eight months, and one- and two-year survival rates of 28 and 0
percent
• Surgery best hope for early stages + systemic chemotherapy as adjuvant Rx
• Choice of chemotherapy based on SCLC experiences: Eto+Cis

BORDERLINE PERFORMANCE STATUS
 Best Supportive care
 Pain palliation
 Single agent Gemcitabine ( RR 15-60%)
 Single Agent Capecitabine ( ORR up to 50%)

OUTLINE
Disease Burden
Introduction
Guidelines
Conclusion

MOLECULARLY TARGETED THERAPY
FUTURE DIRECTIONS
• dMMR/MSI- tumour agnostic indication
• NTRK targets- tumour agnostic – options: Entrectinib/Larotrectinib
• But percentage of NTRK fusions was 0.75% (ASCO 2020)
• NGS testing and appropriate targeted options
• Feasibility in Indian context??

• MOSCATO-01 trial, in which 43 / 1035 adults with advanced cancer had a biliary
tract malignancy
• Potentially actionable molecular aberrations were identified in 23 (68%), 18 of
whom received a targeted treatment
• mPFS 5.2 months, and there were six objective responses (33 percent)
• FGFR (Erdafitinib/Pemigatinib) , HER2 ( Trastuzumab), IDH (Ivosidenib) etc.
potential targets
Verlingue et al, 2017, Eur J Cancer

IMMUNO-ONCOLOGICAL DRUGS
• MSI-H/dMMR tumors susceptible to immune checkpoint inhibition
• ORR upto 53% of patients, and CXR in 21% of patients MSI-H/dMMR frequency
5% in GBC
• Pembrolizumab has been approved by FDA- no specific GBC only evidence though
• Nivolumab: phase-2 trial. pMMR 10/46 PR, 4/46 durable response
• Nivolumab + Ipilimumab: 4/13 PR, 15% Gr 3 or more toxicities
Le DT etal. 2017, Science
Kim et al, 2020, JAMA Oncology

ANGIOGENESIS INHIBITORS
• VEGF is overexpressed in biliary tract cancers
• Role remains uncertain due to the lack of controlled trials
• Bevacizumab + chemotherapy: needs prospective validation
• Experimental option only

METRONOMIC CHEMOTHERAPY
 Promising choice for poor PS patients
 Limited evidence
 SA weekly 5FU
 Metronomic Capecitabine appropriate option for select patients
 Multicenter prospective validation lacking…but feasible

BEST SUPPORTIVE CARE
• Poor PS
• Obstructive jaundice, Cholangitis
• Patient and family preferences
• Metronomic Therapy
• Hospice services availability and acceptance
• Palliative RT- especially Bone mets
• Palliative Surgery- GI Obstruction

OUTLINE
Disease Burden
Introduction
Guidelines
Conclusion

GUIDELINES
• ICMR-2015
• ESMO-2016
• NCCN-2021

NCCN-2021

NCCN…

OUTLINE
Disease Burden
Introduction
Guidelines
Conclusion

CONCLUSION
• Majority of GBC advanced/metastatic
• Paucity of high-quality evidence
• Surgery is the only curative option but only limited patients eligible for the same
• Majority require palliative and supportive measures
• Goals of palliation include care of Jaundice, pain
• No consensus as to the optimal Neo-adjuvant approach for LA GBC
• GBC only prospective trials must be planned from Indian set-up

THANK YOU

Dealing with unresectable and metastatic Gall Bladder Cancer

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