Case Report
Medwave 2019;19(10):e7725 doi: 10.5867/medwave.2019.10.7725
Resective surgery versus palliative care in advanced gallbladder cancer
Jai-sen Leung , Eduardo Viñuela
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Key Words: advanced gallbladder cancer, resective surgery, palliative, Epistemonikos, GRADE..

Abstract

INTRODUCTION
Despite multiple advances in medicine, gallbladder cancer remains a disease with poor prognosis. In advanced stages, the main options are surgical management or palliative non-surgical care. However, it is not clear which therapy constitutes a better alternative.

METHODS
We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified one systematic review including three primary studies, none of them randomized. We concluded that resective surgery may increase survival rates in patients with advanced gallbladder cancer, but the certainty of the evidence is low.


 
Problem

Gallbladder cancer is an uncommon cancer, but it is the most common biliary duct cancer, representing  85-90% [1]. However, diagnosis is frequently done at a late stage, since it does not present with symptoms or signs in earlier stages, and prognosis remains ominous in comparison to other types of cancer. Five-year overall survival is 18%, while in advanced stages it might be as low as 2 to 8 percent [2]. Thus, it is imperative to clarify the best type of treatment, particularly in stages considered incurable.
Traditionally, two distinct forms of treatment have been proposed in advanced stages: resective surgery and palliative non-surgical care.  Unlike resective surgery which has curative intent in early stages, in advanced gallbladder cancer the aim is to reduce tumor size, and to improve quality of life and survival.
However, its comparative effectiveness against other palliative alternatives such as chemotherapy, endoscopic therapy, interventional radiology or other medical therapies is still a matter of controversy.

Methods

We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.  

Key messages

  •  Resective surgery compared to palliative care may increase survival rate in patients with advanced gallbladder cancer (low certainty of evidence).
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

Only one systematic review [3] was found, which included three primary studies [4], [5], [6], none of them a randomized trial.

What types of patients were included*

All primary studies included adult patients with advanced gallbladder cancer.
Average participant age ranged from 64 to 68 years.
All studies included patients in stages IVA and IVB, according to the American Joint Committee on Cancer (AJCC) classification scale.
In one of the studies 78% of patients were classified IVB and 22% IVA [4]. In another study [5], 88% were IVB and 12% IVA. In the last study, 55% of patients were IVA and 45% IVB [6].

What types of interventions were included*

All primary studies assessed surgical treatment in comparison to any type of palliative non-surgical treatment. One study [4] assessed resective surgery, palliative chemotherapy and best available supportive care (biliary duct prosthesis, external biliary drain and radiotherapy). Another study [5] evaluated resective surgery and palliative care (chemotherapy and radiotherapy). The last study [6] compared surgical treatment to chemotherapy and other palliative treatments.

What types of outcomes
were measured

All studies and the review reported survival as main outcome.
Average follow-up was 10.6 years, with a range of seven to 16 years. Only one of them reported the number of patients with R0 borders after surgery.

* Information about primary studies is not extracted directly from primary studies but from identified systematic reviews, unless otherwise stated.

Summary of findings

Information about the effects of resective surgery on advanced gallbladder cancer is based on three studies, that included 2990 participants overall [4], [5], [6].
All of the  studies assessed overall survival rate. The review reported the data were not suitable for incorporation into a meta-analysis, so the information is presented as a narrative synthesis.
The summary of findings is as follows:

  • Resective surgery may increase survival rate in advanced gallbladder cancer (low certainty of evidence)
  • No studies were found that assessed quality of life.
  • No studies were found that assessed adverse effects.

Other considerations for decision-making

To whom this evidence does and does not apply

  • The results presented are applicable to patients with advanced gallbladder cancer, in which conventional therapy with curative intention has been ruled out. All three included studies consider patient with gallbladder adenocarcinoma in stages IVA and IVB of the American Joint Committee on Cancer (AJCC). In absence of direct evidence, it seems reasonable to extrapolate these conclusions to other stages considered incurable such as IIIA or IIIB. It is important to mention that the studies did not report functionality of patients prior to surgery, which should be considered when interpreting the results.
  • The results are not applicable to patients presenting with gallbladder cancer in early stages, in which treatment with curative intent is an option, being cholecystectomy or hepatic wedge in accordance with staging. Similarly, these results are not applicable to with other histological types or to incidental diagnosis of gallbladder cancer after cholecystectomy, which are usually eligible for curative treatment.
About the outcomes included in this summary
  • The outcome included by the systematic review and reported as main outcome by the primary studies is overall survival. The authors of this summary agree this outcome corresponds to the critical outcome for decision making 
    Additionally, the authors agree that it is necessary to consider other outcomes at the time of making decisions, such as quality of life after either intervention and adverse effects associated with them. These are not reported by the systematic review.
    The authors agree that in cases of poor prognosis histology, such as advanced gallbladder cancer, one-year survival rate usually is more relevant for decision-making, however, the studies report the outcomes differently, two of them dichotomously [4], [5] and one as extra months of survival [6].
Balance between benefits and risks, and certainty of the evidence
  • In relation to the comparison between resective surgery and non-surgical palliative care in patients with advanced gallbladder cancer, there is a substantial lack of information. Furthermore, the analysis of the little data available is troublesome given the impossibility of conducting a meta-analysis. Considering the former, and the high risk of bias of the studies presented in this review, the quality of the evidence is considered to be low in accordance with GRADE working group criteria.
  • Considering that surgical treatment may have better results regarding survival rate in patients with advanced gallbladder cancer, it is necessary to evaluate risks and complications associated with surgery, considering the patient's underlying conditions and the accessibility to existing alternative treatments. In any case, the authors agree that any decision and evaluation must be made in conjunction with the patient.
Resource considerations
  • The systematic review analysed does not report costs associated to the surgical treatment versus non-surgical palliative care in advanced stage gallbladder cancer.
    Given the current uncertainty about the survival benefit, and the lack of data on other relevant outcomes, it is not possible to estimate the balance between costs and benefits.
What would patients and their doctors think about this intervention
  • The generalized clinical opinion about gallbladder cancer treatment is frequently biased by the ominous prognosis of this disease, which is greater in advanced stages, where prognosis is poor regardless of the treatment strategy. Whether there are clinically significant benefits associated with resective surgery despite not achieving negative margins (R0) is a matter of unresolved controversy, therefore, most clinicians choose to dismiss the possibility of surgical treatment when curative intention is not possible, especially considering the risks and complications of surgery in the fragile condition of most patients. This approach might disregard the potential benefits on survival for patients with residual disease after surgery.
    In relation to the opinion of patients at the moment of choosing between treatments, there should be great variability depending on the underlying values and preferences. Notwithstanding, it is common to find patients agreeing with the surgical option after a clear explanation about the aim of the surgery, in terms of survival and quality of life, particularly among younger patients.
    There is a special group of patients whom, given their baseline condition, cannot opt ​​for surgical treatment. In this group, palliative treatment plays a fundamental role in their care.

Differences between this summary and other sources

  • In general, the results presented in this summary, agree with those presented in the systematic review [3]. However, given the lack of information regarding other critical outcomes, new primary studies and systematic reviews are needed.
    We found three guidelines regarding treatment of advanced gallbladder cancer. The first [7] reached a similar conclusion, recommending that all TNM classified cancers in stage T2 or over should be treated with extended cholecystectomy including hepatic wedge or segmentectomy of segments IVB/V, associated or not to lymph node dissection or resection of bile duct, based on a low-certainty evidence. On the other hand, the other two guidelines [8], [9], state that in cases where curative treatment is not an option or resectability has not been evaluated, surgical treatment is not recommended and palliative care based on chemotherapy and/or radiotherapy is preferred.
Could this evidence change in the future?
  • The results in relation to survival presented in this summary are likely to change with future, evidence, considering the limited certainty of the existing evidence.
  • We found three primary studies relevant for this question [10], [11], [12], which were not included in any systematic review. All of them evaluated survival in patients with gallbladder cancer. One [10] evaluated surgery with curative intent compared to other non-surgical palliative therapies. Other [11] cytoreductive surgery associated with radiotherapy in relation to palliative chemotherapy. The last one [12] compared non-surgical palliative treatment and aborted surgery.
  • We did not identify ongoing trials or systematic reviews in the International Clinical Trials Registry Platform of the World Health Organization, or the PROSPERO database respectively.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version:  Resective surgery versus palliative care in advanced gallbladder cancer  

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

INTRODUCCIÓN
A pesar de los múltiples avances de la medicina, el cáncer de vesícula sigue siendo una enfermedad con mal pronóstico. En su etapa avanzada, se plantea el tratamiento quirúrgico o paliativo no quirúrgico, pero no está claro cual de las alternativas constituye una mejor opción.

MÉTODOS
Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios y preparamos una tabla de resumen de los resultados utilizando el método GRADE.

RESULTADOS Y CONCLUSIONES
Identificamos sólo una revisión sistemática que incluyó tres estudios primarios, de los cuales ninguno corresponde a un ensayo aleatorizado. Concluimos que la cirugía resectiva podría aumentar la sobrevida en los pacientes con cáncer de vesícula avanzado, pero la certeza de la evidencia es baja.

Authors: Jai-sen Leung [1,2], Eduardo Viñuela[2,3]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
[2] Proyecto Epistemonikos, Santiago, Chile.
[3] Departamento de Cirugía, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

E-mail: evinuela@uc.cl

Author address:
[1] Centro Evidencia UC
Pontificia Universidad Católica de Chile
Diagonal Paraguay 476
Santiago
Chile

Citation: Leung J, Viñuela E. Resective surgery versus palliative care in advanced gallbladder cancer. Medwave 2019;19(10):e7725 doi: 10.5867/medwave.2019.10.7725

Submission date: 4/8/2019

Acceptance date: 21/11/2019

Publication date: 26/11/2019

Origin: This article is a product of the Evidence Synthesis Project of Epistemonikos Fundation, in collaboration with Medwave for its publication.

Type of review: Non-blinded peer review by members of the methodological team of Epistemonikos Evidence Synthesis Project.

PubMed record

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  1. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome [Internet]. Clinical epidemiology. Dove Medical Press; 2014 . | CrossRef | PubMed | Link |
  2. Survival Rates for Gallbladder Cancer [Internet]. American Cancer Society. 2018. | Link |
  3. Surgical treatment for gallbladder cancer – a systematic literature review. Scandinavian Journal of Gastroenterology . 2017 ;52(5):505-514. | CrossRef | PubMed | Link |
  4. Ishikawa T, Horimi T, Shima Y, Okabayashi T, Nishioka Y, Hamada M et al. Evaluation of aggressive surgical treatment for advanced carcinoma of the gallbladder. Journal of Hepato-Biliary-Pancreatic Surgery. 2003;10(3):233-238. | CrossRef | PubMed |
  5. Kayahara M, Nagakawa T, Nakagawara H, Kitagawa H, Ohta T. Prognostic Factors for Gallbladder Cancer in Japan. Annals of Surgery. 2008;248(5):807-814. | CrossRef | PubMed |
  6. Meng H, Wang X, Fong Y, Wang Z, Wang Y, Zhang Z. Outcomes of Radical Surgery for Gallbladder Cancer Patients with Lymphatic Metastases. Japanese Journal of Clinical Oncology. 2011;41(8):992-998. | CrossRef | PubMed |
  7. Lee S, Kim K, Kim W, Kim I, Nah Y, Ryu D et al. Practical Guidelines for the Surgical Treatment of Gallbladder Cancer. Journal of Korean Medical Science. 2014;29(10):1333. | CrossRef | PubMed |
  8. Benson A, Abrams T, Ben-Josef E, Bloomston P, Botha J, Clary B et al. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw. 2009;7(4):350-391. | PubMed |
  9. Bethesda. Gallbladder Cancer Treatment . National Cancer Institute. 2019. | Link |
  10. Matull W, Dhar D, Ayaru L, Sandanayake N, Chapman M, Dias A et al. R0 but not R1/R2 resection is associated with better survival than palliative photodynamic therapy in biliary tract cancer. Liver International. 2010;31(1):99-107. | CrossRef | PubMed |
  11. Amblard I, Mercier F, Bartlett D, Ahrendt S, Lee K, Zeh H et al. Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups. European Journal of Surgical Oncology. 2018;44(9):1378-1383. | CrossRef | PubMed |
  12. Buettner S, Wilson A, Margonis G, Gani F, Ethun C, Poultsides G et al. Assessing Trends in Palliative Surgery for Extrahepatic Biliary Malignancies: A 15-Year Multicenter Study. Journal of Gastrointestinal Surgery. 2016;20(8):1444-1452. | CrossRef | PubMed |
Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome [Internet]. Clinical epidemiology. Dove Medical Press; 2014 . | CrossRef | PubMed | Link |

Survival Rates for Gallbladder Cancer [Internet]. American Cancer Society. 2018. | Link |

Surgical treatment for gallbladder cancer – a systematic literature review. Scandinavian Journal of Gastroenterology . 2017 ;52(5):505-514. | CrossRef | PubMed | Link |

Ishikawa T, Horimi T, Shima Y, Okabayashi T, Nishioka Y, Hamada M et al. Evaluation of aggressive surgical treatment for advanced carcinoma of the gallbladder. Journal of Hepato-Biliary-Pancreatic Surgery. 2003;10(3):233-238. | CrossRef | PubMed |

Kayahara M, Nagakawa T, Nakagawara H, Kitagawa H, Ohta T. Prognostic Factors for Gallbladder Cancer in Japan. Annals of Surgery. 2008;248(5):807-814. | CrossRef | PubMed |

Meng H, Wang X, Fong Y, Wang Z, Wang Y, Zhang Z. Outcomes of Radical Surgery for Gallbladder Cancer Patients with Lymphatic Metastases. Japanese Journal of Clinical Oncology. 2011;41(8):992-998. | CrossRef | PubMed |

Lee S, Kim K, Kim W, Kim I, Nah Y, Ryu D et al. Practical Guidelines for the Surgical Treatment of Gallbladder Cancer. Journal of Korean Medical Science. 2014;29(10):1333. | CrossRef | PubMed |

Benson A, Abrams T, Ben-Josef E, Bloomston P, Botha J, Clary B et al. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw. 2009;7(4):350-391. | PubMed |

Bethesda. Gallbladder Cancer Treatment . National Cancer Institute. 2019. | Link |

Matull W, Dhar D, Ayaru L, Sandanayake N, Chapman M, Dias A et al. R0 but not R1/R2 resection is associated with better survival than palliative photodynamic therapy in biliary tract cancer. Liver International. 2010;31(1):99-107. | CrossRef | PubMed |

Amblard I, Mercier F, Bartlett D, Ahrendt S, Lee K, Zeh H et al. Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups. European Journal of Surgical Oncology. 2018;44(9):1378-1383. | CrossRef | PubMed |

Buettner S, Wilson A, Margonis G, Gani F, Ethun C, Poultsides G et al. Assessing Trends in Palliative Surgery for Extrahepatic Biliary Malignancies: A 15-Year Multicenter Study. Journal of Gastrointestinal Surgery. 2016;20(8):1444-1452. | CrossRef | PubMed |