Modification and Implementation of NCCN Guidelines™ on Hepatobiliary Cancers in the Middle East and North Africa Region

Authors: Muhammed Aasim Yusuf FRCP Edina, Vinay Kumar Kapoor MS, FRCSa, Refaat Refaat Kamel FRCSa, Ather Kazmi MRCP, FRCRa, Najam Uddin FRCRa, Nehal Masood MDa, and Abdulmajeed Al-Abdulkareem MD, FRCSC, FACSa
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  • a From the Department of Gastroenterology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; Surgical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; Hepatobiliary Surgery & Liver Transplantation, Ein Shams University, Cairo, Egypt; Clinical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; Interventional Radiology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; Medical Oncology, Aga Khan University Hospital, Karachi, Pakistan; and Department of Hepatobiliary Sciences and Liver Transplantation, King Abdul Aziz Medical City, King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Hepatobiliary Cancers address hepatocellular cancer, cancer of the gallbladder, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma. Hepatocellular cancer incidence is higher in the Middle East and North Africa (MENA) region than in the West, and hepatitis B and C infections are particularly important; the incidence of gallbladder cancer is among the highest in the world. Regional problems include delay in diagnosis, shortage of trained staff, and insufficient liver transplant facilities. Furthermore, costs associated with molecular and targeted therapies are an increasing concern. A committee was formed, consisting of leading specialists and decision-makers from the region, with each member being tasked to suggest modifications to the existing guidelines based on review of the literature and consultations with local colleagues. This committee met as a group, and then continued to discuss and debate the suggested modifications electronically. Several recommendations were finalized after vigorous debate. The final approved recommendations were then presented in April 2009 to the chair of the NCCN Hepatobiliary Cancers Panel for onward transmission and approval. This project represents an effort to modify and implement the NCCN Guidelines on Hepatobiliary Cancers in the MENA region, while taking into consideration local differences in patient and disease characteristics. The hope is that this will form the basis of future local, regional, and international cooperation in guideline development and research.

The 2009 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Hepatobiliary Cancers (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org) addresses 4 main tumor groups: hepatocellular cancer, cancer of the gallbladder, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma.

The incidence of hepatocellular cancer seems to be significantly higher in the Middle East and North Africa (MENA) region than in the West. The age-standardized incidence rate is 12.8 per 100,000 population in Egypt,1 8 per 100,000 in Pakistan,2 and 4.2 per 100,000 in Saudi Arabia,3 compared with 2.5 per 100,000 in the United States.4

The region also shares some unique regional risk factors. Hepatitis B and C infections seem to be particularly important. A predominance of hepatitis B virus surface antigen is seen in patients with hepatocellular cancer from most Asian, African, and Latin American countries; hepatitis C predominates in Japan, Pakistan, Mongolia, and Egypt.5

Although the MENA region is not homogeneous, most countries represented in the committee have some common issues, albeit to a variable extent. These include delay in diagnosis, often from an absence of screening programs in those infected with hepatitis B or C, and a shortage of trained staff required for diagnosis and treatment, including gastroenterologists/hepatologists, radiologists, hepatobiliary surgeons, and oncologists. Furthermore, insufficient or, in some cases, nonexistent liver transplant facilities are a serious limitation to treatment for some patients. Pakistan, with a population of more than 170 million, has no liver transplant program. India has 3 centers, performing a total of 550 transplants annually. Egypt has 10 centers, with 150 to 200 transplants performed per year, whereas Saudi Arabia has 3 centers, performing 120 transplants annually.

The costs associated with diagnosis and treatment are an increasing concern in an age of molecular and targeted therapies. Sorafenib for treating hepatocellular carcinoma, for example, is too expensive to be used by most eligible patients in many countries. It is currently recommended primarily in patients with Child's A disease, precluding its use in most patients in the MENA region. Additionally, the modest benefit in survival improvement means that both patients and physicians question the cost/benefit analysis.

Shortage of trained staff is a major problem in many countries in the region. Interventional radiologists are a rare species in many countries. Currently, only 4 centers in Pakistan offer transarterial chemoembolization, with each performing fewer than 500 procedures per year, for an estimated 15,000 new cases per year. A dearth of surgical expertise for liver resection and transplantation exists across the region.

Therefore, numerous challenges exist in the region. A large number of patients have hepatitis B and C infections, suggesting a huge tumor load in the future. Patients present at an advanced stage, with poor background liver function in up to half, thus precluding many treatment options. A culture of cooperation between different specialties is often lacking, with multidisciplinary care the exception rather than the norm. This results in squandering of research opportunities and lack of progress at the local, national, and regional levels.

Typical Journey of a Patient With Hepatocellular Carcinoma in Pakistan

Abdominal pain leads to investigation, and usually the discovery of hepatitis C infection. Abdominal imaging, usually with ultrasonography, leads to the finding of a mass or masses in the liver. Most patients will have access to biphasic CT scanning, usually at a referral center or in the private sector. However, up to 85% may be unsuitable for treatment based on extent of disease or poor liver function. The remainder are offered various treatments, but cost issues often limit patient acceptance, especially for sorafenib, which only 1 in 8 patients will accept at Shaukat Khanum Memorial Cancer Hospital in Lahore.

In a single-center experience in Pakistan,2 586 patients were diagnosed with hepatocellular cancer over a 10-year period. Most presented with large, multifocal tumors (mean cross-sectional diameter, 8 cm). Background liver function, assessed according to Child-Pugh status, was poor (B to C) in 46%. Median survival after diagnosis was 10.5 months, with 1-, 3-, and 5-year survival rates of 45%, 20%, and 10%, respectively (Figure 1).

Regarding gall bladder cancer, the highest incidence rates worldwide were reported for women in Delhi, India (21.5/100,000); South Karachi, Pakistan (13.8/100,000); and Quito, Ecuador (12.9/100,000).6 Risk factors for gallbladder cancer include gallstones, particularly those associated with chronic cholecystitis; calcified (porcelain) gallbladder; gallbladder polyps; typhoid carrier; obesity; multiparity; and chronic infection with Helicobacter bilis and H pylori.6,7 Gallstone disease has been shown to start at a younger age in Northern India and Kashmir.8 Decreasing biliary tract cancer mortality worldwide reflects more widespread and earlier adoption of cholecystectomy. However, in many high-risk areas, including Pakistan and India, access to gallbladder surgery remains patchy and inadequate.9

Methods

After the successful development of regional NCCN guidelines for Korea and China, a committee was formulated in November 2008 to begin developing regional guidelines for the MENA region. The committee also had major representation from South Asia. The initial group consisted of the various committee chairs. Each committee chair then began identifying and inviting leading specialists and decision-makers from the region to participate. Each member was asked to suggest modifications to the existing guidelines, based on review of the literature and after consultations with local colleagues. The committee met in Dubai in January 2009 to discuss and debate the various suggested modifications. Further modifications followed, with most discussion and changes occurring by email. All members were required to provide references from the literature for any modifications to be approved. The committee then met again, on the sidelines of the NCCN–MENA meeting in Abu Dhabi in April 2009, to finalize the presentation and recommendations. These were then presented to the chair of the NCCN Hepatobiliary Cancers Panel for onward transmission and approval.

Figure 1
Figure 1

Overall survival of patients with hepatocellular carcinoma.

From Yusuf MA, Badar F, Meerza F, et al. Survival from hepatocellular carcinoma at a cancer hospital in Pakistan. Asian Pac J Cancer Prev 2007;8:273; with permission.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, Suppl_3; 10.6004/jnccn.2010.0123

Recommended Modifications

Table of Contents

The committee suggested adding “The NCCN believes that all cancer patients should be managed by a multidisciplinary team, and preferably in a specialist center.”

Hepatocellular Carcinoma

Screening: The committee suggested modifying footnote “b” to read “Imaging of those with elevated AFP [alpha-fetoprotein] should be with CT/MR, and not with ultrasound scan [USS]. If CT/MR is normal, then follow-up imaging will be with USS.”10 This recommendation was made because contrast-enhanced ultrasound scan is not widely available in the MENA region.

Diagnosis: The committee suggested amending “biopsy” to read “FNAC/biopsy” and adding a footnote stating that “FNAC appropriate if cytopathology expertise available.” The rationale for this recommendation is that fine-needle aspiration (FNA) may be easier and safer and requires less monitoring. Furthermore, it may be associated with fewer complications and is often less expensive than liver biopsy.

Workup: The committee recommended amending footnote “g” to read “assess liver reserve using combination of Child-Pugh score, estimation of residual liver volume, and assessment of portal hypertension (e.g., varices, splenomegaly, thrombocytopenia, and measurement of portal vein pressure, where available).”1012 The committee believed that these additional modalities helped to more appropriately select patients who would be suitable for surgery, particularly resection.

The committee also suggested adding a footnote after “AFP” stating “AFP > 1000 is suggestive of microvascular invasion in tumors > 5 cm. These patients are not suitable for transplantation.”13

Surgical Assessment: The committee suggested replacing “Child's A, B” with “Child's A” because they believed that this was more in agreement with the American Association for the Study of Liver Disease (AASLD) guidelines, which state that “Patients who have a single lesion can be offered surgical resection if they are noncirrhotic or have cirrhosis but still have well-preserved liver function, normal bilirubin, and hepatic vein pressure gradient < 10 mm Hg.”10 The committee believed that those with poorer liver function (i.e., patients with Child's B) probably should be considered for transplantation rather than resection.

For transplant candidates, the committee suggested adding a footnote stating “Ablation techniques can be considered in selected patients waiting for a transplant, especially when the waiting time is more than 6 months.”10,14 The committee also suggested adding a footnote stating “Patients originally deemed unsuitable for transplant may be reconsidered for transplant after ablative therapies.”15

Unresectable Clinical Presentation: The committee recommended changing footnote “r,” dealing with the use of sorafenib, from “There are limited safety data available for patients with Child-Pugh class B. Use with extreme caution in patients with elevated bilirubin levels” to read “There are limited safety data available for patients with Child-Pugh class B and dosing is uncertain. Extreme caution is required and participation in clinical trials is recommended.” The committee members believed that data were insufficient to recommend anything more than this.

Gallbladder

For workup of jaundiced patients, the committee suggested changing “cholangiography” to “ERCP/PTC + biliary drainage (+ biopsy if possible) if obstruction confirmed.” The committee members believed that magnetic resonance cholangiopancreatography was less likely to be useful in jaundiced patients, because many or most would also require a biliary drainage procedure.

The committee also believed that “biliary drainage” should be removed from the primary treatment column, because this should be performed normally during the diagnostic workup.

Intrahepatic Cholangiocarcinoma

Although not disagreeing with resection as a possible treatment for intrahepatic cholangiocarcinoma, the committee believed it important to add a footnote stating that “There is no level 1 data with regard to the value of hepatic resection in this situation.”

Extrahepatic Cholangiocarcinoma

In workup, the committee suggested changing “cholangiography” to “ERCP/PTC + biliary drainage (+ biopsy if possible) if obstruction confirmed.” The committee also believed that “biliary drainage” should be removed from the primary treatment column, because this should be performed normally during the diagnostic workup.

For “Resected, negative margin (R0), negative regional nodes,” the committee recommended removing the chemotherapy option because they believed the benefit of adjuvant chemotherapy remains unproven, and the only randomized trial examining this did not show any benefit in treating cholangiocarcinoma.16 The committee also recommended that the chemotherapy + radiation therapy (XRT) option be removed because of conflicting data regarding adjuvant chemoradiation. No randomized trials specifically address this treatment, and most retrospective series consisted of a mix of R0 and R1 tumors. No clear evidence shows that adjuvant chemoradiation “improves” outcomes in patients with R0 cancers. The committee believed it reasonable to leave “Observe or clinical trial” as the only 2 available options.

Conclusions

This initiative represents the first effort in the MENA region to implement transnational guidelines, with content based on the NCCN guidelines but modified to take into consideration local differences in patient and disease characteristics. Every effort was made to recommend modifications based on the literature or, at the minimum, best practice in the region, and backed by expert opinion. This project could form the basis of future cooperation, not only in guideline development and modification, but also in research. It became painfully obvious to all involved in this effort that little local research data was available on which to base suggested modifications. This finding highlighted the need for regional cooperation and the development of research protocols to study these common diseases in the MENA region. Great disparity exists within the MENA region in terms of patients and resources, but many similarities are also present. The committee members hope to revisit this subject at regular intervals, and look forward to when all cancer care in this region follows treatment guidelines derived from robust local data.

The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

The following also contributed to the process of guideline formulation and revision, as members of the NCCN–MENA Hepatobiliary Guidelines Review Committee: Khalid Omer Abdullah, King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia; Hassan Jaafar, Tawam Hospital, Al-Ain, United Arab Emirates; Kakil Ibrahim Rasul, Hamad Medical Corporation, Doha, Qatar; Suayib Yalcin, Hacettepe University Institute of Oncology, Ankara, Turkey; and Abdel-Rahman El-Zayadi, Ain Shams University, Cairo, Egypt.

References

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    • Search Google Scholar
    • Export Citation
  • 2.

    Yusuf MA, Badar F, Meerza F et al.. Survival from hepatocellular carcinoma at a cancer hospital in Pakistan. Asian Pac J Cancer Prev 2007;8:272274.

    • Search Google Scholar
    • Export Citation
  • 3.

    Kindgom of Saudi Arabia Ministry of Health National Cancer Registry. Cancer incidence report Saudi Arabia 2003. Available at: http://www.kfshrc.edu.sa/oncology/files/NCR2003.pdf. Accessed March 31, 2010.

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    • Export Citation
  • 4.

    Carr BI, ed. Hepatocellular cancer: diagnosis and treatment. Totowa (NJ): Humana Press; 2005.

  • 5.

    Raza SA, Clifford GM, Franceschi S. Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review. Br J Cancer 2007;96:11271134.

    • Search Google Scholar
    • Export Citation
  • 6.

    Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006;118:15911602.

    • Search Google Scholar
    • Export Citation
  • 7.

    Kapoor VK, McMichael AJ. Gallbladder cancer: an `Indian' disease. Natl Med J India 2003;16:209213.

  • 8.

    Khuroo MS, Mahajan R, Zargar SA et al.. Prevalence of biliary tract disease in India: a sonographic study in adult population in Kashmir. Gut 1989;30:201205.

    • Search Google Scholar
    • Export Citation
  • 9.

    Randi G, Malvezzi M, Levi F et al.. Epidemiology of biliary tract cancers: an update. Ann Oncol 2009;20:146159.

  • 10.

    Bruix J, Sherman M. AASLD practice guideline: management of hepatocellular carcinoma. Hepatology 2005;42:12081236.

  • 11.

    Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:14341440.

    • Search Google Scholar
    • Export Citation
  • 12.

    Bruix J, Castells A, Bosch J et al.. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:10181022.

    • Search Google Scholar
    • Export Citation
  • 13.

    Pawlik TM, Delman KA, Vauthey JN et al.. Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl 2005;11:10861092.

    • Search Google Scholar
    • Export Citation
  • 14.

    Llovet JM, Mas X, Aponte JJ et al.. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123128.

    • Search Google Scholar
    • Export Citation
  • 15.

    Yao FY, Kerlan RK Jr, Hirose R et al.. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008;48:819827.

    • Search Google Scholar
    • Export Citation
  • 16.

    Takada T, Amano H, Yasuda H et al.. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreatobiliary carcinoma. Cancer 2002;95:16851695.

    • Search Google Scholar
    • Export Citation

Correspondence: Muhammed Aasim Yusuf, FRCP Edin, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. E-mail: aasim@skm.org.pk
  • View in gallery

    Overall survival of patients with hepatocellular carcinoma.

    From Yusuf MA, Badar F, Meerza F, et al. Survival from hepatocellular carcinoma at a cancer hospital in Pakistan. Asian Pac J Cancer Prev 2007;8:273; with permission.

  • 1.

    Ibrahim AS. Liver and intrahepatic bile duct cancer. Available at: http://seer.cancer.gov/publications/mecc/mecc_liver.pdf. Accessed March 31, 2010.

    • Search Google Scholar
    • Export Citation
  • 2.

    Yusuf MA, Badar F, Meerza F et al.. Survival from hepatocellular carcinoma at a cancer hospital in Pakistan. Asian Pac J Cancer Prev 2007;8:272274.

    • Search Google Scholar
    • Export Citation
  • 3.

    Kindgom of Saudi Arabia Ministry of Health National Cancer Registry. Cancer incidence report Saudi Arabia 2003. Available at: http://www.kfshrc.edu.sa/oncology/files/NCR2003.pdf. Accessed March 31, 2010.

    • Search Google Scholar
    • Export Citation
  • 4.

    Carr BI, ed. Hepatocellular cancer: diagnosis and treatment. Totowa (NJ): Humana Press; 2005.

  • 5.

    Raza SA, Clifford GM, Franceschi S. Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review. Br J Cancer 2007;96:11271134.

    • Search Google Scholar
    • Export Citation
  • 6.

    Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006;118:15911602.

    • Search Google Scholar
    • Export Citation
  • 7.

    Kapoor VK, McMichael AJ. Gallbladder cancer: an `Indian' disease. Natl Med J India 2003;16:209213.

  • 8.

    Khuroo MS, Mahajan R, Zargar SA et al.. Prevalence of biliary tract disease in India: a sonographic study in adult population in Kashmir. Gut 1989;30:201205.

    • Search Google Scholar
    • Export Citation
  • 9.

    Randi G, Malvezzi M, Levi F et al.. Epidemiology of biliary tract cancers: an update. Ann Oncol 2009;20:146159.

  • 10.

    Bruix J, Sherman M. AASLD practice guideline: management of hepatocellular carcinoma. Hepatology 2005;42:12081236.

  • 11.

    Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:14341440.

    • Search Google Scholar
    • Export Citation
  • 12.

    Bruix J, Castells A, Bosch J et al.. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:10181022.

    • Search Google Scholar
    • Export Citation
  • 13.

    Pawlik TM, Delman KA, Vauthey JN et al.. Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl 2005;11:10861092.

    • Search Google Scholar
    • Export Citation
  • 14.

    Llovet JM, Mas X, Aponte JJ et al.. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123128.

    • Search Google Scholar
    • Export Citation
  • 15.

    Yao FY, Kerlan RK Jr, Hirose R et al.. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008;48:819827.

    • Search Google Scholar
    • Export Citation
  • 16.

    Takada T, Amano H, Yasuda H et al.. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreatobiliary carcinoma. Cancer 2002;95:16851695.

    • Search Google Scholar
    • Export Citation
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