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NCCN Flash Updates: NCCN Guidelines Updated for Hepatocellular Carcinoma and Biliary Tract Cancers

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Drugs and Biologics Compendium (NCCN Compendium^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Hepatocellular Carcinoma. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Hepatocellular Carcinoma

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.

HCC-1

• HCC Screening
  • Column 1 was extensively revised.
• Footnote b revised: Adapted with permission from Marrero JA, et al. Hepatology 2018;68:723-750. Singal AG, et al. Hepatology 2023;78:1922-1965. (Also for HCC-2)
• Footnote h revised: Schiff ER, Sorrell MF, and Maddrey WC. Schiff's Diseases of the Liver. Philadelphia: Lippincott Williams & Wilkins (LWW); 2007. Schiff ER, Maddrey WC, Reddy KR. Schiff's Diseases of the Liver, 12th ed. Wiley-Blackwell; 2017.
• Footnote i revised: Additional risk factors include HBV carrier with family history of HCC, Asian males ≥40 y, Asian females ≥50 y, and African/North American Black individuals with hepatitis B. Additional risk factors for these patients include platelet, age, and gender-HBV score ≥10, family history of HCC, man from endemic country >40 y, woman from endemic country age >50 y, and person from Africa at earlier age.
• Footnote j revised: Most clinical practice guidelines recommend US for HCC screening. US exams should be done by qualified sonographers or physicians. Liver dynamic CT or dynamic MRI may be performed as an alternative to US if US fails to detect nodules or if visualization is poor. Korean Liver Cancer Association; National Cancer Center. Gut Liver 2019;13:227-299. Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. Clin Mol Hepatol 2022;28:583-705.

HCC-2

• Footnote p revised: The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B). (Also for HCC-6, HCC-A)
• Footnote r added: Principles of Mixed HCC-CCA (HCC-C). (Also for HCC-4 through HCC-6)
• Footnote s added: Principles of Pathology (HCC-D). (Also for HCC-4 through HCC-6)

HCC-3

• Column 3
  • Top pathway revised: Potentially resectable or transplantable by tumor burden; and , operable by performance status or comorbidity (HCC-4).
  • Middle pathway revised: Liver-confined, unresectable, and deemed ineligible for transplant (HCC-5).
  • Bottom pathway revised: Metastatic disease or extensive liver tumor burden Extrahepatic/metastatic disease; and deemed ineligible for resection, transplant, or locoregional therapy (HCC-6).
  • Pathway removed: Liver-confined disease, inoperable by performance status, comorbidity, or with minimal or uncertain extrahepatic disease (HCC-6).

HCC-4

• Clinical Presentation
  • Pathway revised: Potentially resectable or transplantable by tumor burden; and operable by performance status or comorbidity.
• Surgical Assessment
  • Added subheaders: "Resection Criteria" and "Transplant Criteria".
  • Column 3,top pathway added: Met resection ± transplant criteria.
  • Column 3, bottom pathway added: Met transplant criteria only.
• Treatment
  • Top pathway revised:
    • If feasible (preferred)
    • Resection (preferred).
    • Transplant (preferred) (if met transplant criteria).
      • Refer to liver transplant center.
      • Bridge therapy as indicated.
    • Locoregional therapy
      • Ablation (preferred).
  • Bottom pathway added: If deemed ineligible for transplant, see HCC-5.

• Footnote w added: Patients should be evaluated by a multidisciplinary team.
• Footnote ee added: Adjuvant therapy with atezolizumab + bevacizumab may be considered in patients at high risk for recurrence (defined as size >5 cm, >3 tumors, macrovascular invasion or microvessel invasion on histology, or grade 3/4 histology based on the trial) on a case by case basis. Interim analysis of the phase III study of adjuvant therapy with atezolizumab + bevacizumab for 12 months in patients at high risk for recurrence after resection or ablation showed a higher rate of recurrence-free survival at 12 months compared to active surveillance, though overall survival benefit has not been established. Qin S, et al. Lancet 2023;402:1835-1847. An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
• Footnote ii revised: Consider biopsy if imaging is not consistent or to confirm imaging diagnosis if it does not meet AASLD or LIRADS-5 criteria. See Principles of Imaging (HCC-A). The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B). (Also for HCC-5)

HCC-5

• Clinical Presentation
  • Pathway revised: Liver-confined, unresectable, and deemed ineligible for transplant.
• New column 3: Response Assessment.
• Surveillance
  • Bullet 3 revised: See relevant pathway (HCC-2 through HCC-6) if disease recurs progresses.
  • Bullet 4 revised: Consider early imaging per local protocol (for locoregional therapy).

HCC-6

• Clinical Presentation
  • Pathway revised: Metastatic disease or extensive liver tumor burden Extrahepatic/metastatic disease; and deemed ineligible for resection, transplant, or locoregional therapy.
  • Column 2 revised: Consider biopsy (preferred) for histologic confirmation if not previously done.
  • Pathway removed: Liver-confined disease, inoperable by performance status, comorbidity, or with minimal or uncertain extrahepatic disease.
• New last column: Response Assessment.
• Footnote removed: Principles of Locoregional Therapy (HCC-G).
• Footnote removed: Principles of Radiation Therapy (HCC-H).

HCC-A (2 of 3)

• Imaging Protocol for Response Assessment After Treatment
  • Sentence removed: Overall nodule size does not reliably indicate treatment response since a variety of factors may cause a successfully treated lesion to appear stable in size or even larger after treatment.
• Sub-header revised: Role of FDG-PET.
  • Paragraph revised: "FDG-PET/CT has limited sensitivity but high specificity, and may be considered when there is an equivocal finding. When HCC is detected by CT or MRI and has increased metabolic activity on FDG-PET/CT..."

HCC-A (3 of 3)

• References were updated.

HCC-B

• First sentence revised: The optimal diagnostic method is core needle biopsy. Indicators for consideration of core needle biopsy may include:
• Footnote a added: Principles of Pathology (HCC-D).
• Footnote b added: Principles of Molecular Testing (HCC-H).

HCC-C

• New section added: Principles of Mixed HCC-CCA.

HCC-D

• New section added: Principles of Pathology.

HCC-E (1 of 2)

• New section: Principles of Liver Functional Assessment.

HCC-E (2 of 2)

• Header revised: Child-Pugh Score Principles of Liver Functional Assessment.
• Tables and references added for MELD Score and ALBI Grade.

HCC-F

• Header revised: Principles of Surgery Resection and Transplant.
  • Bullet 2 added: All patients should be evaluated for possible transplant candidacy with multidisciplinary review.
  • Bullet 8 revised: "...Furthermore, there are patients who are downstaged to within criteria that can also be considered for transplantation. Candidates are eligible for a standardized MELD exception if, before completing locoregional therapy, they have lesions that meet one of the following criteria: One lesion >5 cm and ≤8 cm, 2 or 3 lesions that meet all of the following: Each lesion ≤5 cm, with at least one lesion >3 cm. A total diameter of all lesions ≤8 cm, 4 or 5 lesions each <3 cm, and a total diameter of all lesions ≤8 cm. For more information, see: https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09 See Principles of Liver Functional Assessment (HCC-E).
  • Last bullet added: For appropriate patients, adjuvant therapy with atezolizumab + bevacizumab may be considered in patients at high risk for recurrence (defined as size >5 cm, >3 tumors, macrovascular invasion or microvessel invasion on histology, or grade 3/4 histology) on a case by case basis. Interim analysis of the phase III study of adjuvant therapy with atezolizumab + bevacizumab for 12 months in patients at high risk for recurrence after resection or ablation showed a higher rate of recurrence-free survival at 12 months compared to active surveillance, though overall survival benefit has not been established.
  • Bullet removed: To date, no adjuvant therapies have been shown to have benefit but there are ongoing clinical trials.
• Footnote a added: An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
• Reference 7 added: Qin S, Chen M, Cheng AL, et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023;402:1835-1847.

HCC-G (1 of 2)

• Principles of Locoregional Therapy
  • General Principles
    • Bullet 1, new last sentence: Multidisciplinary review is recommended.
  • Treatment Information, Ablation
    • Header revised: Ablation (microwave/radiofrequency, cryoablation, surgical or percutaneous ethanol alcohol injection, microwave):
    • Bullet removed: Currently, no adjuvant therapies have been shown to have added value post-ablation.
  • Treatment Information, Arterially Directed Therapies
    • Bullet 3, sub-bullet 2 revised: A dose of greater than 400 Gy to 25% of the liver or less in patients with Child-Pugh A liver function is recommended. For anatomically limited disease, radiation segmentectomy with Y90 or ablative dose stereotactic body radiation therapy (SBRT) should be considered.
    • Last bullet, sentence removed: The safety and efficacy of the use of sorafenib concomitantly with arterially directed therapies has not been associated with significant benefit in three randomized trials; other randomized phase lll trials are ongoing to investigate other systemic therapies including immunotherapy in combination with arterial therapies.

HCC-G (2 of 2)

• References were updated.

HCC-H (1 of 2)

• Principles of Radiation Therapy
  • RT dosing, SBRT sub-sub-bullet revised: 30–50 Gy (typically in 3–5 fractions) Doses ranging between 40–60 Gy (in 3–5 fractions; BED10 >100) is preferred if dose constraints can be met.

HCC-H (2 of 2)

• References were updated.

HCC-I (1 of 2)

• Principles of Systemic Therapy
  • Child-Pugh classification removed throughout.
• First-Line Systemic Therapy
  • Useful in Certain Circumstances
    • Regimens removed: Nivolumab, atezolizumab + bevacizumab, nivolumab + ipilimumab (for TMB-H tumors).
• Subsequent-Line Systemic Therapy if Disease Progression
  • Useful in Certain Circumstances
    • Regimen removed: Nivolumab + ipilimumab (for TMB-H tumors).
• Footnote a added: Order does not indicate preference.
• Footnote c revised: Caution: There are Therapies listed may have limited safety data available for patients with Child-Pugh Class B or C liver function. and dosing is uncertain. Use with extreme caution in patients with elevated bilirubin levels. Consult the prescribing information for individual agents. (Miller AA, et al. J Clin Oncol 2009;27:1800-1805). The impact of sorafenib on patients potentially eligible for transplant is unknown.
• Footnote l removed: For patients with disease refractory to standard therapies or who have no standard treatment options available.

HCC-I (2 of 2)

• References were updated.

HCC-J

• Principles of Molecular Testing
  • Bullet 2 revised: Molecular profiling in HCC: There is no established indication for routine molecular profiling in HCC, but it should be considered on a case-by-case basis. Clinical trials of molecular profiling and/or targeted therapies are encouraged in this population. Tumor molecular testing may be warranted in patients with atypical histology, cHCC-CCA histology, or unusual clinical presentations, or for clinical trial enrollment.

 

NCCN has published updates to the NCCN Guidelines, the NCCN Compendium^® , the NCCN Radiation Therapy Compendium™, and the NCCN Imaging AUC™ for Biliary Tract Cancers. These NCCN Guidelines are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Biliary Tract Cancers

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.

Gallbladder Cancer

GALL-1

• Footnote d added: Principles of Pathology (GALL-B). (Also for GALL-2 through GALL-5)
• Footnote removed: The optimal diagnostic method is core needle biopsy. (Also for GALL-2, GALL-4, GALL-5)

GALL-2

• Footnote k revised: For locoregionally advanced disease, consider neoadjuvant systemic chemotherapy to rule out rapid progression and avoid futile surgery. There are limited clinical trial data to define a standard regimen or definitive benefit. See Principles of Systemic Therapy (BIL-C). (Also for GALL-3 through GALL-5)

GALL-6

• Post-Surgical Treatment
  • Top pathway, Options
    • Fluoropyrimidine-based chemoradiation reworded as "chemoradiation". (Also for middle pathway)
  • Middle pathway, Options
    • Bullet 3: Added: Combination of chemotherapy and chemoradiation.
    • Removed: Fluoropyrimidine- or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiation.
    • Removed: Fluoropyrimidine-based chemoradiation followed by fluoropyrimidine- or gemcitabine-based chemotherapy.

GALL-A (1 of 2)

• Header revised: Principles of Surgery and Pathology
  • Incidental Finding of Suspicious Mass During Surgery
    • Last bullet added: Consider neoadjuvant systemic therapy for locoregionally advanced disease to rule out rapid progression and avoid futile surgery (biopsy required). (Also for Mass on Imaging on GALL-A 2 of 2)
  • Incidental Finding on Pathologic Review
    • Last bullet added: Consider neoadjuvant systemic therapy for locoregionally advanced disease to rule out rapid progression and avoid futile surgery. (Also for Gallbladder Cancer and Jaundice on GALL-A 2 of 2)
• Footnote a added: Principles of Pathology (GALL-B). (Also for GALL-A 2 of 2)
• Footnote removed: The optimal diagnostic method is core needle biopsy. (Also for GALL-A 2 of 2)

GALL-B

• New section: Principles of Pathology.

Intrahepatic Cholangiocarcinoma

INTRA-1

• Primary Treatment
  • Resectable
    • Bullet 3 added: Consider ablation.
  • Unresectable
    • Bullet 3: Added: Combination of chemotherapy and chemoradiation. (Also for EXTRA-1 and R1 on INTRA-2 and EXTRA-2)
    • Bullet 4: Fluoropyrimidine-based chemoradiation reworded as "chemoradiation". (Also for R1 on INTRA-2)
    • Best supportive care bullet moved to a separate pathway. (Also for Metastatic disease pathway)

• Last column, middle and bottom pathways
  • Revised: Assess for response and.
    • Reconsider resection or locoregional therapy or.
    • Subsequent-line systemic therapy if progression on or after systemic therapy.
• Footnote g added: Principles of Mixed HCC-CCA (INTRA-B).
• Footnote h added: Principles of Pathology (INTRA-C).
• Footnote l: added: Principles of Principles of Arterial/Locoregional Therapy for Intrahepatic Cholangiocarcinoma (INTRA-D).
• Footnote m added: For small single tumors <3 cm.
• Footnote q added: For a list of gemcitabine-based regimens and fluoropyrimidine-based regimens to be used before or after chemoradiation, see Adjuvant Chemotherapy (BIL-C, 1 of 5).
• Footnote removed: The optimal diagnostic method is core needle biopsy.

INTRA-2

• Post-surgical Treatment
  • R1
    • Bullet removed: Fluoropyrimidine-based or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiation. (Also for EXTRA-2)
    • Bullet removed: Fluoropyrimidine-based chemoradiation followed by fluoropyrimidine-based or gemcitabine-based chemotherapy. (Also for EXTRA-2)

INTRA-B

• New section added: Principles of Mixed HCC-CCA.

INTRA-C

• New section added: Principles of Pathology.

INTRA-D

• New section added: Principles of Arterial/Locoregional Therapy for Intrahepatic Cholangiocarcinoma.

Extrahepatic Cholangiocarcinoma

EXTRA-1

• Primary Treatment
• Unresectable
  • Bullet 4: Fluoropyrimidine-based chemoradiation reworded as "chemoradiation". (Also for R1 on EXTRA-2)
• Footnote i added: Principles of Pathology (EXTRA-B).
• Footnote removed: The optimal diagnostic method is core needle biopsy.
• Footnote o added: For a list of gemcitabine-based regimens and fluoropyrimidine-based regimens to be used before or after chemoradiation, see Adjuvant Chemotherapy (BIL-C, 1 of 5).

EXTRA-B

• New section added: Principles of Pathology.

Biliary Tract Cancers

BIL-A

• General Principles
  • Bullet 2 revised: PET/CT has limited sensitivity but high specificity and may be considered when there is an equivocal finding or on a case-by-case basis. The routine use of PET/CT in the preoperative setting has not been established in prospective trials.

BIL-B (2 of 8)

• Table 1
  • Last row added: KRAS G12C. (Also for Table 2 on BIL-B 3 of 8)

BIL-B (6 of 8)

• Other Biomarkers (RET/ROS1, KRAS G12C/Other KRAS, Other Tumor-Agnostic Markers)
  • Bullet 3 added: Recommendation: Testing for KRAS G12C mutations is recommended for patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA.

BIL-B (7 of 8 and 8 of 8)

• References were updated.

BIL-C (1 of 5)

• Principles of Systemic Therapy
  • Header revised: Neoadjuvant Therapy (for gallbladder cancer only).
  • Other Recommended Regimens
    • Bullet 1 added: See Principles of Systemic Therapy, Primary Treatment for Unresectable and Metastatic Disease (BIL-C 2 of 5).
    • Bullets removed:
      • FOLFOX (Also for adjuvant therapy).
      • Capecitabine + oxaliplatin (Also for adjuvant therapy).
      • Gemcitabine + capecitabine.
      • Gemcitabine + cisplatin (Also for adjuvant therapy).
      • Durvalumab + gemcitabine + cisplatin.
      • Gemcitabine + cisplatin + albumin-bound paclitaxel (category 2B).
  • Adjuvant Therapy
    • Other Recommended Regimens
      • Bullet removed: Capecitabine + cisplatin (category 3).
• Footnote a added: Order does not indicate preference. (Also for BIL-C 2 of 5 and BIL-C 3 of 5)

BIL-C (2 of 5)

• Primary Treatment for Unresectable and Metastatic Disease
  • Other recommended regimens, recommendation removed: Gemcitabine + cisplatin + albumin-bound paclitaxel (category 2B).
  • Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression
    • Other Recommended Regimens
      • FOLFIRI changed from a category 2B to a category 2A recommendation.
    • Useful in Certain Circumstances
      • Recommendation removed: Lenvatinib + pembrolizumab (category 2B).

BIL-C (3 of 5)

• Primary Treatment for Unresectable and Metastatic Disease
  • For RET gene fusion-positive tumors:
    • Sub-bullet 2 revised: Selpercatinib for CCA (category 2B).
• Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression
  • For HER-2 positive tumors:
    • Bullet 2: Tucatinib + trastuzumab was added as a category 2A recommendation.
  • Added For KRAS G12C mutation-positive tumors:
    • Adagrasib was added as a category 2A recommendation.

BIL-C (4 of 5 and 5 of 5)

• References were updated.

BIL-D

• Principles of Radiation Therapy
  • Section significantly revised.

 

For the complete updated versions of the NCCN Guidelines, NCCN Guidelines with NCCN Evidence Blocks™, the NCCN Drugs & Biologics Compendium (NCCN Compendium^®), the NCCN Biomarkers Compendium^®, the NCCN Chemotherapy Order Templates (NCCN Templates^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), please visit NCCN.org.

To view the NCCN Guidelines for Patients^®, please visit NCCN.org/patientguidelines.

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