Biliary Tract Cancers1 Treatment Regimens

Biliary Tract Cancers1 Treatment Regimens

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶Neoadjuvant Therapy1

REGIMEN

DOSING

Other Recommended Regimens (no preferred regimens)

Capecitabine2-4,a

Days 1-14: Capecitabine 1,250mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 8 cycles.

Capecitabine + Oxaliplatin5,a

Day 1: Oxaliplatin 100-130mg/m2 IV over 2 hours.

Days 1-14: Capecitabine 1,000mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Fluorouracil6,a,b

Days 1-5: Leucovorin 25mg/m2 IV over 2 hours daily, followed by:

Days 1-5: Fluorouracil 375mg/m2 IV push over 15 minutes daily.

Repeat cycle every 3 or 4 weeks.

Fluorouracil + Oxaliplatin7,8,a-d

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 200mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 400mg/m2 IV push over 15 minutes daily, followed by:

Days 1-2: Fluorouracil 600mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

OR

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 500mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 1500-2000mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

Gemcitabine9-12

Days 1,8,15: Gemcitabine 800-1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks (3 weeks on and 1 week off treatment).

Gemcitabine + Capecitabine13-15,a,e

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Days 1-14: Capecitabine 750mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 4 cycles.

Gemcitabine + Cisplatin9,16-18,f

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Days 1,8: Cisplatin 25-30mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks

OR

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Day 1: Cisplatin 70mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

Gemcitabine + Cisplatin + Albumin-bound Paclitaxel (Category 2B)19,20,f,g

Days 1,8: Albumin-bound Paclitaxel 100mg/m2 IV over 30 minutes.

Days 1,8: Cisplatin 25mg/m2 IV over 60 minutes.

Days 1,8: Gemcitabine 800mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

Gemcitabine + Oxaliplatin

(Category 2B)21-24

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Day 1: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 3 weeks.

OR

Days 1,8,15: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1,15: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 4 weeks.

OR

Day 1: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Day 2: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 2 weeks.

OR

Days 1,8: Gemcitabine 900mg/m2 IV over 30 minutes.

Days 1,8: Oxaliplatin 80mg/m2 IV over 2 hours.

Repeat cycle every 3 weeks.

▶Adjuvant Therapy1,25

Preferred Regimens

Capecitabine (Category 1)2-4,a

Days 1-14: Capecitabine 1,250mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 8 cycles.

Other Recommended Regimens

Capecitabine + Cisplatin (Category 3)25,26,a,f

Day 1: Cisplatin 60mg/m2 IV over 60 minutes.

Days 1-14: Capecitabine 1,250mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Capecitabine + Oxaliplatin5,a

Day 1: Oxaliplatin 100-130mg/m2 IV over 2 hours.

Days1-14: Capecitabine 1,000mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Fluorouracil6,a,b

Days 1-5: Leucovorin 25mg/m2 IV over 2 hours daily, followed by:

Days 1-5: Fluorouracil 375mg/m2 IV push over 15 minutes daily.

Repeat cycle every 3 or 4 weeks.

Fluorouracil + Oxaliplatin7,8,a-d

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 200mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 400mg/m2 IV push over 15 minutes daily, followed by:

Days 1-2: Fluorouracil 600mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

OR

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 500mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 1500-2000mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

Gemcitabine9-12

Days 1,8,15: Gemcitabine 800-1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Gemcitabine + Capecitabine13-15,a,e

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Days 1-14: Capecitabine 750mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 4 cycles.

Gemcitabine + Cisplatin9,16-18,f

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Days 1, 8: Cisplatin 25-30mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

OR

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Day 1: Cisplatin 70mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

▶Agents Used with Concurrent Radiation

Capecitabine4,15,27,a,b,h

On the days of radiation: Capecitabine 800-900mg/m2 orally twice daily.

OR

Days 1-7 (weekly cycle with concurrent radiation): Capecitabine 665mg/m2 orally twice daily.

Fluorouracil28,29,b

Days 1-3, 29-31: Fluorouracil 500mg/m2 IV push daily.

Administer for one 5-week cycle with concurrent radiation.

▶Primary Treatment for Unresectable and Metastatic Disease

Preferred Regimens

Gemcitabine + Cisplatin (Category 1)9,16-18,f

Days 1, 8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Days 1, 8: Cisplatin 25-30mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

OR

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Day 1: Cisplatin 70mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

Other Recommended Regimens

Capecitabine2-4,a

Days 1-14: Capecitabine 1,000mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Capecitabine + Cisplatin (Category 2B)26,a,f

Day 1: Cisplatin 60mg/m2 IV over 60 minutes.

Days 1-14: Capecitabine 1,250mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Capecitabine + Oxaliplatin5,a

Day 1: Oxaliplatin 100-130mg/m2 IV over 2 hours.

Days 1-14: Capecitabine 1,000mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Fluorouracil6,a,b

Days 1-5: Leucovorin 25mg/m2 IV over 2 hours daily, followed by;

Days 1-5: Fluorouracil 375mg/m2 IV push over 15 minutes daily.

Repeat cycle every 3 or 4 weeks.

Fluorouracil + Cisplatin (Category 2B)30,31,a,b,d,f

Days 1,4: Cisplatin 3-6mg/m2 IV over 30 minutes

Days 1-7: Fluorouracil 160mg/m2 IV continuous infusion over 24 hours daily (1,120mg/m2 IV over 1 week).

Repeat cycle every week.

OR

Days 1, 15, 29: Cisplatin 50mg/m2 IV over 60 minutes

Days 1,8,15,22,29,36: Leucovorin 500mg/m2 IV over 2 hours, followed by:

Days 1,8,15,22,29,36: Fluorouracil 2,000mg/m2 IV over 24 hours.

Repeat cycle every 7 weeks (6 weeks on followed by 1 week off treatment).

Fluorouracil + Oxaliplatin7,8,a-d

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 200mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 400mg/m2 IV push over 15 minutes daily, followed by:

Days 1-2: Fluorouracil 600mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

OR

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 500mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 1500-2000mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

Gemcitabine9-12

Days 1,8,15: Gemcitabine 800-1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Gemcitabine + Albumin-bound Paclitaxel32,g

Days 1,8,15: 125mg/m2 IV over 30 minutes.

Days 1,8,15: 1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Gemcitabine + Capecitabine13-15,a,e

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-14: Capecitabine 650mg/m2 orally twice daily

Repeat cycle every 3 weeks.

Gemcitabine + Cisplatin + Albumin-bound Paclitaxel (Category 2B)19,20,f,g

Days 1,8: Albumin-bound Paclitaxel 100mg/m2 IV over 30 minutes.

Days 1,8: Cisplatin 25mg/m2 IV over 60 minutes.

Days 1,8: Gemcitabine 800mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

Gemcitabine + Oxaliplatin21-24

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Day 1: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 3 weeks.

OR

Days 1,8,15: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Days 1,15: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 4 weeks.

OR

Day 1: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Day 2: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 2 weeks.

OR

Days 1,8: Gemcitabine 900mg/m2 IV over 30 minutes.

Days 1,8: Oxaliplatin 80mg/m2 IV over 2 hours.

Repeat cycle every 3 weeks.

Useful in Certain Circumstances

Entrectinib (NTRK gene fusion-positive tumors)33-36

Days 1-28: Entrectinib 600mg orally once daily.

Repeat cycle every 4 weeks.

Larotrectinib (NTRK gene fusion-positive tumors)37,38

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Pembrolizumab (MSI-H/MMR tumors)39-46,i,j

Day 1: Pembrolizumab 200mg IV over 30 minutes

Repeat cycle every 3 weeks for up to 2 years.

OR

Day 1: Pembrolizumab 400mg IV over 30 minutes

Repeat cycle every 6 weeks for up to 2 years.

▶Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progressionk,l

Preferred Regimens

FOLFOX7,8,47,a-d

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 200mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 400mg/m2 IV push over 15 minutes daily, followed by:

Days 1-2: Fluorouracil 600mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

OR

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Days 1-2: Leucovorin 500mg/m2 IV over 2 hours daily, followed by:

Days 1-2: Fluorouracil 1500-2000mg/m2 IV continuous infusion over 22 hours daily.

Repeat cycle every 2 weeks.

Other Recommended Regimens

FOLFIRI (Category 2B)48-50,a,b,d,m

Day 1: Irinotecan 180mg/m2 IV over 30-90 minutes, with:

Day 1: Leucovorin 400mg/m2 IV over 30-90 minutes, followed by:

Day 1: Fluorouracil 400mg/m2 IV push, followed by:

Days 1,2: Fluorouracil 1,200mg/m2 IV continuous infusion daily (2,400mg/m2 IV over 46-48 hours).

Repeat cycle every 2 weeks.

Regorafenib (Category 2B)51,52

Days 1-21: Regorafenib 120mg orally once daily.

Repeat cycle every 4 weeks.

Useful in Certain Circumstancesm

Dabrafenib + Trametinib (BRAF-V600E mutated tumors)53-56

Days 1-28: Dabrafenib 150mg orally twice daily.

Days 1-28: Trametinib 2mg orally once daily.

Repeat cycle every 4 weeks.

Entrectinib (NTRK gene fusion-positive tumors)33-36

Days 1-28: Entrectinib 600mg orally once daily.

Repeat cycle every 4 weeks.

Infigratinib (for cholangiocarcinoma with FGFR2 fusions or rearrangements)57,58

Days 1-21: Infigratinib 125mg orally once daily.

Repeat cycle every 4 weeks.

Ivosidenib (for cholangiocarcinoma with IDH1 mutations)59,60,n

Days 1-28: Ivosidenib 500mg orally once daily.

Repeat cycle every 4 weeks.

Larotrectinib (NTRK gene fusion-positive tumors)37,38

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Lenvatinib + Pembrolizumab (Category 2B)61,62

Days 1-21: Lenvatinib 20mg orally once daily.

Days 1-21: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 3 weeks up to 2 years.

Nivolumab (Category 2B)63,64

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 2 weeks for 16 weeks, followed by:

Day 1 (Week 16): Nivolumab 480mg IV over 30 minutes.

Repeat cycle every 4 weeks.

Pembrolizumab (MSI-H/MMR tumors/TMB-H tumors)39-46,i,j

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 3 weeks up to 2 years.

OR

Day 1: Pembrolizumab 400mg IV over 30 minutes

Repeat cycle every 6 weeks up to 2 years.

Pemigatinib (for cholangiocarcinoma with FGFR2 fusions or rearrangements)65,66,n

Days 1-14: Pemigatinib 13.5mg orally once daily.

Repeat cycle every 3 weeks.

  a Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are unable to metabolize Capecitabine or Fluorouracil normally and may have severe unexpected toxicity.

  b The dose listed above is based on racemic leucovorin product. LEVOleucovorin is not interchangeable, and the product doses are not equivalent.

  c Leucovorin infusion time should match the infusion time of Oxaliplatin when these agents are given concurrently.

  d Fluorouracil IV requires a central venous access device for administration in this regimen.

  e Given before concurrent chemotherapy/radiation (Capecitabine/radiation).

  f Hydration is required with supplemental electrolytes pre- and post-administration of Cisplatin.

  g Albumin-bound PACLitaxel may have altered functional properties relative to standard PACLitaxel. Do not substitute for or with other PACLitaxel formulations. Product doses are not equivalent.

  h Given after 4 cycles of chemotherapy with Gemcitabine/Capecitabine.

  i MSI-H/MMR = Microsatellite instability high/mismatch repair deficient; TMB-H = Tumor mutational burden-high.

  j There are limited clinical trial data to support pembrolizumab in this setting.

  k See also: Preferred and Other Recommended Regimens for Unresectable and Metastatic Disease above.

  l Treatment selection depends on clinical factors including previous treatment regimen/agent and extent of liver dysfunction.

  m Patients who are homozygous for the UGT1A1*28 allele or who have a clinical diagnosis of Gilbert’s Syndrome have an increased risk of neutropenia when started on irinotecan, possibly due to a decreased level of glucuronidation of the active metabolite of irinotecan, resulting in its accumulation.

  n Do not administer with a high fat meal.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V3.2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed June 23, 2021.

2. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663-673.

3. Patt YZ, Hassan MM, Aguayo A, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004;101(3):578-586.

4. Capecitabine (Xeloda) [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2021.

5. Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer. 2008;98(2):309- 315.

6. Choi CW, Choi IK, Seo JH, et al. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol. 2000;23(4):425-428.

7. Qin S, Bai Y, Thongprasert S, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013;31(28):3501-3508.

8. Nehls O, Klump B, Arkenau HT, et al. Oxaliplatin, fluorouracil and leucovorin for advanced biliary system adenocarcinomas: a prospective phase II trial. Br J Cancer. 2002;87(7):702-704.

9. Valle J, Wasan H, Palmet DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281.

10. Tsavaris N, Kosmas C, Gouveris P, et al. Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs. 2004;22(2):193-198.

11. Gallardo JO, Rubio B, Fodor M, et al. A phase II study of gemcitabine in gallbladder carcinoma. Ann Oncol. 2001;12(10):1403-1406.

12. Gemcitabine (Gemzar) [package insert]. Indianapolis, IN: Lilly USA, LLC; 2019.

13. Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol. 2005;23(10):2332- 2338.

14. Riechelmann RP, Townsley CA, Chin SN, et al. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer. 2007;110(6):1307-1312.

15. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. J Clin Oncol. 2015;33(24):2617-2622.

16. Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer. 2010;103(4):469-474.

17. Meyerhardt JA, Zhu AX, Stuart K, et al. Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer. Dig Dis Sci. 2008;53(2):564-570.

18. Doval DC, Sekhon JS, Gupta SK, et al. A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer. 2004;90(8): 1516-1520.

19. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5:824-830.

20. Albumin-bound Palitaxel (Abraxane) [package insert]. Summit, NJ: Celgene Corporation; 2020

21. Verderame F, Russo A, Di Leo R, et al. Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers. Ann Oncol. 2006;17 Suppl 7:vii68-72.

22. Harder J, Riecken B, Kummer O, et al. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer. 2006;95(7):848-852.

23. André T, Reyes-Vidal JM, Fartoux L, et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer. 2008;99(6):862-867.

24. Sharma A, Dwary AD, Mohanti BK, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol. 2010;28(30):4581-4586.

25. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systemic review and meta-analysis. J Clin Oncol. 2012;30:1934-1940.

26. Hong YS, Lee J, Lee SC, et al. Phase II study of capecitabine and cisplatin in previously untreated advanced biliary tract cancer. Cancer Chemother Pharmacol. 2007;60(3):321-328.

27. Das P, Wolff RA, Abbruzzesse JL, et al. Concurrent capecitabine and upper abdominal radiation therapy is well tolerated. Radiat Oncol. 2006;1:41.

28. Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys. 2002;52(1):167-175.

29. Czito BG, Hurwitz HI, Clough RW, et al. Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys. 2005;62(4):1030-1034.

30. Kobayashi K, Tsuji A, Morita S, et al. A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma. BMC Cancer. 2006;6:121.

31. Ducreux M, Cutsem EV, Van Laethem JL, et al. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial. Eur J Cancer. 2005;41(3):398-403.

32. Sahai V, Catalano PJ, Zalupski MM, et al. Nab-paclitaxel and gemcitabine as first-line treatment of advanced or metastatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2018;4(12):1707- 1712.

33. Demetri GD, Paz-Ares LG, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. ESMO Congress 2018.

34. Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: Combined results from two phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7:400-409.

35. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21:271-282.

36. Entrectinib (Rozlytrek) [package insert]. South San Francisco, CA: Genentech, Inc.; 2019.

37. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731-739.

38. Larotrectinib (Vitrakvi) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2021.

39. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-413.

40. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940- 952.

41. Sicklick JK, Kato S, Okamura R, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med. 2019;25:744-750.

42. Piha-Paul SA, Oh DY, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020;147(8):2190-2198.

43. Lala M, Li T, De Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020;131:68-75.

44. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10.

45. Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer. 2020;8(1).

46. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2021.

47. Lamarca A, Palmer DH, Wasan HS, et al. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/ gemcitabine (CisGem) chemotherapy [abstract]. J Clin Oncol. 2019; 37(Suppl 15): Abstract 4003.

48. Caparica R, Lengele A, Bekolo W, Hendlisz A. FOLFIRI as second-line treatment of metastatic biliary tract cancer patients. Autopsy Case Rep. 2019;9:e2019087.

49. Mizrahi JD , Gunchick V, Mody K, et al. FOLFIRI as second-line treatment of metastatic biliary tract cancer patients. World J Gastrointest Oncol. 2020;12(1):83-91.

50. Irinotecan (Camptosar) [package insert]. New York, NY: Pfizer Inc.; 2020.

51. Sun W, Patel A, Normolle D, et al. A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory, advanced, and metastatic biliary tract adenocarcinoma. Cancer. 2019;125:902-909.

52. Regorafenib (Stivarga) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2020.

53. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020;21:1234-1243.

54. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAF-V600E mutations: Results of the NCI-MATCH trial subprotocol H. J Clin Oncol. 2020;38:3895-3904.

55. Dabrafenib (Tafinlar) [package insert] East Hanover. NJ: Novartis Pharmaceutical Corporation; 2020.

56. Trametinib (Mekinist) [package insert] East Hanover. NJ: Novartis Pharmaceutical Corporation; 2020.

57. Javle M, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement [abstract]. J Clin Oncol. 2021;39:Abstract AB051.

58. Infigratinib (Truseltiq) [package insert]. Brisbane, CA: QED Therapeutics, Inc.; 2021.

59. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796-807.

60. Ivosidenib (Tibsovo) [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc.; 2019.

61. Lwin, Z, Gomez-Roca, C, Saada-Bouzid E, et al. LEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumors [abstract]. Ann. Oncol. 2020;31: Abstract LBA41.

62. Lenvatinib (Lenvima) [package insert] Woodcliff Lake, NJ: Eisai Inc.; 2021.

63. Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 2020;6: 888-894.

64. Nivolumab (Opdivo) [package insert] Princeton. NJ: Bristol-Myers Squibb Company; 2021.

65. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671-684.

66. Pemigatinib (Pemazyre) [package insert]. Wilmington, DE: Incyte Corporation; 2021.

(Revised 7/2021; NCCN Hepatobiliary Cancers Guidelines v3.2021) © 2021 by Haymarket Media, Inc.

Topics:

Gastrointestinal Cancer Treatment Regimens