HIMALAYA Phase III trial exploratory results support the benefit of tremelimumab added to IMFINZIin unresectable liver cancer regardless of etiology
WILMINGTON, Del. -- (Business Wire)
Updated results from the TOPAZ-1 Phase III trial showed AstraZeneca's IMFINZI(TM) (durvalumab), in combination with standard-of-care chemotherapy demonstrated a clinically meaningful and durable overall survival (OS) benefit as a treatment for patients with advanced biliary tract cancer (BTC).
These results from TOPAZ-1, the first Phase III trial to show improved OS with an immunotherapy combination in this setting, will be presented today at the European Society for Medical Oncology (ESMO) Congress 2022 in Paris (abstract #56P).
The updated results for IMFINZI plus chemotherapy (gemcitabine plus cisplatin) showed enhanced clinical efficacy after an additional 6.5 months of follow-up, demonstrating a 24% reduction in the risk of death versus chemotherapy alone (based on an HR of 0.76; 95% CI, 0.64-0.91). Updated median OS was 12.9 months versus 11.3 with chemotherapy. More than two times as many patients were estimated to be alive at two years versus chemotherapy alone (23.6% versus 11.5%). Results were seen across all prespecified subgroups, regardless of disease status, tumor location or PD-L1 expression. In addition, OS benefit was observed in patients whose tumors stayed the same size (stable disease) as well as in patients whose tumors got smaller or disappeared (responders).
The safety profile of IMFINZI plus chemotherapy continued to be well-tolerated, with no new safety signals observed with longer follow-up. Grade 3 or 4 treatment-related AEs were experienced by 60.9% of patients treated with IMFINZI and chemotherapy, and by 63.5% of patients receiving chemotherapy alone. IMFINZI plus chemotherapy did not increase the discontinuation rate due to adverse events (AEs) compared to chemotherapy alone (8.9% for the IMFINZI combination versus 11.4% for chemotherapy).
Do-Youn Oh, MD, PhD, Professor, Division of Medical Oncology, Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine, and principal investigator in the TOPAZ-1 Phase III trial, said: "It's exciting to see the improved overall survival delivered by durvalumab plus chemotherapy over the current standard of care for patients with advanced biliary tract cancer after a median follow-up of nearly two years. With limited treatment advances over the past decade, these patients have long faced a dismal prognosis. For the first time, an immunotherapy-based combination has shown the ability to alter the course of treatment for this disease and should become the new standard of care."
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These longer-term data reinforce the survival benefit and well-tolerated safety profile of IMFINZI added to standard-of-care chemotherapy for patients with advanced biliary tract cancer. With these results, the exploratory data from the HIMALAYA trial and the recent FDA approval based on the TOPAZ-1 trial, we are continuing to advance our commitment to extend survival for patients with gastrointestinal tumors who desperately need new treatment options."
Summary of updated results: TOPAZ-1
IMFINZI+ chemotherapy (N=341)
Median OS (95% CI) (in months)
HR (95% CI)iii
0.76 (0.64, 0.91)
OS rate at 12 months (95% CI) (%)iv
OS rate at 24 months (95% CI) (%)
OS by BoRv,vi
Median OS (95% CI), responders, months
HR (95% CI) respondersiii
0.69 (0.46, 1.04)
Median OS (95% CI), stable disease (SD), months
HR (95% CI) SDiii
0.77 (0.62, 0.96)
12-month OS rate in responders (95% CI) (%)iv
12-month OS rate in SD (95% CI) (%)iv
24-month OS rate in responders (95% CI) (%)iv
24-month OS rate in SD (95% CI) (%)iv
6.5 months of additional follow-up (data cut-off: 25 February 2022) after the primary analysis, with 76.9% overall OS event maturity
At data cut-off for this analysis, median (95% CI) follow-up time (calculated using the inverse Kaplan-Meier techniques with the censoring indicator of OS reversed) was 23.4 (20.6-25.2) months for IMFINZIplus chemotherapy and 22.4 (21.4-23.8) months for chemotherapy
HRs were calculated using a Cox proportional hazards model.
OS rates calculated using Kaplan-Meier techniques
To avoid immortal time bias, only participants surviving >= 3 months were included in this OS by best objective response analysis
BoR was assessed by the investigator per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 in all randomized participants with measurable disease at baseline and defined as response (complete response or partial response), SD or progressive disease (PD); BoR was determined based on the IA data cut-off (11 August 2021)
Earlier this month, IMFINZIin combination with chemotherapy was granted approval in the US as a treatment for adults with locally advanced or metastatic BTC based on results from TOPAZ-1. Regulatory applications are also currently under review in Europe, Japan and several other countries based on the TOPAZ-1 results.
In October 2021, the TOPAZ-1 trial met the OS primary endpoint at a predefined interim analysis, reducing the risk of death by 20% versus chemotherapy (based on a hazard ratio [HR] of 0.80; 95% confidence interval [CI], 0.66-0.97; 2-sided p=0.021).
HIMALAYA Phase III trial exploratory analysis by aetiology in unresectable hepatocellular carcinoma at ESMO
Also at ESMO, an exploratory analysis from the HIMALAYA Phase III trial evaluated the impact of disease causes on outcomes for patients with unresectable hepatocellular carcinoma (abstract #714P). Data from HIMALAYA suggest a trend for OS benefit over sorafenib with the STRIDE regimen regardless of the underlying disease cause (hepatitis B virus [HBV], hepatitis C virus [HCV] or nonviral). Similar trends were observed with IMFINZI versus sorafenib across subsets.
In 2021, positive results from the HIMALAYA Phase III trial showed a single priming dose of tremelimumab, an anti-CTLA4 antibody, added to IMFINZI(STRIDE regimen) demonstrated a statistically significant and clinically meaningful improvement in OS versus sorafenib as a 1st-line treatment for patients with unresectable hepatocellular carcinoma (HCC) who had not received prior systemic therapy and were not eligible for localized treatment.
When subsets were adjusted for prognostic factor imbalances, patients with HBV treated with the STRIDE regimen experienced a 36% reduction in the risk of death versus sorafenib (based on a HR of 0.64, 95% CI 0.47-0.86). Median duration of response was 25.69 months versus 17.00 months for sorafenib. Patients with HCV treated with the STRIDE regimen experienced an 11% reduction in the risk of death versus sorafenib (based on a HR of 0.89; 95% CI 0.63-1.25). Median duration of response was 13.5 months versus 15.7 months for sorafenib. Nonviral patients treated with the STRIDE regimen experienced a 23% reduction in the risk of death versus sorafenib (based on a HR of 0.77; 95% CI 0.59-1.00). Median duration of response was 13.21 months versus 6.01 months for sorafenib. The safety profiles of STRIDE and durvalumab were consistent across etiology subgroups.
In the past, viral HCC (disease associated with cirrhosis related to chronic hepatitis B or hepatitis C) has been the primary etiology of the disease. Over the last two decades, the prevalence of non-viral HCC (disease associated with non-viral factors including liver disease, obesity and diabetes) has significantly increased. HIMALAYA is the only Phase III trial to demonstrate a survival benefit for immunotherapy in participants with non-viral HCC.1,2
The STRIDE regimen is under review by global regulatory authorities in unresectable HCC based on the results of the HIMALAYA trial.
IMPORTANT SAFETY INFORMATION
There are no contraindications for IMFINZI(TM) (durvalumab).
Immune-Mediated Adverse Reactions
Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.
IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when in combination with chemotherapy.
IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions.
IMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions.
- Adrenal Insufficiency:IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
- Hypophysitis:IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI.
- Thyroid Disorders:IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.
- Thyroiditis: Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
- Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI.
- Hypothyroidism:Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
- Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Grade 3 immune-mediated type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI.
Immune-Mediated Nephritis with Renal Dysfunction
IMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
Immune-Mediated Dermatology Reactions
IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), have occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions.
Other Immune-Mediated Adverse Reactions
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies.
- Cardiac/vascular: Myocarditis, pericarditis, vasculitis.
- Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy.
- Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
- Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.
- Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.
- Endocrine: Hypoparathyroidism
- Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.
IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.
Complications of Allogeneic HSCT after IMFINZI
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.
Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and advise them to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of IMFINZI.
There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for at least 3 months after the last dose.
In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse reactions (occurring in >=20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia
In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to adverse reactions occurred in 6% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), upper gastrointestinal hemorrhage (2 patients)
The safety and effectiveness of IMFINZI have not been established in pediatric patients.
IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).
Please see complete Prescribing Information, including Medication Guide.
Biliary tract cancer
BTC is a group of rare and aggressive gastrointestinal (GI) cancers that form in the cells of the bile ducts (cholangiocarcinoma), gallbladder or ampulla of Vater (where the bile duct and pancreatic duct connect to the small intestine).3,4
Cholangiocarcinoma is more common in China and South-East Asia and is on the rise in Western countries.3,5 Gallbladder cancer is more common in certain regions of South America, India and Japan.7
Early-stage BTC affecting the bile ducts and gallbladder often presents without clear symptoms and most new cases of BTC are therefore diagnosed at an advanced stage, when treatment options are limited and the prognosis is poor.5,7,8
TOPAZ-1 is a randomized, double-blind, placebo controlled, multicenter, global Phase III trial of IMFINZI in combination with chemotherapy (gemcitabine plus cisplatin) versus placebo in combination with chemotherapy as a 1st-line treatment in 685 patients with unresectable advanced or metastatic BTC including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer. Patients with ampullary carcinoma were excluded.
The primary endpoint is overall survival and key secondary endpoints included progression-free survival, objective response rate and safety. The trial was conducted in 105 centers across 17 countries including in the US, Europe, South America and several countries in Asia including South Korea, Thailand, Japan and China.
HIMALAYA was a randomized, open-label, multicenter, global Phase III trial of Imfinzi monotherapy and the STRIDE regimen, comprising a single priming dose of tremelimumab 300mg added to IMFINZI1500mg followed by IMFINZI every four weeks versus sorafenib, a standard-of-care multi-kinase inhibitor.
The trial included a total of 1,324 adult patients with unresectable HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue).
The trial was conducted in 190 centers across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint was OS for STRIDE versus sorafenib and key secondary endpoints included OS for IMFINZIversus sorafenib, objective response rate and progression-free survival (PFS) for STRIDE and for IMFINZI alone.
IMFINZI(TM)(durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor's immune-evading tactics and releasing the inhibition of immune responses.
In addition to the approval in BTC, IMFINZI is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy and is the global standard of care in this setting based on the PACIFIC Phase III trial.
IMFINZI is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial. In 2021, updated results from the CASPIAN trial showed IMFINZIplus chemotherapy tripled patient survival at three years versus chemotherapy alone.
IMFINZIis also approved for previously treated patients with advanced bladder cancer in several countries.
Since the first approval in May 2017, more than 100,000 patients have been treated with IMFINZI.
As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several GI cancers, ovarian cancer, endometrial cancer, and other solid tumors.
IMFINZIcombinations have demonstrated clinical benefit in multiple additional cancer settings with positive Phase III trials in unresectable advanced liver cancer (HIMALAYA) and metastatic NSCLC (POSEIDON).
AstraZeneca in GI cancers
AstraZeneca has a broad development program for the treatment of GI cancers across several medicines and a variety of tumor types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new cancer cases leading to approximately 3.6 million deaths.6
Within this program, the Company is committed to improving outcomes in gastric, liver, BTC, esophageal, pancreatic, and colorectal cancers.
IMFINZI is being assessed in combinations in liver, BTC, esophageal and gastric cancers in an extensive development program spanning early to late-stage disease.
The Company aims to understand the potential of fam-trastuzumab deruxtecan-nxki, a HER2-directed antibody drug conjugate, in the two most common GI cancers, colorectal and gastric cancers. Fam-trastuzumab deruxtecan-nxkiis jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.
Olaparib is a first-in-class PARP inhibitor with a broad and advanced clinical trial program across multiple GI tumor types including pancreatic and colorectal cancers. Olaparib is developed and commercialized in collaboration with Merck & Co., Inc., known as MSD outside the US and Canada.
AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate the body's immune system to attack tumors. The Company's Immuno-Oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumor immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumor types.
The Company is pursuing a comprehensive clinical-trial program that includes IMFINZI as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumor types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.
In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca's oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumors.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.
Toyoda H, et al. Improved survival of viral hepatocellular carcinoma but not non-viral hepatocellular carcinoma from 2000 to 2020: A multi-centre cohort study of 6007 patients from high-volume academic centres in Japan. Aliment Pharmacol Ther. 2022; 56: 694- 701.
Hamed MA, et al. Non-viral factors contributing to hepatocellular carcinoma. World J Hepatol. 2013 Jun 27;5(6):311-22.
Marcano-Bonilla L, et al. Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations. CCO. 2016;5(5).
ESMO. What is Biliary Tract Cancer. Available at: https://www.esmo.org/content/download/266801/5310983/1/EN-Biliary-Tract-Cancer-Guide-for-Patients.pdf. Accessed September 2022.
Turkes F, et al. Contemporary Tailored Oncology Treatment of Biliary Tract Cancers. Gastroenterol Res Pract. 2019:7698786.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(TM)) for Breast Cancer V2.2022. copyright National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed September 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. 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.
Rawla P, et al. Epidemiology of gallbladder cancer. Clin Exp Hepatol. 2019;5(2):93-102.
Banales JM, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-588.
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