Chapter 3: Biliary: Gallbladder Cancer and Cholangiocarcinoma

Tim Greten; Susanna Ulahannan; Werner Scheithauer

INTRODUCTION

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Epidemiology

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Epidemiology

Gallbladder Cancer & Other Biliary Incidence:

10,650 (male: 4,960; female: 5,690. Estimated new cases for 2014 in the United States)

Deaths:

Estimated 3,630 in 2014 (male: 1,610; female: 2,020)

Median age, cholangiocarcinoma:

65 years

Gallbladder:

7th decade

Gallbladder cancer:

Women are two to six times more likely to develop gallbladder cancer than men

Cholangiocarcinoma:

Slighlty more common in men

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Work-up

Early diagnosis of gallbladder or cholangiocellular carcinoma is nearly impossible or can only be realized in exceptional cases
In a patient with specific clinical symptoms or ultrasound suspicion of biliary tract cancer, a spiral CT and chest x-ray should be performed
Medically fit, nonjaundiced patients whose disease appears potentially resectable may proceed directly to surgical exploration without needle biopsy to avoid tumor spread. Consider a laparoscopic evaluation before open surgery owing to the common occurrence of otherwise nonvisible metastatic spread to the peritoneum
If the potential to perform a resection remains uncertain and for those with jaundice, a more precise assessment of tumor extent and lymph node involvement should be obtained with MRCP ± MRA, which may help to rule out vascular invasion and anomalous anatomic findings for surgical planning
If it is obvious that a resection will not be possible or if distant metastases are present, fine-needle biopsy for tissue confirmation should be obtained
In nonresectable jaundiced patients, depending on the location of the biliary obstruction, a percutaneous transhepatic cholangiography (PTC) or an endoscopic retrograde cholangiography (ERC) should be considered to guide placement of a stent

Fong Y et al. Cancer of the liver and biliary tree. In: Principles and Practice of Oncology, 6th ed. Baltimore, MD: Lippincott Williams & Wilkins 2001:1162–1203

Pathology

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Pathology

1. Gallbladder cancer

(60%)

2. Cholangiocarcinoma

(40%)

Intrahepatic

10%

Perihilar (Klatskin tumor)

40–60%

Distal

20–30%

Multifocal

<10%

Histopathology

1. Adenocarcinoma Papillary, nodular, tubular, medullary

80–90%

2. Pleomorphic giant cell carcinoma

>10%

3. Squamous cell carcinoma

4. Mucoid carcinoma

<1%

5. Anaplastic carcinoma

<1%

6. Cystadenocarcinoma

<1%

7. Clear cell carcinoma

<1%

8. Other rare forms

<1%

Lazcano-Ponce EC et al. CA Cancer J Clin 2001;51:349–364

Nakeeb A et al. Ann Surg 1996;224:463–475

Five-Year Survival (Cholangiocarcinoma and Gallbladder Cancer)^✫

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Five-Year Survival (Cholangiocarcinoma and Gallbladder Cancer)^✫

Stage IA

85–100%

Stage IB

30–40% to 70–90%

Stage II

10–60%

Stage III

10–40%

Stage IV

^✫Statistics for gallbladder cancer not certain because few cases reported in the literature

Staging

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Staging

Gallbladder Cancer

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Tis

Carcinoma in situ

Tumor invades lamina propria or muscular layer

T1a

Tumor invades lamina propria

T1b

Tumor invades muscular layer

Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver

Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts

Tumor invades main portal vein or hepatic artery or invades 2 or more extrahepatic organs or structures

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Staging

Gallbladder Cancer

Regional Lymph Nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein

Metastases to periaortic, pericaval, superior mesentery artery, and/or celiac artery lymph nodes

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Staging

Gallbladder Cancer

Distant Metastasis (M)

No distant metastasis

Distant metastasis

Group

Tis

IIIA

IIIB

T1-3

IVA

N0-1

IVB

Any T

N 2

Any T

Any N

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Staging

Intrahepatic Bile Duct Staging

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Tis

Carcinoma in situ (intraductal tumor)

Solitary tumor without vascular invasion

T2a

Solitary tumor with vascular invasion

T2b

Multiple tumors, with or without vascular invasion

Tumor perforating the visceral peritoneum or involving the local extra hepatic structures by direct invasion

Tumor with periductal invasion

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Staging

Intrahepatic Bile Duct Staging

Regional Lymph Nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Regional lymph node metastasis present

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Staging

Intrahepatic Bile Duct Staging

Distant Metastasis (M)

No distant metastasis

Distant metastasis

Group

Tis

III

IVA

IVB

Any T

Any N

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Staging

Perihilar Bile Ducts Staging

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Tis

Carcinoma in situ

Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue

T2a

Tumor invades beyond the wall of the bile duct to surrounding adipose tissue

T2b

Tumor invades adjacent hepatic parenchyma

Tumor invades unilateral branches of the portal vein or hepatic artery

Tumor invades main portal vein or its branches bilaterally; or the common hepatic artery; or the second-order biliary radicals bilaterally; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement

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Staging

Perihilar Bile Ducts Staging

Regional Lymph Nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Regional lymph node metastasis (including nodes along the cystic duct, common bile duct, hepatic artery, and portal vein)

Metastasis to periaortic, pericaval, superior mesentery artery, and/or celiac artery lymph nodes

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Staging

Perihilar Bile Ducts Staging

Distant Metastasis (M)

No distant metastasis

Distant metastasis

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Staging

Distal Bile Duct Staging

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Tis

Carcinoma in situ

Tumor confined to the bile duct histologically

Tumor invades beyond the wall of the bile duct

Tumor invades the gallbladder, pancreas, duodenum or other adjacent organs without involvement of the celiac axis, or the superior mesenteric artery

Tumor involves the celiac axis, or the superior mesenteric artery

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Staging

Distal Bile Duct Staging

Regional Lymph Nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Regional lymph node metastasis

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Staging

Distal Bile Duct Staging

Distant Metastasis (M)

No distant metastasis

Distant metastasis

Group

Tis

IIA

IIB

III

Any N

Any T

Any N

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010

Expert Opinion

Biliary tract malignancies include carcinoma of the gallbladder as well as of the intrahepatic, perihilar, and distal bile ducts. Complete surgical resection remains the only curative modality for gallbladder cancer (cholecystectomy, en bloc hepatic resection, and lymphadenectomy with or without bile duct excision). Postoperative therapy for patients who undergo an operative resection might be considered with adjuvant chemotherapy and/or fluoropyrimidine-based radiochemotherapy, in selected cases. Patients with unresectable tumor without obvious metastatic disease and without jaundice may benefit from a regimen of fluorouracil- or capecitabine-based chemotherapy ± radiation. Metastatic disease is typically treated with systemic chemotherapy. Interventional procedures including brachytherapy and photodynamic therapy represent a therapeutic option for selected patients. However, overall survival of such patients remains poor (Razumilava and Gores, 2013)

Less than 20% of all patients have disease that is deemed resectable, and even after having undergone potential curative resection, recurrence rates are high. Thus for the majority of patients, systemic chemotherapy is the mainstay of treatment. The problem concerning chemotherapy is the fact that most studies conducted in the past have been single-center, nonrandomized, phase II studies with relatively small patient numbers (Hezel and Zhu, 2008). Heterogeneous inclusion criteria, inherent difficulties in measuring tumor response, and the lack of studies having applied RECIST (Response Evaluation Criteria in Solid Tumors) methodology for confirmation of treatment effects further contribute to our limited knowledge how to best treat patients with advanced tumors (Eckel and Schmid, 2007)

In the absence of validated data from prospective randomized studies, patients with biliary cancer were usually treated with gemcitabine or fluoropyrimidines ± platinum compounds. This, however, changed with the publication of the results from the ABC-01 trial that evaluated patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer (Valle et al, 2010). After a median follow-up of 8.2 months, the median overall survival was 11.7 months in the cisplatin plus gemcitabine group and 8.1 months in the gemcitabine group (HR, 0.64; 95% CI, 0.52 to 0.80; P <0.001). The median progression-free survival was 8 months in the cisplatin plus gemcitabine group and 5 months in the gemcitabine-only group (P <0.001). Adverse events were similar in both groups, with the exception of neutropenia—higher in the cisplatin plus gemcitabine group—although the number of neutropenia-associated infections was similar in the 2 groups. Consequently, a cisplatin + gemcitabine regimen has become the standard of care on this indication

Novel agents, such as epidermal growth factor receptor blockers, MEK inhibitors and angiogenesis inhibitors, may hold promise for improving the therapeutic results obtained with conventional chemotherapy alone, but clinical study results are pending (Sasaki et al, 2013)

Intrahepatic cholangiocarcinoma

Patients who have undergone a tumor resection with or without ablation with negative margins may be followed up with observation, because there is no definitive adjuvant regimen to improve their overall survival. For individuals whose disease is resectable but who are left with positive margins after resection: (a) consider additional resection, (b) ablative therapy, or (c) combined radiation with or without chemotherapy using either fluorouracil- or capecitabine-based regimens or gemcitabine (Horgan et al, 2012). For patients with unresectable disease, therapeutic options include, depending on tumor location, extent of disease, and performance status: (a) chemotherapy with cisplatin plus gemcitabine or a fluorouracil- or capecitabine-based regimen, (b) combined radiochemotherapy, or (c) best supportive care

Extrahepatic cholangiocarcinoma

Patients with positive margins after resection should be considered candidates for either cisplatin plus gemcitabine or fluorouracil- or capecitabine-based chemotherapy with radiation (external beam therapy or brachytherapy) (Valero et al, 2012). The addition of adjuvant therapy in patients after potential curative surgical resection remains a subject of clinical investigation. Patients whose disease is deemed unresectable at the time of surgery should undergo biliary drainage if required, ideally nonsurgically; that is, by using a stent. Photodynamic therapy has demonstrated to be even more effective than stenting alone (Ortner et al, 2003). Given their overall poor prognosis, further options for patients with unresectable disease, include: (a) chemotherapy with cisplatin plus gemcitabine, (b) a clinical trial, (c) chemoradiation (fluorouracil- or capecitabine-based chemotherapy/RT), and (d) best supportive care

Eckel F et al. Br J Cancer 2007;96:896–902

Hezel AF et al. Oncologist 2008;13:415–423

Horgan AM et al. J Clin Oncol 2012; 30:1934–1940

Ortner ME et al. Gastroenterology 2003;125:1355–1363

Razumilava N, Gores GJ. Clin Gastroenterol Hepatol 2013;11:13–21

Sasaki T et al. Korean J Intern Med 2013;28:515–524

Valero V et al. Expert Rev Gastroenterol Hepatol 2012;6:481–495

Valle J et al. N Engl J Med 2010;362:1273–1281

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First-Line Chemotherapy in Advanced Biliary Cancer Phase III and Randomized Phase II Trials

Regimen

%RR

PFS/TTP^✫

OS^✫

References

Phase III

GEM + CDDP

204

26.1^†

8.0

P<0.001

11.7

HR = 0.64 (95% CI, 0.52–0.80) P<0.001

Valle

GEM

206

15.5^†

5.0

8.1

GEM + oxaliplatin

30.8^‡

8.5

P<0.001

9.5

P = 0.039

Sharma

5-FU + folinic acid

14.3^‡

3.5

4.6

BSC

2.8

4.5

Randomized Phase II

GEM + CDDP

19.5

5.8

HR = 0.66 (95% CI, 0.41–1.05)

P = 0.077

11.2

HR = 0.69 (95% CI, 0.42–1.13)

P = 0.139

Okusaka

GEM

11.9

3.7

7.7

GEM + S-1

20.0

5.6

95% CI 2.0–10.5

8.9

95% CI 5.8–11.9

Sasaki

GEM

9.4

4.3

95% CI 1.9–5.7

9.2

95% CI 5.2–14.6

GEM + S-1

36.4

7.1

HR = 0.437 (95% CI, 0.286–0.669)

P<0.0001

12.5

HR = 0.859 (95% CI, 0.543–1.360) P = 0.52

Morizane

S-1

17.4

4.2

9.0

GEM + CDDP

19.6

5.7

HR = 0.85 (95% CI 0.52–1.36)

P = 0.488

10.1

HR = 0.72 (95% CI 0.45–1.17)

P = 0.187

Kang

S-1 + CDDP

23.8

5.4

9.9

#, number of patients enrolled; %RR, percent response rate; BSC, best supportive care; CDDP, cisplatin; 5FU, Fluorouracil; GEM, gemcitabine; S-1, an oral anticancer drug, consisting of the fluorouracil prodrug tegafur and 2 biochemical modulators, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo)

^✫Median values in months

^†Not significant

^‡p<0.001

Kang et al. Acta Oncol 2012;51:860–866

Morizane et al. Cancer Sci 2013;104:1211–1216

Okusaka et al. Br J Cancer 2010;103(4):469–474

Sasaki et al. Cancer Chemother Pharmacol 2013;71:973–979

Sharma et al. J Clin Oncol 2010;28:4581–4586

Valle J et al. N Engl J Med 2010;362:1273–1281

ADVANCED DISEASE REGIMEN: CISPLATIN + GEMCITABINE

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Advanced Disease Regimen: Cisplatin + Gemcitabine

Valle J et al. N Engl J Med 2010;362:1273–1281

Note: Biliary obstruction per se is not considered to be disease progression in the absence of radiologically confirmed disease progression, and treatment can be recommenced after initial or further biliary stenting and normalization of liver function

Hydration before cisplatin: ≥1000 mL 0.9% sodium chloride injection (0.9% NS); administer by intravenous infusion over ≥1 hour

Cisplatin 25 mg/m² per dose; administer intravenously in 50–1000 mL 0.9% NS over 1 hour for 2 doses on days 1 and 8, every 3 weeks for 4 cycles (total dosage/cycle = 50 mg/m²), followed by:

Hydration after cisplatin: ≥1000 mL 0.9% NS; administer by intravenous infusion over ≥1 hour

Gemcitabine 1000 mg/m² per dose; administer intravenously in 50–250 mL 0.9% NS over 30 minutes for 2 doses on days 1 and 8, every 3 weeks, for 4 cycles (total dosage/cycle = 2000 mg/m²)

Gemcitabine may be administered concurrently with hydration after cisplatin administration is completed

Note: In the absence of disease progression at 12 weeks, treatment with the same regimen may continue for an additional 12 weeks

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Cisplatin

Any G ≥3 adverse event

Hematologic toxicity, abnormal renal function, nausea, vomiting, edema, or tinnitus

Decrease cisplatin dosage by 25%

Reduction in creatinine clearance^✫ to ≤60% of onstudy value

Delay therapy 1 week. If creatinine clearance does not recover to pretreatment values, then consider reducing cisplatin dose

Creatinine clearance^✫ 40–60 mL/min (0.66–1 mL/s)

Consider reducing cisplatin so that dose in milligrams equals the creatinine clearance^✫ value in mL/min (mL/s × 1/0.0166)^†

Creatinine clearance^✫ <40 mL/min (<0.66 mL/s)

Hold cisplatin

Clinically significant ototoxicity

Discontinue cisplatin

Persistent (>14 days) peripheral neuropathy without functional impairment

Decrease cisplatin dosage by 50%

Clinically significant sensory loss—persistent (>14 days) peripheral neuropathy with functional impairment

Discontinue cisplatin

Day 1 WBC count

<2000/mm³ or platelet count <100,000/mm³

Delay cisplatin and gemcitabine for 1 week or until myelosuppression resolves

Recurrent treatment delay because of myelosuppression

Delay cisplatin for 1 week, or until myelosuppression resolves, then decrease cisplatin and gemcitabine dosages by 25% during subsequent treatments

Sepsis during an episode of neutropenia

^✫Creatinine clearance is used as a measure of glomerular filtration rate

^†This also applies to patients with creatinine clearance (GFR) of 40–60 mL/min at the outset of treatment

Patient Population Studied

Patients with a diagnosis of nonresectable, recurrent, or metastatic biliary tract carcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma); an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; and an estimated life expectancy of more than 3 months. Other eligibility criteria included a total bilirubin level ≤1.5 times the upper limit of the normal range; liver-enzyme levels that were ≤5 times the upper limit of the normal range; renal function with levels of serum urea and serum creatinine that were <1.5 times the upper limit of the normal range; and an estimated glomerular filtration rate ≥45 mL/minute (≥0.75 mL/s)

Efficacy (N = 161)^✫

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Efficacy (N = 161)^✫

All Patients (N = 161)

Gallbladder Tumors^† (N = 61)

Bile Duct and Ampullary Tumors^† (N = 100)

Complete response

0.6%

Partial response

25.5%

37.7%

18%

Stable disease^‡

55.3%

47.5%

60%

Progressive disease

18.6%

14.8%

21%

Median progression-free survival

8.0 months

—

Median overall survival

11.7 months

—

^✫RECIST (Response Evaluation Criteria in Solid Tumors) (Therasse P et al. J Natl Cancer Inst 2000;92:205–216)

^†No differences in RR between gallbladder and cholangiocarcinoma subgroups

^‡Not defined

Toxicity (N = 198)

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Toxicity (N = 198)

% G3/4

Hematologic

Decreased WBC

15.7

Decreased platelet counts

8.6

Decreased hemoglobin concentration

7.6

Decreased ANC

25.3

Any hematologic toxic effect

32.3

Liver Function

Increased alanine amino transferase level

9.6

Other abnormal liver function

13.1

Any abnormal liver function

16.7

Nonhematologic

Alopecia

Anorexia

Fatigue

18.7

Nausea

Vomiting

5.1

Impaired renal function

1.5

Infection

Without neutropenia

6.1

With neutropenia

10.1

Biliary sepsis

4.0

Any type

18.2

Deep vein thrombosis

2.0

Thromboembolic event

3.5

Other

54.5

Any G3/4 toxic effect

70.7

NCI Common Terminology Criteria for Adverse Events v3.0

Therapy Monitoring

Between days 8 and 10: CBC with differential
Before each cycle: Electrolytes, renal function, LFTs
Response assessment: Every 2–3 cycles

ADVANCED DISEASE REGIMEN: GEMCITABINE + OXALIPLATIN (GEMOX)

Listen

Advanced Disease Regimen: Gemcitabine + Oxaliplatin (GEMOX)

André T et al. Ann Oncol 2004;15:1339–1343

Gemcitabine 1000 mg/m²; administer by intravenous infusion in 250 mL 0.9% sodium chloride injection at an infusion rate of 10 mg/m² per minute (over 100 minutes) on day 1, every 2 weeks (total dosage every 2 weeks = 1000 mg/m²)

Oxaliplatin 100 mg/m²; administer by intravenous infusion in 250–500 mL of 5% dextrose injection over 2 hours on day 2, every 2 weeks (total dosage every 2 weeks = 100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with gemcitabine (day 1) is LOW

Emetogenic potential with oxaliplatin (day 2) is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 33 patients with advanced biliary tract carcinoma

Efficacy (N = 31)

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Efficacy (N = 31)^✫

Overall response rate

35.5%

Stable disease

26%

Progressive disease

38.5%

Median progression-free survival

5.7 months

Overall survival

14.3 months

^✫André T et al. Ann Oncol 2004;15:1339–1343

Complete Response

7.7%

Partial Response

23%

Stable Disease

38%

Progressive Disease

31%

Median Overall Survival

9.5 months

Median Progression-free Survival

8.5 months

Sharma et al. J Clin Oncol 2010;28:4581–4586

Toxicity (N = 56)

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Toxicity (N = 56)

G3 Neutropenia

12.5%

G3 Thrombocytopenia

Peripheral sensory neuropathy

7.1%

G2 Alopecia

5.3%

G3 Nausea/vomiting

3.5%

G3 Diarrhea

—

NCI, CTC, National Cancer Institute (USA) Common Toxicity Criteria, version 2.0. At: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm [accessed December 7, 2013]

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Nadir WBC <1000/mm³, ANC <500/mm³, or platelets <50,000/mm³

Decrease gemcitabine and oxaliplatin dosages by 25% in subsequent cycles

G ≥3 nonhematologic adverse event during the previous treatment cycle

WBC <3000/mm³ or platelets <75,000/mm³ on day of treatment

Delay chemotherapy for up to 2 weeks

Treatment delay >2 weeks for recovery from hematologic adverse events

Discontinue treatment

Therapy Monitoring

Every week: CBCs with differential
Before each cycle: Complete biochemical profile
Response assessment: Every 2 months

ADVANCED DISEASE REGIMEN: GEMCITABINE + CAPECITABINE

Listen

Advanced Disease Regimen: Gemcitabine + Capecitabine

Koeberle D et al. J Clin Oncol 2008;26:3702–3708

Gemcitabine 1000 mg/m² per dose; administer intravenously in 50–250 mL 0.9% Sodium Chloride Injection over 30 minutes for 2 doses on days 1 and 8, every 3 weeks (total dosage/cycle = 2000 mg/m²)

Capecitabine 650 mg/m² per dose; administer orally twice daily (approximately every 12 hours) for 14 consecutive days (28 doses), days 1–14, every 3 weeks (total dosage/cycle = 18,200 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Nadir WBC <1000/mm³, ANC <500/mm³, or Platelets <50,000/mm³

Delay chemotherapy for up to 3 weeks until adverse events are G ≤1, then reduce gemcitabine dosage by 25%

Any G3 nonhematologic toxicity during a previous cycle

Delay chemotherapy for up to 3 weeks until adverse events are G ≤1, then decrease gemcitabine and capecitabine dosages by 25%

Any G4 nonhematologic toxicity during a previous cycle

Delay chemotherapy for up to 3 weeks until adverse events are G ≤1, then decrease gemcitabine and capecitabine dosages by 50%

Patient Population Studied

A study of 44 chemotherapy-naïve patients with unresectable, locally advanced or metastatic biliary tract cancer. Patients were required to be symptomatic and have at least 1 of the following characteristics at baseline: Karnofsky performance score between 60 and 80, average analgesic consumption of ≥10 mg of morphine equivalents per day, and average pain intensity score of ≥20 mm out of a maximum of 100 mm based on a linear analog self-assessment (LASA ≥2/10) scale. No prior chemotherapy for advanced disease was allowed

Efficacy (N = 44)

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Efficacy (N = 44)

Complete response

1 (2%)

Partial responses

10 (23%)

Stable disease^✫

24 (55%)

Progression/nonassessable

9 (20%)

Median time to progression

7.2 months

Median overall survival

13.2 months

^✫Stable disease lasting for ≥8 weeks

RECIST Criteria (Response Evaluation Criteria in Solid Tumors) (Therasse P et al. J Natl Cancer Inst 2000;92:205–216)

Toxicity (N = 44)

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Toxicity (N = 44)

% G1/2

% G3/4

Hematologic

Anemia

Leukocytopenia

Thrombocytopenia

Nonhematologic

Nausea

Vomiting

Diarrhea

Stomatitis

Anorexia

Fatigue

Hand-foot syndrome

NCI, CTC, National Cancer Institute (USA) Common Toxicity Criteria, version 2.0. At: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm [accessed December 7, 2013]

Therapy Monitoring

Between days 8 and 10: CBC with differential
Before each cycle: Electrolytes, renal function, LFTs
Response assessment: Every 3 cycles

ADVANCED DISEASE REGIMEN: CAPECITABINE + OXALIPLATIN

Listen

Advanced Disease Regimen: Capecitabine + Oxaliplatin

Nehls O et al. Br J Cancer 2008;98:309–315

Capecitabine 1000 mg/m² per dose; administer orally twice daily (approximately every 12 hours) for 14 consecutive days (28 doses) on days 1–14, every 3 weeks (total dosage/cycle = 28,000 mg/m²)

Oxaliplatin 130 mg/m²; administer intravenously in 250–500 mL 5% dextrose injection over 2 hours on day 1, every 3 weeks (total dosage/cycle = 130 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential for oxaliplatin is MODERATE

Emetogenic potential on days with capecitabine alone is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Capecitabine

Any G ≥2 adverse event except alopecia

Interrupt/delay capecitabine until adverse event improves to G ≤1, and decrease capecitabine dosage by 25% during subsequent cycles

Second occurrence of G ≥2 adverse event

Interrupt/delay capecitabine until adverse event improves to G ≤1 and decrease capecitabine dosage by 50% during subsequent cycles

Third occurrence of G ≥2 adverse event

Discontinue capecitabine use permanently

Oxaliplatin

Any G ≥3 adverse event

Decrease oxaliplatin dosage by 25%

Persistent (>14 days) peripheral neuropathy without functional impairment

Decrease oxaliplatin dosage by 50%

Persistent (>14 days) peripheral neuropathy with functional impairment

Discontinue oxaliplatin use permanently

Patient Population Studied

A study of 65 chemotherapy-naïve patients with advanced biliary tract cancer (adenocarcinomas of the gallbladder [GBC] or the intrahepatic [ICC] or extrahepatic [ECC] biliary tract) not amenable to curative surgical treatment strategies, ECOG performance status ≤2. Patients were stratified prospectively between 2 groups based on location of the primary, that is, gallbladder cancer or extrahepatic cholangiocarcinoma versus intrahepatic cholangiocarcinoma

Efficacy^✫

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Efficacy^✫

GBC/ECC (N = 47)

ICC (N = 18)

Complete response

2 (4%)

Partial response

11 (23%)

Stable disease^†

23 (49%)

6 (33%)

Progression

11 (23%)

12 (67%)

Median time to progression

6.5 months

2.2 months

Median overall survival

12.8 months

5.2 months

^✫WHO Criteria

^†Stable disease was defined as a reduction <50% for an unspecified duration or an increase <25% of measurable lesions according to the previous method, with the absence of any new lesions

Toxicity (N = 65)

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Toxicity (N = 65)

% G2

% G3

% G4

Hematologic

Anemia

Neutropenia

Thrombocytopenia

Nonhematologic

Nausea/vomiting

Diarrhea

Stomatitis

Hand-foot syndrome

Infection

Thromboembolic event

Peripheral neuropathy

NCI, CTC, National Cancer Institute (USA) Common Toxicity Criteria, version 2.0. At: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm [accessed December 7, 2013]

Therapy Monitoring

Between days 8 and 10: CBC with differential
Before each cycle: Electrolytes, renal function, LFTs
Response assessment: Every 2–3 cycles

REGIMEN: GEMCITABINE

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Regimen: Gemcitabine

Penz M et al. Ann Oncol 2001;12:183–186

Gemcitabine 2200 mg/m²; administer by intravenous infusion in 250 mL 0.9% sodium chloride injection over 30 minutes on day 1, every 2 weeks for 6 months (total dosage per 2-week cycle = 2200 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 32 chemotherapy-naïve patients with locally advanced or metastatic biliary tract cancer

Efficacy (N = 32)

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Efficacy (N = 32)

Overall response rate

21.9%

Stable disease

43.7%

Progressive disease

34.4%

Median progression-free survival

5.6 months

Median overall survival

11.5 months

WHO criteria

Toxicity (N = 32)

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Toxicity (N = 32)

% G1

% G2

% G3

Hematologic

Neutropenia

Thrombocytopenia

Anemia

Nonhematologic

Nausea/vomiting

—

Diarrhea

—

Constipation

—

Stomatitis

—

Fatigue

—

Alopecia

—

Fever

—

Cutaneous

—

Serum transaminases

—

No grade 4 toxicities

WHO criteria

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Nadir WBC <1000/mm³, ANC <500/mm³, or platelets <50,000/mm³

Reduce gemcitabine dosage by 25% in subsequent cycles

G ≥3 nonhematologic adverse event during the previous treatment cycle

WBC <3000/mm³ or platelets <75,000/mm³ on day of treatment

Delay chemotherapy for up to 2 weeks

Treatment delay >2 weeks for recovery from hematologic adverse event

Discontinue treatment

Therapy Monitoring

Every week: CBCs with differential LFTs
Before each cycle: Complete biochemical profile
Response assessment: Every 2 months

REGIMEN: MITOMYCIN + CAPECITABINE

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Regimen: Mitomycin + Capecitabine

Kornek GV et al. Ann Oncol 2004;15:478–483

Mitomycin 8 mg/m²; administer by intravenous injection over 2–3 minutes on day 1, every 4 weeks (total dosage/cycle = 8 mg/m²)

Capecitabine 1000 mg/m² per dose; administer orally twice daily (approximately every 12 hours) for 14 consecutive days (28 doses) on days 1–14, every 4 weeks (total dosage/cycle = 28,000 mg/m²)

(Capecitabine is taken with water within 30 minutes after food ingestion)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with capecitabine with or without mitomycin is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 26 chemotherapy-naïve patients with advanced biliary tract cancer

Efficacy (N = 26)

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Efficacy (N = 26)

Partial responses

30.8%

Stable disease

34.6%

Progressive disease

34.6%

Median progression-free survival

5.35 months

Median overall survival

9.25 months

WHO Criteria

Toxicity (N = 24)

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Toxicity (N = 24)

% G1/2

% G3

Hematologic

Neutropenia

N/A

Thrombocytopenia

Nonhematologic

Nausea/vomiting

—

Fatigue

—

Diarrhea

—

Hand-foot syndrome

—

Alopecia

—

Increased liver function results^✫

—

Fever without documented infection: 8%

^✫Possibly a result of progressive disease because >80% of patients had liver involvement

WHO criteria

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Nadir WBC <1000/mm³, ANC <500/mm³, or platelets <50,000/mm³

Delay chemotherapy for up to 2 weeks until adverse events are G ≤1, then decrease subsequent mitomycin and capecitabine dosages by 25%

Any G ≥3 nonhematologic adverse events during the previous treatment cycle

Duration of treatment delay >2 weeks for recovery from adverse events

Discontinue treatment

Therapy Monitoring

Weekly: CBC with differential
Before each cycle: Biochemical profile
Response assessment: Every 2 cycles

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Chapter 3: Biliary: Gallbladder Cancer and Cholangiocarcinoma

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INTRODUCTION

Expert Opinion

ADVANCED DISEASE REGIMEN: CISPLATIN + GEMCITABINE

ADVANCED DISEASE REGIMEN: GEMCITABINE + OXALIPLATIN (GEMOX)

ADVANCED DISEASE REGIMEN: GEMCITABINE + CAPECITABINE

ADVANCED DISEASE REGIMEN: CAPECITABINE + OXALIPLATIN

REGIMEN: GEMCITABINE

REGIMEN: MITOMYCIN + CAPECITABINE

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