A phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma

Annals of Oncology 12 501-504.2001 © 2001 Kluwer Academic Publishers Printed in the Netherlands

Original article A phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma P.M. Sanz-Altamira,1 E. O'Reilly,2 K. E. Stuart,1 L. Raeburn,1 C. Steger,2 N.E. Kemeny2& L.B. Saltz2 'Division of Hemutology/Oncology, Boston Center for Liver Cancer, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston. Massachusetts, 2Department of medicine. Division of Gastrointestinal Oncology, Memorial Sloan Kellenng Cancer Center, New York, USA

Summary Background Unresectable adenocarcinomas of the biliary tree have a very poor prognosis No good chemotherapeutic regimen is available Irinotecan has not yet been fully tested in this disease. We evaluated its activity in unresectable bile duct cancers Patients and methods Twenty-five consecutive eligible patients at our two institutions were treated with irinotecan at a starting dose of 125 mg/m 2 A cycle consisted of once-a-week treatments for four consecutive weeks, followed by two weeks of rest. All patients were required to have histologically confirmed diagnosis, clinically documented metastatic or unresectable carcinoma and measurable disease Patients were evaluated for response, toxicity, and survival

Introduction Adenocarcinomas of the biliary tree are relatively uncommon in North America, with approximately 7500 diagnoses and more than 4000 deaths annually [1^4] While some patients present with operable cancer [5, 6], most have unresectable disease and a dismal prognosis Five-year survival rates are less than 12% [7-10]. The etiology of human biliary tract cancers remains unknown even though certain associations have been found, such as liver flukes, inflammatory bowel disease, biliary atresia, congenital abnormalities of the intrahepatic bile ducts, hepatohthiasis, sclerosing cholangitis [4], certain body mass index ranges, races, and dietary factors [11]. Biliary cancers can be classified according to location Gallbladder carcinoma is an aggressive disease with a median survival of approximately six months [4] while cholangiocarcinoma can be more indolent with median survivals of about one year [4, 12] Both cancers are histologically identical, have similar poor responses to chemotherapeutic agents, and have been evaluated together in most recent studies [13-21]. The main goal of our phase II study was to evaluate response; we therefore elected to include both types of biliary cancers in our trial.

Results A total of 83 cycles of therapy were delivered Two patients had a partial response (8%, 95% confidence interval (CI) 0%-18%) and ten additional patients had stable disease for at least two months (40%, 95% CI 20.8%-59 2%) The therapy was well tolerated, with moderate myelosuppression and diarrhea as the main toxicities The overall median survival was 10 months Conclusions Irinotecan has minimal activity in biliary tree carcinomas, but is well tolerated with appropriate supportive care, and produces occasional objective responses.

Key words biliary tree carcinoma, cholangiocarcinoma, gallbladder carcinoma, irinotecan, phase II trial

There are only minimal data to support the use of a specific chemotherapeutic regimen in this setting Studies where pancreatic cancers are included together with biliary tract cancer [22] are difficult to interpret. The most commonly used single agent in biliary tree tumors has been 5-fluorouracil (5-FU), with response rates of 10%—20% [23]. Mitomycin C has been active as a single agent, and when combined with 5-FU and doxorubicin (FAM) yielded response rates of 20%-30% with median survivals in the range of 8-11 months [24]. Carboplatin, 5-FU, and leucovorin has been recently reported to produce a response rate of approximately 21% [21] New chemotherapy regimens are needed to increase response rates and improve survival in patients with advanced biliary tract tumors. Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, a plant alkaloid obtained from the Camplotheca acummata tree. Both camptothecin and irinotecan are potent inhibitors of topoisomerase 1 [25], a nuclear enzyme that plays a critical role in DNA replication and transcription. The enzyme functions normally to cause transient breaks in a single strand of DNA to release the torsional strain caused by synthesis of a new strand of DNA or RNA around a double helix The camptothecins act on the topoisomerase 1-DNA

502 complex, inhibiting reanneahng of the parent DNA [25, 26], thereby stopping nucleic acid synthesis and leading to cell death The enzymatic cleavage of CPT-11 to form the more active species SN-38, taken up by hepatic and biliary cells, has been found to be mediated by hepatic microsomal and serum carboxylesterases [27, 28]. Human liver is thought to be the major site of bioactivation of CPT-11 [28, 29] Innotecan has shown significant activity in colorectal cancer [30], even in patients resistant to 5-FU [31, 32]. Interesting results have also been obtained in other cancers [32-36] The present phase II study evaluates response rate, time to progression, overall survival and toxicity of a regimen of innotecan for biliary tree carcinoma

Patients and methods Patients Twenty-five consecutive eligible patients were enrolled onto this protocol All patients were required to have histologically confirmed unresectable or metastatic carcinoma of the gallbladder or biliary tree Patients also needed to have measurable disease, be at least 18 years old, have an ECOG performance status of 0-2, no brain metastases. no uncontrolled infectious process or known HIV positivity. no more than one previous chemotherapeutic regimen, no previous treatment with camptothecins. and no prior history of malignancy Adequate bone marrow function (WBC > 3500 cells/ul, neutrophil count > 1500 cells/ul, and platelet count >75,OOO/ul). hepatic function (serum bihrubin < 2 0 mg/dl and aspartate aminotransferase < five times the upper limit of normal), and renal function (serum creatinine concentration < 2 0 mg/dl) were also required The study was approved by internal review boards at both institutions and all patients provided written informed consent guidelines prior to initiation of treatment

Treatment plan Therapy was administered on an outpatient basis and patients were premedicated with appropriate antiemetics The regimen used was innotecan 125 mg/nr l v infused over 90 minutes Treatments were repeated every week for four consecutive weeks followed by two weeks of rest, a full cycle consisted of six weeks The dose was adjusted for toxicities in 25 mg/m 2 dose levels or decrements to as low as 50 mg/m 2 The dose was decreased by one dose level for grade 2 hematologic toxicity. held until resolved for more severe hematologic toxicity and then decreased by one dose level if it had been a grade 3 toxicity and by two dose levels if it had been a grade 4 The dose was decreased by one dose level for National Cancer Institute (NCI) grade 2 nonhematologic toxicities. including diarrhea, and by two dose levels for NCI grade 3 or 4 non-hematologic toxicities Therapy was interrupted for diarrhea that persisted longer than 3 days despite adequate loperamide treatment or when other intolerable toxicity was observed Loperamide was given according to standard criteria

Patient evaluation Weekly complete blood counts were obtained to determine the level of myelosuppression Before each course a full clinical evaluation noting the performance status and a physical exam was performed and a complete chemistry panel was obtained Patients were evaluated for response after every two courses of therapy Computerized tomography scans of the abdomen were used for evaluation of response The sizes of measurable lesions were calculated as the products of the two greatest perpendicular diameters

Table I Patient characteristics Number of patients Sex Male Female Age (years) Median Range ECOG performance status 0 1 2 Primary site Gallbladder Bile ducts Pretreatment chemistries Albumin (g/dl) Median Range Total bihrubin (mg/dl) Median Range Alkaline phosphatase (35-120 MIU/I") Median Range Lactale dehydrogenase (120-250 M1 U/l") Median Range Aspartate aminotransferase (10-35 MIU/1") Median Range CA 19-9 K 3 7 U/ml a )(« = 12) Median Range 1

25 18 7 57 34-77 8 15 2 10 15

38 3 1-5 1 07 0 2-1 5 211 5 50-732 218 112-1390 36 12-72 2941 21-149,729

Considered normal levels at our institution

A complete response was defined as disappearance of all evidence of tumor at re-staging and normalization of tumor markers, and a partial response was defined as a greater than a 50% reduction in the sum of the products of the greatest perpendicular diameters of indicator lesions, without progression of any lesion or appearance of new ones All responding patients had their response confirmed four to six weeks after the first documentation of response This trial evaluated response rate and duration, toxicities and overall survival

Results Patient characteristics The patient population consisted of 18 men and 7 women There were a total of 10 cases of primary gallbladder carcinoma, of which 3 were women (Table 1). All patients had adenocarcinoma. The median age was 57 years and the median ECOG performance status was 1 Baseline chemistries included a median total bihrubin of 0.7 mg/dl (range 0.2-1 5) and median albumin of 3.8 g/dl (range 3 1-5 1) Baseline lactate dehydrogenase levels were 218 MIU/1 (range 112-1390) and were elevated in 10 patients. Baseline CA 19-9 levels were checked on 12 patients and were elevated in ten of them All patients had measurable disease within the liver and/or gallbladder fossa

503 Table 2 Relationship of tumor location with response and survival

Table 4 Studies of chemotherapy in biliary tree carcinoma (// 10)

Number of patients

Responses (partial)

Stable disease

Progression

First author [reference]

Number of patients

Chemotherapy

Response rate (%)

Bile ducts (n= 15) Gallbladder (/; = 10)

1 1

6 4

8 5

Taal[13]

30

Mitomycin C

10

Kajanty[14]

21

EMFL

Okada[l5]

13

Cisplatin

Rougier[16]

18

CI 5-FU. cisplalin

32

Patt [17]

18

5-FU, rIFNa

39

Jones [18]

14

Paclitaxel

DiUuro[l9]

15

Table 3 Grade 3 or 4 non-hematologic toxicity Diarrhea

Gallbladder cancer (n = 10) 2 Biliary tree cancer (n •= 15) 4 Total (n = 25) 6

Bilirubin elevation

Emesis Asthenia

2 2 4

2 2 4

0 1 1

Responses, loxicities, and survival A total of 83 cycles of therapy were delivered during the trial. No patient had a complete response Two of the 25 patients (8%; 95% CI: 0%-18%) had a partial response Ten additional patients (40%, 95% CI. 20.8%-59 2%) had stable disease for a median duration of five months (range 2-9 months). Overall, the therapy was well tolerated Diarrhea and myelosuppression were the major toxicities. Five patients (20%) were hospitalized for fever and neutropenia and three patients (12%) for infections from specific sites. The median neutrophil nadir for all courses was 3400 cells/ul (range 200-12,500) The median platelet nadir was 183,000 plt/ul (range 22-510). Anemia was usually mild to moderate, but three patients required transfusions for symptomatic anemia during therapy. Nausea and vomiting were usually mild. Four patients had grade 3 or 4 nausea/vomiting. Grades 3 or 4 diarrhea occurred in six patients In addition to gastrointestinal and hematologic effects, no grade 3-4 toxicity was present, except for one case of severe asthenia (Table 3). No deaths occurred on study. The overall median actuarial survival was 10 months (range 0.25-23.8). The 15 patients with biliary tree carcinoma had a median survival of 12 months (range 0.2523.8) and the 10 patients with gallbladder cancer had a median survival of 9.2 months (range 2 8-15 1). Progressive disease was observed in 13 patients (52%) with a median survival of 3.2 months (range 0 25-12.7) (Table 2).

Discussion Studies of chemotherapy for carcinoma of the biliary tree are relatively few and the number of included patients is generally small (Table 4) 5-FU has been the most commonly evaluated single agent, followed by mitomycin C. Both have response rates of 10%—20% [13, 23, 27]. Paclitaxel as a single agent has shown no objective responses [18]. Gemcitabine has shown no responses in a small phase II trial [20] but there are anecdotal case

5-FU. cisplatin.

0 8

0 33

epirubicin Mezger [20]

11

Gemcitabine

0

Sanz-Altamira[21]

14

5-FU, leucovonn.

Takada[22]

18

5-FU

0

18

5-FU. mitomycin C. doxorubicin 5-FU. mitomycin C.

0

21

carboplatin

Harvey [24]

13

31

doxorubicin Falkson[37]

30

5-FU

26

5-FU. streptozotocm

10 8

31 5-FU, methyl-CCNU 10 Abbreviations CI - continuous infusion, rIFNa - recombinant alpha interferon, EMFL - epirubicin-methotre.\ate-5-FU-leucovonn

reports were significant activity has been documented [38, 39]. Information on combination chemotherapy regimens is also poor. 5-FU has also been the most commonly studied drug within combination chemotherapy regimens [14, 16, 19, 21, 22, 24, 37, 40] Response rates range between 0% and 33% in most studies [14, 16, 19, 21, 22, 24, 37] except in very small trials with numbers that are difficult to reproduce [40, 41]. The combination of 5-FU, mitomycin C, and doxorubicin (FAM) has been evaluated in a few studies. Harvey et al [24] found four partial responses in 13 treated patients (31%) On the other hand, the same drugs in a different regimen, did not produce any objective response in 18 patients in another trial [22] Recombinant alpha interferon was combined with 5-FU in a phase II trial [17], and 7 of 18 evaluable patients (39%) achieved a partial response To our knowledge, irinotecan has not been used for the treatment of biliary tree carcinoma, with the exception of a very preliminary report of a phase II trial that is now ongoing [42]. Our present report tries to address this issue Our phase II trial only found an 8% partial response rate and stable disease for at least two months in 40% of the patients. The median survival achieved by our patients was similar to other published reports With appropriate supportive care, we found our regimen to be well tolerated in biliary tree carcinoma, with moderate myelosuppression and diarrhea as the major dose-limiting toxicities

504 This phase II trial demonstrates that lnnotecan has minimal activity but may produce occasional objective responses in biliary tree carcinoma and suggests a possible role in the salvage setting

23 24

25

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Received 13 November 2000, accepted 4 December 2000 Correspondence to K E Stuart, MD Beth Israel Deaconess Medical Center 330 Brookhne Avenue Boston, MA 02215 USA E-mail kstuart@caregroup harvard edu