Docetaxel in the Management of Advanced Pancreatic Cancer

Docetaxel in the Management of Advanced Pancreatic Cancer Gilberto Lopesa and Caio Max S. Rocha Limaa The poor outcome of pancreatic cancer with conventional treatment options emphasizes the need for continued research. The benefits of gemcitabine in improving quality of life and survival have been established in patients with advanced pancreatic cancer. Randomized clinical trials studying the addition of a second drug to gemcitabine, either a classic cytotoxic (5-fluorouracil, cisplatin, irinotecan, pemetrexed, oxaliplatin, or exatecan) or targeted agents (ie, the farnesyl transferase inhibitor R115777 or the metalloproteinase inhibitor marimastat) have not resulted in improvement in survival compared with gemcitabine alone. Although limited activity of docetaxel in patients with pancreatic adenocarcinoma has been reported in single-agent studies, attractive efficacy results have been documented with docetaxel in combination with other chemotherapeutic agents for the management of advanced pancreatic cancer. Phase I and II trials of docetaxel in combination with gemcitabine, irinotecan, 5-fluorouracil, or thalidomide, as well as trials of docetaxel and radiotherapy, suggest that docetaxel combinations in pancreatic cancer should be further studied in randomized trials. Semin Oncol 32(suppl 4):S10-S23 © 2005 Elsevier Inc. All rights reserved.

P

ancreatic cancer was the fourth leading cause of cancer death in men and the fifth leading cause of cancer death in women in the United States in 2004.1 Considering all stages at diagnosis, the 1- and 5-year survival rates are 24% and 4%, respectively.1 Advances in the management of this disease are urgently needed. The current standard of care for patients with pancreatic cancer involves surgical resection when feasible with or without postoperative chemotherapy or chemoradiation therapy.2 Treatment for patients with locally unresectable disease involves radiation therapy and systemic chemotherapy2 or chemotherapy alone.3 When patients present with metastatic disease, standard treatment comprises single-agent gemcitabine chemotherapy,4 while radiation therapy and surgery have a palliative role. Attempts to improve on the efficacy results of single-agent gemcitabine have, thus far, been unsuccessful (Table 1).5-13 Docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ), a semisynthetic taxane, promotes the assembly of aThe

Department of Medicine, University of Miami, Miami, FL; Supported by Aventis Pharmaceuticals, Bridgewater, NJ. Dr Rocha Lima is a consultant for Aventis, has received research grant support from Aventis, Eli Lilly, Sanofi, and Genentech, and is a member of the Aventis, Eli Lilly, and Genentech speaker bureaus. Address reprint requests to Caio Max S. Rocha Lima, MD, Department of Medicine, University of Miami and Sylvester Cancer Center, 1475 NW 12th Ave (D8-4), Suite 3310, Miami, FL; e-mail: [email protected]

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0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.04.003

microtubules and inhibits the depolymerization of tubulin, thereby leading to cell death.14 Preclinical experience with docetaxel showed activity in a murine model of pancreatic ductal adenocarcinoma, with a 100% cure rate in early stage disease and more than 80% regression of advanced disease.15 Based on these findings, clinical trials have evaluated the efficacy and tolerability of docetaxel either singly or in combination with other agents or other treatment modalities in patients with advanced pancreatic cancer.

Single-Agent Docetaxel Single-agent docetaxel for patients with locally advanced or metastatic pancreatic cancer has been explored in several trials (Table 2).16-20 Patients were generally chemotherapy naive (status not reported in one study),18 and received docetaxel 100 mg/m2 intravenously (IV) every 3 weeks (four studies) or docetaxel 60 mg/m2 IV every 3 to 4 weeks (one study). The single-agent activity of docetaxel 75 mg/m2 every 3 weeks is not known because no data are available for this dose schedule in patients with advanced pancreatic cancer. Overall response rates ranged from 5% to 15% in trials that evaluated docetaxel 100 mg/m2,16,17,19,20 with no responses observed in the lower-dose trial.18 A complete response (CR) was shown in only one trial (observed in 3% of patients).16 Across all five trials, stable disease was observed in 33% to 67% of patients.16-20 Median survival durations for patients

Study

Regimens

Gemcitabine ⴙ Traditional Cytotoxics G 1,000 mg/m2 IV d 1, 8, 15 Berlin et al, 20025 OR G 1,000 mg/m2 IV ⴙ 5-FU 600 mg/m2 IV d 1, 8, 15 Both every 4 weeks Heinemann et al, 2003*6 G 1,000 mg/m2 IV d 1, 8, 15 OR G 1,000 mg/m2 IV ⴙ Cis 50 mg/m2 IV d 1, 15 Both every 4 weeks Louvet et al, 2003*7 G 1,000 mg/m2 IV d 1, 8, 15 every 4 weeks† OR G 1,000 mg/m2 IV d 1 ⴙ O 100 mg/m2 IV d 2 every 2 weeks O’Reilly et al, 2004*9 G 1,000 mg/m2 IV d 1, 8, 15 every 4 weeks† OR G 1,000 mg/m2 IV ⴙ DX 2.0 mg/m2 IV d 1, 8 every 3 weeks Richards et al, 2004*10 G 1,000 mg/m2 IV d 1, 8, 15 every 4 weeks OR G 1,250 mg/m2 IV d 1, 8 ⴙ pemetrexed 500 mg/m2 IV d 8 every 3 weeks Rocha Lima et al, 2003*11 G 1,000 mg/m2 IV d 1, 8, 15 every 4 weeks† OR G 1,000 mg/m2 IV ⴙ I 100 mg/m2 IV d 1, 8 every 3 weeks Gemcitabine ⴙ Targeted Agents Bramhall et al, 200212 G 1,000 mg/m2 IV d 1, 8, 15 every 4 weeks† ⴙ placebo orally, twice daily OR G 1,000 mg/m2 IV d 1, 8, 15 every 4 weeks† ⴙ marimastat 10 mg orally, twice daily Van Cutsem et al, 2002*13 G 1,000 mg/m2 IV d 1, 8, 15 ⴙ placebo orally twice daily OR G as above ⴙ R115777 200 mg orally twice daily Both every 4 weeks†

Response Rate (%)

Median TTP

Median PFS

Median Survival

1-Year Survival (%)

5.6

NR

2.2 mo

5.4 mo

NR

6.9

NR 2.5 mo

6.7 mo (P ⴝ NS) 6.0 mo

NR

8.0

3.4 mo (P ⴝ .022) NR

10.2 (P ⴝ NS) 16.1

4.6 mo (P ⴝ .016) NR

NR

7.6 mo (P ⴝ NS) NR

NR

25.8 (P ⴝ .03) 7.1

NR

NR

NR

6.2 mo

21 23 20.1

8.2

3.8 mo

16 wk 25 wk (P ⴝ .05) NR

NR

NR

9.1

4.1 mo (P ⴝ NS) 3.6 mo

3.3 mo

6.7 mo (P ⴝ NS) 6.3 mo

18.3 (P ⴝ .006) 4.4

5.2 mo (P ⴝ .042) 3.0 mo

3.9 mo (P ⴝ NS) NR

6.2 mo (P ⴝ NS) 6.6 mo

21.4 (P ⴝ NS) 22

16.1 (P <.001)

3.5 mo (P ⴝ NS)

NR

6.3 mo (P ⴝ NS)

21 (P ⴝ NS)

NR

96 d

NR

92.5 d (P ⴝ NS) 109 d

165.5 d (P ⴝ NS) 182 d

18

112 d (P ⴝ NS)

193 d (P ⴝ NS)

27

11

16 (P ⴝ NS) 8

NR

6

NR

NR

164 d

Docetaxel in pancreatic cancer

Table 1 Phase III Trials of Single-Agent Gemcitabine Versus Gemcitabine-Based Doublets for Advanced Pancreatic Cancer

17

24

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Abbreviations: TTP, time to progression; PFS, progression-free survival; G, gemcitabine; IV, intravenously; NR, not reported; 5-FU, 5-fluorouracil; NS, not significant; Cis, cisplatin; O, oxaliplatin; I, irinotecan; DX, exatecan mesylate. *All data are from the oral presentations and may differ from the published abstract. †Cycle 1 consisted of weekly administration ⴛ 7 weeks followed by a 1-week rest, consistent with the product labeling.8

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Table 2 Trials of Single-Agent Docetaxel in Patients With Metastatic or Locally Advanced Pancreatic Cancer

Study

No. of Evaluable Patients

Patient/Disease Characteristics

Efficacy Results

Safety Results (%)

CR: 3% PR: 3% SD: 58% Median survival duration: 36 wk

Grade III/IV neutropenia (36); nail changes (12); anemia (9); asthenia (9); febrile neutropenia (6); neurotoxicity (6)

CR: 0% PR: 5% SD: 35% Median survival duration: 5.9 mo

Metastatic PC ECOG PS 0 –2 No prior CT

T 60 mg/m2 IV Every 3– 4 weeks

CR: 0% PR: 0% SD: 33% Median survival duration: 118 d

Metastatic PC WHO PS 0 –2

T 100 mg/m2 IV Every 3 weeks

CR: 0% PR: 7% SD: 67% Median survival duration: NR

Locally advanced/metastatic PC WHO PS 0 –2 No prior CT

T 100 mg/m2 IV Every 3 weeks

CR: 0% PR: 15% SD: 38% Median survival duration: 7 mo

Grade III/IV toxicities: neutropenia (88); alopecia (66); fatigue (47); anemia (13); abdominal pain (16); skin reaction (9); vomiting (5) Grade III/IV toxicities: neutropenia (86); leukocytopenia (67); malaise/fatigue (33); nausea/vomiting (29); anorexia (29); alopecia (24); 1 alkaline phosphatase (14); anemia (10); 1 ALT/AST (10); thrombocytopenia (5) Grade IV neutropenia (73); grade III/IV anemia (13); grade III/IV asthenia (13); grade III/IV vomiting (6); grade III/IV stomatitis (6); grade III/IV edema (6) Grade III/IV toxicities: neutropenia (95); asthenia (23); anemia (16); febrile neutropenia (9); vomiting (7); skin toxicity (7); edema/effusion (7); hypersensitivity (5); infection (5); stomatitis (5)

Locally advanced/metastatic PC WHO PS 0 –2 No prior CT or RT

Lenzi et al, 200217

21 safety 20 efficacy

Locally advanced/metastatic PC Zubrod PS 0 –2 No prior CT

Okada et al, 199918

21

Preusser et al, 199919

15

Rougier et al, 200020

43 safety 40 efficacy

Abbreviations: PC, pancreatic cancer; WHO, World Health Organization; PS, performance status; CT, chemotherapy; RT, radiotherapy; T, docetaxel; IV, intravenously; Dex, dexamethasone; G-CSF, granulocyte colony-stimulating factor; CR, complete response; PR, partial response; SD, stable disease; ECOG, Eastern Cooperative Oncology Group; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NR, not reported.

G. Lopes and C.M.S. Rocha Lima

Regimen T 100 mg/m2 IV d 1 Plus Dex 4 mg orally twice daily on d 1–3, G-CSF 150 mg/m2 d 2– 10 Every 3 weeks T 100 mg/m2 IV Plus pretreatment with Dex, diphenhydramine Every 3 weeks

33

Androulakis et al, 199916

Docetaxel in pancreatic cancer treated with docetaxel 100 mg/m2, reported for all but one study, ranged from 5.9 months to 8.3 months. The median survival duration for the single study of docetaxel 60 mg/m2 was 3.9 months.16-18,20 Neutropenia was the most frequently observed grade III/IV toxicity (36% to 95% of patients), with anemia (9% to 16%) and fatigue (33% to 47%) also commonly reported.16-20 Not surprisingly, less severe neutropenia was observed in the trial that included treatment with granulocyte colony-stimulating factor.16 In summary, singleagent docetaxel in advanced and metastatic pancreatic cancer was tolerable, with some antitumor activity observed in trials of docetaxel 100 mg/m2.

Docetaxel-Containing Combination Regimens Based on the favorable toxicity profile and antitumor activity of single-agent docetaxel in patients with pancreatic cancer,16-20 several phase I and II trials evaluated its use in combination with other chemotherapeutic agents, including gemcitabine, irinotecan, or 5-fluorouracil (5-FU) (Table 3).21-50

Docetaxel/Gemcitabine Gemcitabine hydrochloride (Gemzar, Eli Lilly and Company, Indianapolis, IN), a deoxycytidine antimetabolite closely related to cytarabine, is approved as first-line therapy for locally advanced metastatic pancreatic cancer.8 Combination regimens of docetaxel and gemcitabine have been evaluated in trials of patients with pancreatic cancer.21-42 This collective experience includes seven phase I trials, four of which included patients with other types of cancer.21-27 Treatment regimens were similar in two phase I trials of treatment-naive patients with advanced or metastatic pancreatic cancer.21,22 Patients received docetaxel 25 to 45 mg/m2 IV and gemcitabine (800 mg/m2 IV in one trial, 800 to 1,000 mg/m2 IV in the other) weekly. In both trials, subjects were pretreated with dexamethasone 8 mg orally and tropisetron (5 mg IV in one trial, 4 mg IV in the other). In the first trial, grade III/IV toxicities included vomiting, diarrhea, and leukopenia/thrombocytopenia, each occurring in 20% of patients and each occurring only in the highest dosing group (docetaxel 45 mg/m2, gemcitabine 800 mg/m2).21 In the second trial, grade III/IV toxicities included gastrointestinal events (12%) and leukopenia (8%).22 Two and five patients, respectively, died as a result of disease progression during the trials. Recommended doses were docetaxel 35 mg/m2 (both studies) and the highest gemcitabine dose evaluated (800 mg/m2 and 1,000 mg/m2, respectively). Efficacy was not reported for either trial. In a third phase I trial, 16 patients with advanced carcinoma (12 with pancreatic cancer) received docetaxel 25 to 35 mg/m2 IV and gemcitabine 600 to 900 mg/m2 IV on days 1, 8, and 15 every 28 days.23 All patients were pretreated with dexamethasone 8 mg orally, diphenhydramine 50 mg IV, and cimetidine 300 mg IV or ranitidine 50 mg IV before each docetaxel dose.23 One patient (8%) with pancreatic cancer

S13 experienced a partial response (PR) and seven (58%) demonstrated stable disease for a median of 8 weeks.23 Grade III/IV toxicities included neutropenia (47% of patients), febrile neutropenia (7%), anemia (7%), and diarrhea (7%).23 Of the additional phase I trials that evaluated docetaxel and gemcitabine in heterogeneous populations, CR rates ranged from 0% to 8%, with PR rates ranging from 0% to 15%.24-26 In these trials, neutropenia was the most frequently observed grade III/IV toxicity.24-27 A randomized phase II trial of docetaxel and gemcitabine in pancreatic cancer was conducted by the European Organisation for Research and Treatment of Cancer GI Cancer Group (Fig 1).28 The purpose of this randomized trial, conducted in patients with metastatic or locoregionally advanced unresectable adenocarcinoma of the pancreas previously untreated with chemotherapy or immunotherapy, was to evaluate the efficacy of gemcitabine (800 mg/m2 IV administered on day 1 and 8) and docetaxel (85 mg/m2 IV administered on day 8) compared with docetaxel (75 mg/m2 IV administered on day 1) and cisplatin (75 mg/m2 IV administered on day 1) during a 21-day cycle.51 In 61 evaluable patients, 16% in each group demonstrated a PR, and median survival was approximately 7 months.28 Toxicities included grade III neutropenia (24% [docetaxel plus gemcitabine] and 27% [docetaxel plus cisplatin] of patients), grade IV neutropenia (16% and 23%, respectively), grade III/IV anemia (20% and 9%, respectively), thrombocytopenia (8% and 5%, respectively), and diarrhea (8% and 5%, respectively). One patient in each treatment group experienced a pulmonary embolism. Results suggest that docetaxel combined with either gemcitabine or cisplatin is tolerable and has promising antitumor activity in this patient population.28 Additional phase II studies have similarly reported favorable preliminary results with combinations of docetaxel and gemcitabine in patients with advanced pancreatic cancer (Table 3).22,29-42

Docetaxel/Irinotecan Irinotecan hydrochloride (Camptosar, Pfizer Inc, New York, NY) is a topoisomerase I inhibitor indicated as a component of first-line therapy in combination with 5-FU and leucovorin for patients with metastatic carcinoma of the colon or rectum, and for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial 5-FU-based therapy.52 Two phase II trials evaluating the efficacy of the irinotecan and docetaxel combination have been reported.46,48,53 Kurtz et al,46 building on a phase I experience from Couteau et al,54 tested docetaxel 60 mg/m2 and irinotecan 250 mg/m2 administered on day 1 every 3 weeks. Of the 27 patients included in this trial, three (11%) had a PR and 11 (41%) had stable disease, with median progression-free survival of 4.3 months. Median survival for all patients was 8.5 months. Seventy-eight percent of patients experienced neutropenia, with 52% of patients experiencing leukopenia.46 Burtness et al48,53 tested a different schedule (docetaxel 35 mg/m2 and irinotecan 50 mg/m2 administered on days 1, 8, 15, and 21 of a 35-day cycle) in 37

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Table 3 Trials of Docetaxel-based Chemotherapy Regimens in Patients With Metastatic or Locally Advanced Pancreatic Cancer

Study

Phase

Docetaxel/Gemcitabine Lück et al, 199821 I

No. of Evaluable Patients

Patient/Disease Characteristics

20 safety 12 efficacy

PC No prior CT

I

25

PC No prior CT

Ganjoo et al, 200223

I

15

Advanced cancer, including pancreatic (12), other (4) ECOG PS 0 –2

Ryan et al, 200024

I

26

Poole et al, 200325

I

28

Boyer et al, 199926

I

21

Metastatic solid tumors, including pancreatic (9), NSCLC (3), gastric, ovarian, colorectal, hepatocellular, mesothelioma (each 2), esophageal, prostate, head and neck, unknown primary (each 1) ECOG PS 0 –1 50% prior CT Metastatic or locally advanced cancer, including pancreas (7), head and neck (5), sarcoma (5), stomach (4), esophagus (3), gallbladder (2), liver (2) ECOG PS 0 –2 Advanced cancer, including NSCLC (6), gastric (6), breast (4), unknown primary (3), pancreas (2), mesothelioma (2), other (8) WHO PS 0 –2

Efficacy Results

T 25– 45 mg/m2 IV G 800 mg/m2 IV Plus Dex 8 mg orally, Trop 5 mg IV Weekly for 12 cycles T 25– 45 mg/m2 IV G 800 –1,000 mg/m2 IV Plus Dex 8 mg orally, Trop 4 mg IV Weekly for 12 cycles T 25–35 mg/m2 IV d 1, 8, 15 G 600 –900 mg/m2 IV d 1, 8, 15 Plus Dex 8 mg orally, diphenhydramine 50 mg IV, cimetidine 300 mg IV, or ranitidine 50 mg IV before each T dose Every 28 days T 60 mg/m2 IV on d 1 G 600 – 800 mg/m2 IV on d 1, 8, 15 Plus Cipro 500 mg orally, twice daily on d 8 –18 Every 28 days

CR: 0% PR: 0% SD: 58% NR

Safety Results (%) Grade III/IV toxicities: vomiting (20); diarrhea (20); leukopenia/thrombocytopenia (20) Grade III/IV toxicities: GI (12); leukopenia (8)

CR: 0% Pancreatic PR: 8% Pancreatic SD: 58%

Grade III/IV toxicities: neutropenia (47); febrile neutropenia (7); anemia (7); diarrhea (7)

CR: 8% PR: 15% Pancreatic PR: 43%

Grade III/IV toxicities: neutropenia (42); asthenia (15); thrombocytopenia (12); pneumonitis (12); diarrhea (8)

T 50 mg/m2 IV on d 1, with 10 mg/m2 increases until DLT G 800 mg/m2 IV on d 1, 8, 15 Every 28 days

CR: 0% PR: 4% SD: 21%

Grade III/IV toxicities: neutropenia (18); thrombocytopenia (7) Grade >II toxicities: fatigue (57); grade III/IV nausea (11); rash (7)

T 60 –100 mg/m2 d 8 G 800 –1,200 mg/m2 d 1, 8 Every 21 days Plus Cipro 500 mg orally, twice daily from d 11 until neutrophil >1.0

CR: 5% PR: 10%

Grade III/IV neutropenia (76% of cycles); grade III thrombocytopenia (14% of cycles)

G. Lopes and C.M.S. Rocha Lima

Lueck et al, 200022

Treatment Regimen

I

62

Advanced solid tumors, including pancreas, lung, head and neck, gastric, esophagus, breast, colon, ovary, anal, cervix, renal cell, salivary gland, unknown primary 24% no prior CT

Lutz et al, 200228

II

31 efficacy in T/G 30 efficacy in T/Cis

PC 80% metastatic disease WHO PS 0 –1

Androulakis et al, 199929

II

56 safety 43 efficacy

Advanced or metastatic PC 100% no prior tx

Jacobs et al, 200030

I/II

29 safety 25 efficacy

Unresectable PC

Lueck et al, 200022

II

13

PC No prior CT

T 35– 65 mg/m2 IV d 1 G 2,000 – 4,000 mg/m2 as 30 min IV d 1 OR T 35– 65 mg/m2 on d 1 G 1,000 –1,200 mg/m2 as 10 mg/m2/min IV d 1 Plus pre-/postchemo corticosteroids in both schedules Every 2 weeks T 85 mg/m2 IV d 8 G 800 mg/m2 IV d 1, 8 OR T 75 mg/m2 IV d 1 Cis 75 mg/m2 IV d 1 Every 21 days T 100 mg/m2 IV d 8 G 1,000 mg/m2 IV d 1, 8 Plus G-CSF d 9 –15 Every 3 weeks

Antitumor activity in pancreatic, lung, head and neck, gastric, and breast cancer

Grade III/IV leukopenia; grade III/IV neutropenia; grade III thrombocytopenia; febrile neutropenia

CR: 0%/0% PR: 16%/16% Progression-free survival: 3.0/3.9 mo Mean duration survival: 7.6/7.1 mo CR: 0% PR: 12% SD: 40% 1-yr survival: 32%

T 75 mg/m2 IV d 1 G 800 mg/m2 IV d 1, 8, 15 Every 28 days Due to toxicities, reduced to: T 40 mg/m2 IV d 1, 8 G 1,000 mg/m2 IV d 1, 8 Every 21 days T 25– 45 mg/m2/wk IV G 800 –1,000 mg/m2/wk IV Plus Dex 8 mg orally, Trop 4 mg IV Weekly for 12 cycles

CR: 0% PR: 28% Minor response or SD: 40% Median time to progression: 5.3 mo

Grade IV neutropenia (16/23); grade III neutropenia (24/27) grade III/IV toxicities: anemia (20/9); thrombocytopenia (8/ 5); diarrhea (8/5); mucositis (8/0); dyspnea (8/0) Moderate fluid retention (25); grade III/IV neutropenia (23); grade III/IV thrombocytopenia (18); grade III/IV fatigue (13); neutropenic fever (11); grade III anemia (11); moderate hypersensitivity reaction (7) Higher dosage: grade II/III hemotoxicity (28/44); grade III vomiting (6); grade III fatigue (6) Lower dosage: grade II hemotoxicity (18)

CR: 0% PR: 23% SD: 46%

Docetaxel in pancreatic cancer

Rigas et al, 199927

NR

(continued)

S15

S16

Table 3 (Continued)

Phase

Schneider et al, 200231

II

37

PC Metastatic (29) Locally advanced (9)

T 35 mg/m2/wk IV G 750 mg/m2/wk IV For 3 weeks every 28 days

CR: 0% PR: 24% SD: 35% Median time to progression: 22.4 wk

Schmidt et al, 200332

II

57

PC Metastatic (39) Inoperable locally advanced (19)

T 35 mg/m2 IV d 1, 8, 15 G 1,000 mg/m2 d 1, 8, 15 Every 28 days

Ryan et al, 200233

II

33

PC ECOG PS: 0 –1 No prior tx for metastatic PC

T 60 mg/m2 IV d 1 G 600 mg/m2 IV d 1, 8, 15 Plus Dex 8 mg orally, twice daily on d 0 –3, Cipro 500 mg orally twice daily on d 8 –18 Every 28 days

Gonzalez Cao et al, 200134

II

24

Metastatic PC

T 60 mg/m2 IV d 1 G 800 mg/m2 IV d 1, 14 (cycle length NR)

Sherman and Fine, 200135

II

15

Advanced PC ECOG PS 1–2 80% no prior tx

T 90 mg/m2/wk IV G 900 mg/m2/wk IV Every 3 weeks for >2 cycles

CR: 2% PR: 18% SD: 53% Median time to progression: 4.5 mo Median survival duration: 8 mo CR: 0% PR: 18% SD: 39% Median duration of SD: 4.2 mo Median progression-free survival: 3.8 mo Median survival duration: 8.9 mo 1-yr survival: 29% CR: 0% PR: 17% SD: 63% Median survival duration: 6 mo 1-yr survival: 25% CR: 7% PR: 20% SD: 13% 1-yr survival: 21%

Patient/Disease Characteristics

Treatment Regimen

Efficacy Results

Safety Results (%) Grade IV toxicities: granulocytopenia (14); pulmonary dysfunction (5) Grade III toxicities: leukopenia (30); granulocytopenia (24); nausea/vomiting (16); pain (16); fatigue (11); anemia (11); diarrhea (8); pulmonary dysfunction (8); hepatic dysfunction (8) Grade III/IV toxicities: neutropenia (15); diarrhea (15); nausea (15); leukopenia (13); 1 alkaline phosphatase (6)

Grade III/IV toxicities: neutropenia (49); fatigue (27); dyspnea/pneumonitis (15); anorexia (15); febrile neutropenia (12); nausea/ emesis (12); diarrhea (12); motor neuropathy (9); venous thromboembolism (9)

Grade III/IV toxicities: neutropenia (13)

WBC counts <1,000 (13); fever (7)

G. Lopes and C.M.S. Rocha Lima

Study

No. of Evaluable Patients

II

32

Advanced PC

T 75 mg/m2/wk IV G 2,000 mg/m2/wk IV Every 2 weeks for 4 cycles

Petrovic, 200137

II

14

Advanced PC

T 75 mg/m2 IV d 1 G 800 mg/m2 IV d 1, 8, 15 Plus Dex d 0 – 4 Every 3 weeks

Ridwelski et al, 200138

II

43

T 35 mg/m2 IV d 1, 8, 15 G 1,000 mg/m2 IV d 1, 8, 15 Every 29 days

Stathopoulos et al, 200139

II

54

Advanced or recurrent PC Locally advanced inoperable (10) Metastatic (24) Relapsed after surgery (9) Advanced or metastatic PC Inoperable (8) WHO PS 0 –2 74% no prior tx

Clark et al, 200040

II

32 safety 24 efficacy

Metastatic PC

T 60 mg/m2 IV d 1 G 600 mg/m2 IV d 1, 8, 15 Plus Cipro d 8 –18 Every 28 days

Fahlke et al, 200441

II

55

Kulke et al, 200442

II*

61

Metastatic (33) Locally advanced (17) Relapsed after surgery (5) Metastatic PC

T 35 mg/m2 IV d 1, 8, 15 G 1,000 mg/m2 IV d 1, 8, 15 Every 28 days T 40 mg/m2 d 1, 8 G 1,000 mg/m2 d 1, 8 Every 21 days

T 100 mg/m2 d 8 G 1,000 mg/m2 d 1, 8 Plus G-CSF d 9 –15 Every 21 days

CR: 6% PR: 3% SD: 9% Median survival duration: 4.7 mo CR: 0% PR: 7% SD: 36% Median survival duration: 6.1 mo CR: 7% PR: 19% SD: 42% Median survival duration: 9 mo CR: 0% PR: 13% SD: 33% Median duration of response: 24 wk Median survival duration: 26 wk 1-yr survival: 30% CR: 4% PR: 4% SD: 29%

CR: 1.8% PR: 18.2% SD: 50.9% Confirmed radiologic objective response rate: 11.5%

Grade III neutropenia (31); dehydration (22); fatigue (19)

Grade III/IV neutropenia (14); mild hypersensitivity (14); febrile neutropenia (7); grade III/IV thrombocytopenia (7); grade III diarrhea (7) No grade IV toxicities Toxicities, except alopecia, were mild to moderate in the majority of cases

Docetaxel in pancreatic cancer

Shepard et al, 200136

Grade III/IV toxicities: granulocyte (32); neutropenia (31); asthenia (13); febrile neutropenia (11); platelets (7); diarrhea (6)

Febrile neutropenia (22); grade III/IV fatigue (13); grade III/IV diarrhea (9); grade III/IV nausea (6); depression (3); neuropathy (3) Not available

Grade III/IV toxicities: neutropenia (29); infection/ febrile neutropenia (13); anemia (13); thrombocytopenia (10); fatigue (19); nausea (8); vomiting (8); diarrhea (8); hyponatremia (6); hyperglycemia (29) (continued)

S17

S18

Table 3 (Continued)

Study

Phase

No. of Evaluable Patients

Docetaxel/Gemcitabine/Carboplatin Long et al, 200043 I 13 safety 7 efficacy

Docetaxel/Gemcitabine/Oxaliplatin Wunderlich et al, I 31 safety 200044 22 efficacy

Docetaxel/Gemcitabine/Capecitabine I 32 Fine et al, 200245

Docetaxel/Irinotecan Kurtz et al, 200346

Treatment Regimen

Efficacy Results

Safety Results (%)

Advanced solid tumors, including pancreatic (4), esophageal (3), NSCLC (2), unknown primary (2), small cell lung (1), melanoma (1)

T 55– 65 mg/m2 IV on d 1 G 600 – 800 mg/m2 IV on d 1, 8 Carbo AUC ⴝ 5 d 1 With/without G-CSF Every 21 days T reduced to 55 mg/m2 on d 1 due to toxicities

CR: 0% PR: 29% PR for PC: 25%

Neutropenia (77); thrombocytopenia (54); anemia (23); diarrhea (23)

Refractory solid tumors, including head and neck (12), sarcoma (5), cholangiocarcinoma (3), pancreatic (3), unknown primary (3), NSCLC (2), gastric (1), adrenal (1), ovarian (1)

T 35–55 mg/m2 IV d 1 G 500 –1,300 mg/m2 IV day 1 O 65– 80 mg/m2 d 2 Every 14 days

CR: 0% PR: 23% SD: 59%

Skin (29); neurologic (20); WBC (17)

Metastatic PC: (24) Inoperable with no metastasis: (8) 25% failed prior CT

C 1,500 –2,000 mg/m2 orally, twice daily on d 1–14 T 30 mg/m2 IV d 4, 11 G 750 –1,000 mg/m2 IV d 4, 11 Every 2 weeks for 3 cycles Inoperable pts also received radiation ⴙ Whipple procedure

Metastatic pts CR (successful Whipple): 0% PR: 50% SD: 25% Inoperable pts CR (successful Whipple): 63% SD: 38%

Grade II/III diarrhea and handfoot syndrome (40); grade II neutropenia (30)

T 60 mg/m2 IV d 1 I 250 mg/m2 IV d 1 Plus prednisolone, 5-HT3 receptor antagonist Every 3 weeks T 40 –70 mg/m2 IV d 1 I 140 –300 mg/m2 IV d 1 Plus methylprednisolone 64 mg orally d 0 –2, metoclopramide (100 mg) or alizapride (100 mg) prior to T Every 3 weeks

CR: 0% PR: 11% SD: 41% Median progression-free survival: 4.3 mo CR: 0% PR: 10% SD: 48%

Grade III/IV neutropenia (78); grade III/IV leucopenia (52); grade III/IV anemia (7); grade III/IV thrombocytopenia (7)

II

27 safety 24 efficacy

Advanced PC 93% metastatic PC 100% no prior tx

I

40

Advanced solid tumors, including pancreatic (8), NSCLC (8), gastric (4), mesothelioma (4), bladder (3), cholangiocarcinoma (2), nasopharyngeal (2), esophageal (1), others (8) 100% prior CT 35% prior radiotherapy

Grade IV neutropenia (85); grade III/IV asthenia (15); grade III/IV febrile neutropenia (23); grade III/IV infection (8); grade III/IV diarrhea (8); grade III/IV nausea (5)

G. Lopes and C.M.S. Rocha Lima

Couteau et al, 200047

Patient/Disease Characteristics

Abbreviations: PC, pancreatic cancer; CT, chemotherapy; T, docetaxel; IV, intravenously; G, gemcitabine; Dex, dexamethasone; Trop, tropisetron; CR, complete response; PR, partial response; SD, stable disease; NR, not reported; GI, gastrointestinal; ECOG, Eastern Cooperative Oncology Group; PS, performance status; NSCLC, non–small cell lung carcinoma; Cipro, ciprofloxacin; DLT, dose-limiting toxicity; WHO, World Health Organization; Cis, cisplatin; tx, treatment; WBC, white blood cell; G-CSF, granulocyte colony-stimulating factor; Carbo, carboplatin; AUC, area under the concentration-time curve; O, oxaliplatin; C, capecitabine; I, irinotecan; 5-FU, 5-fluorouracil; Leuco, leucovorin. *Randomized trial of four different gemcitabine-based regimens, one of which was docetaxel/gemcitabine.

Grade III/IV leukopenia (20/40); febrile neutropenia (13); grade III fatigue (7) T 50 – 60 mg/m2 IV d 1 5-FU 200 – 400 mg/m2 IV d 1–5 Leuco 20 mg/m2 IV d 1–5 Cis 75 mg/m2 IV d 2 Every 3 weeks Docetaxel/5-FU/Cisplatin/Leucovorin Mulcahy et al, I 15 safety 200150 12 efficacy

Advanced GI tumors, including esophageal (5), colon (3), gastric (3), gallbladder (2), pancreas (1), cholangiocarcinoma (1)

CR: 0% PR: 17%

Grade IV neutropenia; febrile neutropenia; fluid retention T 25–75 mg/m2 IV d 1 5-FU 100 –300 mg/m2 IV d 1–5 Plus Dex 8 mg orally, twice daily from d 0 –2 Every 4 weeks Advanced solid tumors, including NSCLC (8), stomach (6), pancreas (5), breast (4), unknown primary (4), soft tissue carcinoma (3), other (7) 37 I Docetaxel/5-FU Petit et al, 199949

Burtness et al, 200248

II

14

T 35 mg/m2 IV d 1, 8, 15, 21 I 50 mg/m2 IV d 1, 8, 15, 21 Every 35 days

CR: 5% PR: NR SD: NR

S19

Unresectable or metastatic PC ECOG PS 0 –1 100% no prior CT

CR: 0% PR: 36% SD: 36% Median survival duration: 8 mo

Grade III/IV toxicities: diarrhea; neutropenia; hyperglycemia

Docetaxel in pancreatic cancer

Figure 1 European Organisation for Research and Treatment of Cancer phase II randomized trial of docetaxel/gemcitabine versus docetaxel/cisplatin for advanced pancreatic cancer. WHO, World Health Organization; PS, performance status; IV, intravenously.

patients; 33 patients were evaluable for response, with seven (21.2%) PR and one (3%) CR.

Docetaxel/5-Fluorouracil The antineoplastic antimetabolite 5-FU is indicated for the palliative management of pancreatic cancer.55 Two published trials have explored the utilization of docetaxel in combination with 5-FU in patients with advanced solid tumors, including patients with pancreatic cancer. One trial evaluated the combination of docetaxel (25 to 75 mg/m2 on day 1) and 5-FU (100 to 300 mg/m2 on days 1 to 5) administered every 4 weeks,49 while the other evaluated the combination of docetaxel (50 to 60 mg/m2 on day 1), 5-FU (200 to 400 mg/m2 on days 1 to 5), leucovorin (20 mg/m2 on days 1 to 5), and cisplatin (75 mg/m2 on day 2) every 3 weeks.50 These chemotherapeutic treatment combinations were tolerable, with antitumor activity documented in a small number of patients.49,50

Gemcitabine/Docetaxel/Capecitabine (GTX) Capecitabine (Xeloda, Roche Pharmaceuticals, Nutley, NJ) is a fluoropyrimidine carbamate with antineoplastic activity that, in combination with docetaxel, is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.56 Capecitabine in combination with docetaxel and gemcitabine was evaluated in a trial of 32 previously treated patients with advanced pancreatic cancer.45 Doses used were capecitabine 750 to 1,000 mg/m2 on days 1 to 14, with gemcitabine 1,000 mg/m2 followed by docetaxel 30 mg/m2 on days 4 and 11. Of 24 patients with liver metastases, 50% had a PR and 25% had stable disease. Of the remaining eight patients (all with inoperable disease), five (63%) had a successful Whipple procedure with normal CA19-9 and three (38%) had stable disease. Major toxicities included grade II/III diarrhea and handfoot syndrome (40% of patients) and grade II neutropenia (30%). No deaths occurred.45 In a recent update to this trial,57 median survival was at least 10.4 months; and two of the patients were alive after 3 years with metastatic disease. The same authors also reported on an alternate regimen used for patients who had failed or did not tolerate GTX.58 Based on laboratory data that supported the separation of G1/S agents

S20 (gemcitabine, capecitabine) from G2/M (docetaxel) to overcome resistance, 15 patients were treated with GTX. Patients received docetaxel 40 mg/m2 on the Wednesdays of weeks 1 and 3, capecitabine 1,500 mg/m2/day Monday through Friday of weeks 2 and 4, and gemcitabine 750 mg/m2 over 75 minutes on the Wednesday of weeks 2 and 4. A 2-week break followed each cycle. Response was assessed after two cycles. Seven patients were treated for disease progression on or after GTX, while five patients began the regimen because of intolerable symptoms on GTX. Three patients switched to reduce chemotherapy exposure. With two CR and two PR, the overall response rate was 27% on an intent-to-treat basis. Five other patients had stable disease (33%). The clinical benefit rate was 60%. Median survival was 5.5 months from the start of salvage therapy. Toxicity data were available for 14 patients and included four cases of grade III leukopenia, one report of grade III thrombocytopenia, and no grade III/IV anemia. Diarrhea (n ⫽ 4) and abdominal cramps (n ⫽ 3) were the most common toxicities; three patients experienced a deep-vein thrombosis (DVT).58

Gemcitabine/Docetaxel/Platinum Agent Two trials evaluated the addition of a platinum agent to the docetaxel/gemcitabine combination in patients with advanced carcinoma (including pancreatic cancer).43,44 One trial added carboplatin area under the concentration-time curve ⫽ 5 on day 1 to docetaxel 55 to 65 mg/m2 IV on day 1 and gemcitabine 600 to 800 mg/m2 on days 1 and 8 administered every 21 days with and without granulocyte colonystimulating factor. However, hematologic toxicity necessitated a reduction of the docetaxel dose to 55 mg/m2. A PR was observed in 29% of patients (including one of four patients with pancreatic cancer). Grade III/IV toxicities included neutropenia (77% of patients), thrombocytopenia (54%), anemia (23%), and diarrhea (23%); one patient died from progressive disease.43 The second trial added oxaliplatin 65 mg/m2 on day 2 to docetaxel 35 to 55 mg/m2 on day 1 and gemcitabine 500 to 1,300 mg/m2 on day 1 administered every 14 days.44 The PR rate was 23%, with 59% of patients demonstrating stable disease. Grade III/IV toxicities included those involving the skin (29% of patients), central nervous system (20%), and white blood cells (15%).44

Docetaxel/Thalidomide A phase I trial evaluated the safety of the combination of docetaxel and thalidomide when used in patients with advanced pancreatic cancer who had failed gemcitabine-based chemotherapy.59 The first two patients received weekly doses of docetaxel at 33 mg/m2, followed by thalidomide started on day 8 at an initial dose of 50 mg orally per day, with dose escalation of 50 mg per week to a maximum of 400 mg per day. As both patients developed grade III neuropathy, subsequent patients were given docetaxel at a dose of 20 mg/m2 weekly. Neuropathy was the most common toxicity, experienced by four of eight patients. Other toxicities included neutropenia (grade III, 25%), thrombocytopenia (grade II, 12.5%), fatigue (grade II, 12.5%), infections (grade III, 25%),

G. Lopes and C.M.S. Rocha Lima edema (grade III, 12.5%), and elevated liver enzymes (grade III, 12.5%). Stable disease was seen in 50% of the patients at 8 weeks. No objective responses were seen.59

Docetaxel-Based Combined-Modality Regimens Docetaxel in combination with radiotherapy is effective and well tolerated in patients with non-small cell lung cancer (the reader is referred to Kim & Khuri60 2002 for a complete review). Results of trials in non-small cell lung cancer prompted the evaluation of docetaxel combined with radiation therapy in patients with pancreatic cancer.61,62 In a phase I trial, 13 patients with locally nonresectable advanced adenocarcinoma of the pancreas received four weekly doses of docetaxel 20 to 35 mg/m2/ week (via 10 mg/m2 dose escalation increments until maximum tolerated dose) with concurrent external beam radiation therapy of 40 Gy administered over 4 weeks.61 Patients with a demonstrated response or disease stabilization received two additional cycles of docetaxel and an additional 10 Gy of radiotherapy. The most common toxicities were nausea, vomiting, asthenia, and abdominal pain. In all but one patient, these toxicities were reversible and not worse than grade III. Hematologic toxicities were mild and did not require interruption of treatment. Although the maximal tolerated dose was not reached, dose escalation was stopped at docetaxel 35 mg/m2/week, a dose comparable with those used in other studies of docetaxel combined with radiation. No objective response was observed, with four patients achieving stable disease.61 A phase II trial evaluated docetaxel and gemcitabine followed by gemcitabine and radiotherapy in 13 patients with stage I to III untreated pancreatic cancer.62 Patients received docetaxel 65 mg/m2 IV and gemcitabine 4,000 mg/m2 IV on days 1, 15, and 29. On day 43, radiation therapy 1.8 Gy per fraction to a dose of 50 Gy plus gemcitabine 50 mg/m2 twice weekly for 12 doses were administered. A proton pump inhibitor (type not reported) was given prophylactically. Toxicities included grade III nausea and vomiting, fatigue, and dehydration. Four patients experienced grade III/IV hematologic toxicities, with no treatment discontinuations because of toxicities. Preliminary analysis showed that six patients (57%) responded by Response Evaluation Criteria in Solid Tumors (RECIST), including one CR. Although all patients demonstrated unresectable or borderline unresectable disease before treatment, four patients underwent a Whipple procedure; three of these patients had negative margins.62 This trial was updated in 2004, and of 24 patients enrolled, 19 completed treatment and were evaluable for response. Using RECIST criteria, 11 responses (57%) were seen, including one CR. Fourteen patients underwent resection. Negative margins were seen in 11 patients, including eight whose disease was considered unresectable or borderline unresectable before treatment.63

Docetaxel in pancreatic cancer

Docetaxel Neoadjuvant Trials Neoadjuvant docetaxel alone or in combination with other chemotherapeutic agents recently has been evaluated in carcinoma of the breast,64,65 non–small cell lung,66,67 head and neck,68,69 and prostate.70 Neoadjuvant docetaxel also has been evaluated in locally advanced pancreatic cancer.71 In a phase II dose-escalation trial, a total of 18 patients were assigned to receive gemcitabine 800, 850, 900, 950, or 1,000 mg/m2 IV followed by docetaxel 25, 30, 35, 40, or 45 mg/m2 IV on days 1, 8, and 15 of a 28-day cycle, with two cycles administered as preoperative treatment. No grade III or IV toxicities were observed at the two lowest dose levels (gemcitabine/docetaxel: 800/25 and 850/30). One patient treated with gemcitabine 900 mg/m2 and docetaxel 35 mg/m2 experienced a grade III hematologic toxicity, with further dose escalation stopped after two patients treated with gemcitabine 950 mg/m2 and docetaxel 40 mg/m2 experienced doselimiting grade III/IV toxicities. Remaining patients were treated with gemcitabine 900 mg/m2 and docetaxel 35 mg/ m2. The updated efficacy results reported that 79% of the patients underwent a successful Whipple resection. The 1-year survival rate was 85%, and actuarial 3-year survival was 69%.72

Planned/Ongoing Combination Trials Current evaluations of docetaxel-containing treatment combinations in patients with metastatic pancreatic adenocarcinoma have expanded on the results observed in other phase II studies in this population. An ongoing phase II trial conduced by the Eastern Cooperative Oncology Group is evaluating the efficacy of docetaxel and irinotecan (both administered IV on days 1, 8, 15, and 22) with or without cetuximab (administered IV on days 1, 8, 15, 22, 29, and 36) in patients with metastatic pancreatic adenocarcinoma. Courses will be repeated every 6 weeks in the absence of disease progression or unacceptable toxicity.73

Summary/Future Directions Although docetaxel has limited activity as a single-agent for pancreatic cancer, results of early phase I trials of docetaxel in combination with gemcitabine, irinotecan, or cisplatin appear promising. Additional phase II and III trials designed to further investigate the efficacy of docetaxel-containing combinations are either planned or ongoing. It is unclear if triplet regimens will have a role in pancreatic cancer therapy; the results of one trial of GTX are encouraging, but confirmatory multicenter and/or randomized trials of the GTX regimen are needed. Initial trials of docetaxel as neoadjuvant treatment, as well as combined with radiotherapy, suggest that these treatment regimens deserve further study in patients with pancreatic cancer. These efforts may position docetaxel-containing regimens as a viable treatment option for advanced or metastatic pancreatic cancer.

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