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Phase II trial of docetaxel (Taxotere®) in metastatic colorectal carcinoma
Annals of Oncology 5: 468-470, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Phase II trial of docetaxel (Taxotere®) in metastatic colorectal carcinoma R. Pazdur,1 Y. Lassere,1 L. T. Soh,2 J. A. Ajani,1 B. Bready,1 E. Soo,1 S. Sugarman,1 Y. Patt,1 J. L. Abbruzzese1 & B. Levin1 1
Divisions of Medicine and Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas U.S^A.; 2Department of Medical Oncology, Singapore General Hospital, Singapore
Results: No complete or partial responses were observed. Granulocytopenia was the dose-limiting toxic effect. SevenBackground: Docetaxel (Taxotere*) is prepared from a non- teen patients had grade 4 granulocytopenia; 8 of these pacytotoxic precursor extracted from the needles of the Taxus tients received antibiotics for neutropenic fevers. Twelve baccata. Preclinical investigations have demonstrated that patients experienced hypersensitivity reactions, and 15 padocetaxel is very active in colon adenocarcinoma murine tients experienced cutaneous toxic reactions. One patient models. Phase I studies revealed granulocytopenia to be the demonstrated evidence of fluid retention. dose-limiting toxicity. Initial clinical trials also demonstrated Conclusions: Administered at the stated dose and scheddocetaxel's activity in ovarian, breast, and non-small cell lung ule, docetaxel has little activity against metastatic colorectal cancer. Because of this encouraging preclinical and clinical carcinomas. The toxicity profile, consisting of granulocytoactivity, we initiated a phase II study of docetaxel in patients penia, hypersensitivity reactions, cutaneous reactions, and with metastatic colorectal carcinoma. edema, has been previously described in patients receiving Patients and methods: Docetaxel, 100 mg/m2, was admin- docetaxel. istered as a 1-hour intravenous infusion every 21 days. Nineteen patients were entered on the trial. All patients had measurable disease and had not received prior chemother- Key words: docetaxel, Taxotere*, paclitaxel, Taxol®, colorecapy for metastatic disease. tal carcinomas, colon carcinoma, rectal carcinoma Summary
Introduction
Little progress has been made in the treatment of metastatic colorectal carcinoma. Fluorouracil remains the agent most active against this disease. Attempts to biochemically modulate this drug with folinic acid have led to improved response rates but have had little impact on patient survival [1]. Thus, enrollment of patients into well-designed clinical trials examining new agents or treatment strategies should be actively pursued. Researchers from Rhone-Poulenc (Antony, France) in conjunction with the French Centre National de la Recherche Scientifique have developed docetaxel (Taxotere® RP 56976, NSC-628503), a compound structurally related to paclitaxel (Taxol*). Like paclitaxel, docetaxel promotes microtubule assembly and inhibits the depolymerization of tubulin, thus stabilizing microtubules [3]. Docetaxel was very active in colon adenocarcinoma murine models and in the B16 melanoma model caused a total log cell kill 2.7 times greater than that of paclitaxel at equitoxic doses [4]. Phase I clinical testing of docetaxel revealed granulocytopenia to be the dose-limiting toxicity; however, schedules that induced oral mucositis also had lower maximum tolerated doses [2, 5]. Other toxic effects observed included
hypersensitivity reactions (HSRs), cutaneous toxic effects, asthenia, and paresthesias. We report here results of a phase II trial of docetaxel in patients with metastatic colorectal carcinoma. Patients and methods Patient eligibility criteria included histologically confirmed colorectal adenocarcinoma, bidimensionally measurable disease, adequate performance status (>60%, Karnofsky), and a life expectancy >3 months. Informed consent was also required of all patients. In addition, patients could not have received systemic chemotherapy for advanced colorectal carcinoma, though prior adjuvant chemotherapy was allowable if it had been completed at least 1 year before study entry. Other study inclusion criteria were adequate hematologic function (absolute granulocyte count >2000/ul, platelet count >100,000/nl), renal function (serum creatinine level <2.0 mg/dl), and hepatic function (total serum bilirubin level <1.5 mg/dl and serum alanine aminotransferase level < 2 x upper limit of normal). Prior radiotherapy did not preclude a patient's eligibility provided that the radiation field had not included the site of the measurable disease. Standard response and toxicity criteria were used [6]. Docetaxel was provided by Rhone-Poulenc Rorer (Collegeville, Pennsylvania, U.S.A.) as a concentrated sterile solution containing 40 mg/ml in polysorbate 80 (Tween 80) for intravenous administration. The final drug was diluted in 250 ml of 5% dextrose solution and then administered via a peristaltic infusion pump. Docetaxel was administered as a 1-hour infusion at a dose of 100
469 mg/m2 every 21 days. Neither antiemetics nor hematologic growth factors were given prophylactically. Upon recovery, patients who had experienced grade 3 or 4 neutropenia with associated fever requiring parenteral antibiotics received docetaxel at a 25% dose reduction, as did those recovered patients who had developed gTade 4 thrombocytopenia. Patients with less severe degrees of myelosuppression resumed docetaxel treatment at their original dose level upon adequate hematologic recovery. Grade 4 vomiting, gTade 2 peripheral neuropathy, and all other toxic effects of grade 3 or higher also required a 25% docetaxel dose reduction. Patients in whom doses were reduced did not have subsequent re-escalation of their doses. A patient was permitted a maximum of two dose reductions of 25% each; patients who continued to experience severe toxic reactions after these reductions were removed from the study. The protocol was amended after the entry of patient #7 to allow for the routine use of prophylactic diphenhydramine to prevent hypersensitivity reactions (HSRs). Patients who experienced an HSR during treatment received a second dose of diphenhydramine (50 mg intravenously) plus dexamethasone (10 mg intravenously), after which docetaxel infusion resumed.
Results
Nineteen patients (11 men and 8 women) with a median age of 54 years (range, 35 to 75 years) were entered on the trial. In all 19, tumor response and drug toxicity were evaluable. Two patients had received prior adjuvant chemotherapy, which was completed 24 and 16 months before entry onto the study. Sites of measurable disease included the liver (18 patients), lung (5 patients), abdominal lymph nodes (5 patients), and abdominal wall (1 patient). We observed no partial or complete responses. Two patients experienced minor responses lasting 14 and 6 weeks. The median survival time for all patients was 12 months. Toxic reactions observed in 19 patients entered on the trial are listed in Table 1. Granulocytopenia was the dose-limiting toxic effect. The median granulocyte nadir, occurring on day 9, was 200/ul (range, 0-5700/ li\), with a median duration of suppression of 6 days
(range, 1-14 days). Five patients were hospitalized to receive parenteral antibiotic therapy for granulocytopenic fevers. There were 41 courses of docetaxel administered at 100 mg/m2 and 2 courses administered at 75 mg/m2. HSRs were noted in 12 patients (16 courses). Nine patients had only mild HSRs manifested by pruritus, flushing, skin rash, or drug-associated fever. Three patients had severe HSRs characterized by hypotension, dyspnea, and/or bronchospasm. Of the 12 patients who received prophylactic diphenhydramine, 5 experienced mild HSRs and 2 had severe HSRs. These reactions occurred during the initial 1-3 minutes of the docetaxel infusion and required its interruption. Docetaxel treatments were continued with the use of intravenous diphenhydramine and corticosteroids as prophylaxis for HSRs. Most HSRs occurred during the first course; 6 patients did not have HSRs during the first course but experienced this toxic effect during the second course. One patient had periorbital angioedema, which responded to oral corticosteroids. Of 12 patients who had HSRs, 10 completed docetaxel therapy after receiving prophylactic treatment. Cutaneous toxic effects included maculopapular eruptions (13 patients), usually occurring at pressure points or sites of tissue trauma or sun exposure. Also observed was onycholysis of the fingernails and toenails (5 patients). One patient had evidence of fluid retention manifested by pleural effusions. We observed neither motor nor sensory toxic effects.
Discussion
Docetaxel at this dose and schedule failed to demonstrate clinical activity significant to warrant further investigation of this agent in metastatic colorectal carcinomas. The activity of docetaxel in ovarian, breast, non-small cell lung carcinomas, and head and neck cancers, which was observed in phase I testing, has Table 1. Incidence of major toxic effects of docetaxel (according to been corroborated in extensive phase II testing. Likewise, the toxic effects of docetaxel have also grade) in 19 patients with metastatic colorectal carcinoma. been further elucidated during phase II testing. As sugIncidence by grade1 Toxic effect (by grade) gested by phase I test results, granulocytopenia is the acute dose-limiting toxicity. Brief but severe granulo1 2 3 4 cytopenia was documented in our clinical trial. Serious _ _ Granulocytopenia 17 thrombocytopenia was not noted. 6 Thrombocytopenia 1 Patients entered on phase I studies of docetaxel did Anemia 3 not receive premedication as prophylaxis for HSRs. 11 Hypersensitivity reactions 12 The overall incidence of HSRs in phase I trials was Oral mucositis 3 4 Skin reactions 7 8 18%; 4% of those patients had severe HSRs [2]. Phase 1 Fatigue 9 5 II trials of docetaxel were also initiated without preAlopecia 18 1 medications. However, increased occurrences of HSRs Stomatitis 3 4 caused most U.S. and Canadian trials to be amended to Diarrhea 11 3 Myalgia 6 3 provide for HSR prophylaxis. Our trial was amended Edema/pleural effusion 1 to include the use of prophylactic diphenhydramine. Headache 2 This medication did little to reduce the incidence of HSRs, however; of the 12 patients who received it, 7 Number of patients per grade. experienced HSRs. Grade 3 bronchospasm or requiring parenteral medication.
470
A fluid retention syndrome manifested by peripheral edema, ascites, and pleura] effusions has been observed in phase II trials [2, 7, 8]. This toxic effect may be related to the cumulative dose of docetaxel, as more than half the patients who received >A courses of docetaxel experienced this syndrome, which frequently caused treatment delays or discontinuation [7j. Since most of our patients only received 2 courses, this syndrome was noted in only 1 patient. Phase n trials of docetaxel have further elucidated toxic effects of the skin that appear to be noncumulative. We observed changes in the fingernails and toenails, including thinning and ridging of the nail plates and proximal and distal shedding of the nails. Acral erythema, a previously characterized toxic effect of 5-fluorouracil administered as protracted infusion, was not observed in our patients. An interesting cutaneous phenomenon observed was the predilection of skin reactions to occur at sites of previous injury or pressure. Patients developed cutaneous reactions at sites of intravenous line insertions, at monitor pad locations, or on the feet or buttocks. An ointment consisting of glycerin and chlorhexidine has been reported to improve severe skin reactions; however, this intervention was not used in our trial [7]. Prophylactic corticosteroids, administered 12 to 24 hours before docetaxel, were introduced into selected phase II clinical trials. This measure has reduced the incidence of HSRs, skin toxic effects, and the fluid retention syndrome [2,7]. Our study failed to demonstrate significant activity of docetaxel against metastatic colorectal carcinomas. A European clinical trial similarly concluded that docetaxel did not appear active against this disease [8]. Docetaxel's acute toxic effects described in phase I reports were corroborated by our experience. Because most of our patients received only one or two courses of docetaxel, we did not commonly observe the fluid
retention syndrome described in other phase II trials. Acknowledgement
This work was supported in part by a grant from Rhone-Poulenc Rorer (Collegeville, Pennsylvania 19426, U.S.A.). References 1. The Advanced Colorectal Meta-AnaJysis Project. Modulation of fluorouracil with leucovorin in patients with advanced colorectal cancer Evidence in terms of response. J Clin Oncol 1992; 10: 896-903. 2. Pazdur R, Kudelka AP, Kavanagh J et a). The taxoids: Paclitaxel (Taxol) and docetaxel (Taxotere). Cancer Treat Rep 1993; 19: 351-86. 3. Ringel I, Horwitz SB. Studies with RP 56976 Taxotere: A semisynthetic analogue of taxol. J Natl Cancer Inst 1991; 83: 288-91. 4. Bissery M-C, Guenard D, Gueritte-Voegelein F et al. Experimental antitumor activity of Taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res 1991; 51:4845-52. 5. Pazdur R, Newman RA, Newman BM et al. Phase I trial of taxotere: Five-day schedule. J Natl Cancer Inst 1992; 84:1781-8. 6. Ajani JA, Welch SR, Raber MN et al. Comprehensive criteria for survival in therapy-induced toxicity. Cancer Invest 1990; 8: 141-53. 7. Schrijvers D, Wanders J, Dirix L et al. Coping with toxicities of docetaxel (Taxotere). Ann Oncol 4:610-1. 8. Sternberg N, Ten Bokkel Huinink W, Kaye S et al. Taxotere in the treatment of advanced colorectal carcinoma. Eur J Cancer 1993; 29A supplement: S100 (abstract). Received 19 January 1994; accepted 25 January 1994. Correspondence to: Richard Pazdur, MX). Box 92 The University of Texas M.D. Anderson Cancer Center 1515 Holcombe Boulevard Houston, Texas 77030, U.S.A.
Short report Phase II trial of docetaxel (Taxotere®) in metastatic colorectal carcinoma R. Pazdur,1 Y. Lassere,1 L. T. Soh,2 J. A. Ajani,1 B. Bready,1 E. Soo,1 S. Sugarman,1 Y. Patt,1 J. L. Abbruzzese1 & B. Levin1 1
Divisions of Medicine and Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas U.S^A.; 2Department of Medical Oncology, Singapore General Hospital, Singapore
Results: No complete or partial responses were observed. Granulocytopenia was the dose-limiting toxic effect. SevenBackground: Docetaxel (Taxotere*) is prepared from a non- teen patients had grade 4 granulocytopenia; 8 of these pacytotoxic precursor extracted from the needles of the Taxus tients received antibiotics for neutropenic fevers. Twelve baccata. Preclinical investigations have demonstrated that patients experienced hypersensitivity reactions, and 15 padocetaxel is very active in colon adenocarcinoma murine tients experienced cutaneous toxic reactions. One patient models. Phase I studies revealed granulocytopenia to be the demonstrated evidence of fluid retention. dose-limiting toxicity. Initial clinical trials also demonstrated Conclusions: Administered at the stated dose and scheddocetaxel's activity in ovarian, breast, and non-small cell lung ule, docetaxel has little activity against metastatic colorectal cancer. Because of this encouraging preclinical and clinical carcinomas. The toxicity profile, consisting of granulocytoactivity, we initiated a phase II study of docetaxel in patients penia, hypersensitivity reactions, cutaneous reactions, and with metastatic colorectal carcinoma. edema, has been previously described in patients receiving Patients and methods: Docetaxel, 100 mg/m2, was admin- docetaxel. istered as a 1-hour intravenous infusion every 21 days. Nineteen patients were entered on the trial. All patients had measurable disease and had not received prior chemother- Key words: docetaxel, Taxotere*, paclitaxel, Taxol®, colorecapy for metastatic disease. tal carcinomas, colon carcinoma, rectal carcinoma Summary
Introduction
Little progress has been made in the treatment of metastatic colorectal carcinoma. Fluorouracil remains the agent most active against this disease. Attempts to biochemically modulate this drug with folinic acid have led to improved response rates but have had little impact on patient survival [1]. Thus, enrollment of patients into well-designed clinical trials examining new agents or treatment strategies should be actively pursued. Researchers from Rhone-Poulenc (Antony, France) in conjunction with the French Centre National de la Recherche Scientifique have developed docetaxel (Taxotere® RP 56976, NSC-628503), a compound structurally related to paclitaxel (Taxol*). Like paclitaxel, docetaxel promotes microtubule assembly and inhibits the depolymerization of tubulin, thus stabilizing microtubules [3]. Docetaxel was very active in colon adenocarcinoma murine models and in the B16 melanoma model caused a total log cell kill 2.7 times greater than that of paclitaxel at equitoxic doses [4]. Phase I clinical testing of docetaxel revealed granulocytopenia to be the dose-limiting toxicity; however, schedules that induced oral mucositis also had lower maximum tolerated doses [2, 5]. Other toxic effects observed included
hypersensitivity reactions (HSRs), cutaneous toxic effects, asthenia, and paresthesias. We report here results of a phase II trial of docetaxel in patients with metastatic colorectal carcinoma. Patients and methods Patient eligibility criteria included histologically confirmed colorectal adenocarcinoma, bidimensionally measurable disease, adequate performance status (>60%, Karnofsky), and a life expectancy >3 months. Informed consent was also required of all patients. In addition, patients could not have received systemic chemotherapy for advanced colorectal carcinoma, though prior adjuvant chemotherapy was allowable if it had been completed at least 1 year before study entry. Other study inclusion criteria were adequate hematologic function (absolute granulocyte count >2000/ul, platelet count >100,000/nl), renal function (serum creatinine level <2.0 mg/dl), and hepatic function (total serum bilirubin level <1.5 mg/dl and serum alanine aminotransferase level < 2 x upper limit of normal). Prior radiotherapy did not preclude a patient's eligibility provided that the radiation field had not included the site of the measurable disease. Standard response and toxicity criteria were used [6]. Docetaxel was provided by Rhone-Poulenc Rorer (Collegeville, Pennsylvania, U.S.A.) as a concentrated sterile solution containing 40 mg/ml in polysorbate 80 (Tween 80) for intravenous administration. The final drug was diluted in 250 ml of 5% dextrose solution and then administered via a peristaltic infusion pump. Docetaxel was administered as a 1-hour infusion at a dose of 100
469 mg/m2 every 21 days. Neither antiemetics nor hematologic growth factors were given prophylactically. Upon recovery, patients who had experienced grade 3 or 4 neutropenia with associated fever requiring parenteral antibiotics received docetaxel at a 25% dose reduction, as did those recovered patients who had developed gTade 4 thrombocytopenia. Patients with less severe degrees of myelosuppression resumed docetaxel treatment at their original dose level upon adequate hematologic recovery. Grade 4 vomiting, gTade 2 peripheral neuropathy, and all other toxic effects of grade 3 or higher also required a 25% docetaxel dose reduction. Patients in whom doses were reduced did not have subsequent re-escalation of their doses. A patient was permitted a maximum of two dose reductions of 25% each; patients who continued to experience severe toxic reactions after these reductions were removed from the study. The protocol was amended after the entry of patient #7 to allow for the routine use of prophylactic diphenhydramine to prevent hypersensitivity reactions (HSRs). Patients who experienced an HSR during treatment received a second dose of diphenhydramine (50 mg intravenously) plus dexamethasone (10 mg intravenously), after which docetaxel infusion resumed.
Results
Nineteen patients (11 men and 8 women) with a median age of 54 years (range, 35 to 75 years) were entered on the trial. In all 19, tumor response and drug toxicity were evaluable. Two patients had received prior adjuvant chemotherapy, which was completed 24 and 16 months before entry onto the study. Sites of measurable disease included the liver (18 patients), lung (5 patients), abdominal lymph nodes (5 patients), and abdominal wall (1 patient). We observed no partial or complete responses. Two patients experienced minor responses lasting 14 and 6 weeks. The median survival time for all patients was 12 months. Toxic reactions observed in 19 patients entered on the trial are listed in Table 1. Granulocytopenia was the dose-limiting toxic effect. The median granulocyte nadir, occurring on day 9, was 200/ul (range, 0-5700/ li\), with a median duration of suppression of 6 days
(range, 1-14 days). Five patients were hospitalized to receive parenteral antibiotic therapy for granulocytopenic fevers. There were 41 courses of docetaxel administered at 100 mg/m2 and 2 courses administered at 75 mg/m2. HSRs were noted in 12 patients (16 courses). Nine patients had only mild HSRs manifested by pruritus, flushing, skin rash, or drug-associated fever. Three patients had severe HSRs characterized by hypotension, dyspnea, and/or bronchospasm. Of the 12 patients who received prophylactic diphenhydramine, 5 experienced mild HSRs and 2 had severe HSRs. These reactions occurred during the initial 1-3 minutes of the docetaxel infusion and required its interruption. Docetaxel treatments were continued with the use of intravenous diphenhydramine and corticosteroids as prophylaxis for HSRs. Most HSRs occurred during the first course; 6 patients did not have HSRs during the first course but experienced this toxic effect during the second course. One patient had periorbital angioedema, which responded to oral corticosteroids. Of 12 patients who had HSRs, 10 completed docetaxel therapy after receiving prophylactic treatment. Cutaneous toxic effects included maculopapular eruptions (13 patients), usually occurring at pressure points or sites of tissue trauma or sun exposure. Also observed was onycholysis of the fingernails and toenails (5 patients). One patient had evidence of fluid retention manifested by pleural effusions. We observed neither motor nor sensory toxic effects.
Discussion
Docetaxel at this dose and schedule failed to demonstrate clinical activity significant to warrant further investigation of this agent in metastatic colorectal carcinomas. The activity of docetaxel in ovarian, breast, non-small cell lung carcinomas, and head and neck cancers, which was observed in phase I testing, has Table 1. Incidence of major toxic effects of docetaxel (according to been corroborated in extensive phase II testing. Likewise, the toxic effects of docetaxel have also grade) in 19 patients with metastatic colorectal carcinoma. been further elucidated during phase II testing. As sugIncidence by grade1 Toxic effect (by grade) gested by phase I test results, granulocytopenia is the acute dose-limiting toxicity. Brief but severe granulo1 2 3 4 cytopenia was documented in our clinical trial. Serious _ _ Granulocytopenia 17 thrombocytopenia was not noted. 6 Thrombocytopenia 1 Patients entered on phase I studies of docetaxel did Anemia 3 not receive premedication as prophylaxis for HSRs. 11 Hypersensitivity reactions 12 The overall incidence of HSRs in phase I trials was Oral mucositis 3 4 Skin reactions 7 8 18%; 4% of those patients had severe HSRs [2]. Phase 1 Fatigue 9 5 II trials of docetaxel were also initiated without preAlopecia 18 1 medications. However, increased occurrences of HSRs Stomatitis 3 4 caused most U.S. and Canadian trials to be amended to Diarrhea 11 3 Myalgia 6 3 provide for HSR prophylaxis. Our trial was amended Edema/pleural effusion 1 to include the use of prophylactic diphenhydramine. Headache 2 This medication did little to reduce the incidence of HSRs, however; of the 12 patients who received it, 7 Number of patients per grade. experienced HSRs. Grade 3 bronchospasm or requiring parenteral medication.
470
A fluid retention syndrome manifested by peripheral edema, ascites, and pleura] effusions has been observed in phase II trials [2, 7, 8]. This toxic effect may be related to the cumulative dose of docetaxel, as more than half the patients who received >A courses of docetaxel experienced this syndrome, which frequently caused treatment delays or discontinuation [7j. Since most of our patients only received 2 courses, this syndrome was noted in only 1 patient. Phase n trials of docetaxel have further elucidated toxic effects of the skin that appear to be noncumulative. We observed changes in the fingernails and toenails, including thinning and ridging of the nail plates and proximal and distal shedding of the nails. Acral erythema, a previously characterized toxic effect of 5-fluorouracil administered as protracted infusion, was not observed in our patients. An interesting cutaneous phenomenon observed was the predilection of skin reactions to occur at sites of previous injury or pressure. Patients developed cutaneous reactions at sites of intravenous line insertions, at monitor pad locations, or on the feet or buttocks. An ointment consisting of glycerin and chlorhexidine has been reported to improve severe skin reactions; however, this intervention was not used in our trial [7]. Prophylactic corticosteroids, administered 12 to 24 hours before docetaxel, were introduced into selected phase II clinical trials. This measure has reduced the incidence of HSRs, skin toxic effects, and the fluid retention syndrome [2,7]. Our study failed to demonstrate significant activity of docetaxel against metastatic colorectal carcinomas. A European clinical trial similarly concluded that docetaxel did not appear active against this disease [8]. Docetaxel's acute toxic effects described in phase I reports were corroborated by our experience. Because most of our patients received only one or two courses of docetaxel, we did not commonly observe the fluid
retention syndrome described in other phase II trials. Acknowledgement
This work was supported in part by a grant from Rhone-Poulenc Rorer (Collegeville, Pennsylvania 19426, U.S.A.). References 1. The Advanced Colorectal Meta-AnaJysis Project. Modulation of fluorouracil with leucovorin in patients with advanced colorectal cancer Evidence in terms of response. J Clin Oncol 1992; 10: 896-903. 2. Pazdur R, Kudelka AP, Kavanagh J et a). The taxoids: Paclitaxel (Taxol) and docetaxel (Taxotere). Cancer Treat Rep 1993; 19: 351-86. 3. Ringel I, Horwitz SB. Studies with RP 56976 Taxotere: A semisynthetic analogue of taxol. J Natl Cancer Inst 1991; 83: 288-91. 4. Bissery M-C, Guenard D, Gueritte-Voegelein F et al. Experimental antitumor activity of Taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res 1991; 51:4845-52. 5. Pazdur R, Newman RA, Newman BM et al. Phase I trial of taxotere: Five-day schedule. J Natl Cancer Inst 1992; 84:1781-8. 6. Ajani JA, Welch SR, Raber MN et al. Comprehensive criteria for survival in therapy-induced toxicity. Cancer Invest 1990; 8: 141-53. 7. Schrijvers D, Wanders J, Dirix L et al. Coping with toxicities of docetaxel (Taxotere). Ann Oncol 4:610-1. 8. Sternberg N, Ten Bokkel Huinink W, Kaye S et al. Taxotere in the treatment of advanced colorectal carcinoma. Eur J Cancer 1993; 29A supplement: S100 (abstract). Received 19 January 1994; accepted 25 January 1994. Correspondence to: Richard Pazdur, MX). Box 92 The University of Texas M.D. Anderson Cancer Center 1515 Holcombe Boulevard Houston, Texas 77030, U.S.A.