- Email: [email protected]
A phase I clinical trial of intraperitoneal thiotepa for refractory ovarian cancer
GYNECOLOGIC
ONCOLOGY
36,
331-334 (19%)
A Phase I Clinical Trial of lntraperitoneal Thiotepa for Refractory Ovarian Cancer’ SAEEDA KIRMANI,’ LORI MCVEY, Department
of Medicine
and the Cancer
Center,
DAVID Loo, AND STEPHEN B. HOWELL
University
of California,
San Diego,
La Jolla,
California
92093
Received April 4, 1989
Treatment optionsfor patients with ovarian cancer who have failed systemic and intraperitoneal (ip) cisplatin-basedchemotherapy are limited. We conducteda phaseI clinical study of ip thiotepa in patientswith refractory ovarian cancerto determine the maximumtolerated dose(MTD). Ten patientsweregiven 39 coursesof thiotepa (mediannumber of coursesper patient, 3.5; range, l-10+). All patients had received prior ip cisplatin; 7 alsohad receivediv cisplatin, and 5 had had three or moreprior regimens.Thiotepa (30-80 mg/m’) wasgiven ip in 2 liters normal salineevery 4 weeks.The therapy waswell tolerated. There was no vomiting, stomatitis,alopecia,or peritonitis. The dose-limiting toxicity wasmyelosuppression. With repeateddoses,patientshad a delayedmarrow recovery and requireda l- to 2-weekdelay in treatment. Six patients had stable disease(duration 2-14+ months;medianduration 5 months);1 patient had a 50% decrease in CA-125 level, and 1 patient with no measurablediseaseremainedclinically disease-free.In summary,ip thiotepa had clinical activity in heavily pretreatedpatientswith refractory ovarian cancerwith diseasestabilization seenin 6 of 9 evaluablepatients and a partial responseseenin 1 patient. Myelosuppressionwas the only toxicity encountered. A doseof 60 mg/m* ip is recommendedfor phaseII studies, o 1990 Academic PRESS, I~C. INTRODUCTION Patients with ovarian cancer who fail systemic chemotherapy can still respond to intraperitoneal cisplatinbased chemotherapy regimens [1,2]. However, therapeutic options for patients failing salvage intraperitoneal cisplatin are limited. Triethylenethiophosphoramide (thiotepa) is a synthetic polyfunctional alkylating agent with known activity against ovarian cancer that has been in clinical use for more than 35 years [3]. Until very re-
cently, however, its use was limited to intracavitory administration for control of malignant effusions [4-61, intravesical instillation for bladder cancer [7,8], and intrathecal administration for meningeal carcinomatosis [9,10]. In the past several years high dose thiotepa has been used for bone marrow transplantation, and it has resurfaced in low-dose combination chemotherapy for breast cancer [ 11,121. Thiotepa is well tolerated locally when given by any route. Considerable information has now been collected about the maximum tolerated dose and toxicity of thiotepa in the setting of bone marrow transplantation. There is less information about the dose response or the maximum tolerated dose in other situations. One study showed that doubling the thiotepa dose resulted in more than a fivefold increase in tumor response in Hodgkins disease [13], consistent with the observation of steep dose-response curves for many alkylating agents [ 141. Ovarian cancer remains confined to the peritoneal cavity even in advanced stages. Since thiotepa is well tolerated locally and has known activity in ovarian cancer we initiated a phase I trial to determine the maximum tolerated dose of intraperitoneal thiotepa given every 4 weeks. PATIENTS AND METHODS
Patients were eligible for this study if they had a histologically confirmed malignancy, principally confined to the peritoneal cavity, that was refractory to conventional modes of therapy, or for which no effective treatment existed. Patients were required to have recovered from the effects of prior therapy. All patients had a totally implanted peritoneal access system surgically placed prior to beginning chemotherapy. This consisted of a Port-a-Cath connected to a Tenckhoff catheter (Pharmacia Deltec, St. Paul, MN) [15]. All patients were treated in the outpatient setting. Weekly blood counts were obtained. Peritoneal cytology
I Supported in part by Grants CA 35309 and CA 23100 from the National Institutes of Health. This work was conducted in part by the Clayton Foundation for Research-California Division. Dr. Howell is a Clayton Foundation investigator. 2 To whom reprint requests should be addressed. 331
0090-8258/90
$1.50
Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
332
KIRMANI
and CA-125 measurements were obtained every month. An abdominal and pelvic CT scan was obtained prior to treatment and at the end of the study to assess response. The starting dose of thiotepa was 30 mg/m* ip every 4 weeks. The dose was escalated by 20 mg/m’ when at least three courses in two patients were fully evaluable for toxicity and were well tolerated. The drug was given in 2 liters of normal saline and allowed to run into the peritoneal cavity as rapidly as possible. The fluid was not routinely drained. A white blood count of greater than 3000/mm3 and a platelet count of greater than 100,000/mm3 were required before retreatment. Patients were treated until there was evidenc
TABLE 1 Patient Characteristics No. of patients Median age (range) Performance status 0 1 2 3 Prior chemotherapy ip cisplatin iv cisplatin Other alkylators Three or more regimens Prior radiation Extent of disease Bulky Limited Histology Serous Mutinous Other Grade 1 2 3 Not specified
IO 63 (38-71) 3 5 1 1 IO 10 7 7 5 0 6 4 7 2 1 2 0 7 1
ET AL.
mide. Six patients had bulky disease defined as tumor masses larger than 2 cm at the time of study entry. A total of 39 courses of chemotherapy were given. The median number of courses per patient was 3.5 (range llo+). Patients were treated until there was evidence of disease progression or toxicity. The reasons for stopping treatment are presented in Table 2. Patients were removed from study because of hematologic toxicity if they required a greater than 2-week delay in treatment because of myelosuppression despite reducing the dose of thiotepa. One patient had stable disease after 2 courses, but experienced prolonged myelosuppression and had progressive disease when she was restarted on chemotherapy; she is listed twice. The treatment was very well tolerated until a dose of 80 mg/m’ was reached. At this dose significant and prolonged myelosuppression was seen. Three patients received 4 courses at this dose level. Two out of three patients developed grade 4 hematologic toxicity and 3 of 4 courses required a 3-week delay before the next cycle could be given. The hematologic toxicity as a function of dose is presented in Tables 3 and 4. Thirty-five of the 39 courses were evaluable for hematologic toxicity. Three courses were given at a dose of 30 mg/m’. One patient was deescalated to 20 mg/m’ and one patient was started at 25 mg/m’. These courses were analyzed as a group. Sixteen courses were given to seven patients at a dose of 60 mg/m’. The median nadir white blood count at this dose level was 2700/mm3, the median nadir granulocyte count was 1800/mm3, and the median nadir platelet count was 1 12,000/mm3. A dose of 60 mg/m2 is therefore the recommended dose for future studies. The relationship between the time to marrow recovery and cumulative treatment is shown in Fig. 1. In this figure courses in which the thiotepa was given at 30-60 mg/m’ are plotted against the time interval between courses. With repeated doses, patients exhibited a mild prolonged thrombocytopenia which required a delay in starting the next cycle. This delay is statistically significant (correlation of coefficient = 0.52, P value is less than 0.05). By the time patients received their third course of thiotepa, the median interval between treatment was 5 weeks instead of 4, and by the sixth course this had increased to 6 weeks. No nonhematologic toxicity was observed. Specifically, there was no local toxicity or peritonitis, and no TABLE 2 Reasonsfor Discontinuing Treatment Progressive disease Progressive disease after initial stabilization Hematologic toxicity Technical problems Still on treatment
2 3 3 2 1
INTRAPERITONEAL
THIOTEPA
FOR OVARIAN
333
CANCER
TABLE 3 Hematologic Toxicity as a Function of Dose Dose (w/m’) 30 40 60 80
Median nadir counts x lO’/pliter No. of courses
No. of patients treated
New patients entered
WBC
5 10 16 4
4 5 7 3
3 2 3 2
3.1(2.4-4.9)” 2.9(2.1-5.0) 2.7(1.0-4.6) 1.9(0.2-3.1)
Granulocytes
Platelets
1.9(1.8-2.8) 1.7(1.2-2.7) 1.8(0.4-3.2) 0.7(0.0-l. 1)
92(77-280) 160(54-237) 112(18-240) 62(15-101)
L?Numbers in parentheses refer to range of nadir counts.
vomiting, stomatitis, alopecia, renal, or hepatic dysfunction. Even though this was a phase I study, nine patients had measurable disease and were evaluable for response. The one patient with no measurable disease received four courses and then her treatment was stopped because of hematologic toxicity. She remained without any clinical evidence of disease throughout her treatment. The other three patients with nonbulky disease had less than 2-cm disease noted on CT scan (retroperitoneal adenopathy, mesenteric adenopathy, and vaginal cuff mass), in addition to a positive peritoneal cytology and elevated CA125 levels. One patient with small volume disease had a 50% decrease in CA-125 after one course, but her treatment was stopped because of catheter malfunction. Six other patients had stable disease for 2 to 14+ months (median duration, 5 months). Five of these patients had bulky disease with tumor nodules measuring more than 2 cm. Two patients had disease progression. DISCUSSION This study was done to determine the maximum tolerated dose of thiotepa given as an intraperitoneal instillation every 4 weeks. A dose of 60 mg/m* ip every 4 weeks was well tolerated with acceptable hematologic toxicity. Even at the highest dose of 80 mg/m’ there was no local or systemic nonhematologic toxicity. This complete absence of nonhematologic toxicity has been observed in the setting of autologous bone marrow trans-
plantation where skin toxicity, gastrointestinal toxicity, and central nervous system toxicity is observed only when doses exceeding 900 mg/m’ are used [16]. In another study a dose of 150-200 mg/m* given intravenously produced no toxicity apart from myelosuppression [17]. A recently published study [18] confirmed the absence of local toxicity of intraperitoneal thiotepa and the myelosuppression at 60 mg/m* was very similar to that seen in our study. This is the first time, to our knowledge, that a dose of 80 mg/m* has been given intraperitoneally. No local toxicity was seen at this dose level. Pharmacokinetic analysis was not done in this study; however, Wadler ef al. have reported that thiotepa has a pharmacologic advantage (peritoneal to plasma AUC ratio) of 4.3 [18]. While this is not a very high ratio compared to other drugs that can be given by the ip route, it still means that for each unit of myelosuppression, one still gets a fourfold greater exposure for the peritoneal cavity. This pharmacologic advantage, when combined with the absence of local toxicity, makes the intraperitoneal route an attractive way to administer this drug for malignancies confined to the peritoneal cavity. The ease of administration in the outpatient setting, and the lack of side effects, was a welcome change for patients who had been through 6-12 months of high-dose cisplatin. All these patients were heavily pretreated and most had received prior alkylating agents. Yet in 8 of 10 patients ip thiotepa prevented disease progression for a median duration of 5 months (range 2-14 +). While other treatment regimens clearly need to be found for patients who have failed iv
TABLE
4
Hematologic Toxicity by Grade WBC grade”
Granulocytes grade
Platelets grade
Dose level (w/m’)
No. of courses
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
30 40 60 80
5 10 16 4
1 3 2 0
3 2 4 1
1 5 8 1
0 0 2 1
0” 0 0 1
2 4 4 0
3 4 7 0
0 2 4 1
0 0 0 2
0 0 1 1
2 6 7 0
3 2 4 2
0 2 4 0
0 0 0 1
0 0 1 1
a Common toxicity criteria. b Number of courses on which the indicated grade of toxicity occurred.
334
KIRMANI
IOr 4 .
07-
.
O-
, -
... .
..
.
.
.
2
3
4
6
6
3-
I
I' 1
7
a
9
10
COURSENUMBER FIG. 1. Effect of repeated courses on the time to marrow recovery. The interval between courses in weeks is plotted against the course number. Each square represents a course. Line indicates best linear least mean square fit.
and ip cisplatin, ip thiotepa is a safe and nontoxic drug that can control refractory ovarian cancer for a period of time. A dose of 60 mg/m’ ip every 4 weeks is recommended for phase II studies. REFERENCES Howell, S. B., Zimm, S., Markman, M., Abramson, I. S., Cleary, S., Lucas, W. E., and Weiss, R. J. Long term survival of advanced refractory ovarian carcinoma patients with small volume disease treated with intraperitoneal chemotherapy, J. C/in. Oncol. 5, l6071612 (1987). Kirmani, S., Zimm, S., Cleary, S. M., Horton, C., and Howell, S. B. Intraperitoneal cisplatin and etoposide (ipDDP/VPl6) as salvage therapy for ovarian cancer, Proc. Amer. Sot. Clin. Oncol. 7, 117 (1988). Sykes, M., Karnofsky, D., and Phillips, F. Clinical studies of triethylenephosphoramide and diethylenephosphoramide compounds with nitrogen mustard-like activity, Cancer 6, 142-148 (1953).
ET AL. ’4. Groesbeck, H. O., and Cudmore, J. T. P. Intracavitory thio-TEPA for malignant effusions, Amer. Surg. 28, 90-95 (1962). 5. Bateman, J. C., Moulton, B., and Larson, N. J. Control of neoplastic effusion by phosphoramide chemotherapy, Arch. Int. Med. 95, 713-719 (1955). 6. Anderson, A. P., and Brincker, H. Intracavitory thiotepa in malignant pleural and peritoneal effusions, Acta Radio/. Ther. Phys. Biol. 7, 369-378 (1968). 7. Jones, H. C., and Swinney, J. Thiotepa in the treatment of tumors of the bladder, Lancet 2, 615-618 (1961). 8. Veenema, R. J., Dean, A. L., Jr., and Uson, A. C. Thiotepa bladder instillations: Therapy and prophylaxis for superficial bladder tumors, J. Ural. 101, 711-715 (1969). 9. Gutin, P. H., Levi, J. I., and Wiernik, P. H. Treatment of malignant meningeal disease with intrathecal thiotepa: A phase II study, Cancer Treat. Rep. 61, 885-887 (1977). 10. Trump, D. L., Grossman, S. A., and Thompson, G. Treatment of neoplastic meningitis with intraventricular thiotepa and methotrexate, Cancer Treut. Rep. 66, 1549-1551 (1982). Il. Perloff, M., Hart, R. D., and Holland, J. F. Vinblastine, adriamycin thiotepa and halotestin (VATH): Therapy for advanced breast cancer refractory to prior therapy, Cancer 39, 1289-1293 (1977). 12. Hart, R. D., Perloff, M., and Holland, J. F. One day VATH therapy for advanced breast cancer refractory to prior chemotherapy, Cancer 48, 1522-1527 (1981). 13. Brindley, C. O., Salvin, L. G., and Potee, K. G. Further comparitive trial of triethylene thiophosphoramide and mechlorethamine in patients with melanoma and Hodgkins disease, J. Chronic Dis. 17, 19-30 (1964). 14. Frei, E., III, Cucchi, C. A., and Rosowski, A. Alkylating agent resistance: In vitro studies with human cell lines, Proc. Nat/. Acad. Sci. USA 82, 2158-2162 (1985). 1.5. Pfeifle, C. E., Howell, S. B., and Markman, M. Totally implantable system for peritoneal access, J. C/in. Oncol. 2, 1277-1280 (1984). 16. Herzig, R. H., Fay. J. W., and Herzig, G. P. Phase I-II studies with high-dose thiotepa and autologous marrow transplantation in patients with refractory malignancies, in High-dose thiotepa and nutologous marrow transplantation-Advances in cancer chemotherapy (G. P. Herzig, Ed.), Wiley. New York, pp. 17-23 (1987). 17. Tisman, G. Intermediate dose thiotepa for refractory ovarian cancer, Proc. Amer. Assoc. Cancer Res. 29, 881 (1988). 18. Wadler, S., Egorin, M., and Zuhowski, E. Phase I/ pharmacokinetic (PK) study of intraperitoneal (IP) thio-tepa, Clin. Res. 36, 803A (1988).
ONCOLOGY
36,
331-334 (19%)
A Phase I Clinical Trial of lntraperitoneal Thiotepa for Refractory Ovarian Cancer’ SAEEDA KIRMANI,’ LORI MCVEY, Department
of Medicine
and the Cancer
Center,
DAVID Loo, AND STEPHEN B. HOWELL
University
of California,
San Diego,
La Jolla,
California
92093
Received April 4, 1989
Treatment optionsfor patients with ovarian cancer who have failed systemic and intraperitoneal (ip) cisplatin-basedchemotherapy are limited. We conducteda phaseI clinical study of ip thiotepa in patientswith refractory ovarian cancerto determine the maximumtolerated dose(MTD). Ten patientsweregiven 39 coursesof thiotepa (mediannumber of coursesper patient, 3.5; range, l-10+). All patients had received prior ip cisplatin; 7 alsohad receivediv cisplatin, and 5 had had three or moreprior regimens.Thiotepa (30-80 mg/m’) wasgiven ip in 2 liters normal salineevery 4 weeks.The therapy waswell tolerated. There was no vomiting, stomatitis,alopecia,or peritonitis. The dose-limiting toxicity wasmyelosuppression. With repeateddoses,patientshad a delayedmarrow recovery and requireda l- to 2-weekdelay in treatment. Six patients had stable disease(duration 2-14+ months;medianduration 5 months);1 patient had a 50% decrease in CA-125 level, and 1 patient with no measurablediseaseremainedclinically disease-free.In summary,ip thiotepa had clinical activity in heavily pretreatedpatientswith refractory ovarian cancerwith diseasestabilization seenin 6 of 9 evaluablepatients and a partial responseseenin 1 patient. Myelosuppressionwas the only toxicity encountered. A doseof 60 mg/m* ip is recommendedfor phaseII studies, o 1990 Academic PRESS, I~C. INTRODUCTION Patients with ovarian cancer who fail systemic chemotherapy can still respond to intraperitoneal cisplatinbased chemotherapy regimens [1,2]. However, therapeutic options for patients failing salvage intraperitoneal cisplatin are limited. Triethylenethiophosphoramide (thiotepa) is a synthetic polyfunctional alkylating agent with known activity against ovarian cancer that has been in clinical use for more than 35 years [3]. Until very re-
cently, however, its use was limited to intracavitory administration for control of malignant effusions [4-61, intravesical instillation for bladder cancer [7,8], and intrathecal administration for meningeal carcinomatosis [9,10]. In the past several years high dose thiotepa has been used for bone marrow transplantation, and it has resurfaced in low-dose combination chemotherapy for breast cancer [ 11,121. Thiotepa is well tolerated locally when given by any route. Considerable information has now been collected about the maximum tolerated dose and toxicity of thiotepa in the setting of bone marrow transplantation. There is less information about the dose response or the maximum tolerated dose in other situations. One study showed that doubling the thiotepa dose resulted in more than a fivefold increase in tumor response in Hodgkins disease [13], consistent with the observation of steep dose-response curves for many alkylating agents [ 141. Ovarian cancer remains confined to the peritoneal cavity even in advanced stages. Since thiotepa is well tolerated locally and has known activity in ovarian cancer we initiated a phase I trial to determine the maximum tolerated dose of intraperitoneal thiotepa given every 4 weeks. PATIENTS AND METHODS
Patients were eligible for this study if they had a histologically confirmed malignancy, principally confined to the peritoneal cavity, that was refractory to conventional modes of therapy, or for which no effective treatment existed. Patients were required to have recovered from the effects of prior therapy. All patients had a totally implanted peritoneal access system surgically placed prior to beginning chemotherapy. This consisted of a Port-a-Cath connected to a Tenckhoff catheter (Pharmacia Deltec, St. Paul, MN) [15]. All patients were treated in the outpatient setting. Weekly blood counts were obtained. Peritoneal cytology
I Supported in part by Grants CA 35309 and CA 23100 from the National Institutes of Health. This work was conducted in part by the Clayton Foundation for Research-California Division. Dr. Howell is a Clayton Foundation investigator. 2 To whom reprint requests should be addressed. 331
0090-8258/90
$1.50
Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
332
KIRMANI
and CA-125 measurements were obtained every month. An abdominal and pelvic CT scan was obtained prior to treatment and at the end of the study to assess response. The starting dose of thiotepa was 30 mg/m* ip every 4 weeks. The dose was escalated by 20 mg/m’ when at least three courses in two patients were fully evaluable for toxicity and were well tolerated. The drug was given in 2 liters of normal saline and allowed to run into the peritoneal cavity as rapidly as possible. The fluid was not routinely drained. A white blood count of greater than 3000/mm3 and a platelet count of greater than 100,000/mm3 were required before retreatment. Patients were treated until there was evidenc
TABLE 1 Patient Characteristics No. of patients Median age (range) Performance status 0 1 2 3 Prior chemotherapy ip cisplatin iv cisplatin Other alkylators Three or more regimens Prior radiation Extent of disease Bulky Limited Histology Serous Mutinous Other Grade 1 2 3 Not specified
IO 63 (38-71) 3 5 1 1 IO 10 7 7 5 0 6 4 7 2 1 2 0 7 1
ET AL.
mide. Six patients had bulky disease defined as tumor masses larger than 2 cm at the time of study entry. A total of 39 courses of chemotherapy were given. The median number of courses per patient was 3.5 (range llo+). Patients were treated until there was evidence of disease progression or toxicity. The reasons for stopping treatment are presented in Table 2. Patients were removed from study because of hematologic toxicity if they required a greater than 2-week delay in treatment because of myelosuppression despite reducing the dose of thiotepa. One patient had stable disease after 2 courses, but experienced prolonged myelosuppression and had progressive disease when she was restarted on chemotherapy; she is listed twice. The treatment was very well tolerated until a dose of 80 mg/m’ was reached. At this dose significant and prolonged myelosuppression was seen. Three patients received 4 courses at this dose level. Two out of three patients developed grade 4 hematologic toxicity and 3 of 4 courses required a 3-week delay before the next cycle could be given. The hematologic toxicity as a function of dose is presented in Tables 3 and 4. Thirty-five of the 39 courses were evaluable for hematologic toxicity. Three courses were given at a dose of 30 mg/m’. One patient was deescalated to 20 mg/m’ and one patient was started at 25 mg/m’. These courses were analyzed as a group. Sixteen courses were given to seven patients at a dose of 60 mg/m’. The median nadir white blood count at this dose level was 2700/mm3, the median nadir granulocyte count was 1800/mm3, and the median nadir platelet count was 1 12,000/mm3. A dose of 60 mg/m2 is therefore the recommended dose for future studies. The relationship between the time to marrow recovery and cumulative treatment is shown in Fig. 1. In this figure courses in which the thiotepa was given at 30-60 mg/m’ are plotted against the time interval between courses. With repeated doses, patients exhibited a mild prolonged thrombocytopenia which required a delay in starting the next cycle. This delay is statistically significant (correlation of coefficient = 0.52, P value is less than 0.05). By the time patients received their third course of thiotepa, the median interval between treatment was 5 weeks instead of 4, and by the sixth course this had increased to 6 weeks. No nonhematologic toxicity was observed. Specifically, there was no local toxicity or peritonitis, and no TABLE 2 Reasonsfor Discontinuing Treatment Progressive disease Progressive disease after initial stabilization Hematologic toxicity Technical problems Still on treatment
2 3 3 2 1
INTRAPERITONEAL
THIOTEPA
FOR OVARIAN
333
CANCER
TABLE 3 Hematologic Toxicity as a Function of Dose Dose (w/m’) 30 40 60 80
Median nadir counts x lO’/pliter No. of courses
No. of patients treated
New patients entered
WBC
5 10 16 4
4 5 7 3
3 2 3 2
3.1(2.4-4.9)” 2.9(2.1-5.0) 2.7(1.0-4.6) 1.9(0.2-3.1)
Granulocytes
Platelets
1.9(1.8-2.8) 1.7(1.2-2.7) 1.8(0.4-3.2) 0.7(0.0-l. 1)
92(77-280) 160(54-237) 112(18-240) 62(15-101)
L?Numbers in parentheses refer to range of nadir counts.
vomiting, stomatitis, alopecia, renal, or hepatic dysfunction. Even though this was a phase I study, nine patients had measurable disease and were evaluable for response. The one patient with no measurable disease received four courses and then her treatment was stopped because of hematologic toxicity. She remained without any clinical evidence of disease throughout her treatment. The other three patients with nonbulky disease had less than 2-cm disease noted on CT scan (retroperitoneal adenopathy, mesenteric adenopathy, and vaginal cuff mass), in addition to a positive peritoneal cytology and elevated CA125 levels. One patient with small volume disease had a 50% decrease in CA-125 after one course, but her treatment was stopped because of catheter malfunction. Six other patients had stable disease for 2 to 14+ months (median duration, 5 months). Five of these patients had bulky disease with tumor nodules measuring more than 2 cm. Two patients had disease progression. DISCUSSION This study was done to determine the maximum tolerated dose of thiotepa given as an intraperitoneal instillation every 4 weeks. A dose of 60 mg/m* ip every 4 weeks was well tolerated with acceptable hematologic toxicity. Even at the highest dose of 80 mg/m’ there was no local or systemic nonhematologic toxicity. This complete absence of nonhematologic toxicity has been observed in the setting of autologous bone marrow trans-
plantation where skin toxicity, gastrointestinal toxicity, and central nervous system toxicity is observed only when doses exceeding 900 mg/m’ are used [16]. In another study a dose of 150-200 mg/m* given intravenously produced no toxicity apart from myelosuppression [17]. A recently published study [18] confirmed the absence of local toxicity of intraperitoneal thiotepa and the myelosuppression at 60 mg/m* was very similar to that seen in our study. This is the first time, to our knowledge, that a dose of 80 mg/m* has been given intraperitoneally. No local toxicity was seen at this dose level. Pharmacokinetic analysis was not done in this study; however, Wadler ef al. have reported that thiotepa has a pharmacologic advantage (peritoneal to plasma AUC ratio) of 4.3 [18]. While this is not a very high ratio compared to other drugs that can be given by the ip route, it still means that for each unit of myelosuppression, one still gets a fourfold greater exposure for the peritoneal cavity. This pharmacologic advantage, when combined with the absence of local toxicity, makes the intraperitoneal route an attractive way to administer this drug for malignancies confined to the peritoneal cavity. The ease of administration in the outpatient setting, and the lack of side effects, was a welcome change for patients who had been through 6-12 months of high-dose cisplatin. All these patients were heavily pretreated and most had received prior alkylating agents. Yet in 8 of 10 patients ip thiotepa prevented disease progression for a median duration of 5 months (range 2-14 +). While other treatment regimens clearly need to be found for patients who have failed iv
TABLE
4
Hematologic Toxicity by Grade WBC grade”
Granulocytes grade
Platelets grade
Dose level (w/m’)
No. of courses
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
30 40 60 80
5 10 16 4
1 3 2 0
3 2 4 1
1 5 8 1
0 0 2 1
0” 0 0 1
2 4 4 0
3 4 7 0
0 2 4 1
0 0 0 2
0 0 1 1
2 6 7 0
3 2 4 2
0 2 4 0
0 0 0 1
0 0 1 1
a Common toxicity criteria. b Number of courses on which the indicated grade of toxicity occurred.
334
KIRMANI
IOr 4 .
07-
.
O-
, -
... .
..
.
.
.
2
3
4
6
6
3-
I
I' 1
7
a
9
10
COURSENUMBER FIG. 1. Effect of repeated courses on the time to marrow recovery. The interval between courses in weeks is plotted against the course number. Each square represents a course. Line indicates best linear least mean square fit.
and ip cisplatin, ip thiotepa is a safe and nontoxic drug that can control refractory ovarian cancer for a period of time. A dose of 60 mg/m’ ip every 4 weeks is recommended for phase II studies. REFERENCES Howell, S. B., Zimm, S., Markman, M., Abramson, I. S., Cleary, S., Lucas, W. E., and Weiss, R. J. Long term survival of advanced refractory ovarian carcinoma patients with small volume disease treated with intraperitoneal chemotherapy, J. C/in. Oncol. 5, l6071612 (1987). Kirmani, S., Zimm, S., Cleary, S. M., Horton, C., and Howell, S. B. Intraperitoneal cisplatin and etoposide (ipDDP/VPl6) as salvage therapy for ovarian cancer, Proc. Amer. Sot. Clin. Oncol. 7, 117 (1988). Sykes, M., Karnofsky, D., and Phillips, F. Clinical studies of triethylenephosphoramide and diethylenephosphoramide compounds with nitrogen mustard-like activity, Cancer 6, 142-148 (1953).
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