Cancer Treatment
Keviews
(1991)
18 (Supplement
A), 31-35
Hexamethylmelamine Cancer Institute trialst Robert
(altretamine):
Early
National
C. Young
Fox Chase Cancer Center, Philadelphia,
PA 1911 I, U.S.A.
Initial experience with hexamethylmelamine (altretamine) at the National Cancer Institute began with its use as a single agent in alkylating agent-resistant ovarian carcinoma (2). The traditional dose and schedule (8 mg/kg daily orally) was used in these original trials and established the drug as active but with substantial toxicity, particularly gastrointestinal, hematologic and neurologic. Of 21 patients with ovarian cancer refi-actory to standard alkylating chemotherapy, six (28%) had an objective response with a median duration of 2.5 months. However, dose limiting gastrointestinal toxicity was seen in 5796, hematologic toxicity in 62% and neurologic toxicity in 28%. In over half of the patients the daily oral dose schedule had to be discontinued because of toxicity. On the basis ofinitial trials, it seemed prudent to administer the drug on an intermittent schedule, allowing for rest periods between pulses of therapy. The evidence from this and other similar trials (1, 4) established that the drug was active in ovarian cancer and not invariably cross-resistant to conventional alkylating agents. These two characteristics made it an attractive agent for use in combination. We incorporated hexamethylmelamine into the first randomized prospective trial which compared the prototypical single alkylating agent melphalan, to a four drug combination in previously untreated patients with FIG0 Stage III and IV ovarian cancer (5). Patients randomized to receive melphalan (phenylalanine mustard, L-PAM) were given 0.2 mg/kg by mouth daily for 5 days as a single course. Courses were repeated every 4-5 weeks on the basis of bone marrow recovery. The combination chemotherapy program, known as Hexa-CAF, employed 5-fluorouracil, 600 mg/m* and methotrexate, 40 mg/m’, given intravenously on the first and eighth days. Cyclophosphamide and hexamethylmelamine were given at 150 mg/m’ by mouth daily for the first 14 days of the cycle. From days 15 through 28, no therapy was given. At least six cycles were given at monthly intervals. The drugs in the Hexa-CAF combination (hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil), were selected because all four have considerable activity as single agents against ovarian cancer. Furthermore, some possess different cell-cycle specificity and different pharmacologic properties, including plasma clearance rates and protein binding. Each of the agents has a somewhat different mechanism of action, and, to a certain extent, they have differing patterns of organ toxicities. It was hoped that by t Prcscnted
in
0305-7372/91/18A0031
part at the Hex&n
conference,
Fox Chase,
+ 05 $03.00/O
Cancer
Center,
6 November 0
31
1989
1991 Academic
Press Limited
32
R. Table
1. Hexa-CAF
us. Melphalan
C. YOUNG results
RWlllS
Hexa-CAF
Patients fully restaged (total) No. with response Complete response Partial response No response Median duration of complete Median duration of survival “All
of therapy
40/41 30/40 (7504)
remission (months)”
(months)
13 (33%) 17 (43Y”) 10 (25’1,) >30 29
L-PAM
Pvalue
37139
20/37 (54%) 6 (1’5%) 14 (38':") 17 (467,) 25 17
Keviews
(1991)
18 (Supplement
A), 31-35
Hexamethylmelamine Cancer Institute trialst Robert
(altretamine):
Early
National
C. Young
Fox Chase Cancer Center, Philadelphia,
PA 1911 I, U.S.A.
Initial experience with hexamethylmelamine (altretamine) at the National Cancer Institute began with its use as a single agent in alkylating agent-resistant ovarian carcinoma (2). The traditional dose and schedule (8 mg/kg daily orally) was used in these original trials and established the drug as active but with substantial toxicity, particularly gastrointestinal, hematologic and neurologic. Of 21 patients with ovarian cancer refi-actory to standard alkylating chemotherapy, six (28%) had an objective response with a median duration of 2.5 months. However, dose limiting gastrointestinal toxicity was seen in 5796, hematologic toxicity in 62% and neurologic toxicity in 28%. In over half of the patients the daily oral dose schedule had to be discontinued because of toxicity. On the basis ofinitial trials, it seemed prudent to administer the drug on an intermittent schedule, allowing for rest periods between pulses of therapy. The evidence from this and other similar trials (1, 4) established that the drug was active in ovarian cancer and not invariably cross-resistant to conventional alkylating agents. These two characteristics made it an attractive agent for use in combination. We incorporated hexamethylmelamine into the first randomized prospective trial which compared the prototypical single alkylating agent melphalan, to a four drug combination in previously untreated patients with FIG0 Stage III and IV ovarian cancer (5). Patients randomized to receive melphalan (phenylalanine mustard, L-PAM) were given 0.2 mg/kg by mouth daily for 5 days as a single course. Courses were repeated every 4-5 weeks on the basis of bone marrow recovery. The combination chemotherapy program, known as Hexa-CAF, employed 5-fluorouracil, 600 mg/m* and methotrexate, 40 mg/m’, given intravenously on the first and eighth days. Cyclophosphamide and hexamethylmelamine were given at 150 mg/m’ by mouth daily for the first 14 days of the cycle. From days 15 through 28, no therapy was given. At least six cycles were given at monthly intervals. The drugs in the Hexa-CAF combination (hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil), were selected because all four have considerable activity as single agents against ovarian cancer. Furthermore, some possess different cell-cycle specificity and different pharmacologic properties, including plasma clearance rates and protein binding. Each of the agents has a somewhat different mechanism of action, and, to a certain extent, they have differing patterns of organ toxicities. It was hoped that by t Prcscnted
in
0305-7372/91/18A0031
part at the Hex&n
conference,
Fox Chase,
+ 05 $03.00/O
Cancer
Center,
6 November 0
31
1989
1991 Academic
Press Limited
32
R. Table
1. Hexa-CAF
us. Melphalan
C. YOUNG results
RWlllS
Hexa-CAF
Patients fully restaged (total) No. with response Complete response Partial response No response Median duration of complete Median duration of survival “All
of therapy
40/41 30/40 (7504)
remission (months)”
(months)
13 (33%) 17 (43Y”) 10 (25’1,) >30 29
L-PAM
Pvalue
37139
20/37 (54%) 6 (1’5%) 14 (38':") 17 (467,) 25 17
