RESULTS WITH METHYL-CCNU AND DTIC IN METASTATIC MELANOMA

MARY E. COSTANZA, MD,* LARRY NATHANSON, MD,* DAVID SCHOENFELD, PHD,' JANET WOLTER, MD,$ JACOB COLSKY, MD,* WILLIAM REGELSON, MD,"

THOMAS CUNNINGHAM, MD, ** AND NELL SEDRANSK, PHD+

This report is the result of an Eastern Cooperative Oncology Group (ECOG) study. Four hundred and 15 patients with inoperable metastatic malignant melanoma, excluding those with cutaneous metastases only, were randomized to one of three drug treatments: DTIC alone, methyl-CCNU alone, or the combination DTIC plus methyl-CCNU. Responses were seen in 14% of DTIC patients (19/127), 15% of methyl-CCNU patients (18/119) and 14% of DTIC plus methyl-CCNU patients (18/122). Duration of response was the same (14 weeks) for all three treatment groups. There was no difference among the treatments in achieving complete responses. Survival was improved sig- nificantly for responders (50 weeks) compared with nonresponders (15 weeks) regardless of treatment regimen. Toxicities were generally tolerable. DTIC caused significantly more gastrointestinal toxicity than methyl-CCNU. Methyl- CCNU caused significantly more bone marrow toxicity than DTIC. There were three drug-related deaths. All occurred in patients on combination DTIC plus methyl-CCNU. Important pretreatment characteristics that favor response are ambulatory status, female, less than 50 years old, no prior chemotherapy and no liver o r brain metastases. Patients with favorable characteristics combina- tions had a 30% response rate, while those with unfavorable characteristic combinations had only a 9% response rate.

Cancer 4O:lOlO-1015, 1977

HE RESPONSE RATES WITH CHEMOTHERAPY cluded 5(3,3-dimethyl-l-triazeno)-irnidazole-4- T in disseminated malignant melanoma have carboxamide (NSC 45388: DTIC); 1,3-bis-(2- been consistently disappointing, with objective chlorethy1)- 1-nitrosourea (NSC 409962; response rates for the more effective single drugs BCNU) and hydroxyurea (NSC 32065).' Com- in the ranpe of 15-2590.'' These drugs have in- bination chemotherapy, so effective in the leu-

This study was done by the Eastern Cooperative On- cology Group (Paul P. Carbone, Chairman).

Supported by Public Health Service grants from the NCI, Yational Institutes of Health, Department of Health, Educa- .ion and Welfare.

* Tufts University School of Medicine, Boston, Mas- sachusetts (CA 07190). ' State University of New York at Buffalo, Amherst, New

York (CA 12721). t Rush-Presbyterian-St. Luke's Hospital, Chicago, Illinois

(CA 10948). 8 University of Miami, Miami, Florida (CA 02822). I ' Medical College of Virginia, Kichmond, Virginia (CA

10572). ** Albany Medical College of Union University, Albany,

New York (CA 06594). Other participating institutions include: Albert Einstein

College of Yeshiva University, Bronx, NY (CA 14958); Bos- ton University Medical Center, Boston, MA (CA 11 109); Brookdale Hospital Center, Brooklyn, NY; Brown Univer- sity and Roger Williams General Hospital, Providence, RI (CA 15947); Chicago Medical School, Chicago, IL (CA 14144); Case Western Reserve University, Cleveland, O H (CA 02824); Hahnemann Medical College, Philadelphia,

PA (CA 13611); University of Iowa, Iowa City, IA; Univer- sity of Florida, Jacksonville, FL (CA 19818); Jefferson Medi- cal College, Philadelphia, PA (CA 14215); Johns Hopkins University, Baltimore, MD (CA 161 16); Lahey Clinic, Bos- ton, MA (CA 12880); Maimonides Medical Center, Brooklyn, NY (CA 05588); University of Manitoba, Winne- peg, Manitoba; Mount Sinai Medical Center, New York, NY (CA 171 52); National Cancer Institute, Bethesda, MD; New York University Medical Center, New York, NY (CA 16395); Northwestern Medical Center, Chicago, IL (CA 17145); University of Ottawa, Ottawa, Ontario; Pennsylva- nia Hospital, Philadelphia, PA (CA 13613); University of Pennsylvania, Philadelphia, PA (CA 15488); University of Pittsburgh, Pittsburgh, PA (CA 18653); University of Roch- ester, Rochester, NY (CA 11083); Roswell Park Memorial Institute, Buffalo, NY (CA 12296); University of Pretoria, Pretoria, South Africa; Springfield Hospital Medical Center, Springfield, MA (CA 20182); SUNY Stonybrook Program, East Meadow, NY (CA 20161); Yale School of Medicine, New Haven, C T (CA 15485)

Address for reprints : Mary E. Costanza, MD, Medical Oncology Service, New England Medical Center Hospitals, Tufts University School of Medicine, 171 Harrison Avenue, Boston, MA 021 11.

Accepted for publication December 29, 1976.

1010

No. 3 METHYL-CCNU AND DTIC IN MELANOMA Costanea et al. 101 1

kemias and lymphomas, has been less impres- sive in melanoma. We have previously reported unimproved response rates utilizing DTIC in combination with several nitrosoureas. 173*4,g

While other investigators have reported higher response rates with three-drug combinations in- cluding DTIC and a nitrosourea,6,8 these combi- nations have not been randomized against a single drug control arm. A comprehensive re- view of effective various single drugs and combi- nation chemotherapy in melanoma has been re- cently published by Comis.' He argues that there is no conclusive evidence that combination chemotherapy has improved response rate or survival.

In December 1972, the Eastern Cooperative Oncology Group (ECOG) initiated a prospec- tive randomized study (EST 1672) in patients with advanced melanoma designed to test the effectiveness of a newer oral nitrosourea, methyl-CCNU [ 1 -(2-chlorethyl)-3-(4-methyl- cyclohexy1)- 1 -nitrosourea, NSC 95441 ] alone and in combination with DTIC against DTIC alone. This was the third ECOG melanoma study utilizing DTIC as a single standard drug. The trial was terminated in October, 1974, and the survival updated as of April, 1976. Early results of this trial have been previously pub- lished in abstract or brief preliminary report form. '*'v9

MATERIALS AND METHODS

Over a 22-month period, 415 patients with histologically proven, surgically incurable and measurable melanoma involving viscera, soft tis- sue or lymph nodes were randomized into three drug treatment groups. Patients were stratified according to whether they had received prior therapy or not. Basic laboratory investigations were obtained on all patients at entry to study. These included hemogram, platelet count, blood urea nitrogen and liver function studies; roent- genograms and nuclear scanning studies were to be performed when clinically appropriate. Phys- ical examination, tumor measurement, repeated blood and pertinent x-ray studies were to be repeated regularly.

Patient Selection Requirements for entry included the follow-

ing: life expectancy greater than 2 months, ini- tial white blood cell count (WBC) greater than 5,000/mm8, initial platelet count greater than 1 50,000/mm3, and normal blood urea nitrogen. Patients with prior treatment were eligible if

TABLE 1. Grading of Bone Marrow Suppression ~~ ~~~

Platelet WBC nadir count nadir

None X . O O O / ~ ' 2 100,000/mm 23, 5 0 0 / r n a >80,000/ mm' Mild 2 2 , 5 0 0 / m 3 ~50,000/mm3

Moderate 2 1,00o/mm ' 220,000/mm Severe

Lethal - - Life-t hreatening ~ 1 , 0 0 0 / ~ ~ 3 ~20,000/mm3

greater than 4 weeks had elapsed since that treatment. Patients who had previously received DTIC or methyl-CCNU were excluded from the study. Patients with predominant intradermal lesions and without visceral disease were also excluded. These latter were enrolled into a sepa- rate study evaluating the use of BCG alone.'

Drug Dosage Patients were assigned one of the following

treatment schedules: I) DTIC 200 mg/m' i.v. for 5 days repeated every 3 weeks; 11) Methyl- CCNU 200 mg/m'* p.0. once every 6 weeks; and 111) DTIC 150 mg/mai.v. for 5 days every 3 weeks and methyl-CCNU 130 mg/m2 p.0. once every 6 weeks.

Dose modifications based on changes in WBC, platelet count, hemoglobin or BUN were specified. However, no drug was given if WBC was less than 3,000/mms or platelets were less than 75,000/mma

Toxicity Toxicity was graded for nausea and vomiting

as none, mild, moderate or severe. Bone marrow suppression was graded as shown in Table 1.

Response Criteria Partial response was defined as 50% or greater

decrease in the sum of the products of the diam- eters of all measured lesions for at least two successive occasions at a minimal interval of 2 weeks. Complete response was defined as the disappearance of all measurable disease over a similar period. Progression or relapse was de- fined as measurable increase of at least 50% in the sum of the products of lesion diameters.

Patients who had progression of disease by day 21 (if on DTIC) or by day 42 (if on methyl- CCNU) were considered treatment failures and were crossed over to receive the other drug. Pa-

*Originally this dose was 250 mg/m* but was decreased in March, 1973.

1012 CANCER September 1977 Vol. 40

TABLE 2. Toxicity*

DTIC Methyl- methyl-

DTIC CCNU CCNU No. patients evaluable 129 119 122

Toxicity

GI moderate mild

severe

mild Bone moderate marrow severe

life threatening lethal

Liver lethal

20% 19% 22% 40% 18% 37%

7% 11% 11%

9% 19% 11% 5% 20% 15% 5% 11% 14% 1% 3% 11% 0% 0% 2%

Percent of patients experiencing toxicity.

tients with progression of tumor on combined DTIC and methyl-CCNU were taken off study.

RESULTS

Of 415 patients entered into the study, 36 cases were invalidated; 12 from DTIC, 9 from DTIC and methyl-CCNU, and 15 from methyl- CCNU. The reasons for case invalidation were: 23 ineligible for study, 6 nonrandomized or given incorrect drug, 5 inadequate therapy, 2 miscellaneous. In addition, nine follow-up rec- ords were never received (five from the DTIC and methyl-CCNU group and four from methyl- CCNU group). Thus, of 415 patients entered, 370 cases or 89% were considered valid and available for final analysis.

TABLE 3. Number of Early Deaths Among Evaluable Patients, Early Death Rate (Number/Total)

Characteristic Percent

Total

Sex female male

Site of metastatic disease CNS liver without CNS visceral without CNS or liver

Performance status ambulatory nonambulatory unknown

25% (94/370)

19% (30/152) 29% (64/218)

44% (16/36) 44% (38/86)

7% (7/93)

14% (39/265) 51% (50/98) 71% (5/7)

Patient Characteristics By selection criteria, all patients had to be

inoperable and to have either visceral disease or advanced soft tissue disease. At entry, 10% of these had central nervous system metastases, 26% had liver metastases, and 41% had lung metastases. Only 25% had soft tissue disease without evidence of visceral metastases. Seventy- two percent were either asymptomatic or had minimal symptomatology (called “ambu- latory”), 26% had symptoms which made them less than fully ambulatory (called “non- ambulatory”). The median age was 51 years. Fifty-nine percent of the patients were male and 41% female.

Various features that, might influence the re- sponse to chemotherapy-age, sex, previous therapy, primary site of lesion, ambulatory status and site(s) of tumor metastases-were analyzed for each drug group. There were no significant differences among the drug groups.

Toxicity Gastrointestinal toxicity was in general, toler-

able. Nausea and vomiting were the worst for DTIC therapy alone, and least for methyl- CCNU alone. These differences were significant (Table 2). Bone marrow toxicity was also toler- able. The combination of DTIC and methyl- CCNU had significantly more hematologic tox- icity than DTIC when used alone (Table 2).

Of the 415 patients entered on study, there were but three reported as drug deaths, all oc- curring on combined DTIC and methyl-CCNU therapy. Two patients died as a direct result of thrombocytopenia; one, an autopsy-proven complete responder, died of hepatic failure. In- cluding these three drug-incriminated deaths and in spite of a stipulation that patients should be expected to survive for more than 2 months, 97 patients (25%) died within 60 days of entry onto study. Review of these 97 cases revealed several interesting observations. Firstly, apart from the three reported drug deaths, there were six instances where investigators thought drug- induced leukopenia, thrombocytopenia or hem- orrhagic necrosis might have contributed to death, although they judged death to ~ t : due to the progression of disease and/or to the greatly advanced state of disease. Second, two patients died of unrelated causes and one died of acci- dental drug overdose (150% calculated dose). Third, with the exception of these 12 cases, in- vestigators felt that in the remaining 85 patients, disease either was very advanced or was advanc-

No. 3 METHYL-CCNU AND DTIC IN MELANOMA Costawa et a f . 1013

ing rapidly and that death was related to such disease either wholly or in part.

There were no excess of early deaths on any of the drug protocols. Thirty-seven of 142 DTIC patients, 32 of 142 methyl-CCNU and 31 of 131 combination therapy patients died in less than 60 days. These included some patients in the “invalid” group. However, no patient was put into the “invalid” group simply on the basis of early death. A comparison of the frequency of early death for valid patients in selected patient subgroups is given by Table 3. Notice that fully 44% of those with CNS or liver metastases died early. Note also that 51% of nonambulatory pa- tients also died within 60 days of entry onto study.

Responses

The overall response rate including complete and partial responses was 15%. There were no significant differences among the treatment groups, either in terms of response rate, type of response, duration of response or survival. Complete and partial responses were 4%, 1 1 % for DTIC; 7%, 7% for DTIC plus methyl-CCNU and 5%, 10% for methyl-CCNU. Duration of response was 14 weeks for each treatment group. Median survival from treatment was 21 weeks.

Response rates and the duration of the re- sponse were affected by initial performance status, major organ involvement and type of re- sponse. The unfavorable implication of liver or CNS involvement or nonambulatory status for response rate is clearly seen (Table 4). In addi- tion, the lengths of response for patients with or without liver metastases are significantly differ- ent as are those of men and women (Table 5). It is important to note that not every patient who had liver metastases and who was said to be a responder actually had response of metastases in the liver. O n the contrary, of eight such respond- ers, only three had documented greater than 50% decrease in liver tumor size. Thus, of 97 patients on the study with known liver metas- tases, only three patients had objective response which included the liver. Of the 36 patients with brain metastases, only one was judged to have a partial response and in that patient, the brain metastases did not respond to treatment.

Characteristics that were favorable for re- sponse were several and included being female, ambulatory, under 50 years of age, and having had a lower limb primary, as well as having no previous chemotherapy, no liver or CNS metas- tases. These favorable characteristics were

TABLE 4. Response by Prognostic Variables: Response Rate (Number/Total)

Response (number/ total)

Total

Sex female male

15% (55/370)

19% (30/152) 1 1 % (25/218)

Performance status ambulatory 17% (46/265) nonambulatory 8% (8/98) unknown 14% (1/7)

Prior chemotherapy no 15% (51/323) Yes 8% (4/47)

Site of metastatic disease CNS 2% (1/36) liver 9% (8/86) other visceral 16% (25/ 155) soft tissue only 22% (21/93)

evenly distributed through each of the treatment groups.

Finally, survival was influenced by several pa- tient characteristics such as performance status and metastatic site. Responders had much bet- ter survival than nonresponders. This difference is highly significant even when one accounts for prognostic variables (Table 6). Notice that the few nonambulatory patients who did respond had a longer median survival than ambulatory patients who did not respond. In this disease,

TABLE 5. Duration of Response in Weeks by Patient Subgroups

Median (number relapsed/total)

Total

Sex male female

Performance status ambulatory nonambulatory

Metastatic site liver without CNS other

Type of response complete partial

16 (46/55)

27 (18/25) 10 (28/30)

17 (39/47) 9 (7/8)

4 (1/1) 7 (8/8)

18 (37/46)

26 (17/20) 12 (29/35)

1014 CANCER September 1977 Vol. 40

TABLE 6. Survival in Weeks for Responders and Non- responders in Different Prognostic Groups

Median (number dead/total) Responders Nonresponders

Overall 50 N o prior chemotherapy 50 Prior chemotherapy 47

Ambulatory 53 Nonambulatory 26

CNS metastasis 6 N o CNS metastasis 51

Liver metastasis 27 N o liver metastasis 52

15 (279/315) 15 (241/272) 15 (38/43)

20 (193/225) 8 (86/90)

9 (35/35) 17 (244/280)

9 (84/89) 20 (195/226)

response is clearly an early indicator of in- creased survival.

Cross-Over In addition to the 370 evaluable patients who

were induced on therapy, there were an addi- tional 138 patients who, on progression or re- lapse, were crossed over from their original treatment. Those who had been on DTIC were crossed over to receive methyl-CCNU (74 pa- tients); or methyl-CCNU to DTIC (64 pa- tients). There were only three responses among this entire group of 138 cross-over patients. Pa- tients failing or progressing on the combination DTIC-methyl-CCNU were taken off study.

DISCUSSION

The lack of improvement either in overall re- sponse rate or the complete response rate with methyl-CCNU alone or with combination ther- apy was disappointing. Earlier in the study, there was some suggestion that combined

methyl-CCNU and DTIC therapy afforded an increased number of complete response rates but this was not borne out in the final analysis. While the negative aspect of this large random- ized study is that it failed to demonstrate any improved usefulness of combined nitrosourea and DTIC therapy, on the positive side it did demonstrate that methyl-CCNU alone is as ef- fective in inducing complete and partial re- sponse rates and in increasing survival in those responders as DTIC alone is. While the bone marrow toxicity of methyl-CCNU alone is sig- nificantly more severe than DTIC, its gastroin- testinal toxicity (most distressing to patients) is less than that from DTIC. In addition, the ease of oral methyl-CCNU administration (com- pared to the 5-day intravenous DTIC treat- ment) makes methyl-CCNU a more attractive candidate for standard melanoma therapy in future trials in the ECOG.

The low level of responses in the cross-over group of patients is not surprising. In general, patients previously treated with chemotherapy tend to have lesser response rates when retreated with other agents. For example, in this study, entering patients who had been previously treated with non-study drugs had a response rate of only 8% when put on the induction pro- tocol. When patients who had been treated ei- ther with methyl-CCNU or with DTIC failed and were then crossed over to receive the other drug, only 2% responded to that second drug.

It should also be noted that the combination of a nitrosourea (methyl-CCNU) with DTIC did not increase median survival compared with ei- ther drug alone. The median survival of all the evaluable patients on study was 21 weeks. This compares with the most recently published data from the BCNU-hydroxyurea-DTIC (BHD) study. The initial report from this study sug-

TABLE 7. Favorable and Unfavorable Patient Groups

Group

Early Median survival Median survival Number in Response death of non- of

group rate rate responders responders

Unfavorable (weeks) (weeks) (These patients had CNS or liver involve- 171 (46%) 9% 45% 9 (147/156) 27 (13/15) ment or were nonambulatory)

Favorable (These patients were not in the unfavorable 70 (19%) 30% 4% 28 (37/49) 51 (16/21) group and either the primary was in a lower limb or they were women under 50 years)

Middle group (Thesepatients were not in theothergroups) 129 (35%) 15% 1 1 % 23 (95/110) 58 (14/19)

No. 3 METHYL-CCNU AND DTIC IN MELANOMA Costawa et al. 1015

gested a quite prolonged median survival of 17 months. But in a more recent re-evaluation of this study’ the median survival of the group was only 21 weeks. This figure is the same as our results with combined or single drug therapy.

The large number (25%) of people who died within 60 days of entry into the study is disturb- ing. With very few exceptions, their deaths ap- pear to be related to the extent of their under- lying disease. There is an excess number of patients with CNS and liver metastases, and an excess number of nonambulatory patients. Moreover, these are the same patient character- istics that prognosticate for infrequent response. This large number of “sick” patients, as well as the lack of patients with cutaneous metastasis only, is undoubtedly the reason why our overall response rate with DTIC was only 14%. Re-

sponses clearly vary as a function of such impor- tant characteristics. These characteristics and their relation to death, response, and survival are summarized in Table 7. O n the positive side, patients who fall into the favorable group can be encouraged regarding their expected increased rate of response of 30%. By contrast, the re- sponse rate of patients who fall in the “unfavor- able” category is only 9%. Moreover, the few patients who do respond have unquestionable improvement in survival (7 months versus 2 months). Is this infrequently expected benefit worth the trial of drug in the unfavorable group? Until chemotherapeutic drugs or regimens for melanoma are greatly improved, knowing the expected response rates for various subgroups of patients ought to help oncologists weigh the bal- ance of benefit versus harm for each patient.

REFERENCES

1. Carbone, P. P., and Costello, W.: Eastern Cooperative Oncology Group Studies with DTIC (NSC-45388). Cancer Treat. Rep. 60:193-198, 1976.

2. Comis, R. L. : DTIC (NSC-45388) in malignant mela- noma-A perspective. Cancer Treat. Rep. 60:165-176, 1976.

3. Costanza, M. E., Nathanson, L., Lenhard, R., White, J., Colsky, J., Oberfield, R. A., and Schilling, A.: Therapy of malignant melanoma with an imidozole carboxamide and bis-chloroethyl nitrosourea. Cancer 30:1457-1461, 1972.

4. Costanza, M. E., and Nathanson, L.: Combination DTIC and methyl CCNU vs. single agents in disseminated malignant melanoma-Preliminary report. Proc. Am. Assoc. Cancer Res. Am. Soc. Clin. Oncol. 15 : 173, 1974.

5. Costanzi, J. J.: DTIC (NSC-45388) studies in the

Southwest Oncology Group. Cancer ?rear. Rep. 30:189-192, 1976.

6. Costanzi, J. J., Vaitkevicius, V. K., Quagliana, J. M., ct al. : Combination chemotherapy for disseminated malignant melanoma. Cancer 36:342-346, 1975.

7. Costanzi, J. J.: Combination chemoimmunotherapy for disseminated malignant melanoma. Proc Am. Assoc. Cancer Res. 17241, 1976.

8. Luce, J. K.: Chemotherapy of malignant melanoma. Cancer 30:1604-1615, 1972.

9. Nathanson, L., Costanza, M. E., Wolter, J., cl al.: Therapy of malignant melanoma with DTIC, methyl CCNU and BCG. In Pigment Cell, vol. 2. V. Riley, Ed. Basel, Karger, 1976; pp. 407-413.