METHYL-CCNU, ALONE AND IN COMBINATION WITH VINCRISTINE, OR VINCRISTINE AND METHOTREXATE, IN

ADVANCED BRONCHOGENIC CARCINOMA FREDERICK RICHARDS, 11, MD, M. ROBERT COOPER, MD, HYMAN B. MUSS, M D , DOUGLAS R.

WHITE, MD, AND CHARLES L. SPURR, MD

Ninety-two patients with advanced bronchogenic carcinoma were prospec- tively randomized according to performance status, histology, and extent of disease to methyl-CCNU alone; methyl-CCNU and vincristine; or methyl- CCNU, vincristine, and methotrexate. Seventy-three patients were evaluable. Randomization to methyl-CCNU alone was discontinued when only three brief L'static" responses were noted in 11 patients and the survival (p < .01) and time on study (p < .05) were noted to be significantly less than with the combination. Two of 32 patients treated with methyl-CCNU and vincristine, and two of 30 patients treated with methyl-CCNU, vincristine, and methotrexate had mixed responses with a median of 67.5 days. A static response was seen in eight of 3 2 and nine of 30 patients, respectively. Minimal toxicity occurred in all regimens. Methyl-CCNU alone or in combination with vincristine or vincristine and methotrexate is of limited benefit in patients with lung cancer, although our data suggest ( p = 0.15) that the addition of methotrexate increases time on study and survival in patients with extensive disease.

Cancer 38:1077-1082, 1976.

ETHYL-CCNU (NSC-95441) ( 1 - (2 - M chloroethyl) - 3 - (4-methylcyclohexyl)-l- nitrosourea) is one of several nitrosoureas with activity against a wide range of animal tumors. I t is unique among the nitrosoureas in its high degree of effectiveness against the Lewis lung cancer ~ y s t e m . ~ Methyl-CCNU differs from CCNU only in having a methyl group on the 4- position of the cyclohexyl ring. T h e mechanism of action of methyl-CCNU is largely unknown. It acts not only as a n alkylating agent but also inhibits key enzymatic processes involved in DNA synthesis.' Several investigators have

found that methyl-CCNU alone has activity against bronchogenic carcinoma, with a n overall response rate of about l j % . 3 * 5 * 9 9 1 0 Vincristine and methotrexate have induced regressions in bronchogenic Combina t ion chemotherapy has been found to be more effec- tive in Hodgkin's disease, acute leukemia, and breast cancer than single-agent therapy." This study was designed to test the hypothesis that the combination of methyl-CCNU with vincris- tine with or without methotrexate might be more effective than methyl-CCNU alone for the treatment of advanced brochogenic carcinoma.

Presented in part at the 11th Annual Xleetin? of t he American Society of Clinical Oncology, San IXego. Califor- nia, May 7, 1975.

From thc Oncology Research Center of the Bowman Gray School of hledicinc ol Wake Forest University, Winston- Salem, North Carolina.

Supported in part by the National Institutes of Health (;rants (:A-12197 and T12-8037.

:\ddrcss lor reprints: Frederick Richards 11, ill), How- man Gray School of hledicine of Wake Forest University. Winston-Salem, N C 27 103.

'l'his clinical study reHects the collaboration of colleague physicians who relerrcd and supported the care of the patients, a n d the attention of resident physicians. The i r aid is gratefully acknowledged. T h e authors also acknowledge the contributions of the supporting personnel of the Oncology Research Center.

Kecrived lor publication December 5, 1975.

MATERIALS A N D METHODS Patient Sample

This study comprised 92 patients who had histologically proven carcinoma of the lung with a t least one measurable lesion. All patients were inoperable with progressive disease and had an adequate hemogram (WBC 2 4000/mm3 and platelets 2 1 00,000/mm3), adequate renal func- tion (BUN < 25 mg/100 ml and/or creatinine < 1.1 mg/100 ml), and adequate hepatic function (bilirubin < 2.5 mg/100 ml). No patient had previous therapy with a nitrosourea, meth- otrexate, or vincristine. A treatment-free obser-

1077

1078 CANCER Sefitember 1976 Vol. 38

TABLE 1 . Patient Characteristics

Methyl-CCNU

Methyl-CCNIJ vincristine methotrexate Methyl-CCNU vincristine

No. (%) No. (%) No. (%) Total no. patients 11 32 30

White/black 10/1 31/1 2812

Mean age in years 58 56 59

Malelfemale 1011 2616 2416

Weeks from symptoms to treatment Prior therapy

None Radiation Surgery Chemotherapy

Performance st,itus* Normal or ,imbulatory mith symptoms Limited

Extent of disease* Limited Exteniive

Liver Brain Bone

Histology* Epidermoid Adenoca-cinomn Small cell Large cell

* p (x*) > .10

vation period of at least 2 weeks for patients who had had previous surgery, radiation therapy, or chemotherapy was observed. All patients were seen and followed throughout their treatment course at the Oncology Research Center of the Bowman Gray School of Medicine of Wake For- est University.

After a full explanation of the investigational aspects of the study, all patients who qualified for entry were prospectively randomized accord- ing to their performance status (normal or am- bulatory with symptoms versus limited activity due to disease), their histology (epidermoid, adenocarcinoma, small cell, large cell), and their extent of disease (limited disease, limited to one hemithorax with or without involvement of ipsilateral scalene lymph nodes versus those with more extensive disease) to one of three different treatment regimens. There were 73 evaluable patients of the 92 prospectively randomized patients. Nineteen patients were eliminated from the final analysis for the follow-

ing reasons: two, never treated; six, lost to fol- low-up; two, refused to complete first course of treatment; and nine, receiving concurrent radi- ation to the measurable lesion(s). Of the nine who received concurrent radiation, four had ob- jective regressions of the lesions. The description of the patient population is given in Table 1 . 'The population groups treated in each regimen were similar with regard to performance status, extent of disease, and histology (p (x') > . lo) .

Outline of Treatment

The treatment regimens are presented in Table 2. In regimen I, methyl-CCNU was given as a single dose orally on a n empty stomach every 6 weeks as tolerated. In regimen 11, vin- cristine was added once weekly intravenously (i.v.) for the first 3 weeks of each 6-week cycle. In regimen 111, methotrexate was added twice weekly for the first 3 weeks of each 6-week cycle. There was a reduction in the dose of methyl- C(:NU to 100 mg/m' when used in conjunction

No. 3 CHEMOTHERAPY OF BRONCHOGENIC CARCINOMA Richards et al. 1079

TABLE 2. Outline of 'Treatment

I. Methyl-CCNU-150 mg/ni2 p.0. Day 1 11. Methyl-CCNU--1.50 mg/m2 p.0. Day 1

111. Methyl-CCNU--100 mg/m2 p.0. Day 1 Vincristine-0.02.5 mg/kg i.v. Day 1, 8, 1.5

Vincristine-0.025 mg/kg i.v. Day 1, 8, 15 Methotrexate-0.1.5 mg/kg twice weekly for 3 weeks

* Each regimen was repeated every 6 weeks.

with methotrexate. Subsequent courses of methyl-CCNU and methotrexate were modified according to the nadir of the leukocyte (WBC) count and platelet count. If WBC dropped be- low 3000/mm3 or platelets below 120,000/mm3 during the last preceding treatment interval, the dose was reduced by 25%. If WBC dropped to 2000/mm3 or less or platelets to S0,000/mm3 or less, the dose was reduced by 50%. If the WBC remained less than 4500/mm or platelet count less than 120,000/mm3, methyl-CCNU and methotrexate were withheld pending recovery to these levels. Vincristine was omitted if the deep tendon reflexes were absent or severe pares- thesias were present. The patient began receiv- ing vincristine again when these symptoms abated. hlethotrexate dosage was modified if the patient developed any evidence of stomatitis, ab- dominal pain, or persistent diarrhea (2 three watery stools over a 24-hour period). Nausea and vomiting per se did not constitute a n in- dication for reduction of drug dose.

RESULTS

The results of chemotherapy were evaluated on the basis of objective tumor regression (long- est time widest perpendicular diameter), with the following criteria of assessment of response. A complete response (CK) required complete disappearance of all mesaurable disease. A par- tial response (good) (PK-G) was regression of measurable disease by 50% or more. Partial re- sponse (fair) (PK-F) was a regression of measur- able disease by 25-4970. Static response (SR) was defined as no progression or less than a 25'% regression in a progressing lesion. A mixed re- sponse (h1K) was regression of measurable tu- mor by 50% or more with progression, or no change in other measurable tumors. No re- sponse (NK) was defined as progression of dis- ease. T o qualify as a response, the regression period required was 42 days. Time on study was from the date of first treatment until the patient died or was removed from study. Survival time

was calculated from the beginning treatment date to the date of last contact. Time on study and survival time were analyzed by the Wilcoxon-Gehan test' comparing the regimens in question. The same analyses were also per- formed on patients of the same histologic cell type, risk group, metastatic status, or response status. The incidence and degree of toxicity was compared by either Fisher's Exact Test or a chi- square test.

Seventy-three patients were evaluable. Thirty- two patients received methyl-CCNU and vin- cristine; 30 received methyl-CCNU, vincris- tine, and methotrexate; only 11 patients were treated with methyl-CCNU alone. Preliminary analysis of our data was done at 6 months into the study. Kandomization to methyl-CCNU alone was discontinued when only three brief static responses were noted in 11 patients and the survival (p < .01) and time on study (p < .05) were significantly less than the combination (Figs. 1 and 2) .

The maximal responders in the study con- sisted of four patients whose responses were de- fined as mixed response (regression of measur- able tumor by SO% or more with no change in

lo(

9c

ac

7c

2 : 60 9 . ? P . .

40

9" 30

20

10

0

T a r n I n Day*

FIG. 1. 'I'ime on study for responders and nonresponders from onset of treatment. Comparison of regimen 1 (Methyl- CCNU) , regimen I1 (hlethyl-CCNU, vincristine) and regi- men 111 (llethyl-CCX'JU, vincristine, methotrexate). Regi- men I = 1 ; Regimen I1 = 2 ; Regimen I11 = 3.

1080 CANCER September 1976

0 0

Vol. 38

60 120 180 240 300- 360

100

90

80

70

u 1 . 60

4 C u

9“ 50 . 0

5 40 9“

30

20

10

?

other evaluable lesions) (Table 3). These were true “mixed responses;” none of these patients had received previous radiation. By the criteria of response which many groups employ, our “mixed” responses could be called partial re- sponses. Two were treated with methyl-CCNU and vincristine and two with methyl-CCNU, vincristine, and methotrexate. Two had limited disease, two had extensive disease, two were men and two were women, two had small cell carcinoma and two had adenocarcinoma. The duration of these four mixed responses ranged from 60-107 days with a median of 67.5 days.

100 r

70

; 60

2

$ 50 Q

a 40

9,

. aJ

? &‘ 30

20

I0

0

+Srnoll Cell (1411) - Lorqe Cell (171 I I

Squarnous ( I9 ) Adenocorcinomo (19/2 1

I

0 60 120 180 2 4 0 300 360 Time in Doys

FIG. 3. EfTect of cell type on survival

Less than a 2570 regression or “static” response was reported as the maximal response in 3/11 (27%) on methyl-CCNU, 8/32 (25%) on methyl- CCNU and vincristine, and 9/30 (30%) on methyl-CCNU vincristine, and methotrexate. T o qualify for a static response, there must be no change in an indicator lesion over a 42-day pe- riod where it had previously been progressing. The duration of these “static” responses ranged from 40-210 days, with a median of 63.3 days. Progression of disease was seen in 60-70% of patients.

When the above criteria of response as an in- dication of the activity of agents employed are considered, 33% (24/77) of thepatients benefited from chemotherapy. Six of 19 (32%) with epi- dermoid carcinoma responded, nine of 21. (43%)

TABLE 3. Results of Therapy ~

Mean Mean MeCCNU Mean Me-CCNU duration Me-CCNU, vcr duration vcr, mtx duration No. (%I (Days) No. ( % I (Days) No. ( % I (Days)

Total no.

Mixed response 0 (0%) 2 (6 .3%) 8 3 . 5 2 (6 .7%) 67 .5 <25% or static

Progression 8 (72.7%) 22 (68.7%) 19 (63 .3%)

patients 11 32 30

response 3 (27%) 51 8 (25%) 56 .6 9 (30%) 74.1

No. 3 CHEMOTHERAPY OF BRONCHOCENIC CARCINOMA Rzchards et al. 1081

TABLE 4. Rronchogenic Carcinoma-Survival According to Histological Type

Histological type Percent patients Epidermoid Adenocarcinorna Large cell Small cell

alive (days) (days) (days) (days)

75% 41.3 52.8 29.0 49.2

50% 83.5 109.0 68.0 71 0 25% 119.8 151.3 141 . 0 122.5

with adenocarcinoma responded, four of 18 (22%) with large cell carcinoma responded, and five of 15 (33%) with small cell carcinoma re- sponded. There was no significant difference in survival among the histiological subgroups (p > 0.05) (Fig. 3) (Table 4 ) .

Nausea and vomiting occurred frequently with methyl-CCNU, but not invariably, and was partially controlled with phenothiazine adminis- tration. Onset was usually within 2-3 hours af- ter ingestion with recovery in a few hours, al- though sometimes days were required. Sixty-six percent of patients experienced only mild tox- icity, probably because the great majority of patients only received one or two doses of ther- apy. Seventy-seven percent had no hemato- poietic toxicity. Hematopoietic toxicity (Table 5) usually occurred between the third and fifth week. There was a wide variability in recovery, but it usually occurred in 1-2 weeks, although it was delayed at times for several weeks. Thirteen of 62 patients (21%) receiving vincristine had to have dose modification due to toxicity (absent deep tendon reflexes or severe paresthesias). Three of 30 (10%) treated with methyl-CCNU, vincristine, and methotrexate developed severe gastrointestinal symptoms requiring hospi- talization for treatment of their dehydration. No case of metabolic encephalopathy occurred.

The time on study and duration of survival of patients with limited disease treated with two or three drugs did not differ significantly but were significantly shorter (p < 0.05) in patients treated with methyl-CCNU alone. Patients with extensive disease appeared to live longer and remained on study longer when treated with methyl-CCNU, methotrexate, and vincristine, but more patients are needed to verify this (p = .1S). There was a significant difference in time on study and survival between those patients with extensive and limited disease.

Patients with limited disease had longer time on study (p = ,007) and survival (p = ,008) than those with extensive disease (Fig. 4). In the good-risk group, time on study (p = .13) and survival (p = .09) was better than that of the poor-risk group. Kesponders (mixed and static) remained on study longer and lived longer than nonresponders (p = ,002) (Fig. 5). Survival (p = .05) and time on study (p = .13) in patients with squamous cell carcinoma was better with Kegi- men 111 than 11.

DISCUSSION

Our study demonstrates that the combination of methyl-CCNU and vincristine with or with-

TABLE 5. Comparative Toxicity

Total no. p a t‘ ienti

\Z‘R c 2000-4000 /mi11

\\‘RC 2000/mm?

Platelets 50-100.000/mm~

Hgb9-11 ~ / 1 0 0 t n l

Hgb < 9 g/100 nil

GI (ievere) Nerirotoxici ty

1082 CANCER September 1976 Vol. 38

008

0 I I

0 60 I20 180 240 300 360 Time in Doys

FIG. 4. Correlation of staging to survival

out methotrexate is of more benefit than methyl- CCNU alone (p < .05), in terms of both time on study and survival in patients with advanced bronchogenic carcinoma. The addition of meth- otrexate to methyl-CCNU and vincristine ap- peared to increase the time on study and sur- vival in patients with extensive disease and also in patients with squamous cell carcinoma. The

IOC

90

80

70 . . 7

$' 60 0 i

8 x 50 . 4

40

d 30

20

I0

0

I >T '*

T *\ I

T \.

i I '.

I

I . Nonresponder 149/01 Responders 120 /4 I

L~

T '* I \

\* '( W ! l c o x ~ n / G e h a n l ' . ~ ~ ~ T '.

'* '\ I

0

Ox., *\* !,

' 9 1. \

'\ *\. 9

! *\

I I *;>. , ) 60 I 2 0 I80 240 300 360

Time in Doys

FIG. 5 Effect of response of survival

chemotherapy regimens were well tolerated and response was seen in all types of bronchogenic carcinoma.

The quality of response in terms of objective criteria was poor but the responders had signifi- cant subjective improvement. In addition, re- sponders survived twice as long as non- responders.

KEFEKEKCES

I . Rurdette, h'. J., and Gehan, E. A . : Planning and Anal- ysis of Clinical Studies. Springfield, Charles C 'l'homas. 1970; pp. 72-79.

2. Hroder, I , . E., and Chrtrr, S. K . : Clinical brochure: (2- chloroethyl)-3-(4-meth~l-cyclohexyl)-I-nitrosourea (hle- (:(;NU) NSC 94441. National Cancer Institute, Rethesda, hld, 1972. 3. (iailani, S., and Kutcher, J . : Preliminary clinical trial

of l-(2-chlorethyl)-3-(4-methylcyclohexyl)-l nitrosourea (NSC 95411) (b1eCC:NU) in human neoplasms. 3. Med. (BasrlJ 4:209--218, 1973. 4. hlayo. I . G.. Laster. W. P., J r , , Andrews, C. X I . , and

Schabcl, F. hl., J r . : Success and failure in the treatment 0 1 solid tumors. I l l . "Cure" of metastatic Lewis lung carci- noma with methyl-CCNU (NSC 9.5441) and surgery-rhemo- therapy. Cancer Chemother. Rep. 56:193-195, 1972.

-5. Richards, F., Pajak, '1. I:., Cooper, M. K. , and Spurr,

C. L.: Study of methyl-CCNU (NSC 95441) in the treatment of lung cancer. Cancer Chemother. Rep. 57:419-422, 1973.

6 . Ross, C . A, , and Selawry, 0. S.: Comparison of three dose schedules of methotrexate in lung cancer. Proc. Am. A r ~ o c . Cancer Res. 6:54, 1965 (Abstr.). 7. Sartorelli, A. C., and Creasey, W. A.: Combination

Chemotherapy in Cancer Medicine, J. F. Holland and E. Frei, Eds. Philadelphia, 1973; pp 707-717. 8. Shaw, I<. K., and Bruner, J. A. : Clinical evaluation of

vincristine. CancPr Chemother. Rep. 42:45-48, 1964. 9. Takita, H., Brugarolas, A. , Mittelman, A., and Vin-

cent K: Phase 11 study of the effect of methyl-CCNU (NSC 9544 I ) on bronchogenic carcinoma. Cancer Chemuther. Rep. 59:257-250, 1973.

10. Tranum, H. L., Haut, A., Kivkin, S., et al.: A phase I1 study of methyl-CCKU in the treatment of solid tumors and lymphoma-a Southeast Oncology Group Study. Cancer 35:l 148-1 153, 197.5.