Single-drug therapy in ovarian cancer

GYNECOLOGIC

ONCOLOGY

1,220-232

Single-Drug

(1973)

Therapy

Factors

Influencing

MYR~SLAW

in Ovarian

Cancer’,’

Response

M. HRESHCHYSHYN

GYN Oncology Services, State Urcioersity of New York at Buffulo, School of Medicine

Roswell

Park Memorial Institute, Buffulo, New York

Received June 14, I973 Patients with advanced ovarian cancer, 150 treated with chemotherapy alone and IO7 treated with combination of chemotherapy and radiation, were analyzed. Direct correlation was found between tumor regression and patient survival. Alkylating agents were the single most effective drugs. The drug dose and the amount of tumor removed prior to the onset of chemotherapy correlated directly with the response. Serous and poorly differentiated carcinomas were more likely to regress on chemotherapy than mutinous and well-differentiated carcinomas hut the long-term survival of patients with these tumors was just the opposite. Survival of patients with Stage III and Stage IV disease treated with combination of chemotherapy and radiation was longer than with either therapeutic modality alone.

Ovarian cancer is relatively susceptible to treatment with cytotoxic drugs. The quality of response depends on the tumor type and the mode of chemotherapy. With the multitude of chemotherapeutic approaches now in use and the continuous modification of same, it is important for us to examine our experience in search of general principles which could guide us in our efforts to improve the efficacy of this therapeutic modality. Our experience in chemotherapy of ovarian cancer has been in part previously reported [l-6]. This analysis is based on a retrospective reevaluation of 257 patients with extrapelvic spread of ovarian cancer (equivalent to Stages III and IV, F.I.G.O. classification) [7] treated by the author with various drugs, either alone (150 patients) or in combination with radiation (107 patients) over the last 12 years. During that time various changes in chemotherapy were introduced. Initially, only patients unsuitable for further surgery and radiation were considered for chemotherapy. Then, for a transient period of time, patients with nonresectable advanced ovarian cancer were randomly treated with radiotherapy or chemotherapy alone. More recently, when fea’ Presented in part at the 20th Annual Clinical Meeting of the American College tricians and Gynecologists, May 1972, Chicago, Illinois. ’ Supported in part by United States Public Health Service Grant CA 12476.

Copyright All rights

@ 1973 by Academic Press, Inc. of reproduction in any form reserved

of Ohste-

SINGLE-DRUG

THERAPY

IN

OVARIAN

CANCER

221

sible, chemotherapy was combined with radiation and, in patients with marked tumor regression, a “second look” laparotomy with the intent of complete tumor resection was encouraged. The scheme of chemotherapy during the first few years involved administration of a drug for 6 weeks and only patients who during that time showed regression of the tumor were continued on treatment for the duration of response. In subsequent years patients were maintained on drug for the duration of the progression-free interval, that is, even if no detectable regression of the tumor occurred. Drug was discontinued if the tumor progressed during the first 6 weeks of treatment or whenever reactivation of the tumor occurred and these patients were considered for another form of therapy. The drug dose was usually reduced to half when the white blood count decreased to 3000-5000/mm3 or the platelet count decreased to 75,000-100,000/mm”, and with further decrease in the counts, the drug dose was completely omitted for the duration of bone marrow depression. With some drugs other forms of toxicity, e.g., gastrointestinal toxicity, necessitated drug reduction or omission for the duration of the toxicity. Except for patients with severe hematopoietic depression, e.g., white blood count of less than 1000/mm3, no corticoids were administered in order to avoid difficulties in interpreting objective changes in the tumor size. No patients, once started on a drug, were excluded from the analysis even if they received an “inadequate trial.” The response was measured in terms of objective changes in the tumor and the patient, and patients’ survival from onset of chemotherapy. The criteria for response remained constant throughout the years. Clinically significant or “good response” was defined as regression of the tumor mass, 25% measurable or 50% palpable in one diameter, lasting more than 3 months and associated with symptomatic improvement. Regression of tumor not fulfilling the above criteria were classified as “some response.” Regressions of pleural and peritoneal effusions did not, by themselves, qualify for definition of objec-

FIG. 1. CA ovary, Stages III and IV Rx: Alkylating 0 Good (N= 25); 0 Some (N = 36); A No (N = 89).

agents,

Respdnse-Survival.

Response:

HRESHCHYSHYN

\

‘,\\ .--.--.--.--.--.--.--.--.--.--.--.--.

‘\ ‘L. \ l -.-,

29.~.- .. . . . . STAGES 10 .-mm.. STAGE

I-I IIB

\.

,\

IA

-*\ .N.

III-IV

107.m.STAGES

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--

*-.-.-

.-.-*\.-*

I

0 0

.

.

6

.,2.

,*,

.

.2&J

months

FIG.

2.

tive response but on the other hand, the appearance or recurrence of effusions was accepted as a sign of tumor reactivation. Objective changes in the tumor mass correlated with the patients’ survival. Thus, patients who sustained clinically significant response lived longer than patients who did not respond (Fig. 1) and the difference in the survival of these two groups coincided with the duration of objective regression of the tumor (Fig. 2). DRUG

REGIMENS

Table I and Table II show the number of responses observed with various drug treatments. Except for one patient with a good response to vinblastine and another patient with mixed tumor of germ cell origin (including choriocarcinema), who responded to vincristine, clinically significant responses were observed with alkylating agents only. It may be significant, however, that alkylating agents were usually employed first and that patients treated with other drugs had more advanced disease not infrequently in the preterminal stage. Re-treatment with alkylating agents (Table III) resulted in clinically significant response in 4 of 28 patients and an additional nine patients showed some response. It may be that in the majority of these patients the initial treatment was inadequate or rather prematurely terminated and that in the case of cyclophosphamide we may be dealing with a measure of drug specificity absent in other alkylating drugs.

SINGLE-DRUG

THERAPY

CA TREATMENT

IN

OVARIAN

TABLE I STAGES III ALKYLATING

OVARYWITH

223

CANCER

AND IV AGENTS ALONE

Dose h&g) Drug Thio-TEPA Thio-TEPA Thio-TEPA Thio-TEPA

Initial (TSPA) (TSPA) (TSPA) plus chlorambucil

O.l/day 0.4lday 0.8lday 0.4/day

Chlorambucil Cyclophosphamide Mechlorethamine Melphalan Bayer

A-139

Uracil mustard CL 25477 N-N’diethylene ethyln” (1,3,4 thiodiazol phosphoramide ‘I Drug

administration

N” - 2-yl)

Response

Maintenance x x x x

2 2 2 2

No. pts.

0.05lweek 0.2lweek 0.4/week

Some

None

11

0 8 4

0 20 1

5 48 6

19”

7

5 76

iv iv iv iv po I

O.Z/day 0.2-0.4/day po 2-20/day iv 15/week iv 0.2/day x 2 O.l/week iv O.l/day po 0.2/day x 4/month po I O.l-0.3/day iv O.G/week iv 0.15/week po 0.4-1.3/day x 4 q 2 weeks po

was continued

Good

for the duration

9"

1

6 2

6 6

12

2

3

7

7

1

2

4

4

0

2

2

3

2

0

1

3

0

0

3

1

0

0

1

of progression-free

interval.

No appreciable differences in response rate with various alkylating agents are seen although the uneven distribution of patients and other variables prevent a definite assessment. Duration of drug administration and the drug dose, however, appear to be important factors. Thus, patients who were maintained on drug even if no tumor regression occurred prior to 6 weeks from the onset of treatment, had a higher response rate than the remaining patients (Table IV). Drug dose in patients receiving Thio-TEPA correlated with the

TREAT~~ENT

CA WITH

TABLE OVARY-STAGES DRUGS OTHER

II III THAN

AND

IV

ALKYLATING

AGENTS

Response Dose

Drug Delalutin Provera Delatestryl 5-Fluorouracil Methotrexate Dichloromethotrexate Vinblastine Vincristine Dactinomycin

No. pts.

1 g/week im 100 mg/day

po 2.9 mg q 2 weeks im 7.5-15 mg/kg/day x 5-7 15 mglkglweek iv Various 0.1-0.3

50-75 0.5-l

mglkglweek iv pg/kg/week iv mg/day x 5 iv

months

iv

Good

Some

None

8

0

1

7

2

0

0

2

9

0

1

8

6

0

0

6

16

1 1

1 1 1

14

7 2

0

5 1

224

HRESHCHYSHYN TABLE III CA OVARY-STAGES III AND RE-TREATMENT WITH ALKYLATIKG

IV AGENTS

Response Drug

Some

Good 4 0 0 0 0 0 4

TSPA 0.4 Cytoxan HN, A-139 Melphalan CL 25477 Total

None

Total

4 2 1 1 1 6 15

13 6 1 1 1 6 28

5 4 0 0 0 0 9

TABLE IV CA OVARY-STAGES III AND IV TREATMENT WITHTHIO-TEPAANu CHLOUMBUCIL DURATION 0~ TREAThlENT AND RESPONSE

ALONE"

Response Good No. pts. A B Total

92 28 120

Some

None

No.

(So)

No.

(%)

No.

(“rc)

12 8

(13)

21 8 29

(23)

59 12 7i

(64)

(29)

56

(29) (17)

I’ Re-treatment cases not included. A, drug regression occurred; B, drug administration interval.

administration continued

(24)

(42) (59)

discontinued at 6 weeks unless tumor for the duration of progression-free

TABLE V CA OVARY-STAGES III AND IV TREAThlENT WITH THIO-TEPA DRUG DOSE AND RESPONSE Response Drug dose (m&P

a Mg/kg/day

No. pts.

Thio-TEPA Thio-TEPA Thio-TEPA

0.1 0.4 0.8

5 76 11

x 2 as an initial

course

and then

Good 0 8 4 one-half

Some

None

0 20 1

5 48 6

of same dose weekly

for maintenance.

SINGLE-DRUG

THERAPY

IN

OVARIAN

225

CANCER

0 2

4

FIG. 3. CA ovary, (A’ = 76); . TSPA,

6

8

10

12 MONTHI

Stages III and IV. Drug 0.8 (N = 11).

14

16

dose-Survival.

18

A TSPA,

20

22

01 (N =5);

24

0 TSPA,

0.4

response rate (Table V) and patient survival (Fig. 3). Because increasing amounts of drugs tend to increase toxicity, we correlated the severity of bone marrow depression with the tumor-response rate (Table VI), and found that the number of responses in the group of patients who sustained severe toxicity was greater than among the patients with lesser or no toxicity. Still a number of patients who suffered no obvious toxicity responded with marked tumor regression. Thus, toxicity per se could not have been the determining factor and it was obviously detrimental when it led to fatality. Our material did not lend itself to evaluation of other factors, e.g., drug spacing, which could affect the response. TUMOR Clinical status of the disease with respect to whether the disease was primary or recurrent (Fig. 4), whether the patient had or did not have previous radiation (Fig. 5) and whether the stage of the disease was equivalent to III or

TABLE

VI

OVARY-STAGES III AND IV TREATMENT WITH ALKYLATING AGENTS ALONE SEVERITY OF LEUKOPENIA AND RESPONSE CA

Response Leukopenia (WBC in thousands) >3 <3
>l

Good No. 12 9 4

Some

None

(%)

No.

(%)

(12) (24

21 10 5

(21) (27) (42)

(33)

No.

(%)

68 18 3

(49)

(67) (25)

226

FIG. 0.4/kg.

HRESHCHYSHYN

4. CA ovary, Stages 0 Primary (N = 69);

III

l

and IV, No previous Recurrent (N = 31).

radiation.

Rx:

Radiation

+ TSPA,

0.1 and

20 -

FIG. 5. CA 0 No previous

ovary, Stages III atid IV. radiation (N = 26).

2

FIG. 6. CA ovary, (N = 62); 0 Stages

9

Stages III and

6

8

Rx: TSPA,

10

u “DYTHS

III and IV. Rx: Alkylating IV (N = 150).

0.4/kg.

14

agents.

l

Had

16

previous

18

0 Stage

radiation

20

III

22

(N =

69);

2i

(hJ = 88); A Stage

IV

SINGLE-DRUG

THERAPY

IN

TABLE

OVARIAN

227

CANCER

VII

OVARY-STAGE III TREATMENT WITH ALKYLATING AGENTS % OF TUMOR REMOVED AND RESPONSE CA

Response Good % Tumor

removed”

No. pts.

No.

20 11 9

4 2 5

<25 26-75 76-99 a Only

patients

operated

upon

Some (%)

less than 4 weeks

None

No.

(%)

No.

(%)

(20) (18)

2 2

(56)

1

(IO) (18) (11)

14 7 3

(70) 64 (33)

prior

to onset

of chemotherapy

were

evaluated.

IV (Fig. 6) did not affect greatly the survival of patients on chemotherapy. But the amount of tumor removed just prior to chemotherapy affected greatly both the response (Table VII) and the survival (Fig. ‘7) of these patients. Thus, patients with more than 75% of the tumor removed generally responded better and survived longer. Another factor which to some extent may effect the response to chemotherapy is the tumor type (Table VIII and Fig. 8) and the degree of tumor differentiation (Table IX and Fig. 9). Therefore, in terms of tumor regression, a serous and poorly differentiated carcinoma appears to be more likely to respond to chemotherapy than a mutinous and well-differentiated carcinoma. But the overall survival of these groups of patients, which is affected by the natural course of the disease [8], is just the opposite. COMBINATION

OF CHEMOTHERAPY

WITH

RADIATION

Of the 107 patients treated with a combination of chemotherapy (ThioTEPA 0.4 mg/kg/day x 2, iv, followed 2 weeks later by chlorambucil 0.1

ZO-

0

I

2 FIG. 7. CA ovary, Percent

tumor

I

4 Stage removed:

6 III.

l

I

a

10

I

12 WITRJ

14

I

16

I

la

I

20

1

22

1

24

Survival on alkylating agents in relation to the % tumor removed. < 25% (N = 20); 0 26-75% (N = 77); A 76-99% (N = 9).

228

HRESHCHYSHYN TABLE

VIII

OVARY-STAGES III AND IV TREATMENT WITH ALKYLATING AGENTS TUMOR TYPE AND RESPONSE CA

Response Some

Good Tumor

type

Serous Mutinous Adenoca

FIG. 8. CA ovary, (N = 62); 0 Mutinous

None

No.

(%I

No.

(%)

No.

(%)

Total no.

10 2 12

(16)

13

(21)

39

(63)

62

(11) (23)

(61)

(28) 1:

(26)

Stages III and IV. Rx: Alkylating (N = 18); A Adeno (N = 53).

TABLE

agents,

8:

tumor

(51)

.i;

l

type-survival.

IX

OVARY-STAGES III AND IV TREATMENT WITH ALKYLATING AGENTS TUMOR DIFFERENTIATION AND RESPONSE CA

Response Some

Good Tumor differentiation Well + mod Poor Unspecified

No. 3 13 9

(%)

No.

(%)

No.

(%)

Total no.

1: 16

(15) (27) (34)

i; 22

(73) (52) (47)

26 60 47

(12) (21) (19)

None

Serous

SINGLE-DRUG

THERAPY

IN

OVARIAN

229

CANCER

100

80

fl 60 5 a - 40

20

0 2

FIG.

l

Well

4

6

8

1u

12 Mo”THI

14

16

18

20

22

24

9. CA ovary, Stages III and IV. Rx: Alkylating agents. Tumor differentiation-Response. and Moderate (N = 26); 0 Poor (N = 60); A Unspecified (N = 47).

mg/kg/day, p.o. for the duration of response), 100 patients received chemotherapy and radiation (usually 2500 rads to the center of the abdomen in 4-6 weeks) concomitantly and seven patients were pretreated for 6-8 weeks with chemotherapy before starting on radiation. In approximately one-third of all the patients who received chemotherapy and radiotherapy concomitantly, the radiotherapy had to be interrupted for a transient period of time because of bone marrow depression. The median survival and the survival at 6, 12, and 24 months was significantly higher in patients receiving chemotherapy in combination with radiation as opposed to patients who received chemotherapy or radiation alone (Fig. 10). This was true not only of patients with Stage III but also in patients with Stage IV disease, that is, patients who did not receive radiation to the entire tumor (Fig. 11). Seven of the patients lal

8)

fM -4

20

0 2

4

6

8

lo

l2 lQill4

14

16

18

?I

z2

24

FIG. 10. CA ovary, Stages III and IV. Rx: Radiation and chemotherapy (TSPA and chlorambucil) - Survival. A Radiation alone (N = 114); l Alkylating agents alone, no previous radiation (N = 66); 0 Combined alkylating agents and radiation, no previous radiation or chemotherapy (N = 100).

230

HRESHCHYSHYN

FIG. 11. CA ovary, Stage and survival. Rx: Radiation +TSPA, (N = 93); 0 Stage IV (N = 14); A Stages III and IV (N = 107).

0.1 and

0.4/kg.

l

Stage

III

lea

20

0

FIG.

previous

I 2

I 4

I 6

1 a

10

1 12 pY)WT”J

12. CA ovary, Stages III and IV. Rx: Radiation radiation (N = 100); l Had previous radiation

I 14

8 16

+TSPA, (N =7).

I 18

I 20

0.1 and 0.4/kg.

FIG. 13. CA ovary, Stage III. Survival on TSPA + radiation in relation tumor removed. Percentage tumor removed: l < 25% (N = 31); 0 26-75% (N = 12).

, 22

Survival:

I 21(

0 No

to the percentage of (N = 24); A 76-99%

SINGLE-DRUG

THERAPY

IN

OVARIAN

CANCER

231

treated with radiation and chemotherapy who had radiation previously had their survival indistinguishable from patients receiving chemotherapy alone (Fig. 12). Tumor type and tumor differentiation, as well as the amount of tumor removed just prior to initiation of the combined treatment with chemotherapy and radiation, played essentially the same role as in patients treated with chemotherapy alone (Fig. 13). In 10 of 13 patients who underwent second-look procedure, either no residual tumor was found or the residual tumor could be completely removed. Only 3 of the 10 patients subsequently developed clinical recurrence of the tumor. Several patients refused second-look procedure and some of them remain clinically free of detectable disease. DISCUSSION Data derived from this retrospective analysis of clinical observations extending over a prolonged period of time, which includes many changes in the approach to chemotherapy of ovarian cancer, do not have the validity of a controlled prospective study. Still some of the findings are significant, they corroborate current laboratory concepts of tumor behavior and response to chemotherapy and they should be helpful in our strategy planning of a more successful attack on this disease. Alkylating agents appear to be the only cytotoxic drugs consistently effective in the treatment of some patients with advanced common ovarian cancer. Other compounds rarely produce significant clinical response in patients previously treated with alkylating agents. What their effect might be in patients in earlier stages of the disease and with a smaller amount of tumor has not been established in our material; however, others have reported higher response rates [3]. Still the situation is different from that encountered in other types of cancer, e.g., malignant trophoblastic neoplasia, leukemia, in which drugs with a different mode of action are about equally as effective against the tumor. This is of importance in considering multiple drug therapy in ovarian carcinoma. No conclusions can be drawn as to the relative effectiveness of various alkylating agents. The drug dose, however, correlates directly with the response rate and premature termination of treatment results in fewer patients responding. Dose spacing, which no doubt is also an important factor, could not be evaluated in this material. Tumor type and tumor differentiation effect the natural course of the disease [8] and, in a reverse fashion the response to chemotherapy. Thus, patients with slowly progressing disease are less likely to respond to chemotherapy with cytotoxic drugs than patients with a more rapidly growing tumor, This variable is one that we can do little about except to consider it in designing the overall treatment. A significant decrease in the size of the tumor by whatever means, whether it be surgery, chemotherapy, or, one can assume radiotherapy, has two complementary effects: (1) the decrease in the tumor by itself prolongs the patients’ survival [6] and (2) the reduction in the tumor mass by one treatment increases the efficacy of subsequent therapeutic modalities. The available

232

HRESHCHYSHYN

data suggest that for the present aggressive therapy using all means of therapy (surgery, radiotherapy, chemotherapy) integrated in a fashion designed to the specific needs of a particular patient but avoiding irreparable damage, is the best way of assuring maximal benefits. Our future effort should be directed at increasing the efficacy of all therapies in terms of their ability to reduce the size of the tumor and in establishing an optimal sequence for their employment. REFERENCES J, B. Chemotherapy of patients with gynecologic neoplasms with three different alkylating agents: TSPA, A-139, and B-518. Proc. Amer. ASS. Cancer Res. 3,28 (1959). 2. HRESHCHYSHYN, M. M. A critical review of chemotherapy in the treatment of ovarian carcinoma, Clin. Obstet. Gynecol. 4, 885-900 (1961). 3. HRESHCHYSHYN, M. M., AND HOLLAND, J. F. Chemotherapy in patients with gynecologic cancer, Amer. I. Obstet. Gynecol. 83,468-489 (1962). 4. HRESHCHYSHYN, M. M. Experiences with chemotherapy in gynecologic cancer, N. Y. StateJ. Med. 64,2431-2434 (1964). 5. HRESHCHYSHYN, M. M. Chemotherapy of ovarian cancer, in new concepts in gyneco~ogkd oncology (G. E. Lewis, Jr., W. B. Wentz, and R. M. Jaffe, Eds.), Davis, Philadelphia, pp. 341-346 (1966). 6. HRESHCHYSHYN, M. M., AND GRAHAM, J. B. Chemotherapy of ovarian cancer, Int. Surg. 47, 398-401 (1967). 7. Classification and staging of malignant tumors of the female pelvis, ACOG Technical Bulletin, No. 12 (1969). 8. HRESHCHYSHYN,M.M.,SCHUELLER,E.F.,ANDRANDALL,C.L.P~~~~~~S inmanagementof patients with ovarian cancer, Clin. Obstet. Gynecol. 10, 599-624 (1967). 1.

HHESHCHYSHYN,

M.

M.,

AND

GRAHAM,