cis-Platinum in gynecologic cancer

GYNECOLOGY

cis-Platinum in gynecologic cancer I. Epithelial ovarian cancer DON ]. HALL, M.D. ROBERT DIASIO, M.D. DEAN R. GOPLERUD, M.D.

Knoxville, Tennessee, and Richmond, Virginia Eighteen patients with epithelial ovarian cancer were treated with cls-dlchlorodiammineplatlnum at a dose of 60 mg/m 2 • ThEire Were two (11%) complete reaponses; seven (38%) partial respon1$8S, seven (38%) with stable disease, and two (11%) with progressive disease. The overall response rate was 49'%. In nine patients previously untreated, there was an overall response rate of 66.6% (six of nine). (AM. J. 0SSTET. GYNECOL. 141:299, 1981.)

CIS- DIA MM I NED I CLOROPLA TINU M (II)

(cis-platinum or DDP) (Platinol, Bristol Laboratories, Division of Bristol-Myers Co., Syracuse, New York) was first shown to be active in ovarian cancer by Wiltshaw and Kroner 1 in 1976. Since that time DDP has become incorporated in a number of multidrug treatment protocols for ovarian cance::r. 2 Despite its popularity there have been a limited number of studies showirig the efficacy of DDP when used as a single agent (Table I). The majority of studies have been carried out in patients with advanced ovarian cancer previously treated with other chemotherapeutic drugs. Our study presents 18 patients with epithelial ovarian cancer, nine of From tJu· Gynecologic Oncology Service, Deparlment of Obstetrics and Gynecology, University of Tennessee College of Medicine; and the Division of Medical Oncology Service, Deparlment of Internal Medicine, and the Gynecologic Oncology Service, Department of Obsretrics and Gynecology, Medical College of Virginia. Received for publication December 18, 1980. Accepred May 1, 1981. Reprint reqtU'sts: Don]. Hall, M.D., University of Tennessee College of Medicine, Department of Obstetrics and Gynecology, 1924 Alcoa Highway, U-27, Knoxville, Tennessee 37920. 0002-9378/81/190299+06$00.60/0 © 1981 The C. V. Mosby Co.

whom were not previously treated with chemotherapeutic agents. A high overall response rate was achieved by use of a drug dosage different from that in previous reported studies. Previous studies have often not included a description of the type of epithelial tumor or the histologic grade. Our study evaluates these additional parameters with tumor response to therapy.

Material and methods DDP was administered to 18 patients with epithelial ovarian caocer at the Medical College of Virginia Hospital. All but one patient was evaluable. Sixteen patients had measurable lesions, which were serially measured every fourth treatment cycle or when advancement was suspected by physical examination. Lesions were measured by chest x-ray examination, computerized tomography, or ultrasound or by direct measurement in the case of visible or palpable nodules. The histology of all lesions was documented by fine-needle aspiration biopsy, open biopsy, or laparotomy. All pathology slides from patients having surgery outside of the Medical College of Virginia were reviewed in the Department of Surgical Pathology by a single pathologist. The tumor type and grade were established from the origi299

300

lhtobc, L 10~1

Hall, Diasio, and Goplerud .\tn

Table I. Single-agent platinum in ovarian cancer

()b.,.-tet_ (..vn.co,i

·------,------Re.,fmmr mtr

Author

Dose (mg/m 2 )

:Schedule

So. of)atients

Wiltshaw and Kroner'

30

D4ily X 3, every l wk Every 2 to 3 wk Every 3 wk Every 3 wk Every :l wk Every 3 wk Every 3 wk Every 3 wk Dailv >< 5

:\4

~~0

Rossof et al.' Bruckner et al." Bruckner et al 9 Piver et a!.'" Thigpen et al. 4 Young et al.' Stewart et al. ''

VViltshaw et aL.s

Stehman et al." Our study

75 50 50 50 to 100 50 70 20 50 to 100 30 30 100 20 50 60

Dailv x 3. everv 4 wk . Every 3 wk Every 4 wk Daily x -l, every 3 to 4 wk . Every 3 f(; 4 wk Everv 3 wk

material in all cases. Patients were considered to lave a complete response if they had no clinical disease for longer than 3 months or the resolution of all clinical ¥.Jcites for longer than 3 months. Patients were consid~red to have a partial response if they demonstrated ~reater than 50% reduction in the measurement of their tumor volume for longer than 3 months. Patients were considered to have stable disease if the response was less than 50% or remained unchanged for longer than 3 months. Progressive disease was determined in patients whose lesion increased by more than 50% duriwr theranv. 0 -./ Patients received 60 mg/m 2 DDP. every 3 weeks either as outpatients or as inpatients. Written consent was obtained from all patients. Outpatient therapy consisted of administering l ,000 ml 5% dextrose in 0.5N saline at 200 ml/hr or more. With the last l OOml fluid DDP was administered intravenously. Most patients were given the initial Huid therapy with 25 mg chlorpromazine and 5 mg diazepam intramuscularly. Two patients preferred premedication of a different type. Patients receiving outpatient therapy were encouraged to f(n·ce ftuids orally at home and were given prescriptions for 25 mg chlorpromazine rectal suppositories and 5 mg diazepam tablets, which were to he raken simultaneously .every 4 hours as needed for nausea. Mannitol, 12.5 gm, was administered intravenously immediately prior to DDP therapy to induce diuresis. lnpatient chemotherapy was administered to those patients who were unable to cope wi.th outpatient ther-apy because of other medical conditions, fear, living alone, or a desire expressed by the patient to be treated in the hospital. Several patients received their first 1'1al

15 17 19 ~()

:>4

1

(~~~) ,,~

··'

u 3~

V.'

5

29

24

~y

1~

..::-.

23

'27

:.!9

:.:~

!)

:zo

7

~9

It\

!9

·w

-9

,)._

course as inpatients, and all subsequent COltrses as outpatients. These patients were gi.wfJJ,OOO-ml 57( dex-· trose in 0.5N ,~aline at 150 ml/hr fo.r 4 hour~ prjor to DDP administration and then hydr;ttion waHontinued until the following morning. Mannitol, !2.5 gm, was also administered 30 minutes prior to DDP. PatieJ)ts were premedicated with 25 mg Gnlorpromazine and 5 mg diazepam intramttscularly 2 hours before and simultaneouslv with DDP administrati(m and then every '\ hour·s ;rs needed for mwsea and vnmiting throughout the night. Prior to each treatment cvde a complete blood count,_ platelet count, serum creatinine, ,-n-ine dipstick for protein, SMA-6, ami SMA-12 were determined. A complete physical, induding pelvic exaniination, was performed before each treatment b)' one ot us. Serial creatinine clearances were obtained, and audi H g~n/ 100 ml werec given ~ full course of therapy- Therapy was cont.inut~d until disease progression occurred.

Results A total of l70 courses of DDP were administered tp the I H patients. Their mean age \vas .56 }·ears, with a

Volume HI Number 3

range of 34 to 73 years. There were I3 white patients and five black patients. Three patients had recurrent Stage I cancer: one had Stage lA, one Stage IB, and one Stage IC. Three patients had Stage liB, eight patients had Stage Ill, and four patients had Stage IV cancer. Of the I8 patients with epithelial ovarian cancer two (II%) had complete responses; however, both were inpatients who did not have measurable lesions, and one was evaluable only by means of ascites. Patient 2 had minimal residual disease at the time of her original surgery, and patient 18 had ascites with innumerable small peritoneal tumor nodules throughout the abdominal cavity. Patient 2 died unexpectedly at home after 6 months of therapy during which there was no clinical sign of disease. No autopsy was obtained. The patient had a known cardiac arrhythmia, for which she was taking quinidine, and exhibited cardiomegaly on chest x-ray examination. Patient 18 experienced complete resolution of her ascites after the first two courses of chemotherapy and had no further evidence of clinical disease. The patient refused a second-look laparotomy and further therapy after 17 courses of DDP. Followup by telephone 5 months following the last course of therapy revealed the patient to be doing well without evidence of recurrent disease. Seven of 18 patients had partial responses, for a 38% partial response rate and an overall response rate of 49%. A similar rate of 38% (seven of I8) was found for those with stable disease. Two patients ( ll %) had objectively documented progressive disease, imd both subsequently died of their disease despite aggressive multidrug chemotherapy. Duration of response. The durations of response for the two complete responders were 6 and 13 months, respectively. For patients with partial response the median duration of response was 6 months, with a range from 4 to 8+ months, with two patients still receiving therapy. For patients with stable disease the median range of response was 5 months, with a range from 3 to I5 months. Time of response and number of courses. Of the I8 patients studied seven had a partial response. The median time to produce a partial response was 3 months, with a range from 2 to 5 months. The median number of courses required to produce this partial response was 5, with a range from 4 to 7 months. Response related to reduce therapy. All except Patient 2 received reduced do5-es of chemotherapy two or more times during the course of therapy (Table III). Both of these patients had progressive disease. Twelve patients received more than 50% of their therapy at one half reduced dose because of anemia, leukopenia,

cis-Platinum in gynecologic cancer. I 301

Table II. Toxicity criteria

I

Full dosel Half dose

2:4.5 WBC x 10 3 2:130 Platelets x 10 3 2:11 Hgb (gm/100 ml) :s20 BUN (mg/100 mi) Creatinine (mg/100 ml) :sl.2 Dipstick protein Negative

Therapy withheld

2.0 to 4.5 <2.0 50 to 130 <50 9.5 to 10.9 Transfusion* 21 to 60 >60 1.3 to 4.0 >4.0 l+to3+ 4+

Legend: WBC, white blood cell count; Hgb, hemoglobin; BUN, blood urea nitrogen. If Hgb 2:8 gmllOO ml administer full dose. If Hgb :58 gm/100 ml transfuse and administer full dose. *Initially several patients were given a reduced dose; thereafter the hemoglobin value was treated with transfusion and

the patient's DDP was prescribed as by other parameters. or elevated serum creatinine. Despite the fact that these patients received 30 mg/m 2 (half dose) during most of their therapy, DDP proved to be effective in control of tumor growth. Response related to tumor type. Of the 18 patients with epithelial ovarian cancer, the distribution of the histologic type of tumor was as follows: serous, nine; endometrioid, three; mucinous, two; clear cell, two; and undifferentiated, two (Table IV). The clear cell type showed no response to DDP therapy, with one patient having stable disease and the other progressive disease. The two patients with undifferentiated tumors both showed a partial response to therapy. Of the two patients who had complete responses one had an endometrioid and the other a mucinous type. Half of the patients had serous tumors; with five showing a partial response and four showing stable disease. Tumor grade and response. High tumor grade did not appear to prevent the antitumor activity of DDP (Table V). Of the 18 patients 10 had poorly differentiated or undifferentiated tumors, of which seven showed a response to therapy, for a response rate of 70% in the more anaplastic lesions. Because in seven of the I8 patients initial surgery was performed at another institution, it was impossible to evaluate accurately the amount of residual tumor remaining. Response related to previous radiation therapy. Of the 18 patients studied nine had had previous radiation therapy of some type (Table VI). Two had local therapy; one underwent intracavitary treatment for what was initially diagnosed as endometrial cancer at another institution and was subsequently found to have an endometrioid ovarian cancer with metastases to the uterine corpus. The second patient who received local therapy received only 800 rads to both inguinal areas. The remaining seven patients received whole-pelvis ir-

302

Hall, Diasio, and Goplerud

Inpatient/ outpatient

Half dose Rxf total Rx

I. M. V.

Out

0/4

225

2. A. B.

Out Out

4/7

3. C. P. 4. c. R. 5. L. R.

Out Out

5/13

6. L.T.

7. J. w. 8. M.H. 9. M.J.

10. F. J.

Out Out In In Out

9/ll 4/4 5/6 2/9 4/25

330 765 2,2!5

II. A.M.

Out

5/10

l/4

3/5

12. E. N.

In

2/5

13. E. S.

In

10/16

14. M. V. I5. M.W. 16. E. W.

In In

7/9

Out

17. F. W. 18, E. W.

In

7/ll

Out

8il7

8/9 3/5

Tot.al dose

I

Age

! ( lb,t{·\

ir.H·~l

(;\'IHTO]

___ ___

Table III. Patient data for epithelial ovarian cancer and DDP therapy

Patient

1,_

(Jc{,;{)t·i

·\!11.

,,

I I

Measurable Jesum

(yr)

Race

:'>l

w

Inguinal node

Clear cell

405 395

65 48

w

w

N/M CXR

Endometrioirl Endomerrioid

950 320

:H 56

w w

Liver scan, C'I Inguinal node

Serous Clear cell

790

46 67

CT, vaginal nodule Vaginal nodule

71 S9

w w B w w

Serous Serous Serous Serous Mucinous

815

51

B

390 445

w

52

w

CXR, CT CT

Serous Endometrioid

55 56 73

w

B

CT

B

Inguinal node CXR, U/S

U ndifferenti:ated Serous Serous

60

w

CT

45

B

Ascites

(mg)

210

595 460 320

700 1,235

5!

70

CT CT Abdominal U/S, CXR CT

tpithelialtype

lJ ndlfferentiat~d

Serous Mucinous

Legend: BSO, Bilateral salpingo-oophore, intra~ritoneal; L-PAM, melp~n; MWD, m~taklywell differentiated; N/M, nonmeasurable; 0, omentectomy; PD (respol1Se), progressive .disease; PD (grade), poorly differentiated; PH, previous hysterectomy; PR, Piirtial response; Rx, preScril:>ed; SD, sf.ible disea~e; Sub- T, subtotal hyster~my;TAH, tobtfabciomihitl hysterectomy: U/S, ultrasound; WA. whole abdomen: WD, well differentiated: WP. whole pelvis; X-LAP, exploratorylaf,)arotomy. *Surgery at another hospital. . tDied at home, unknown case. tResolution of ascites or hydrothorax in addition to other measurable lesion. §Still receiving treatment.

radiation, whole-abdomen irradiation, or both. Among these treated patients there was one complete response, three partial responses, four with stable disease, and one with progressive disease. In the nine patients not having radiotherapy there was one complete response, four partial responses, three with stable disease, and one with progressive disease. Response related to previous chemotherapy. Of the 18 patients treated nine had received no previous chemotherapy (Table VII). In this subset six of the nine showed a response to DDP, with one complete response and five partial responses, for an overall response rate of66.6%. Two patients had stable disease and one had progressive disease. In the subset of patiems who had received prior chemotherapy only three of nine patients showed a response, with one complete response and two partial responses, for an overall response rate of 33.3%. In this group five patients had sta.ble disease and one had progressive disease. It would appear that

previous chemotherapy red rices the likelihood ·of tumor respons~ to DDP. However, the number Is totT small to be statistically significant.

Comn.nt Cis-platinum is currently induqed in many chemotherapy treatment plans for ovarian cancer.-- Then: have, however. been only IO previously reported serie5 of patients with ovarian cancer treated with DDP as a single agent. These studies are summarized in Table I. The overall response rat.e has raoged (rom .5% to: 52%. with our study showing 49%. This conijrmsthe activitt of DDP in ovarian cancer and records its activity to be similar to standard alkylator therapy. Although onl"~ 11% of patients had a complete r.esponse, 38% had a partial response and 38% had stable disease. This confirms the findings ofot.hers that DDP alone pro· duces few complete respo:nses but dOes have suf6cienl antitumor activity to halt tumor growth} Otl(' half of

cis-Platinum in gynecologic cancer. I 303

Volume 141 Number 3

Response

Previous treatment Stage

Grade

Surgery

MWD

III

TAH, BSO*

PD PD

III

TAH, BSO TAH, BSO

liB

PD MWD

IV

liB III

IV IV

TAH, BSO BSO, PH TAH, BSO TAH, BSO, 0 X-LAP,* Bx only

Undifferentiated

lB

TAH, BSO

MWD PD

Ill

liB

LeftS and 0* TAH, BSO

Undifferentiated PD WD

Ill III III

X-LAP, 0 BSO X-LAP, Bx only

MWD MWD

IC III

TAH, BSO TAH, BSO,O

IA

Radiation (rads)

I

Type

Chemotherapy

Thiotepa-IP, L-PAM ICR WP 5,000; WA 2,000

BSO, 0, PH Sub-T, BSO

PD MWD PD PD WD

IV

I

WP4,900; WA 2,675 WP 5,000

L-PAM L-PAM

WP, unknown

WP 5,000; WA 3,000; strip WP 5,000; WA 3,000 Inguinal node WP5,000; WA 3,000

Table IV. Tumor response versus histologic cell type

L-PAM L-PAM

I

Duration (mo)

PD

2

CR PD

6t

PR SD

8

SD SD PR PR:t SD

8 3 4

5§ 15

PR

7

SD SD

12

2

4

5 6

PRt PR SD

L-PAM Chlorambucil, L-PAM, HMM L-PAM

7§ 4

PR CR:j:

6t 13

Table V. Tumor response versus tumor grade Com-

Partial Stable Progresredissive response sponse ease disease Total

Total

Clear cell Endometrioid Mucinous Serous Undifferentiated

1

1 1

2

5 2

7

4

7

2

2 3 2 9 2

18

plete

Well differentiated Moderately well differentiated Poorly differentiated Undifferentiated

4

6

2

8

2

2

the patients presented in this study did not have prior chemotherapy. In these nine patients the overall response rate was 66.6%; previously treated patients had a 33.3% response rate, showing that prior chemotherapy has an adverse effect on the responsiveness to singleagent platinum therapy (or that patients who have already failed on one regimen have tumor resistant to chemotherapy). This finding suggests that DDP should be included in first-line therapy in ovarian cancer. The median duration of response was 6 months for partial responders and 5 months for patients with stable disease. This exceeds previous reports. 1• 3 The median time required to produce a partial response in this series was 3 months, and the number of courses was five. This is slightly longer than the reports of Young and associates 3 and of Thigpen and colleagues 4 but

2 3

7

7

2

2

2 18

does reaffirm that if a response is going to occur with DDP it will occur within the first 3 to 4 months of treatment. Survival data cannot be calculated from the patients in this series, as some are still receiving therapy and others have been given alternate forms of therapy and are living with disease. Reduced therapy because of altered body chemistries and blood count did not appear to preclude a response to chemotherapy with DDP. Wiltshaw and associates 5 were able to show a 28% response rate using 30 mg/m 2 every 3 weeks. Thus reduced dosage is still compatible with a regression of tumor and less potential harm to the patient. The only previous report showing the histologic type

304

OnviX't I, 1% i

Hall, Diasio, and Goplerud

l)l,r,·t G'''H'C• ,1

Table VI. Tumor response versus previous radiation therapy

Table VII. Tumor respons.e in patients rt.'{:civing prior chemotherapy Total

Prior radiation therapy No prior radiation therapy

4

lj

of epithelial ovarian cancer treated with DDP was that of Stehman and associates 6 concerning 12 patiems. In that report 10 of 12 patients had serous tumors, with one endometrioid and one undifferentiated. both of which had tumor regression. In this study the scatter ot histologic types precludes any dramatic statements but

does illustrate that undifferentiated tumor types can respond to DDP and that dear cell carcinomas appear to do less well. There is little additional information antilable regarding the tumor grade in patients receiv" ing DDP for ovarian cancer. Wiltshaw and associates;; in a review of histology in their patients, found little dif~ ference in response among the histologic grades of tumors. Table V shows no specific trends. Of note is the fact that in the eight patients with poorly differentiated tumors there was one complete response, four partial

Total No prior chemotherapy Prior chemotherapy

responses, two with stable disease. and one with progressive disease, illustrating that poorly- differentiated tumors can, respond to therapy. As seen in Table VI, nine patients had received some type of radiation therapy prior to DDP and nine patients had not. It would appear that pt:ior radiation therapy had no relation ro response to therapy as has been found by others.« In conclusion, it appears from this-series of patients that DDP is an active agent in epithelial ovarian cancer with better results in previously untreated patients. The optimal dosage for DDP has not yet been established. It would appear from thisstudy that mg/m 2 every 3weeks is an effective dosing schedule; yie;:lding a ·t91fr response rate.

no

REFERENCES I. Wiltshaw, E., and Kroner, T.: Phase II study of cisdichlorodiammineplatinum (II) (NSC-119875) in advanced adenocarcinoma of the ovarv, Cancer Treat. Rep. 60:55, 1976. 2, Prestayko, A. W., D'Aoust, J. C., lssell, B. F., et al.: Cis· platin (cis-diamminedichloroplatinmn II), Cancer TreaL Rev. 6:17, 1979. '\. Young, R. C., Von Hoff, D. D., Gormley, P., et al.: Cisdichlorodiammineplatinum (II) for the treatment of advanced ovarian cancer, Cancer Treat. Rep. 63: 1539. 1979. 4, Thigpen, T., Shingleton, H., Homesley, H., et al.: Cisdichlorodiammineplatinum (Ill in the treatment. of gynecologic malignancies: Phase II trials by the Gynecologi<: Oncology Group, Cancer Treat. Rep. 63:1549, 1979. 5. Wiltshaw, E., Subramarian, S., Alexopoulous, C., et aL: Cancer of the ovary: A summary of experience with ci-sdichlorodiammineplatinum (II) at the· Royal Marsden Hospital. Cancer Treat. Rep. 63:1545, 1979. ti. Stehman. F. B .. Bailon, S. C .. Lagasse, L. D., et al. Ci,;-

9

7.

R.

9.

10.

ll.

platinum in advanced gynecologic malignancy, Gynecol Oncol. 7:349, 1979. Rossof, A. H .. Talley, R. W., and Stephens, R. L: Phase II evaluation of single high dose cis-diall'!minedichltiroplatinum (II) (NSC-H9875, CACP) in gynecologil: '(GYN) and genitourinary (GU). neoplasia; Proc. Am. Assoc. Cancer Res. ASCO 18:97, 1977, Bruckner, H. W .. Cohen, C. J., Deppe, G., et aL: Chemo· therapy of gynec(}logical tumors with platinum H ,J, Clin. Hematol. Oncol. 7:619, 1977. Bruckner, H. W., Cohen, C. J., 'Wallach, R. C ... et aL Treatment of advanced ·ovarian <:ancer with cis-dichlorodiamminep1atinum(Il)-: Poor-risk patiet!t:S with i~ienc sive prior therapy, Cancer Treat. Rep: 62t55;i. 1978. Piver, M. S., Barlow, J. J., Lele, S: B:, et al.: cisDichlorodiamroineplatinum (II) as. thlrd~line cherootherapy in advanced ovarian adenocarcinoma, Cancer Treat. Rep. 62:559, 1978. Stewart, J F., Tattersall, .M. H. N., Woods, R. L, et al.: cis-Dichlorodiammineplatimun (II) ill advam;ed ovarian carcinoma, Med. J. Aust. 1:548. 1979.