cis-Platinum in gynecologic cancer

cis-Platinum in gynecologic cancer II. Squamous cell carcinoma of the cervix DOK

J.

HALL. M.D.

ROBERT DIASIO, M.D. DEAN R. GOPLERUD, M.D. Knoxville, Tennf'ssee. and Richmond, Virginia Twenty-eight patients with squamous cell carcinoma of the cervix and one patient with squamous cell carcinoma of the vagina were treated with cis-dichiOrodiammineplatlnum at a dose of 60 mg/ma. Of these patients, 22 were evaluable. No patient had a complete response, two (9%) had partial responses, nine (41%) had stable disease, and 11 (50%) had progressive disease. The overall response rate was 9%. (AM. J. 0BSTET. GYNECOL. 141:305, 1981.)

CIS-DICHLORODIAMMINEPLATrNUM (II) (DDP) (Platinol. Bristol Laboratories, Division of BristolMyers Co., Syracuse, New York) has been shown to be active against a variety of tumors both in monotherapy and in combination therapy. 1 Few studies exist showing the result of single-agent therapy with DDP in squamous cell carcinoma of the cervix. To date five studies have been reported, showing a response rate of 33% to IOO% in a total of 60 patients. 2- 6 We evaluated DDP alone in 29 patients with squamous cell carcinoma, using a dosage different from that in previous reports. Material and methods A total of 29 patients with squamous cell carcinoma were treated at the Medical College of Virginia and the University of Tennessee Memorial Hospital and Research Center. Resulls in six patients are not included because they received less than three courses of therapy and did not receive additional treatment (two died, one patient's htmily refused, one had renal failure, one patient refused and in one there was rapid decline in

From the· Gynecologic Oncology Service, Department of Obstetrics and Gynecology, the University of Tennessee College of Medicine; and the Division of Medical Oncology Sen1ice, Department of lnU!rnal Medicine, and the Gynecologic Oncology Service, Department of Obstetrics and Gynecololgy, Medical Colltge of Virginia. Received for publication December 18, 1980. Accepted for publication May 1, 198 I. Reprint uquests: Don]. HaU, M.D., The University of Tennessee College of Medicine, Department of Obstetrics and Gynecology, 1924 Alcoa Highway, U-27, Knoxrtille, Tennessee 37920. 0002-9378/811190$05+04$00.40/0 © 1981 The C. V. Mosby Co.

performance status). Results in one patient were not evaluable, because she did not have a measurable lesion. Twenty-two patients with biopsy-proven measurable lesions were serially evaluated by objective means to measure tumor response (Table I). Computerized tomography (CT) and ultrasonography were performed after every fourth treatment cycle or when advancement of disease by physical examination was suspected in order to confirm or negate advancement of disease. All patiems included received three or more courses of therapy. Criteria for response, dosage, method of administration, accompanying medication including diuretics and antiemetics, laboratory determinations, and physical examination were the same as those reported in Part I for DDP with ovarian carcinoma (AM. J. 0BSTET. GYNECOL. 141:299, 1981).

ResuHs A total of 163 courses of therapy were administered to 29 patients. Six patients were excluded from the study because they received less than three courses. Of the 23 patients presented the mean age was 53 years, with a range of 27 to 87 years. Fourteen patients were black, and nine were white. Patients were staged according to FIGO.* Eight patients had recurrent Stage IB disease, two had Stage IIA, five had liB, one had Stage IliA, and six had Stage IIIB. All patients had squamous cell carcinoma. One patient had a recurrent Stage I I squamous cell carcinoma of the vagina several years following hysterectomy for carcinoma in situ of *International Federation of Gynecology and Obstetrics.

305

306

o''"'~'' ! J 9"1 1

Hall, Diasio, and Goplerud ,\l!L

Ofrst.
Table I. Patient data for squamous cell carcinoma and DDP therapy !

------·-

I

!

i

i

Inpatient/ outpatient

Age (yr)

Race

L M. F*

Out

50

B

liB

4

405

0

MWD

2. G.K.t

Out

31

B

IB

6

560

:z

PI)

3. M. K.t 4. E. M.

61

w

lB IllB

4

290

~

MWD

4

310

6 3 5

415

!}

PD

6. D. N. 7. D. T. !:!. LT. 9. T. W.

Out In Out In Out Out Out

220

440

I 2

wn

5 5

410 390

I

PD

;:

MWD

10. M. W. IL H. C. 12. c.q

Out In ln

7 15

530

4 12

PD PD MWD

1:). D.J. 14. H.L

'i

MWD

17

16. D. R. 17. A. T.

In Out In In Out

18. G. W. 19. P. W.

In Out

20. M. B. 21. 0. w. 22. M.B.

In In In

62

B

43 45

w w

23. B. R.

In

36

w

Patient

5. B. M.

15. M.P.

46

66 59 55 S7 27 56 66

38

B B

Stag~'

IIIB

w w

lilA

B

IB IHB

B

IB

w

lliB liB

B B

JIVag

IIIB

Total courses

4

t

Total dose

795 295

Half dosage

!

Gmde

PD

WD

52

B B

liiB

8 18 3 7

51)0

·.':i

44

B

liB

9

630

6

PO PD MWD· WD

48

w

3 13

2

MWD

B

IB IB

190

67

685

ll

PD

liB IB

7 4

680 350

liB

8

IB

5

46

64 68

B

w

IIA liA

515 1065

210

i)

PD

710

0 0

MWD PD

440

0

MWD

Legend: Bx, Biopsy; CIS, carcinoma in situ; CT, computerized tomography; CXR, chest x-ray: EBT, external'beam thei'apy: lCR mtracavitary radium; MWD, moderately well differentiated; N/M, nonmeasurable; PA, para~aortic mass·: PD (grade). po9rf} differentiated; PD (response), .Progressive disease; PI.ND, pelvic lymph node dissection; PR, partial res:j:xmse~ RJ\H. rad~ai hysterectomy; SD, stable disease; TAH, total abdominal hysterectomy; VIS, ultrasi:lnography; VC, vaginal cylin~r: WD. wdi differentiated; WP, whole pelvis; X-LAP, exploratory laparotomy; ICRV. intracavitary radium to vagina. *Refused further therapy secondary to pain. +Therapy discontinued secondary to ra8b and allergic reaction. tContinued therapy at another institution. Disease stable for 1 year, then recurred. §Still receiving therapy. I! VaginaL

the uterine cervix. All patients had received prior radiation therapy. and l I patients had had prior surgery, exhausting primary method of treatmem for their disease. Twenty-three of the 29 patients entered in the study received more than three courses of therapy. One patient was nonevaluable, be.cause she did not have mt~asurable disease. This patient had microscopic residual disease following an exenterative procedure. She received three courses of therapy at the Medical College of Virginia and subsequent therapy with DDP at another institution, where she was reported to have progressive disease after 1 year of therapy. Of the 22

evaluable patients all had. measurable disea;se. There were no complete responses (Ta:bte ll}. T wn partial responses were (9%) seen, une documented by CT.scan and the other with complete reStilution ofmu1t1ple pulmonary metastases and· a partial res6lutioh of vulvar and vaginal lesions. Nine pa!tents (41%) ciemol_1strated stable disease, and I I (50%) had progressi\·e disease. Of the two patients who showed a partial ~response. both responses occurred after four cotlrse.s uf therapy. Because both patients are still receiving therapy, the duration of response or survival cann<)t be ev-'tihtated at this time; however, Patientll (H.(:~) has completed ll

cis-Platinum in gynecologic cancer. II 307

Volume l41 !\'umber 3

ICR + WP, perineal boost+ I r 192 WP ICR+WP ICR+WP ICR+WP ICR+WP ICR+WP WP WP ICR+WP ICR+WP VC+WP WP ICR+WP ICR+WP WP ICR+WP, perineal boost+ Ir 192 ICR+WP ICRV+WP 125 1 ICR+WP WP ICR+WP, PA+ EBT WP

Inguinal node, sacrum, vagina, perineum Left upper quadrant

Inguinal node, sacral film U/S

SD

3

SD

3Y2

Pelvis Vagina Pelvis Pulmonary PA mass Pelvis Pelvis Pelvis

NM CT CT CXR CT IVP CT

SD PD PD PD I'D PD PD

3 3 5

Pelvis Vagina, vulva PA

CT CXR CT

PD PR PR

Pulmonary, pelvis Pelvis PA Pelvis Perineum

CXR,CT CT CT CT CT

SD SD PD SD SD

15 2 6 6

Pelvis Inguinal node, pelvis

CT Node

PD SD

3 10

Pelvis Pelvis, pulmonary Pelvis

CT CXR CT

SD PD SD

5

RAH TAH, PA+Bx

3 6

RAH, and nodes

Pelvis

CT

PD

4

RAH+PLND with positive node Total exenteration

X-LAP, RAH+ PLND, with positive nodes TAH for CIS, total exenteration Colostomy X-LAP X-LAP

T AH, anterior exenteration +tad vulva

months of therapy with continued but gradual decrease in her disease. Of the nine patients with stable disease (41 %) the mean duration was 6.9 months (median, 6 months; range, 3 to 15 months). If Patients 1, 2, and 3 are excluded because of conditions as footnoted in Table I, tht~ six remaining patients showed a mean duration of stable disease of R months (median, 6 months; range, 5 to 15 months). The original histology was evaluated in each case. There were three well-differentiated tumors, eight moderately wdl-differentiated tumors, and II poorly differentiated tumors. The two partial responses occurred in one well-differentiated and one moderately well-differentiated tumor. The remainder of patients (Table III) with stable disease or progressive disease showed almost an equal distribution among tumor grades.

Comment It has been stated that DDP has a high degree of antitumor activity in treating squamous cell cancer of

3 4 3 3

5

ll§ 2§

8§

Table II. Response rate of cervical cancer to cis-platinum Toml No. of pa· tients Percentage

0

2

9

11

22

0

9

41

50

100

the cervix. 3 However, only a small number of reports are available evaluating the response of this disease to DDP, as shown in Table IV. The results obtained in this study are in sharp contrast to previous reports concerning the activity of DDP in cervical carcinoma. No complete responses were seen, and only two partial responses occurred, for an overall response rate of 9%. Although the dose utilized in this study (60 mg/m 2) is similar to that in most other reports, in the evaluable patients 78 of the 149 courses administered were given at a reduced dosage because of the criteria established for toxicity as described in Part I. This reduced dosage

Otioh<"~

306 Hall, Diasio, and Goplerud ·\ n"l:

.1 ( lh,te~

!, l':!KI

Cvne<~•.)i

fable III. Tumor response versus histologic grade

--------=---.,...-----=---.::.....,._.-----,-------.-----~----

Stable drsease Nell differentiated 11oderately well differentiated :>oorly differentiated fotal

II

=::omparison of studies

Author

:::ohen et aU fhigpen et aLa )tehman et at.• :::ohen et al. 5 rhigpen et al.6 ::>ur study

3 mg/kg 50 50 120 50 60

diurL\<'

ll

fable IV. Single-agent platinum in cervical cancer:

Dose (mglm 2)

Progressi;~t

No.

of

ResfXm.'e ralf

Schedule

pruients

(%)

q 3 wk q 3 wk q 3 to 4 wk

3 18

100 44 33 45

q 3 wk q 3 wk

:~

II 25

22

44 9

tn:ounts in part fix a lowered response rate. It. should Je noted. however, that Patient II. (H. C.) (Table 1). -vho had a partial response to treatment received 12 l)f 1er 15 courses at a reduced dosage, illustrating that this :oncept may not be valid. What mav be more germane s that, in contrast to other reports, this study utilized a >ariety of techniques (direct measurement of a gross esion, ultrasonography, chest radiography. intrave'l.ous pyelography, and CT) as well as the general physIcal and pelvic examination to obtain objective evidence' c1f tumor response. We believe that these modalities give more reliable evaluation of a change in pelvi( tumor than doe~ the bimanual pelvic examinatim1 alone. This study was designed to represent a fair test of the antitumor activity of DDP. Only patients who received three or more courses of therapy were considered in the study. thus excluding patients who were pretcrmi-

nal and thost:' whil ren~ived roo It'\\· collr~es w allm\ an assessment ol drug activity. ln patients included in the stud)' performance mm1s ,,·as better than 3 or L h was thought that these factors would pre,·em bia~. A.nother factm: that mightexptain the<:hfferemes in response rates may be the f.riteria used fm deteunin-ing responses. Thl~ study utilized the more standard definition" for response and duration as desc'hned in Part I. Other authors have not stati"d their criteria· or haH' used shorter periods tor evaluation (i.e., I month versus :-1 months"). DDP tailed to !iflA-ing nine of :!2 patients (4lo/c) having srable disease for a prolonged period. The mean duration of stable disease was H months Ilnedian, 6 months: range, 5 to 15 months). This demonstrates the dehnite abilit; of DDP to avert tumor gn1wth lor prolongc;;d periods but does not establish siug[e-agenl DDP at the dosage ol 60 mg/m 2 1o be highly ss strid criteria tor dose rcdunion, and incorporation with other agents. DDP can demonstrate more acceptable a-ntuumor actiYit>

REFERENCES l Prestayko. A. W., D'Aoust,]. C., lssell, B. F., and Crooke, S. T.: Cis-platinum (c-is-diamminedichloroplatinum 11), Cancer Treat. Rev. 6: 17. 1979. 2. Cohen, C. J., Deppe. G., Castro-Marin, C. A., et aL: Treatment of advanced squamous cell carcinoma of the cervix with cis-platinum (II) diamminechloride (NSC119875). AM.j. 0BSTET. GYNECOL. 130;853, 1978. 3. Thigpen. T., and Shingleton, H.: Phase II trial of cisplatinum in treatment of advanced squamous cell carcinoma of the cervix, Pnx. Am. Soc Clin. OncoL 19:~~~2. !97R. c

·{. Stehman, F. B., Bailon, S. C., LagMse, L D,, et al.: cisPlatinum in advanced gyneeologic malignancy. GynecoL OncoL 7:349, 1979. 5. Cohen. C. J. Castro-Marin. A., Ik;ppe. . et aL: Chetnoc therapy of advapced recm:rent cel'\'ital cancer with plitinum II: Prdiminary report. Proc Am. Soc. Clin. Oncol. 19:401. 1971:'. 6. Thigpen. T .. Shingleton. H .. Homsclev. H.,_et aL: cisDichlorodiammineplatimuri (Jl) in die treatment of gyne" cologie malignancies: Phasell trialLb) the Grnecol6gk Oncologv Grmlp. Cancer 'Treat. RelY' 63:1549, 1979.