cis-Platinum in gynecologic cancer

cis-Platinum in gynecologic cancer III. Toxicity DON

J.

HALL, M.D.

ROBERT DIASIO, M.D. DEAN R. GOPLERUD, M.D. Knoxville, Tennessee, and Richmond, Virginia The toxicity of cis-dichlorodiammineplatinum was evaluated in 41 patients who were treated for squamous cell carcinoma of the cervix or epithelial carcinoma of the ovary, with a dosage schedule of 60 mg/m2 every 3 weeks. Ototoxicity occurred in 33.3% of the patients serially tested, and anemia occurred in 48.8%. Leukopenia occurred in 29.9% and thrombocytopenia in 2.2"k of courses administered. Nephrotoxicity was seen in 61% of patients as determined by evaluation of blood urea nitrogen and in 70.7% by serum creatinine elevation. Urine dipstick protein and 24 hour urinary protein determinations were evaluated. Suggestions are made In regard to the use of these determinations as a guide to modification of dose and duration of therapy. (AM. J. OssTET. GYNECOL. 141:309, 1981.)

ToXIc SIDE EFFECTS of cis-dichlorodiammineplatinum (DDP) are markedly different from those usually seen with other chemotherapeutic agents. L 2 Leukopenia, thrombocytopenia, stomatitis, and alopecia are not prominent side effects of DDP, as they are with other agents. Nephrotoxicity, ototoxicity, anemia, and severe nausea and vomiting were the major toxicities of DDP encountered in the treatment of 41 patients with squamous cell carcinoma of the cervix or epithelial carcinoma of the ovary. The dose schedule used was 60 mg/m 2 every 3 weeks.

versity of Tennessee Hospital and Research Center. Three hundred twenty courses of chemotherapy were administered at a dose of 60 mg/m 2• Requirements for entry, methods of drug administration, dosage determination, and patient evaluation have been described previously in Parts I and II of this study.

Reprint requests: Dr. Don]. Hall, Department of Obstetrics and Gynecology, The University of Tennessee College of Mt,dicine, 1924 Alcoa Highway, U-27, Knoxville, Tennessee 37920.

Results Ototoxicity. Twenty-one of the 41 patients treated had an initial audiogram and audiograms at various times throughout their treatment. Fourteen patients (66.6%) were unaffected. Seven patients (33.3%) had a loss of hearing in the high-frequency range (Table III), and three of these patients had a clinically detectable loss of hearing. The median age of the unaffected patients was 48.5 yr (range, 27 to 70 yr), whereas that of the affected patients was 56 yr (range, 31 to 71 yr); the median total doses were 383 mg (range, 190 to 900 mg) and 565 mg (range, 395 to 2,115 mg), respectively. Three patients complained of tinnitus during therapy, and one of these patients demonstrated loss of hearing. The loss of hearing was bilateral in all cases. Anemia. Anemia, defined as a greater than 2 gm loss of hemoglobin, occurred in 20 of the 41 patients studied (48.8%) (Table III). Transfusion was required in seven (35%). To produce' anemia, the median number of courses required was three (range, 1 to 13) and the median total dose was 270 mg (range, 60 to 730 mg).

0002-9378/81/190309+04$00.40/0 © 1981 The C. V. Mosby Co.

309

Material and methods Forty-one patients with squamous cell carcinoma of the cervix or epithelial carcinoma of the ovary were treated at the Medical College of Virginia and the U niFrom the Gynecologic Oncology Service, Department of Obstetrics and Gynecology, The University of Tennessee College of Medicine, and the Division of Medical Oncology, Department of Interool Medicine, and Gynecologic Oncology Servict, Department of Obstetrics and Gynecology, Medical College of Virginia. Received for publication Deumber I 8, 1980. Revised April 9, 1981. Accepted May 1, 1981.

310

Hall, Diasio, and Goplerud

Table I. Toxicity of DDP: Myelosuppression Grade 0

l

Platelet count/mm >4.5 3.0-4.5 2.0-2.9 1.0-1.9 <1.0

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Table 11. T oxicitv of DDP: !\ephrotoxi{Jt\ 3

X

!I Serum BUN I treatininl'

10"

>130 90-129

50-89 25-49 <25

WBC = White blood cell count.

Serial reticulocyte counts were obtained in 21 patients who had one or more values greater than 3%, and five ;-,f these patients were anemic. Serial red blood cell inclices were determined in 25 patients, and 13 of these patients developed anemia, with nine (69.1%) having normochromic normocytic anemia. Myelosuppression. Myelosuppression was graded as >hown in Table I. Of the 320 courses of chemotherapy administered, 105 (32.8%) resulted in grade I leukopenia, and I 0 ( 3%) resulted in grade 2 leukopenia, for an overall incidence of 35.8% (Table Ill). There was no grade 3 or 4 toxicity. Three patients had leukopenia before treatment. There were no life-threatening episodes of leukopenia or sepsis. In the majority of cases, leukopenia was transient, sometimes occurring early in therapy, with no recurrence in later courses. Six courses of chemotherapy resulted in grade I thrombocytopenia, eight courses caused grade 2, and one caused grade 3 {Table III). One patient had pretreatment thrombocytopenia, which was persistent. There was no grade 4 toxicity. No patients required platelet transfusion. Thrombocytopenia occurred sporadically and to a mild degree. Nephrotoxicity. The blood urea nitrogen (BUN) and serum creatinine were determined prior to each treatment with DDP. The grades of nephrotoxicity are shown in Table II. Of the 41 patients treated, 25 (6l%} had some degree of elevation of BUN, whereas 16 (39%) had none. One patient had grade l toxicity prior to therapy. Of the 320 courses of DDP administered, 83 (25.9%) resulted in grade I elevation of BUN, with more severe toxicity being infrequent (Table Ill). Most elevations of BUN were transient and sporadic. Twenty-nine patients (70.7%) demonstrated an elevation of serum creatinine;whereas 12 patie1;1ts (29:3%) had none (Table Ill). Grade I nephrotoxicity occurred after 112 courses of DDP (35%), with the remainder of serum creatinine elevations being small (Table III). Two patients had grade l serum creatinine elevation prior to therapy. Patients were arbitrarily divided into five groups on the basis of the total dose of drug received, i.e .. <250

Gra4e

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21-40

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35-50 20-34 <20

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mg, 250 to 499 mg, 500 to 749 mg. 750 to 1.000 mg, and > 1,000 mg. In an evaluation of the elevations of bothBUN and serum creatinine in each group, a direct correlation couki be found. with the average munber of episodes of combined nephrot6xicity per patient being 1.6, 3.0, 6.6, 8.4, 19.0, respectively .. The average dose for all patients for the onset of nephrotoxicity was 257 mg. Serial determinations of creatinine clearance were attempted throughout the course-of therapy in 41 pa· tients. Thirteen patients did t1ot comply. Ofthe 28 patients studied, 16 patients had grade 0 toxirity. Four patients had abnormal creatinine' clearances prior to therapy. The other eight patients (33.3%) had decreases in creatinine clearances, wi.tn four having grade I, three having grade 2, and one with grade :~toxicity. In order to predict and follow nt~phrotoxicity,. unnary dipstick protein \vas determiried on 37 of 41 patients. Seventeen patients demorrstrated proteinnria. Six patients had vaginal mntamination from draining pelvic tumors. Among the other I I patients, 42 courses resulted in grade l proteinuria, and one (ourse, in grade 2. Miscellap.eeus toxicities. There were no consistent abnormalities in serum electrolytes or enzymes or other blood chemistry determinations. Two patients developed hyperuricemia which required treatment. One patient developed an allergic reaction after four courses of therapy and did not receive any further DDP. Four patients developed peripheral neuropathy. The most distressing problem for patienrs was gastrointestinal toxicity. Nausea and vomiti11g occurred in all patients. All patients received a standard antiemetic regimen, with five exceptions. Patients treated \vith DDP on an mitpatiem basis received intramuscular chlorpromazine (25 mg) and diaze}hlm (5 mg) 30 to 00 min prior to infu5ion of DDP. Rectal suppositories of chlorpromazine and oral tablets of _diazepam were then prescribed to be.used every 4 hr as needed fot'riau:>ea. Inpatient infusion utilized the sam€ :doses but in a different sequence, with both drugs being given intramuscularly 2 hr prior to and immediat_elvbefore infusion of

cis-Platinum in gynecologic cancer. Ill 311

Volume 141 Number 3

A. Patient data (41

7/21 20/41

33% 48.8%

BUN

25/41

61%

Serum creatinine

29/41

70.7%

Ototoxicity Anemia Nephrotoxicity

B. Course data (320 courses)

Nephrotoxicity Grade 2 3 4

Totals

Leukopenia 105 (32.8%) 10 (3%) 00-

115/320 (35.8%)

Thrombocytopenia

I

BUN

6 (1.8%)

83 (25.9%)

8 (2.5%)

9 (2.8%)

I (<1%)

3 (<1%)

Serum creatinine 112 (35%) 15 (4.6%) 0

015/320 (<5.3%)

95/320 (<29.9%)

127/320 (39.6%)

C. Miscellaneous toxicity in 41 patients No. Allergic reaction Peripheral neuropathy Gastrointestinal

DDP, then repeated every 4 hr as necessary. This regimen was well tolerated since only one patient refused further therapy because of gastrointestinal toxicity.

Comment Cis-platinum is an ototoxic drug. 2 In this study, one third of the patients treated had demonstrable loss of hearing, an incidence of ototoxicity higher than previously reported. 2-il This study, as well as others, has shown that ototoxicity is more likely to occur in the older patient and appears to be dose related and cumulative.2-7 The presence of tinnitus did riot indicate an impending loss of hearing, which, even though it can be incurred, is generally subclinical in the high-frequency range. Although all patients should be advised of a possible loss of hearing, serial audiometric testing in all patients appears to be unwarranted. The incidence of induced anemia has been reported to be from 7% to 42% of patients treated. 2 • "· 8• 9- 11 The present study found anemia in 48.8% of patients. Reticulocyte co1,1nts and red cell indices did not prove to be of value in predicting or following anemia. In general, the anemia has a delayed onset and may be sudden in its occurrence. The conclusion drawn from this study is that anemia should not be a criterion for reducing dosage, but rather an indication for transfusion and a therapeutic dose based on other laboratory parameters.

of patients I 4 41

This study and others indicate that cis-platinum is a moderate myelosuppressant. 1• 2• 4• 5 • 7 • 10• 12- 16 Leukopenia did not appear to be progressive or cumulative, but was sporadic and transient. It seems that dose reduction for single agent DDP because of leukopenia should be set below the toxicity scales commonly used. Thrombocytopenia occurred to a minimal degree and was transient. DDP does not appear to alter the platelet count, and its effect is not cumulative or dose related. Consideration should be given also to lowering the usual acceptable platelet levels in dose adjustment when DDP is used alone. DDP is a nephrotoxic drug. 16 At 60 mg/m 2 the percentage of patients who developed increases in BUN and serum creatinine was somewhat higher than that reported in studies using 50 mg/m 2.1. 2• 8• 16- 18 Nephrotoxicity was seen to increase in direct proportion to the total dose of DDP administered. Although proteinuria has been found to occur with DDP nephrotoxicity, urine protein dipstick and 24 hour urine protein determinations were of no value in predicting or following nephrotoxicity. Although serial creatinine clearance was found to decrease in one third of the patients, no therapy had to be halted because of nephrotoxicity. On the basis of this study, recommendations for evaluation of nephrotoxicity remain the pretreatment, serial BUN, and serum creatinine levels. A baseline creatinine clearance

312

( ){ 11 JJ,~·I _j

Hall, Diasio, and Goplerud 'ni

s indi~:atcd, but further measmcments should be made ;dertivdy and not on a routine basis. There was one allergic reaction and four cases oi Jeripheral neuropathv, which are side effects that have Jeen reported previously. IH The most difficult and uniwrsal problem tor paienh t·e~:eiving DDP therapy is the severe nausea and omiting. In this sturlY, the combination of chlor-

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promazine and diazep.m! pro1ed to be ;1n <'!kni1e antiemeti(· tlwra py. Ft1rt her evaluarion ol ;uJl R'llH'I J( treatment with such ageuts as dr.)pendine· and metachlopromide will be netTss,trY in an .lltempt 1o n·duce the major side effect of nausea and V\ltniting and improve patient acceptant e of DDP t lwr;qJ\ DDP at 60 mg/m" is an eikctilt' drug with ae
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12. Rossot, A. H .. Slayton, R. E., and Perlia, C. P: Preliminary clinical experience with cis-diarnminedichloroplati· num (Ill (NSC-119875-CACP), Cancer 30:1451, 1972. B. Corder, M. P., Elliott, T. E., and Br>ll, S, J .: Dol<<; limiting myelotoxicitv in absence of significant nephrotoxicitY with a weekly out-patine! sthedvle of cis.platinJJm (ll) diamminedichloridc, J. Clin. Hematol. Oncol. 7:645. 1977. 14. Chary. K. K.. Higby, D.J..and Henderson,.E. S.: A Pbasc I study of high dose cis-diamminedichloroplatlnum II <.:-.ISC-ll9S75) with forced diuresis. J: Clin. Hemawl: Oncol. 76 :l:~. 1977 15. Stehman, F. B., Ballon, S. C., Lagas!IC. L D .. ct aL: Cisdichlorodiammineplatinum in advanced gynecologi.: malignancv, Gynewl. OncoL 7:349, 1979. · 16. Thigpen, T., Shingleton, H., Homesley, H., d al.: Chdichlorodiammineplatinum (II) in the treatment of gynecologic malignancies: Phase I I trials)1y the Gynecpiogic Oncology Group, Can~:er Treat. Rep. 63: 1549, 1979. 17, Madias, N. E. and Harrh:lgton, J. T.: Platimun nephrotoxicity, Am.]. Med. {)5:307, 1978. HI. Salem, P., Hall, S. W:. Benjamin, R. S.. et aL Clinical Phase I-ll study of cis-dichlorodiammineplatinurn (II) given by continuous IV infusion. Cancer Treat. Rep. 62:1553. 1978. 19. Kedar, A .. Cohen, M. E.. and Freeman, A. 1.: Peripheral neuropathy as a complicari(m of ds-uithlurodiammhreplatinum .(Ill treatmem: A case report, Cancer. Treat. Rep. 62:819, 1978. 20. Hadley, D., and Herr, H. W.: Peripheral neuropathy as~ sociated with cis-dichlorodiamminepbitmum (ll} treatment, Cancer 44:2026. 1979. 21. Marin, A. C., and Rierson, B.: Peripheral neuropathy secondary to cis-dlchlorodiammineplatin:um (II) (Piati~ no!). Treatment for advanced ovarian. cancer, /\riz. Med. 36:898, 1979.