J Cancer Res Clin Oncol (1984) 107:57-60 Cancer Research Ci cal �9 �9 Springer-Verlag 1984

Phase II Evaluation of Fractionated Low and Single High Dose Cisplatin in Various Tumors

R. B. Schilcher, M. Wessels 1, N. Niederle, S. Seeber, and C. G. Schmidt 2

Innere Universitfits- und Poliklinik (Tumorforschung), Westdeutsches Tumorzentrum, Hufelandstr. 55, D-4300 Essen 1, Federal Republic of Germany

Summary. Seventy-three evaluable patients with ad- vanced measurable solid tumors were given cis- d ichlorodiammineplat inum (II) (DDP) at a dose o f 20 mg/M 2 IV for 1-5 days every 3 weeks, and 19 patients who failed on this low dose D D P protocol received a single high dose o f 100 mg/M 2 IV once every 3 weeks. Forty-six patients had received prior chemotherapy, and 29 patients were untreated. Results included four complete responses (5.5%) in malignant melanoma, spindle-cell sarcoma, adrenal carcinoma, and bladder carc inoma lasting 2 to 4 months. In 21 patients (28.8%), partial responses were achieved. Twenty- two patients (30.1%) showed stable disease and 26 (35.6%) had tumor progression. A response rate o f 25% (4/16 patients) was found for malignant melanoma, 45.5% (5/11) for nonsmall-cell lung cancer, and 35.3% (6/17) for sarcomas of various types. One patient with terato- carcinoma, who relapsed on low-dose DDP, had an- other partial remission for 4 months after high-dose therapy. Toxicity was mos t commonly seen with gas- trointestinal side effects and myelosuppression. Cumu- lative nephrotoxici ty was prevented by prehydrat ion and/or t reatment with furosemide or mannitol .

Key words: Cisplatin - Phase II s t u d y - Solid tumors

Introduction

Since 1971, numerous clinical trials with cis-dichloro- d iamminepla t inum (II) (NSC-119875; cisplatin; D D P ) have demonstra ted activity in a variety o f solid tumors

1 Results are in part derived fr~ the M" D' Thesis ~ Wessels 2 Supported by Deutsche Forschungsgemeinschaft (SFB N 102,

Project C 3) and Deutsche Krebshilfe e. V. Offprint requests to: Rudolf Burkhart Schilcher, M.D., Wayne State University School of Medicine, Division of Oncology, Department of Internal Medicine, 3990 John R., Detroit, Michigan, 48201, USA

including testicular, ovarian, head and neck, and blad- der cancer [1-5].

Effects against other tumors, e.g. breast cancer, lung cancer o f different histologic entities, resistant lymphomas, sarcomas, and malignant melanomas, are still under clinical investigation. In mos t studies, cis- platin was given at a dose o f 15 to 20 mg/M z IV for 5 days every 3 to 4 weeks [6]. Some authors described a higher response rate for D D P when administered as a single medium or high dose o f 50 or 100 mg/M 2 once every 3 to 4 weeks [7], assuming that larger t ransmem- brane concentrat ion gradients might result in higher cell exposure to free, unbound drug [8]. This broad. phase-II clinical study was aimed to compare a 5-day low-dose versus a single high-dose regimen. Prelimi- nary findings had confirmed an overall response in 24 o f 58 patients, and this is a final report after evaluation of 73 patients [9].

Materials and Methods

Patients with histologically confirmed incurable maIignancies were included in this study. Inclusion requirements were informed con- sent, measurable lesion, an anticipated minimum suvival of at least 10 weeks, a Karnofsky performance status of over 40%, and com- plete hematologic recovery from toxicity due to previous treatment. The white blood cell (WBC) count had to be over 4,000/mm 3 and the platelet count over 100,000/mm 3, renal function had to be normal de- fined as a serum creatinine level of under 1.6 mg-%, there had to be a blood urea nitrogen (BUN) level of 20 rag-%, and no evidence of obstructive uropathy.

Cisplatin, supplied in 10 mg vials with 10 mg mannitol and 9 mg NaC1, was diluted in 10 ml sterile water and given with 1,000 ml 5.0% glucose over 4 to 6 h. Patients were given DDP at a dose of 20 mg/MZ/day for 5 days every 3 to 4 weeks depending on renal function and myelosuppression. After failure on low dose treatment, patients received a single high dose of 100 mg/M 2 once every 3 to 4 weeks un- til the disease progressed. One course of either dosage regimen was considered sufficient for response evaluation. Patients were routinely evaluated during study with complete physical examination, serial tumor burden measurements, laboratory, and radiodiagnostic pa- rameters. Response criteria were defined as follows: complete re- mission (CR) disappearance of ali evidence of disease for more than

58

TaMe 1. Characteristics of patients with malignant tumors under- going cisplatin therapy

Characteristic No. of patients

No. of men/women 61/14 Evaluable patients 73 Median age years (range) 48 (18-73) Median Karnofsky perfor- 70% (40-90)

mance status (range)

Drug treatment 5-Day low dose Single high dose

Previous therapy (%) Surgery 15 (20) Chemotherapy 25 (33) Radiotherapy 14 (19) Chemo- and radiotherapy 21 (28)

20 mg/M2/day every 3 weeks t00 mg/M 2 once every 3~; weeks

1 month; partial remission (PR) over 50% decrease of all measur- able disease for more than 1 month; minor response or no change status (NC) objective (over 25%) tumor decrease, but less than that required for a PR; and progression (p) - objective increase in measur- able disease or the appearance of new tumor lesions.

Twenty-nine untreated (39%) and 46 with chemotherapy pre- treated (61%) patients (61 males and 14 females) with a median age of 48 years (range 18 73 years) and a median Karnofsky perfor- mance status of 70% (range 40-90%) were entered into the study. Two patients (2.7%) were considered unevaluable because of early death within 14 days of entry into the study and lost to follow-up

R. B. Schilcher et al.: Phase II Evaluation of Low and High Dose Cisplatin

(one patient each). However, seventy-three patients were evaluable for response and toxicity, and their characteristics are shown in Table 1. Table 2 outlines tumor types and each histologic subgroup. All preteated patients had exposure to anthracyclines generally as part of prior phase-II or phase-III clinical trials and 33 of these patients (71.7%) had previously been treated with alkylating agents.

After failure on the low-dose regimen, 19 of 73 patients (26%) were put on to single high-dose infusions.

Results

Twenty-five of seventy-three patients (34.3%) re- sponded with CR or PR to cisplatin therapy (Table 2). One CR was seen in a previously treated patients with spindle-cell sarcoma (4 months duration) as well as in untreated paients with adrenal carcinoma (6 months), bladder carcinoma (7 months), and in a female pa- tient with visceral metastatic malignant melanoma (4 months). Response rates of 25 % (4/16 patients) were achieved in melanomas, of 35.7% (5/14 patients) in lung cancer - three of six patients with larger cell and two of five patients with squamous-cell carcinoma had partial remissions - and of 35.3% (6/17 patients) in sar- comas of various types. One patient with teratocar- cinoma had a second partial remission after one high- dose course as outlined in Table 3. Neither response rates (34% and 33%) nor response durations (2.7 and 3.1 months, respectively) were different in pretreated

Table2. Pathologic diagnosis and clinical results in evaluable patients treated with cisplatin (low and high dose therapy)

Histologic subtype No. of Results Median duration patients (range) in months

CR PR NC p (CR + PR)

Head/neck (epidermoid carcinoma) 2 1 1 3.0 Thyroid (undifferentiated carcinoma) 1 1 Lung

Small-cell carcinoma 3 1 2 Large-cell carcinoma 6 3 2 1 2.0 (1-3) Squamous-cell carcinoma 5 2 3 2.5 (2-3)

Sarcoma Spindle cell 3 1 1 1 4.0 Fibro- 4 2 2 6.0 (3-9) Osteo- 2 1 1 Leiomyo- 2 2 Ewing's 1 1 Lipo- 1 1 2.0 Angio- i 1 1.0 Synovialoma 3 1 1 1 4.0

Adrenal carcinoma 2 1 1 3.5 (14) Pheochromocytoma 1 1 3.0 Bladder carcinoma 3 1 1 1 4.0 (1~) Testicular teratoma 8 1 4 3 2.0 Melanoma 16 1 3 3 9 2.0 (1~4) Morbus Hodgkin 3 2 1 1.5 (1-2) Cervical carcinoma 1 1 2.0 Miscellaneous ~ 5 2 3

a Includes hemangiopericytoma [1], primary undertermined-adenocarcinoma [3], plasmocytoma [-1]

R. B. Schilcher et al.: Phase II Evaluation of Low and High Dose Cispiatin 59

Table 3. Response rate in patients receiving single high-dose cisplatin therapy after failure of 5-day fractionated application

Histology No. of Results patients

CR PR NC p

Lung cancer 3 1 2 Malignant melanoma 2 1 1 Bladder carcinoma 1 1 Terato carcinoma 7 1 4 2 Sarcoma 5 3 2 Morbus Hodgkin 1 1

and untreated patients as seen in Table 4. Minor re- sponses (NC) were observed in 30.1% (22/73 patients) including 10/19 patients receiving high dose DDP treatment. Twenty-six of seventy-three patients (35.6%), however, had continuously growing disease.

Major clinical toxicity included nausea and vomit- ing which occurred in 91% of the patients. In most patients, antiemetica were required during the cisplatin application; in seventeen patients, nausea and vomiting continued for 3 to 5 days following the treatment. Alo- pecia occurred during pretreatment and was uncom- mon in untreated patients.

Nephrotoxicity was seen in three patients as mani- fested by a serum creatinine increase from 0.8 to 2.1 rag-% (2/3 patients) during first 5-day therapy and from 1.0 to 2.4 rag-% (1/3 patients) after application of three courses of cisplatin. The nephrotoxicity was not progressive since DDP therapy was discontinued in these patients.

Hematologic toxicity with leukopenia and throm- bocytopenia was tolerable and no patient developed episodes of sepsis. A WBC count of under 2,000/ram 3 was noted in two patients with bone-marrow infiltra- tion due to Hodgkin's disease and cell squamous me- dians carcinoma of the lung. Thrombocytopenia was observed in 9/73 patients with a count of 56,500/mm 3 (range, 30,000-83,000/mm3). In the two patients with bone-marrow infiltration, platele.t counts increased markedly during chemotherapy (57,000 to 83,000/ram 3 and 69,000 to 143,000/mm3). Slight anemia was also associated with treatment - in 12/73 patients, hemoglo- bin fell under 10.0 g-% during chemotherapy (median 8.9 g-%, range 7.5-9.8 g-%).

Discussion

Cisplatin alone has been used in patients with malig- nant melanoma and has resulted in a variety of respon- ses: at a dose of 1 mg/kg twice weekly, four PRs were observed among 15 patients [10] and at a dose of I00 mg/M z repeated every 3 weeks only seven objective re- sponses were found among 67 previously treated patients [11]. Four responses reported here (Table 2) were achieved in patients with advanced disease and no prior treatment.

When used as a single agent in patients with non- small-cell lung cancer, cisplatin showed only slight ac- tivity [12]. A single institutional comparison of high- dose cisplatin (120 mg/M 2) alone versus low-dose (15 mg/M 2 x 5) combination programs revealed a response rate of 16.7% (12/72 patients) for the latter but none for the former [13]. The discrepancy with this study (45.5%, 5 of 11 patients had a PR) needs further inves- tigation.

In a SWOG study of low-dose cisplatin (15 mg/ M 2 • 5) 4 of 50 patients with advanced soft-tissue sar- coma had a remission, but no responses were seen in 18 patients with bony sarcomas [14]. These reports are in agreement with our findings of lack of activity of cis- platin in osteogenic sarcomas, but confirmed the ob- served activity in 6 of 17 patients (35.3%) with metastatic soft-tissue sarcomas (Table 2).

Of particular interest were remissions seen in patients with advanced pheochromocytoma and adre- nal cortical carcinoma. Since mitotane, alkylating com- pounds, and adriamycin are the most commonly used agents in these rare tumor entities, additional trials are necessary to define the activity of cisplatin more pre- cisely [6].

Cisplatin-dose evaluations to determine the highest response rate and to reduce gastrointestinal and renal toxicity are still going on and include a low-dose regi- men especially in combination programs [I5, I6] and high-dose applications [11], and recently an "ultra" high-dose regimen followed by autologous bone-mar/ row transplantation [17]. As a result of our study, a fur- ther increase in response rates might be possible with the use of a single higher dose infusion of cisplatin after failure with fractionated applications (Table 3). Effects of a steep dose-response curve as observed in testicular

Table 4. Response rate and duration in untreated patients given cisplatin

No. of Pre- Clinical results Response rate % patients treatment

CR PR NC p CR + PR

Response duration (months)

73 4 21 23 25 25 (34.3) 46 Yes 1 15 16 14 16 (34.8) 27 No 3 6 7 11 9 (33.3)

2.8 2.7 3.1

60 R.B. Schilcher et al.: Phase II Evaluation of Low and High Dose Cisplatin

cancer [18] would explain these observations only par- tially since total doses were identical. Pharmacological behavior of cisplatin also depends on the infusion rate revealing nonlinear kinetics. Higher single doses and shorter infusion times [8, 19] might therefore result in improved clinical response rates.

A reduced overall response rate in this report com- pared with an earlier report [9] is attributed to patients with unfavorable prognosis. All l 5 additional patients had far advanced disease.

In conclusion, further studies should address phar- macokinetics of cisplatin given at different dose levels and schedules. Clinical responses suggest application of cisplatin alone and in combination regimens in patients with adrenal cancer, pheochromocytomas, soft-tissue sarcomas, and malignant melanomas.

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Received July 4, 1983/Accepted October 21, 1983