A randomized study of sequential versus alternating combination chemotherapy in advanced ovarian carcinoma

Annals of Oncology 1: 134-140,1990. 1990 Kluwer Academic Publishers. Printed in the Netherlands.

Original article A randomized study of sequential versus alternating combination chemotherapy in advanced ovarian carcinoma B. Lund, M. Hansen, H.H. Hansen, H.K. Thomsen, B.L. S0rensen, N.C. Nielsen & F. Lundvall From the Departments of Oncology ONK and Surgery, The Finsen Institute, the Departments of Internal Medicine C, Gynecology and Pathology, Bispebjerg Hospital, and the Department ofGynecology and Obstetrics, Hvidovre Hospital, University Hospitals of Copenhagen, Denmark

Summary. The concept of using either alternating or sequential combination chemotherapy with non-cross-resistant combinations was tested in a randomized trial including 301 previously untreated patients with advanced epithelial ovarian carcinoma. The sequential schedule consisted of CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) followed by PH (cisplatin, hexamethylmelamine) in nonresponders, CAF-> PH (n = 157), and the alternating regimen consisted of CAF/PH (n = 144). With a median observation time of 54 months, no statistically significant differences were found between the pathologically complete response (PCR) rates of 17% and 16%, respectively, nor were there any statistical differences in median disease-free survival for PCR patients (CAF-> PH 34+ months and CAF/PH 26+ months), in overall survival (28 and 24 months, respectively), or in time to treatment failure (10 and 11 months). The overall estimated cure rate was 13%. An equal degree of myelosuppression was seen with the two regimens, whereas neuro- and nephrotoxicity were more pronounced when PH was given sequentially to CAF than with the alternating schedule. We conclude that the sequential and the alternated use of doxorubicin- and platinum-based regimens yield equivalent results and that other approaches should be investigated to improve treatment effects. Key words: combination chemotherapy, ovarian carcinoma

Introduction Combination chemotherapy has resulted in significantly higher response rates than have single therapeutic agents in ovarian cancer, and many trials with a variety of drug combinations have been performed during the past decade in an effort to further improve the results [1]. In the late 1970s it became obvious that cisplatin was the most active drug in patients with epithelial ovarian cancer, and since then it has been included in most combinations [1]. At the same time hexamethylmelamine also showed encouraging activity in patients previously treated for ovarian carcinoma [1]. In patients with advanced ovarian carcinoma significantly higher response rates and response durations were obtained with combination chemotherapy consisting of cyclophosphamide (C), doxorubicin (A), and 5fluorouracil (F) (CAF) than with alkylating single agents such as cyclophosphamide or dihydroxybusulfan, in a phase HI study performed in Copenhagen from 1977 to 1980 [2]. No difference in overall survival was seen. As cyclic alternation between non-cross-resistant combinations had resulted in a significantly higher response duration and overall median survival in small-cell lung cancer [3], a new phase III trial in ovarian carcinoma was initiated in 1981. In this trial the principle of alternating and sequential chemotherapy consisting of cisplatin and hexamethyl-

melamine as a non-cross-resistant combination was tested against CAF.

Material and methods Patient selection Patients with histologically-verified epithelial ovarian carcinoma, FIGO Stages ITB-IV, were eligible [4]. It was required that staging take place during the six weeks preceding entry. Borderline tumors were excluded. All specimens were reviewed by the same senior pathologist, who was experienced in gynecological pathology. The tumors were subtyped according to the classification of WHO and graded (Grades 1 to 3) according to the percentage of solid tumor tissue [5,6]. Other inclusion criteria were: age <, 70, performance status <, 4, no prior chemo- or radiotherapy, no concomitant malignancy other than basal cell carcinoma of the skin, no cardiac disease or severe infection, serum bilirubin < 17 umol/1, normal renal functions [serum creatinine < 120 umol/1; creatinine clearance (i.e. glomerular filtration rate (GFR; ml/minute) x 1.73 as a function of age)], unless these abnormalities were due to tumor obstruction. In addition, WBC counts had to be > 3.0 x 109/! and platelets > 100 x 109/!.

135 Surgery Initial laparotomy and staging were performed at the referring hospitals and consisted, whenever possible, of total abdominal hysterectomy, bilateral salpingooophorectomy (BSOH), complete omentectomy, inspection and biopsy of suspected lymph nodes, peritoneal surfaces and liver abnormalities, diaphragm scrapings, cytologic evaluation of ascitic fluid if present (otherwise peritoneal washings), and maximum tumor debulking. Eighty percent of the second-or third-look laparotomies were performed at the Finsen Institute, Bispebjerg and Hvidovre Hospitals, Copenhagen. The inspection and biopsies were performed as described above. If not done previously, BSOH and further debulking were performed when possible.

ml/minute cisplatin treatment was stopped. Hexamethylmelamine was reduced to 50% or discontinued if neurological toxicity of WHO Grades 2 or 3 developed [7]. Assessment of response Complete blood counts, biochemical tests and physical examination were repeated before each treatment cycle, and pelvic examination, abdominal ultrasound scan, GFR, chest X-ray, and ECG were performed every 2-3 months. A second-look laparotomy was performed after ten months of treatment in patients who had achieved a clinical complete response, and in those without initially measurable or evaluable disease who had not developed progressive disease during treatment. Definition of response and response duration

Clinical staging and randomization General physical and pelvic examination, complete blood count, liver and renal function tests, chest X-ray, and electrocardiography were performed in all patients. In most cases an abdominal ultrasound scan was performed. After stratification based on stage (KB, IIIA, and HEB-IV), and WHO performance status [7], patients were randomized to one of two treatments. Chemotherapy Planned treatment duration was ten months, but the treatment was continued in some patients with late responses according to individual assessment Treatment A (CAF> PH) consisted of CAF: cyclophosphamide 500 mg/m2, doxorubicin 40 mg/m2, and 5-fluorouracil 500 mg/m2, all drugs given intravenously (i.v.) days 1 and 8 every 4 weeks. PH consisting of cisplatin 75 mg/m2 i.v. day 1 and hexamethylmelamine 200 mg/m2 orally days 8 to 21 every 4 weeks was given sequentially to CAF at progression or if residual tumor persisted at second look laparotomy. PH was given for 6-10 months or until progression of disease. Treatment B (CAF/PH) consisted of CAF given alternately with PH every other month. In patients with progression or residual disease at second-look laparotomy, phase I or II drugs were offered as salvage therapy. Patients with a pathological complete response at second-look laparotomy received no further treatment, but were closely followed. Dose modifications of all scheduled drugs were made according to the lowest WBC count of the preceding cycle and to the pretreatment values. The aim was to induce a minimum WBC count between 1.0-2.0 x 109/l, and a minimum platelet count of between 50-100 x 109/!. In case of values above or below the intended levels all drugs were increased or reduced, respectively to 125% or 67%. Doxorubicin treatment was cancelled at a maximum dose of 550 mg/m2 or earlier if cardiac toxicity developed. The dose of cisplatin was reduced to 50% if 5ICr-EDTAclearance (GRF) decreased to below normal limits, but was still between 40-50 ml/minute. If GFR fell below 40

Clinical response was defined according to the WHO classification criteria [7]. A pathological complete response (PCR) was defined at laparotomy as no persistent macroscopical or microscopical disease. Microscopical disease was defined as microscopical lesions persisting at laparotomy. Early death (ED) was defined as death within 28 days [7]. All eligible patients were included in the overall survival analysis. Overall survival was defined as the interval between start of chemotherapy and death from any cause. Disease-free interval (DFI) was calculated from the day of second-look laparotomy to the first day of recurrence. Time to treatment failure (TTF) was defined as the time from start of chemotherapy to the first occurrence of progression, relapse after response, or death from any cause. The cure rate was defined as the rate of patients who had achieved a PCR and remained disease-free for more than four years after the second-look laparotomy [8]. Patients with residual tumor after the primary laparotomy but without clinically evaluable or measurable disease were included only in the analysis of overall survival and TTF. If a second-look laparotomy was performed or if patients developed progressive disease during treatment, they were also analyzed for pathological response. Patients without primary residual tumor, i.e. without both macroscopic tumor and microscopic lesions in the biopsies performed, were analyzed separately for disease-free survival and results at second-look laparotomy. Toxicity was reported according to the WHO criteria [7]. Patients were considered evaluable for response and toxicity after one course of chemotherapy. Statistical methods Survival curves were estimated by the Kaplan-Meier method and analyzed using the logrank test [9,10]. To assess survival after second-look laparotomy a landmark analysis was performed [11]. The significance of differences was assessed by means of either the chi-squared test of contingency tables, Fisher's exact test or the Mann-Whitney test for non-paired differences [12].

136 Table 2. Distribution in percentage of patient and tumor related characteristics.

Results From January 1981 to December 1986, 333 patients were included in the study. The cut-off date was June 1988, when the median observation time was 54 months (range, 18 to 89 months). Three hundred and one patients were eligible: 157 patients were randomized to the CAFregimen, and 144 to the CAF/PH-regimen. Reasons for ineligibility are listed in Table 1. Table 1. Ineligibility in 32 patients. No. of patients Borderline tumors Age > 70 years Wrong stage Other previous or present primary cancer No primary ovarian cancer at histological revision Impaired renal function > 6 weeks after primary laparotomy Patient refusal of treatment

Patients who had no histological review (n = 22) or who were classified at review as not definitely having had primary of secondary ovarian cancer (n = 4), or who were not amenable to revision (n = 10) were not excluded from the analysis, as they had fulfilled the inclusion criteria according to the first pathologist's classification. All patients started chemotherapy within a median of 4 weeks (range, 1 to 6 weeks) after the primary laparotomy. Protocol violation, i.e. patient refusal of treatment or of second-look laparotomy occurred in 22 patients (12 CAF and 10 CAF/PH patients). Nine of these patients were primarily clinically evaluable and were included in the assessment of clinical response rate. Six patients had clinically residual tumor when treatment was terminated after a median of 6 months (range, 4 to 9 months), and were included in the analysis of pathological response rate. One patient was lost to follow-up, but sufficient data were available on clinical response and toxicity. For survival she was censored on the last day of observation. The two treatment regimens were well balanced with regard to patient and tumor-related characteristics (Table 2). Clinical response In the CAF arm 112 patients were clinically evaluable for response compared with 85 in the CAF/PH regimen. The clinical complete and partial response rates (CR + PR) and the CR rate were similar to those with CAF (63% and 39%, respectively) and CAF/PH (61% and 36%, respectively). Eighty-nine CAF patients (57%) were subsequently treated with PH. Fourteen of 64 clinically evaluable patients, (22%) achieved clinical responses (CR + PR); 8 (13%) of these were CRs.

CAF n=157

CAF/PH n = 144

Median age (years)

58 (range 20-69)

57 (range 20-70)

Performance status 0-1 2 3 4

73 17 8 2

71

F1GO stage IIB IIIA IIIB IV

14 20 45 21

12 26 41 21

Initial laparotomy BSOH + omentectomy biopsy only partial debulking total debulking

45 17 70 13

41 15 74 11

Initial residual tumour size 0 microscopic s2cm 2-5 cm >5 cm

13 1 16 23 47

11 6 22 19 42

47 2 4 7 17 11

49 6 3 10 15 6

1 3 8

1 4 6

12 19 38 23 8

13 19 46 16 6

Histological subtypes, review serous mutinous clear cell endometrioid undifferentiated mixed epithelial uncertain primary or secondary ovarian cancer not amenable to subtyping not revised Histological grade, review grade 1 grade 2 grade 3 not amenable to grading no revision

19 7 3

Pathological response Second-look laparotomies were performed in 64 of 133 CAF patients evaluable for pathological response, compared with 67 of 123 in the CAF/PH arm (Table 3). An additional 11 of 82 evaluable patients had second-or thirdlook laparotomies after treatment with PH. The PCR rate was 16% in both the CAF and CAF/PH regimens; similarly, there was no statistically significant difference in the PCR rate obtained with CAF-> PH and CAF/PH. A total of 72 patients still had residual tumor at secondor third-look laparotomy. Forty-one of these patients (57%) could be further debulked, with total tumor debulking being feasible in 6 patients (8%). Four of the latter patients had relapsed during a median period of 17 months (range, 5 to 35 months) after laparotomy. The last two patients are still

137 Table 3. Pathological response rales. 1

Patients with primary residual disease. CAF n=133

PH n = 82

CAF/PH n=123

PCR 21 (16) PPR (microscopic residual) 6 (4) PPR (macroscopic residual) 17 (13) PNC 3 (2) PPD 3 (2) no second-/third look 83 (63)

2 (2) 0 3 (4) 3 (4) 3 (4) 71 (86)

20 (16) 9 (8) 15 (12) 7 (6) 4(3) 68 (55)

Patients without primary residual disease.2 CAF n=15

CAF/PH n=14

still free of tumor PPD no second-look

10 (72) 2 (14) 2 (14)

12 (80) 2 (13) 1 (7)

and two died due to toxicity caused by either neutropenic fever (WBC: 0.8 x \(f/l), or anuresis caused by cisplatin complicated with diffuse bleeding (platelets: 2 x 109/!). No patients from either regimen have been censored. Median TTF was equal in the two treatment arms: 10 months (range, 0 to 70 months) for CAF->PH and 11 months (range, 0 to 58 months) for CAF/PH. No statistically significant differences were found in the overall median survival of all eligible patients: for CAF> PH: 28 months (range, 0 to 89+ months), CAF/PH: 24 months (range, 0 to 87+ months), p > 0.4 (Fig. 1). Eighteen percent of the CAF-> PH and 16% of the CAF/PH patients are estimated to be alive seven years after on-study.

Figures in parentheses denote percentages. 1 n: number of eligible patients minus patients without primary residual tumor and minus protocol violators without clinically evaluable disease at cessation of treatment. 2 n: number of patients without primary residual tumor minus protocol violators without tumor relapse. Abbreviations: CAF: cyclophosphamide, doxorubicin, 5-FU; PH: cisplarin, hexamethylmelamine; P: pathological; CR: complete response; PR: partial response; NC: no change; PD: progressive disease.

alive and clinically free of tumor 9 and 23 months after the debulking. The median DFI for patients with PCR has not been reached in either regimen but exceeds 34 months for CAF (range, 3 to 82+ months) and 26 months for CAF/PH (range, 5 to 80+ months), P > 0.4. At present 14 patients with PCR (33%) have relapsed (CAF->PH: n = 7; CAF/PH: n = 7). The median DFI for relapsing patients was 14 months (range, 5 to 47 months). An equal number of patients had no residual macro- or microscopical tumor after the primary laparotomy and were still disease-free at second-look laparotomy (PNEV) in both treatment arms (Table 3). No statistically significant difference was found in median DFI for this group of patients between CAF: 36+ months (range, 10 to 74+ months), and CAF/PH: 37+ months (range, 3 to 79+ months). Three PNEV patients (14%) relapsed 3, 11, and 18 months postoperatively. Survival, TTF, and cure rate One hundred and one CAF-> PH patients (64%) have died of malignant disease. Additionally, two patients died without recurrence after having achieved PCR: one committed suicide, the other died of bowel obstruction caused by benign adhesions complicated by perforation of the bowel. Toxicity was the cause of death in another four patients: anuresis after the first dose of cisplatin (n = 2), intracranial bleeding caused by preleucemia-induced thrombocytopenia (n = 1), and congestive heart failure caused by doxorubicin (n = 1). Ninety-six CAF/PH patients (67%) died of malignant disease. One additional patient in PCR committed suicide,

Fig. 1. Overall survival in 301 previously untreated patients with advanced ovarian carcinoma treated with sequential CAF-> PH (n = 157) or alternating CAF/PH (N = 144) combination chemotherapy. : CAF-> PH : CAF/PH Logrank statistics: p > 0.4

No statistically significant differences were found between the median time from start of chemotherapy to second-look laparotomy in patients who had obtained PCR: 11 months (range, 7 to 16 months), in patients who had achieved PPR, PNC, and PPD: 11 months (range, 7 to 16 months) or in PNEV patients: 11 months (range, 9 to 13 months). A landmark analysis of survival after second-look laparotomy revealed no statistically significant difference in survival for patients with PCR or PNEV, with an estimated 56% and 88%, respectively, being alive after approximately seven years of observation (Fig. 2). The two treatment arms were analyzed together, as there was no statistically significant difference between them. Both of these two groups lived significantly longer than the group

138 of patients who still had residual tumor at second-look, p < 0.0005. The median survival of the latter group was two years, with an estimate of only 14% of these patients being alive after seven years of observation. Analysis of the group of patients in whom the observation time after a scheduled second-look laparotomy exceeded four years, showed an estimated cure rate of 13%, as 18 PCR of 140 pathologically evaluable patients were still disease-free from 4 to 7.5 years later.

10O

patients (27%) had dose reductions because of neurotoxicity of grades 2-3 than did CAF/PH patients (8%), p < 0.0005. Eighty-one percent of the PH patients and 75% of the CAF/PH patients had a follow-up of GFR during treatment. The degree of GFR decrease caused by PH was significantly more pronounced than that caused by CAF/PH with medians of 14% (range, 71% to +23%) and 10% (range, 84% to +38%), p < 0.01. Accordingly, significantly more PH patients (19%) had dose reductions of cisplatin than did CAF/PH patients (7%), p < 0.025. Table 4. Percentage of patients requiring dose reductions because of nonhematological toxicity.

Gastro-intestinal neurotoxicity nephrotoxicity* cardiac toxicity oto toxicity (4-8000 khz)

CAF->

PH

CAF/PH

n=157

n = 89

n=144

15 4 -

20 27 19 0

23 8 7 1 1

p-values

NS < 0.0005 < 0.025 NS NS

a

number of evaluable patients: PH: 72, CAF/PH: 108 Abbreviations: NS: non-significant

Treatment feasibility

Survival In years after second-took laparotomy

Fig. 2. Landmark analysis of survival after second-look laparotomy in 127 advanced ovarian cancer patients treated with either sequential or alternating combination chemotherapy. Both regimens are analyzed together as there are no treatment related statistical differences. Patients in PCR (n = 41); PNEV: patients without primary or secondary residual tumor (n = 22); patients in PPR, PNC, PPD (n = 64). Day 0: performance of the second-look laparotomy. Logrank statistics: PCR versus PNEV, p > 0.10; PNEV/PCR versus PPR, PNC PPD, p < 0.0005

Toxicity

The median number of CAF cycles was eight (range, 1 to 14) and the median number of PH cycles was five (range, 1 to 14). The median number of CAF/PH cycles was four (range, 1 to 7) for both combinations. When CAF was given every four weeks as in the CAF arm, a median of 77% of the overall stipulated dose could be administered with a comparable dose reduction of all three drugs (79%, 73%, and 77%, respectively). When CAF was given every 8 weeks as in the CAF/PH arm, a median of 82% could be administered, again with a comparable dose reduction of all three drugs (83%, 80%, and 82%). A more pronounced dose reduction was registered when the PH component in both regimens was given every 4 weeks rather than every 8 weeks, with median delivered doses of 68% and 85%, respectively. The most marked dose reduction was for hexamethylmelamine in the CAF> PH arm, as only 68% of the overall stipulated dose was administered compared with 84% in the CAF/PH arm. This was due to a more pronounced neurotoxicity, probably caused by monthly as opposed to bimonthly administration of PH.

Treatment with cisplatin (PH and CAF/PH) caused more pronounced thrombocytopenia (WHO grades 3-4) than did CAF alone (27%, 35%, and 8%, respectively, p < 0.0005). Additionally, more hemoglobin values below 5.0 mmol/1 were seen in patients who received CAF/PH (14%) than in those on CAF (6%), p < 0.05, or PH (1%), p < 0.005 respectively. No differences between CAF->PH and CAF/PH Discussion were found with respect to grades 3—4 lcucopenia (57% and 61%, respectively) and the percentage of patients suffering In the present randomized trial comparing sequential with neutropenic fever (20% and 23%, respectively). alternating combination chemotherapy, no advantages were Dose reductions caused by non-hematological toxicity obtained with the alternating as compared with the sequenare reported in Table 4. Significantly, more CAF-> PH tial regimen. This pertains not only to pathological

139 response rates (PCR: 17% and 16%), but also to median DFI (34+ and 26+ months), median TTF (10 and 11 months), and overall median survival (28 and 24 months). In a trial of this size the statistical power for detecting a survival increase of a factor 1.6 at the 5% significance level is 90%, so the risk of committing a type II error is only moderate [13]. The patients in the two treatment arms were well matched with regard to pretreatment characteristics. Surgical debulking was feasible at an equal rate in all of the patients; nevertheless, 61% in the CAF-> PH arm and 70% in the CAF/PH arm had residual tumor masses above 2 cm. Total debulking with no residual macroscopic tumor and no microscopic lesions in the biopsies performed was possible in 13% and 11%, respectively. Such a subgroup of patients has rarely been presented separately, but when so, have usually been included in the total assessment of PCR rate and response duration [14,15]. In the present trial, this prognostically favoured group of patients was analyzed separately for results at second-look and DFI, as it is impossible to determine whether the chemotherapy changed the natural course of their disease. The overall results were in opposition to the predictions of the Goldie-Coldman model of spontaneous mutation to chemotherapy resistance [16]. According to this model administration of alternating courses of non-cross-resistant combinations should yield a higher probability of cure than sequential administration of the same combination. Our failure to show a superiority for the alternating regimen could be due either to the low dose of cisplatin or to a lack of non-cross-resistance between the combinations. Neijt et al. achieved a significantly higher PCR rate, overall response rate, higher overall survival and progressionfree survival with the cisplatin-containing CHAP-5 regimen than with the Hexa-CAF regimen [17]. In their trial, the non-responding Hexa-CAF patients, like our CAF patients, were given salvage therapy which included cisplatin, and achieved an overall response rate of about 20%, as compared with 22% in our present trial. Methotrexate rather than doxorubicin was included in their CAF regimen, and the dose of cisplatin in their CHAP-5 regimen was higher 20 mg/m2 x 5 every 5 weeks - than in our CAF/PH: 75 mg/ m2 every 8 weeks. According to Levin et al. [18] cisplatin is the only drug which has a clear dose-intensity effect in ovarian cancer. The results achieved with CAF/PH might have been better with a higher dose of cisplatin at shorter intervals compared with CAF alone or with CAF-> PH, especially since only about half of the CAF patients were actually treated with cisplatin. With respect to cross resistance, the PH treatment was clinically active when given sequentially to CAF in our study. Although not strictly comparable to the present results, in a later Phase II study from the same institutions CAF showed no activity when given sequentially to combined platinum (carbo- and cisplatin) [19]. This suggests that CAF is cross-resistant to cisplatin-containing combinations. Thus, the criteria for adherence to the prediction of the Goldie-Coldman model were not fulfilled. The results obtained in other trials applying the alternating principle also indicate that at present there are no true non-

cross-resistant combinations known to be effective in ovarian carcinoma [20,21]. Second-look laparotomy was performed later in this study than in others [14,17]. Although not comparable because of different methods of assessments, our low PCR rate and long DFI may reflect this, as patients with early relapse would not be included in the analysis of these parameters. With an overall median follow-up of 3.5 years after second-look laparotomy, 33% of the patients who obtained PCR in the present study had thus relapsed. Seventy-two percent of the PCR patients were still alive, and of these 94% were clinically free of tumor. The estimated rate of survival after 6 years of observation from second-look laparotomy was 58%. The previously optimistic reports of long-term survival and possibly even cure in 50%-70% of the patients who have achieved a PCR may not, as indicated by Neijt et al., prove correct upon further long-time observation [22]. Our estimated cure rate of only 13% is also indicative of this. Based on our study and those by Young et al. [20] and Bruckner et al. [21], alternating therapy does not improve the overall treatment results in ovarian carcinoma. Considering that the maximum results appear to have been achieved with presently available compounds, there is a pressing need for either new active agents which are non-cross-resistant to the present active drugs, or new treatment modalities.

Acknowledgements This study was supported by grants from the Wedell— Wedellsborg, Lykfeldt, Haensch and Madsen Foundations. Hexamethylmelamine was kindly supplied by RhonePoulenc Pharma Norden, Copenhagen.

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