Ten-Year Outcome of Patients With Advanced Epithelial Ovarian Carcinoma Treated With Cisplatin-Based Multimodality Therapy By P.J. Hoskins, S.E. O'Reilly, K.D. Swenerton, J.J. Spinelli, R.N. Fairey, and J.L. Benedet Purpose: At the end of the 1970s it was thought that advanced epithelial ovarian cancer (EOC) could be cured by multimodality treatment using surgery, cisplatinbased combination chemotherapy, and radiotherapy (RT). Such multimodality treatment was used as standard therapy at our institution. Our long-term results are reviewed. Patients and Methods: One hundred ninety-five previously untreated patients with stage III or IV EOC were treated between April 1979 and December 1982. All patients were to have debulking surgery, when feasible, followed by the administration of doxorubicin and cis2 platin at 50 mg/m every 3 weeks until a total dose of 2 doxorubicin of 450 mg/m had been reached. RT was used in addition in patients with disease remaining after the chemotherapy. Maintenance chemotherapy with oral cyclophosphamide and hexamethylmelamine (altre-
hope in the late 1970s that THERE WAS GREAT progress achieved with the individual
the apparent modalities of surgery, chemotherapy, and radiotherapy (RT) could be combined in an approach that would lead to the cure of patients with advanced epithelial ovarian cancer (EOC). Accordingly, in 1979 the Gynecology Tumor Group of our institution established a multimodality treatment policy for such patients using debulking surgery, chemotherapy, and RT. The rationale for the development of such a protocol was based on the following facts and hypotheses, which were current at that time. Survival seemed to be related inversely to the volume of residual disease after surgery, and both chemotherapy and RT seemed to be more effective in the circumstance of minimal residual disease. Therefore, the concept of maximum tumor reduction, achieved if necessary by repeated operation, became fashionable.' The advent of cisplatin was particularly encouraging because occasional dramatic responses were observed in women with alkylating-agentresistant disease2 and because in previously untreated women, the rapidity of response and the response rate were greater than had been observed previously. Doxorubicin had shown second-line activity in those patients who underwent unsuccessful alkylating agent therapy;
therefore, it seemed logical to include it in the induction 3 chemotherapy regimen rather than cyclophosphamide. Histologic remissions were thought to be durable, and further treatment for such patients was thought not to be needed. 4 In contrast, it was recognized that all other patients needed additional therapy; therefore, maintenance chemotherapy might be beneficial. Although the role of RT in the treatment of advanced ovarian cancer
tamine) was administered to patients who did not have a documented histologic complete remission. Results: The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. Conclusions: Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease. J Clin Oncol 10:1561-1568. © 1992 by American Society of Clinical Oncology.
remained uncertain, there was evidence that gross but localized disease (eg, pelvic or paraaortic masses) and small transperitoneal tumor aggregates might be sterilized by RT.5 Here we report the long-term outcome for the initial group who was treated according to this policy. In addition, we present the results of a multivariate analysis of prognostic factors. PATIENTS AND METHODS Patients
Patients had to have a histologic diagnosis of EOC confirmed on review by our institutional pathologists, be International Federation of Gynecology and Obstetrics stage III or IV, 6 and have had no prior irradiation or chemotherapy, no congestive cardiac failure or other serious illness that precluded treatment, a creatinine clearance of 40 mL/min or more, and a serum creatinine level of less than 1.5 mg/dL (133 pLmol/L). There were no age-related or performance status exclusion criteria. Patients with borderline tumors were excluded. The policy was initiated in April 1979. All 195 patients who were started on this treatment before December 1982 were included in this review. Their pretreatment characteristics are listed in Table 1. This protocol was institutional policy, and there were no competing
From Departments of Medical Oncology, Gynecologic Oncology, Leukemia/Bone Marrow Transplantation Program, and Radiation Oncology, British Columbia CancerAgency, Vancouver Clinic, Vancouver, Canada. Submitted February18, 1992; acceptedJune 10, 1992. Presented in part at the Annual Meeting of American Society of ClinicalOncology, March 1986 and May 1992. Address reprintrequests to PaulJ. Hoskins, FRCP, 600 W I Oth Ave, Vancouver, British Columbia, Canada V5Z 4E6. © 1992 by American Society of ClinicalOncology. 0732-183X/92/1010-0010$3.00/0
Journal of Clinical Oncology, Vol 10, No 10 (October), 1992: pp 1561-1568
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1561
1562
HOSKINS ET AL
Table 1. Patient Characteristics of the 195 Women With Advanced-Stage Epithelial Ova ran Cancer
Karnofsky performance status* 0 1 2 3 Stage Ill IV Grade 1 2 3 4 Unknown Residual disease Microscopic < 1 cm 1-2 cm > 2 cm Unknown Histology Serous Mucinous Endometrioid Clear cell Undifferentiated Age, years Median Range
68 100 16 11
35 51 8 6
148 47
76 24
10 30 112 23 20
5 15 57 13 10
7 13 5 157 13
4 6 3
141 5 5 2 42
80 7
intravenously (tV) every 3 weeks. Prehydralion and posthydration as well as mannitol diuresis were used without exception. Treatwas discontinued if there was evidence of progression or ment % ""No unacceptable toxicity. The dose of doxorubicin was adjusted as follows: if the bilirubin was greater than 1 mg/dL (17 ýpmol/L) but less than 3 mg/dL (51 limol/L), 50% was given. If it was more than 3 mg/dL, then 25% was given. The dosage adjustment for treatment-day neutropenia or thrombocytopenia was as follows: neutrophils over 1,500 and platelets greater than 125,000, full dose; neutrophils 1,000 to 1,499 or platelets 75 to 124,000, 80% dose, neutrophils 999 or less or platelets 74,000 or less, 50%. If mucositis occurred, the dose was reduced to 40 mg/m'. The cisplatin was decreased on the basis of the creatinine clearance: a creatinine clearance of more than 70 mL/min, full dose; 60 to 69 mL/min, 60%; 50 to 59 mL/min, 50%; 40 to 49 mL/min, 40%; 39 mL/min or less, treatment protocol discontinued. Reassessment 1. After the completion of the sixth cycle of doxorubicin-cisplatin, the patients were reassessed. Those patients who had no clinical evidence of disease were to continue on the doxorubicin-cisplatin regimen for at least three more cycles to 2 achieve a total cumulative dose of doxorubicin of 450 mgim . In contrast, those who had responded but still had persistent disease were considered for reoperation and/or RT. Repeat surgery was to
72
2.5 2.5 1
icto Cemontapy
22
-asm
59 27-85
"Eastern Cooperative Oncology Group.
Sn23
protocols. All eligible patients were to be treated on it. A record of eligible but nonpolicy-treated patients was not kept. During the course of the study, we saw 393 (58%) of the women diagnosed with any stage of EOC in the province. Not all patients were treated by us because we have a sister clinic on Vancouver Island. We saw approximately 80% of the patients in our catchment area. Written informed consent was given according to institutional policy.
Treatment
i2binii
FT~RI eo
2
!
e C~••
Response 5 nL;105 O
Noaparotomy
Initial sutgery and asses ment. The treatment schema is shown in Fig 1. The initial surgery usually was performed by either a community gynecologist or a general surgeon and not by a specialist gynecologic oncologist. The desired operative procedure consisted of total abdominal hysterectomy, bilateral salpingoophorectomy and omentectomy. thorough abdominal exploration (including undersides of diaphragm),. and washings on initial abdominal entry. Such an operation occurred in 24% of patients; 39%' had a lesser debulking procedure, and 37% had a biopsy only Reoperation on initial referral to our center was not performed The following standard prechemotherapy investigations were performed: chest x-ray, computed tomographic scan of the abdomen and pelvis, complete blood cell count, liver function tests, serum electrolytes, blood urea nitrogen and creatinine clearance, and 24-hour urine creatinine clearance Induarton chemotherapy rgmen. Ihe chemotherapy regimen used was doxorubicin 50 mg m' and cisplatin 50 mg/ m, both given
Chemotherapy2 eo*t7nr11
Laparatomy
*38
CR1
S
Response n eýn
.
SRT
n·S
i~~lsioiogm Complete Ipon se
Fisogl
L 82 (51
incomplete Response
NaFuRh TolnyR2
Fig 1. Treatment schema and number of patients at the different steps. (1) Doxorubicin and cisplatin every 3 weeks times 6; (2) doxorubicin and cisplatin every 3 weeks 2t 3; (3) cyclophosphamide/ hexamethylmelamine; (4) number in parentheses is the number of patients who did not get maintenance chemotherapy although eligible to do so; and (51 four patients were irradiated.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1563
ADVANCED EPITHELIAL OVARIAN CARCINOMA be performed in patients who responded and who initially had incomplete surgery, if it was anticipated that reoperation would accomplish a substantial reduction in the tumor bulk that remained. If there was clinically evident disease present that was limited to the pelvic or paraaortic nodal areas, RT was to be delivered at a dose of 40 Gy (central) in 4 weeks (20 fractions) by parallel pair, Both fields were treated daily A boost dose of 5 to 10 Gy in an additional week was allowed. After such patients completed their surgery or RT, they went on to receive additional doxorubicin-cisplatin therapy to achieve a total cumulative dose of doxorubicin of 450 mg/m'. The doxorubicin was reduced to 40 mg mI for the first cycle after RT. Progressors went off protocol and were treated at their physician's discretion. Reassssment 2. This was performed at the end of the induction chemotherapy. Patients who had no clinical evidence of disease were to undergo a laparotomy to confirm their remission status. Those who had achieved a histologic complete response (CR) were offered no further therapy. If laparotomy was not performed or if anything other than a histologic CR was documented, then further treatment was offered. Those patients who were not irradiated previously and who had clinically evident disease that was thought to be amenable to RT might receive irradiation as described under Reassessment 1. A second group of patients was also to be irradiated. A our experience with RT increased, we recognized that the acute toxicity was minimal and that whole-abdominal treatment could be used in addition to the pelvic irradiation. Therefore, our initial policy was modified. Those patients who either were presumed to have subclinical intraperitoneal disease (in practice those patients in complete clinical response ICCR] who refused reassessment surgery) or had minimal disease documented at second surgery despite having entered a C(CR were now to be treated. In these patients, treatment to the pelis was by parallel rather than by isocentric anterior-posterior fields, usually 17 cm by 17 cm, that were designed to extend 1 to 2 cm below the obturator foramina, 1 to 2 cm beyond the lateral limits of the true pelvis, and superiorly to the L5-U1 interspace. Field margins represented the 50% isodose. The dose prescribed was 22.5 Gy in 10 fractions during a 2-week period Whole-abdominal RT then continued immediately by an extended source skin distance (usually 130 cm) anterior-posterior parallel opposed pair Anatomical posterior renal shielding was used to reduce the dose to the kidney to 15 Gy. Fields were used to encompass all surfaces of the abdominal cavity including the highest points of the diaphragm during quiet respiration. The lower field margins were at the level of the previous pelvic field's inferior margins. Shielding material generally was used to trim the corners. Shaping of the diaphragm fields was accomplished with curved (errobend blocks The nominal central whole abdominal dose was 22.5 Gy in 22 fractions during a 4,5-week period. All fields were treated daily by a 4 MV linear accelerator. Patients with anything less than a documented histologic CR then went on to receive maintenance therapy with oral cyclophosphamide (100 mg orally daily) and hexamethylmelamine (altretamine, 200 mg orally daily), both for 14 days of every 28 for up to 2 years. Response Assessment A CCR was defined as the complete absence of disease on clinical and imaging examination at the end of chemotherapy, whereas a partial clinical response (PCR) was a greater than 50% decrease in the sum of the products of the perpendicular diameters
of all the measurable bidimensional lesions or, if only unidimensionally measurable lesions were present, then a greater than 50% decrease in the sum of their diameters. Patients with no clinically evident disease after their initial surgery and who did not progress during the chemotherapy were classified as CCRs. Progressive disease was the development of new lesions, ascites, or effusions or a 2.5% increase in diameter of any lesion. A histologic CR was the absence of any disease at surgery, which included washings and random biopsy procedures. Histologic partial response (PR) was a reduction of 50% or more in the total tumor burden compared with that left at end of the primary laparotomy. Patients who grossly were negative but who had microscopic positivity were classified as PCRs.
StatisticalMethods Patient follow-up is ongoing. Information on all patients was available as of September 1991. Date of last follow-up and status at that time (dead of ovarian cancer, dead of other causes with or without ovarian cancer present, alive in continued first remission, alive with ovarian cancer present) were recorded. No patient had an unknown status at last follow-up or had been lost to follow-up. Survival was presented both as overall survival (OS; all deaths included) or failure-free survival (FFS; failure means either primary progression, relapse, or death from toxicity). Survival curves were calculated by the product-limit Kaplan-Meier method. The effect of potential prognostic factors was examined initially by the log-rank test. Cox proportional hazards analysis was then used (on all of the variables) for the multivariate analysis.8
RESULTS Clinical Response Rates
Clinical response rates were assessed at the completion of the doxorubicin-cisplatin chemotherapy. Thirty patients (15%) were primary progressors, 20 (10%) had stable disease, 40 (21%) had a PR, and 105 (54%) had a CR. Histologic Response Rates
Reassessment laparotomy was performed on 67 of the 105 patients who were assessed as having entered a CCR and who were scheduled to have it according to the protocol. Thirty-two had a histologic CR, 17 had microscopic residual, and 18 had macroscopic residual. Twenty (63%) of the histologic CRs have relapsed, and their 10-year FFS was only 31% (Fig 2). Survival Actual OS at 2, 4, 6, and 8 years was 46%, 21%, 13%, and 9%, respectively (Figs 3 and 4). The 10-year actuarial survival was 4%. Median OS was 24 months. The minimum follow-up of the survivors (10 of 195) was 8 years; the maximum was 11 years (median, 10.5 years). FFS (actual) at 2, 4, 6, and 8 years was 32%, 13%, 10%, and 8%, respectively, with a 10-year actuarial rate of
8%.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1564
.
HOSKINS ET AL
1.00
1.00
0.75
>, 0.75 0,
a- 0.50
a- 0.50
c) 0.25
C)
0.25
0
0 0
2
4
6
8
10
0
2
Years Fig 2.
4
6
8
10
Years
FFS for patients with a histologic CR (n = 32).
ChemotherapyDelivery Information on the total delivered dose of cisplatin was available for 159 (82%) patients. The median dose was 343 mg/m2 (range, 0 to 664). Similarly, for doxorubicin (n = 166; 85%) the median dose was 394 mg/m2 (range, 0 to 550 mg). Increasing age, analyzed in 10-year increments, did not diminish our ability to deliver the chemotherapy except in the group of patients 76 years of age or older. Only eight patients were in this age group, and their median dose of cisplatin was 231 mg (range, 50 to 380) and doxorubicin was 296 mg (range, 196 to 377). OS was compared within increasing deciles of the total administered dose of either doxorubicin or cisplatin for all patients except progressors. They were excluded because, a priori, they were taken off treatment early, and thus received a decreased total dose. No
1.00
Fig 4.
FFS for all patients (n = 195).
significant survival benefit was demonstrated for increasing total dose by decile of either doxorubicin or cisplatin (P = .713 and .599, respectively). ChronicChemotherapy Toxicity Functionally significant cardiomyopathy occurred in nine patients (4.6%). There were no toxic deaths. There was no formal reporting of whether neuropathy or ototoxicity was present or absent. Chronic renal dysfunction was not assessed. MaintenanceChemotherapy Eighty-two patients received maintenance therapy with cyclophosphamide-hexamethylmelamine and another 43 patients were given this therapy when they progressed or relapsed. Of these 125 patients, 75 had assessable disease; only one CR and one PR (total response rate 3%) were obtained. RT and Survival It is difficult to assess the effect of the RT because it was given in two different situations: to those patients with clinically evident disease present despite chemotherapy and to those who had entered a CCR. Additionally, the extent of RT varied; 52% received pelvic and/or paraaortic nodal irradiation, and the remainder received pelvic-abdominal irradiation. Figure 5 contrasts the OS for the three different groups of RT patients. Group-1 patients had clinically evident disease. Group-2 patients had achieved a CCR
Z, 0.75 .0
0- 0.50 C) 0.25
0
0
2
4
6
8 10 Yearsreassessment (n = 195). faoi l patients Fig a. OS
u ul tI, A:d 14, H V u1 IIUL uIIlCn
t1 ressCsbfflel tt;
su1geIy,
111
U.U4gtU, grIuI-J
1,
patients were also in CCR but had disease found at surgery. In addition, four patients who achieved a histologic CR were irradiated and are includ-
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1565
ADVANCED EPITHELIAL OVARIAN CARCINOMA • A_
"
1.00
.
"'
IV epithelial ovarian cancer. The 10-year OS and FFS were 4% and 8%, respectively. There was an apparent plateau for FFS after 8 years. Our survival figures matched those reported by Sutton et a19 for patients who were treated with cisplatin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclophosphamide in whom the OS at 10 years was 9%; 7% were considered disease-free. Similarly, Hainsworth et al10 using hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin reported that 18% of patients (10 patients) remained disease-free between 7 and 9 years from diagnosis. A meta-analysis of randomized trials reports a 7-year OS of 14%, which was
0.75
Ca
o 0 a 0.50
oJ 0.25
0
0
2
4
6
8
10
Years Fig 5. OS of patients who received irradiation subdivided by treatment group. Group 1, clinically evid ent disease after > 6 cycles chemotherapy (n = 37). No clinically evidlent disease after 2 9 cycles chemotherapy. Group 2, reassessmen t surgery not performed (n = 34). Group 3, reassessment surgery performed (n = 24).
ed in group 3. No significant sisurvival difference was found. Median survivals were 322, 24, and 24 months, respectively. Radiotherapy Toxicity Chronic bowel dysfunction (cr amps, malabsorption, and constipation/diarrhea) occu rred in eight (9%) of the irradiated patients. Three addditional patients developed bowel obstruction that requi red surgery. In none of these patients was the problem caused by tumor recurrence. Prognostic Variables The significance values obtained by the univariate analysis are listed in Table 2. Multivariate analysis identified residual disease of more than 2 cm after primary laparotomy as the only independent adverse prognostic factor for both OS (relative risk, 2.08; 95% confidence interval [CI], 1.22 to 3.54; P = .0033) and FFS (relative risk, 3.41; 95% CI, 1.81 to 6.41; P = .00012). The multivariate analysis was performed only on 128 (66%) of the patients who had complete information available on all the variables that were included in the analysis. DISCUSSION Our multimodality regimen of maximal surgery plus doxorubicin-cisplatin induction chemotherapy and, for selected patients, RT and maintenance chemotherapy was curative in less than 10% of patients with stage III or
2 identical to ours.'1 In contrast, Neijt et a11 achieved a
21% 10-year survival for patients who were treated with cisplatin-based chemotherapy. Patient selection could
well account for the difference between our results and those reported by Neijt et al. In our multivariate analysis, the only independant adverse prognostic factor was residual disease that measured more than 2 cm after
primary laparotomy. Eighty percent of the patients in our study had a greater than 2 cm residual disease, in contrast to the 56% reported by Neijt et al.13,14 Even though our stated aim was to use maximal surgery, this in practice did not happen. Only 24% of our patients had such surgery at diagnosis, and another 28% had tumor reduction surgery after six cycles of chemotherapy. Whether our results would have been better if more patients had such surgery we cannot say. The amount of residual disease after primary laparotomy was a prognostic factor, but whether it was the surgical debulking or whether it was the ability of the cancer to be debulked (ie, the biology of the cancer) that was important was not clear. Only a randomized study that Table 2. Univariate Analysis of Adverse Prognostic Factors
for Survival Factor
Weight loss Karnofsky performance status Residual disease Initial surgery Age, years Stage Ascites Histology Grade
OS
FFS
P
P
> 20v 10-19 v < 101b 1,2,3 v 0
.0032
.0018
.0037
.023
> 2 v < 2 cm Incomplete v complete* > 65 v 56-65 v < 56 IVv 111 Present v absent Serous v other 3v2
.008 .0051 .0063 .22 .69 .066 .96
.001 .0018 .11 .24 .50 .23 .72
Comparison
Abbreviations: OS, overall survival; FFS, failure-free survival. *Complete: total abdominal hysterectomy, bilateral oophoredomy, and omentedomy.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1566
HOSKINS ET AL
compared chemotherapy alone to chemotherapy and maximal surgery would enable us to delineate the role of the surgery. Until this is settled, we recommend that surgeons experienced in the surgery of ovarian cancer perform the operations with the intent of maximal debulking. Our multivariate analysis of prognostic variables identified the size of the residual cancer as the only independent prognostic factor. This contrasts with two other reports in which long-term follow-up is available. 15 ,16 In both of these, performance status, stage, and the presence of ascites as well as residual tumor were independent predictors. Additionally, grade and treating hospital were important in the Dutch analysis, 15 and cell type, age, measurable disease, tumor volume, and cisplatin chemotherapy were independent predictors. As to why in our study only residual disease was important we cannot explain definitively. However, it was probably a reflection of the lesser power of our analysis because of our smaller patient numbers (n = 126). In addition to providing 10-year survival data, does our experience provide any additional information of value to physicians treating advanced ovarian cancer? We believe that it does. There was no evidence that the addition of RT to platinum-based chemotherapy was beneficial. This conclusion is based on two lines of evidence. First, RT was used in two different situations: in patients with clinically measurable disease that persisted during chemotherapy, and in patients who had entered a CCR after chemotherapy. We would have expected the latter group to have fared better given their lesser apparent tumor burden. However, there was no OS difference, and the median survivals were similar at 32 and 24 months. The group with clinically evident disease had the longer median survival. Second, our survival figures (whether median, 5-year, or 7-year) were similar to those achieved by combination chemotherapy alone.9-14"17 We must stress that our study was not randomized, and thus our data cannot be interpreted as being conclusive. In retrospect, we could be criticized for not administering RT to the group of patients who might be expected to benefit the most, ie, those with a histologic CR, but a review of the literature did not provide supporting evidence for this assumption. Relapses were common (approximately 22%) in such patients who were treated with RT, and this was with a short follow-up.18-20 This was similar to the rate observed in patients who were treated with chemotherapy alone.13 Additionally, RT added substantially to the morbidity of the treatment. Nine percent of our irradiated patients
developed chronic bowel dysfunction, and another 3% needed surgery for bowel obstruction. In all of them it was unrelated to tumor recurrence. Maintenance chemotherapy with cyclophosphamide and hexamethylmelamine did not seem to be beneficial. Our survival figures were similar to those obtained with regimens that did not use such maintenance therapy. For those patients with assessable disease who were given these drugs, the response rate was only 3%, a level of activity that suggests no clinical use. This confirms the low response rate (2%) observed in similarly treated patients in a multicenter Canadian trial. 21 This lack of response to hexamethylmelamine contradicted the results observed in some but not all of the studies of patients with recurrent cancer postcisplatin in which 22 24 response rates from 0% to 25% have been found. We believe that this difference in response rates can be explained by the postulate that hexamethylmelamine and cisplatin are crossresistant agents. Most of our patients were given altretamine because of persistent cancer despite nine or more cycles of cisplatin and doxorubicin, ie, they were truly resistant. In contrast, relapsed patients may still be sensitive to cisplatin and, by inference, hexamethylmelamine. Therefore, response rates will vary depending on the mix of resistant and relapsed patients in the study. Our belief that histologic CRs were durable was not confirmed. Sixty-three percent of our patients who had a histologic CR relapsed during the 10-year period. This confirmed the results of the study by Neijt et al, in which there was a 61% relapse rate. 12 Can we postulate any reasons for our poor long-term results? The concept of dose-intensity is currently in vogue. A meta-analysis that defines dose-intensity as milligrams per meters squared per week of ideal dose has shown a slight improvement in response rates and survival with increased cisplatin intensity. 25 Our target cisplatin dosage of 50 mg/im2 every 3 weeks is not intensive. However, the question whether dose-intensity is important is far from settled. Retrospective metaanalyses (flawed by using ideal and not given doseintensities and insensitive to differences in prognostic characteristics) are not definitive. Those randomized studies that try to define the importance of dose intensity are contradictory in their results with the majority not demonstrating benefit 26-28 and one showing an early survival advantage. 29 Another possible explanation is that we used too few drugs in our combination. Randomized studies so far do not confirm that the use of a larger number of drugs is better,17,30 and cisplatin alone may well be as effective.' 7
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1567
ADVANCED EPITHELIAL OVARIAN CARCINOMA
However, in both of these studies, although not significant, there was a trend for patients on the triple-drug regimens to have improved long-term survival. A metaanalysis that included these two trials has demonstrated a significant survival advantage for the triple-drug regimen of cisplatin, cyclophosphamide, and doxorubicin compared with cisplatin and cyclophosphamide. 31 We believe that our long-term results are disappointing not only because of either too low a dose-intensity or that too few drugs were used but because drug resistance is present, and the currently available drugs are crossresistant. There is no doubt that the advent of cisplatin was a major advance, doubling the median and 5-year
survivals compared with noncisplatin therapy. 14 Unfortunately, anthracyclines and cyclophosphamide are crossresistant with cisplatin, as demonstrated by their ineffectiveness when given to patients who relapse from or are resistant to cisplatin.32-34 The ineffectiveness of the cyclophosphamide-hexamethylmelamine in this study is further evidence for this. We believe that new drugs that are noncrossresistant to cisplatin are needed before any meaningful improvements in the survival of patients with advanced EOC are observed. We must add a caveat to this conclusion. Much of the dogma of the 1970s was wrong. Who is to say that the dogma of the 1990s will fare any better?
REFERENCES 1. Tobias JS, Griffiths CT: Management of ovarian carcinoma. Current concepts and future prospects. N Engl J Med 294:818-823, 1978 2. Wiltshaw E, Kroner T: Phase II study of cis-dichlorodiammineplatinum (II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat Rep 60:55-60, 1976 3. de Palo GM, de Lena M, di Re F, et al: Melphalan versus Adriamycin in the treatment of advanced carcinoma of the ovary. Surg Gynecol Obstet 141:899-902, 1975 4. Young RC, Chabner BA, Hubbard S, et al: Advanced ovarian adenocarcinoma: A prospective clinical trial of melphalan (LPAM) versus combination chemotherapy. N Engl J Med 299:12611266, 1978 5. Rubin P: Understanding the problem of understaging in ovarian cancer. Semin Oncol 2:235-242, 1975 6. Petterson F, Kolstad P, Ludwig H, Ulfeder H (eds): Annual report on the results of treatment in gynecological cancer, vol 19. Stockholm, Sweden, International Federation of Gynecology and Obstetrics, 1985, p 211 7. Oken MM, Cuech RH, Toormey DL, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655 1982 8. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980 9. Sutton GP, Stehman FB, Einhorn LH, et al: Ten-year follow-up of patients receiving cisplatin, doxorubicin, and cyclophosphamide chemotherapy for advanced epithelial ovarian carcinoma. J Clin Oncol 7:223-229, 1989 10. Hainsworth JD, Grosh WW, Burnett LS, et al: Advanced ovarian cancer: Long-term results of treatment with intensive cisplatin-based chemotherapy of brief duration. Ann Int Med 108:165-170, 1988 11. Advanced Ovarian Cancer Trialists Group: Chemotherapy in advanced ovarian cancer: An overview of randomised clinical trials. Br Med J 303:884-893, 1991 12. Neijt JP, ten Bokkel Huinink WW, van der Burg MEL, et al: Long term survival in ovarian cancer. Eur J Cancer 27:1367-1372, 1991 13. Neijt JP, ten Bokkel Huinink WW, van der Burg MEL, et al: Randomized trial comparing two combination chemotherapy regimens (CHAP-5 vCP) in advanced ovarian carcinoma. J Clin Oncol 5:1157-1168, 1987
14. Neijt JP, ten Bokkel Huinink WW, van der Burg MEL, et al: Randomized trial comparing two combination chemotherapy regimens (HEXA-CAF v CHAP-5) in advanced ovarian carcinoma. Lancet 2:594-600, 1984 15. van Houwelingen JC, ten Bokkel Huinink WW, van der Burg MEL, et al: Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol 7:769-773, 1989 16. Omura GA, Brady MF, Homesley HD, et al: Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: The Gynecologic Oncology Group experience. J Clin Oncol 9:1138-1150, 1991 17. Gruppo Interregionale Cooperativo Oncologico Ginecologia: Randomized comparison of cisplatin with cyclophosphamide/ cisplatin and with cyclophosphamide/doxorubicin/cisplatin in advanced ovarian cancer. Lancet 2:353-359, 1987 18. Shelley WE, Starreveld AA, Carmichael JA, et al: Toxicity of abdominopelvic radiation in advanced ovarian carcinoma patients after cisplatin/cyclophosphamide therapy and second-look laparotomy. Obstet Gynecol 71:327-332, 1988 19. Kuten A, Stein M, Stiner M, et al: Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma. Int J Radiat Oncol Biol Phys 14:273-279, 1988 20. Goldhirsch A, Greiner R, Dreher E, et al: Treatment of advanced ovarian cancer with surgery, chemotherapy and consolidation of response by whole abdominal radiotherapy. Cancer 62:40-47, 1988 21. Pater JL, Carmichael JA, Krepart GV, et al: Second-line chemotherapy of stage III-IV ovarian carcinoma. A randomized comparison of melphalan to melphalan and hexamethylmelamine in patients with persistent disease after doxorubicin and cisplatin. Cancer Treat Rep 71:277-281, 1987 22. Stehman FB, Ehrlich CE, Callangan MF: Failure of hexamethylmelamine as salvage therapy in ovarian epithelial adenocarcinoma resistant to combination chemotherapy. Gynecol Oncol 17:189-195, 1984 23. Rosen GF, Lurain JR, Newton M: Hexamethylmelamine in ovarian cancer after failure of cisplatin-based multiple agent chemotherapy. Gynecol Oncol 27:173-179, 1987 24. Moore DH, Fowler WC, Jones CP, et al: Hexamethylmelamine chemotherapy for persistent or recurrent epithelial ovarian cancer. Am J Obstet Gynecol 165:573-576, 1991 25. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 5:756-767, 1987
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1568
HOSKINS ET AL
26. Colombo N, Pittelli MR, Marzola M, et al: Randomized study of two cisplatin(P) dose-intensity regimens in patients with stage III/IV epithelial ovarian cancer (EOC). Proc Am Soc Clin Oncol 9:160, 1990 (abstr 619) 27. Menczer J, Brenner J, Modan M, et al: A comparison of low and high dose cisplatin-based combination chemotherapy as initial postoperative treatment in advanced ovarian adenocarcinoma. Am J Obstet Gynecol 155:974-979, 1986 28. McGuire WP, Hoskins WJ, Brady MS, et al: A phase II trial of dose intense (DI) versus standard dose (DS) cisplatin (CDDP) and cytoxan (CTX) in advanced ovarian cancer (AOC). Proc Am Soc Clin Oncol 11:226, 1992 (abstr 718) 2 29. Kaye SB: High dose cisplatin (100 mg/m ) is more effective 2 than low dose (50 mg/m ) in combination with cyclophosphamide (750 mg/m 2) for the treatment of advanced ovarian cancer. Proc Am Soc Clin Oncol 11:226, 1992 (abstr 717) 30. Conte PF, Bruzzone M, Chiara S, et al: A randomized trial
comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer. J Clin Oncol 4:965-971, 1986 31. The Ovarian Cancer Meta-Analysis Project: Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin and cisplatin chemotherapy of ovarian carcinoma: A meta-analysis. J Clin Oncol 9:1668-1674, 1991 32. Sessa C, D'Incalci M, Colombo N, et al: Lack of activity of cyclophosphamide in ovarian cancer patients refractory to cisdichlorodiammine platinum. Cancer Chemother Pharmacol 11:3334, 1983 33. McGuire WP, Blessing JA, Berman ML: A phase II study of esorubicin (4'deoxydoxorubicin) in advanced epithelial carcinoma of the lung. Invest New Drugs 7:333-336, 1989 34. Hakes TB, Daghestani AN, Dougherty JB, et al: Phase II study of 4-demethoxydaunorubicin in advanced ovarian carcinoma. Cancer Treat Rep 69:559-560, 1985
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
hope in the late 1970s that THERE WAS GREAT progress achieved with the individual
the apparent modalities of surgery, chemotherapy, and radiotherapy (RT) could be combined in an approach that would lead to the cure of patients with advanced epithelial ovarian cancer (EOC). Accordingly, in 1979 the Gynecology Tumor Group of our institution established a multimodality treatment policy for such patients using debulking surgery, chemotherapy, and RT. The rationale for the development of such a protocol was based on the following facts and hypotheses, which were current at that time. Survival seemed to be related inversely to the volume of residual disease after surgery, and both chemotherapy and RT seemed to be more effective in the circumstance of minimal residual disease. Therefore, the concept of maximum tumor reduction, achieved if necessary by repeated operation, became fashionable.' The advent of cisplatin was particularly encouraging because occasional dramatic responses were observed in women with alkylating-agentresistant disease2 and because in previously untreated women, the rapidity of response and the response rate were greater than had been observed previously. Doxorubicin had shown second-line activity in those patients who underwent unsuccessful alkylating agent therapy;
therefore, it seemed logical to include it in the induction 3 chemotherapy regimen rather than cyclophosphamide. Histologic remissions were thought to be durable, and further treatment for such patients was thought not to be needed. 4 In contrast, it was recognized that all other patients needed additional therapy; therefore, maintenance chemotherapy might be beneficial. Although the role of RT in the treatment of advanced ovarian cancer
tamine) was administered to patients who did not have a documented histologic complete remission. Results: The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. Conclusions: Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease. J Clin Oncol 10:1561-1568. © 1992 by American Society of Clinical Oncology.
remained uncertain, there was evidence that gross but localized disease (eg, pelvic or paraaortic masses) and small transperitoneal tumor aggregates might be sterilized by RT.5 Here we report the long-term outcome for the initial group who was treated according to this policy. In addition, we present the results of a multivariate analysis of prognostic factors. PATIENTS AND METHODS Patients
Patients had to have a histologic diagnosis of EOC confirmed on review by our institutional pathologists, be International Federation of Gynecology and Obstetrics stage III or IV, 6 and have had no prior irradiation or chemotherapy, no congestive cardiac failure or other serious illness that precluded treatment, a creatinine clearance of 40 mL/min or more, and a serum creatinine level of less than 1.5 mg/dL (133 pLmol/L). There were no age-related or performance status exclusion criteria. Patients with borderline tumors were excluded. The policy was initiated in April 1979. All 195 patients who were started on this treatment before December 1982 were included in this review. Their pretreatment characteristics are listed in Table 1. This protocol was institutional policy, and there were no competing
From Departments of Medical Oncology, Gynecologic Oncology, Leukemia/Bone Marrow Transplantation Program, and Radiation Oncology, British Columbia CancerAgency, Vancouver Clinic, Vancouver, Canada. Submitted February18, 1992; acceptedJune 10, 1992. Presented in part at the Annual Meeting of American Society of ClinicalOncology, March 1986 and May 1992. Address reprintrequests to PaulJ. Hoskins, FRCP, 600 W I Oth Ave, Vancouver, British Columbia, Canada V5Z 4E6. © 1992 by American Society of ClinicalOncology. 0732-183X/92/1010-0010$3.00/0
Journal of Clinical Oncology, Vol 10, No 10 (October), 1992: pp 1561-1568
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1561
1562
HOSKINS ET AL
Table 1. Patient Characteristics of the 195 Women With Advanced-Stage Epithelial Ova ran Cancer
Karnofsky performance status* 0 1 2 3 Stage Ill IV Grade 1 2 3 4 Unknown Residual disease Microscopic < 1 cm 1-2 cm > 2 cm Unknown Histology Serous Mucinous Endometrioid Clear cell Undifferentiated Age, years Median Range
68 100 16 11
35 51 8 6
148 47
76 24
10 30 112 23 20
5 15 57 13 10
7 13 5 157 13
4 6 3
141 5 5 2 42
80 7
intravenously (tV) every 3 weeks. Prehydralion and posthydration as well as mannitol diuresis were used without exception. Treatwas discontinued if there was evidence of progression or ment % ""No unacceptable toxicity. The dose of doxorubicin was adjusted as follows: if the bilirubin was greater than 1 mg/dL (17 ýpmol/L) but less than 3 mg/dL (51 limol/L), 50% was given. If it was more than 3 mg/dL, then 25% was given. The dosage adjustment for treatment-day neutropenia or thrombocytopenia was as follows: neutrophils over 1,500 and platelets greater than 125,000, full dose; neutrophils 1,000 to 1,499 or platelets 75 to 124,000, 80% dose, neutrophils 999 or less or platelets 74,000 or less, 50%. If mucositis occurred, the dose was reduced to 40 mg/m'. The cisplatin was decreased on the basis of the creatinine clearance: a creatinine clearance of more than 70 mL/min, full dose; 60 to 69 mL/min, 60%; 50 to 59 mL/min, 50%; 40 to 49 mL/min, 40%; 39 mL/min or less, treatment protocol discontinued. Reassessment 1. After the completion of the sixth cycle of doxorubicin-cisplatin, the patients were reassessed. Those patients who had no clinical evidence of disease were to continue on the doxorubicin-cisplatin regimen for at least three more cycles to 2 achieve a total cumulative dose of doxorubicin of 450 mgim . In contrast, those who had responded but still had persistent disease were considered for reoperation and/or RT. Repeat surgery was to
72
2.5 2.5 1
icto Cemontapy
22
-asm
59 27-85
"Eastern Cooperative Oncology Group.
Sn23
protocols. All eligible patients were to be treated on it. A record of eligible but nonpolicy-treated patients was not kept. During the course of the study, we saw 393 (58%) of the women diagnosed with any stage of EOC in the province. Not all patients were treated by us because we have a sister clinic on Vancouver Island. We saw approximately 80% of the patients in our catchment area. Written informed consent was given according to institutional policy.
Treatment
i2binii
FT~RI eo
2
!
e C~••
Response 5 nL;105 O
Noaparotomy
Initial sutgery and asses ment. The treatment schema is shown in Fig 1. The initial surgery usually was performed by either a community gynecologist or a general surgeon and not by a specialist gynecologic oncologist. The desired operative procedure consisted of total abdominal hysterectomy, bilateral salpingoophorectomy and omentectomy. thorough abdominal exploration (including undersides of diaphragm),. and washings on initial abdominal entry. Such an operation occurred in 24% of patients; 39%' had a lesser debulking procedure, and 37% had a biopsy only Reoperation on initial referral to our center was not performed The following standard prechemotherapy investigations were performed: chest x-ray, computed tomographic scan of the abdomen and pelvis, complete blood cell count, liver function tests, serum electrolytes, blood urea nitrogen and creatinine clearance, and 24-hour urine creatinine clearance Induarton chemotherapy rgmen. Ihe chemotherapy regimen used was doxorubicin 50 mg m' and cisplatin 50 mg/ m, both given
Chemotherapy2 eo*t7nr11
Laparatomy
*38
CR1
S
Response n eýn
.
SRT
n·S
i~~lsioiogm Complete Ipon se
Fisogl
L 82 (51
incomplete Response
NaFuRh TolnyR2
Fig 1. Treatment schema and number of patients at the different steps. (1) Doxorubicin and cisplatin every 3 weeks times 6; (2) doxorubicin and cisplatin every 3 weeks 2t 3; (3) cyclophosphamide/ hexamethylmelamine; (4) number in parentheses is the number of patients who did not get maintenance chemotherapy although eligible to do so; and (51 four patients were irradiated.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1563
ADVANCED EPITHELIAL OVARIAN CARCINOMA be performed in patients who responded and who initially had incomplete surgery, if it was anticipated that reoperation would accomplish a substantial reduction in the tumor bulk that remained. If there was clinically evident disease present that was limited to the pelvic or paraaortic nodal areas, RT was to be delivered at a dose of 40 Gy (central) in 4 weeks (20 fractions) by parallel pair, Both fields were treated daily A boost dose of 5 to 10 Gy in an additional week was allowed. After such patients completed their surgery or RT, they went on to receive additional doxorubicin-cisplatin therapy to achieve a total cumulative dose of doxorubicin of 450 mg/m'. The doxorubicin was reduced to 40 mg mI for the first cycle after RT. Progressors went off protocol and were treated at their physician's discretion. Reassssment 2. This was performed at the end of the induction chemotherapy. Patients who had no clinical evidence of disease were to undergo a laparotomy to confirm their remission status. Those who had achieved a histologic complete response (CR) were offered no further therapy. If laparotomy was not performed or if anything other than a histologic CR was documented, then further treatment was offered. Those patients who were not irradiated previously and who had clinically evident disease that was thought to be amenable to RT might receive irradiation as described under Reassessment 1. A second group of patients was also to be irradiated. A our experience with RT increased, we recognized that the acute toxicity was minimal and that whole-abdominal treatment could be used in addition to the pelvic irradiation. Therefore, our initial policy was modified. Those patients who either were presumed to have subclinical intraperitoneal disease (in practice those patients in complete clinical response ICCR] who refused reassessment surgery) or had minimal disease documented at second surgery despite having entered a C(CR were now to be treated. In these patients, treatment to the pelis was by parallel rather than by isocentric anterior-posterior fields, usually 17 cm by 17 cm, that were designed to extend 1 to 2 cm below the obturator foramina, 1 to 2 cm beyond the lateral limits of the true pelvis, and superiorly to the L5-U1 interspace. Field margins represented the 50% isodose. The dose prescribed was 22.5 Gy in 10 fractions during a 2-week period Whole-abdominal RT then continued immediately by an extended source skin distance (usually 130 cm) anterior-posterior parallel opposed pair Anatomical posterior renal shielding was used to reduce the dose to the kidney to 15 Gy. Fields were used to encompass all surfaces of the abdominal cavity including the highest points of the diaphragm during quiet respiration. The lower field margins were at the level of the previous pelvic field's inferior margins. Shielding material generally was used to trim the corners. Shaping of the diaphragm fields was accomplished with curved (errobend blocks The nominal central whole abdominal dose was 22.5 Gy in 22 fractions during a 4,5-week period. All fields were treated daily by a 4 MV linear accelerator. Patients with anything less than a documented histologic CR then went on to receive maintenance therapy with oral cyclophosphamide (100 mg orally daily) and hexamethylmelamine (altretamine, 200 mg orally daily), both for 14 days of every 28 for up to 2 years. Response Assessment A CCR was defined as the complete absence of disease on clinical and imaging examination at the end of chemotherapy, whereas a partial clinical response (PCR) was a greater than 50% decrease in the sum of the products of the perpendicular diameters
of all the measurable bidimensional lesions or, if only unidimensionally measurable lesions were present, then a greater than 50% decrease in the sum of their diameters. Patients with no clinically evident disease after their initial surgery and who did not progress during the chemotherapy were classified as CCRs. Progressive disease was the development of new lesions, ascites, or effusions or a 2.5% increase in diameter of any lesion. A histologic CR was the absence of any disease at surgery, which included washings and random biopsy procedures. Histologic partial response (PR) was a reduction of 50% or more in the total tumor burden compared with that left at end of the primary laparotomy. Patients who grossly were negative but who had microscopic positivity were classified as PCRs.
StatisticalMethods Patient follow-up is ongoing. Information on all patients was available as of September 1991. Date of last follow-up and status at that time (dead of ovarian cancer, dead of other causes with or without ovarian cancer present, alive in continued first remission, alive with ovarian cancer present) were recorded. No patient had an unknown status at last follow-up or had been lost to follow-up. Survival was presented both as overall survival (OS; all deaths included) or failure-free survival (FFS; failure means either primary progression, relapse, or death from toxicity). Survival curves were calculated by the product-limit Kaplan-Meier method. The effect of potential prognostic factors was examined initially by the log-rank test. Cox proportional hazards analysis was then used (on all of the variables) for the multivariate analysis.8
RESULTS Clinical Response Rates
Clinical response rates were assessed at the completion of the doxorubicin-cisplatin chemotherapy. Thirty patients (15%) were primary progressors, 20 (10%) had stable disease, 40 (21%) had a PR, and 105 (54%) had a CR. Histologic Response Rates
Reassessment laparotomy was performed on 67 of the 105 patients who were assessed as having entered a CCR and who were scheduled to have it according to the protocol. Thirty-two had a histologic CR, 17 had microscopic residual, and 18 had macroscopic residual. Twenty (63%) of the histologic CRs have relapsed, and their 10-year FFS was only 31% (Fig 2). Survival Actual OS at 2, 4, 6, and 8 years was 46%, 21%, 13%, and 9%, respectively (Figs 3 and 4). The 10-year actuarial survival was 4%. Median OS was 24 months. The minimum follow-up of the survivors (10 of 195) was 8 years; the maximum was 11 years (median, 10.5 years). FFS (actual) at 2, 4, 6, and 8 years was 32%, 13%, 10%, and 8%, respectively, with a 10-year actuarial rate of
8%.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1564
.
HOSKINS ET AL
1.00
1.00
0.75
>, 0.75 0,
a- 0.50
a- 0.50
c) 0.25
C)
0.25
0
0 0
2
4
6
8
10
0
2
Years Fig 2.
4
6
8
10
Years
FFS for patients with a histologic CR (n = 32).
ChemotherapyDelivery Information on the total delivered dose of cisplatin was available for 159 (82%) patients. The median dose was 343 mg/m2 (range, 0 to 664). Similarly, for doxorubicin (n = 166; 85%) the median dose was 394 mg/m2 (range, 0 to 550 mg). Increasing age, analyzed in 10-year increments, did not diminish our ability to deliver the chemotherapy except in the group of patients 76 years of age or older. Only eight patients were in this age group, and their median dose of cisplatin was 231 mg (range, 50 to 380) and doxorubicin was 296 mg (range, 196 to 377). OS was compared within increasing deciles of the total administered dose of either doxorubicin or cisplatin for all patients except progressors. They were excluded because, a priori, they were taken off treatment early, and thus received a decreased total dose. No
1.00
Fig 4.
FFS for all patients (n = 195).
significant survival benefit was demonstrated for increasing total dose by decile of either doxorubicin or cisplatin (P = .713 and .599, respectively). ChronicChemotherapy Toxicity Functionally significant cardiomyopathy occurred in nine patients (4.6%). There were no toxic deaths. There was no formal reporting of whether neuropathy or ototoxicity was present or absent. Chronic renal dysfunction was not assessed. MaintenanceChemotherapy Eighty-two patients received maintenance therapy with cyclophosphamide-hexamethylmelamine and another 43 patients were given this therapy when they progressed or relapsed. Of these 125 patients, 75 had assessable disease; only one CR and one PR (total response rate 3%) were obtained. RT and Survival It is difficult to assess the effect of the RT because it was given in two different situations: to those patients with clinically evident disease present despite chemotherapy and to those who had entered a CCR. Additionally, the extent of RT varied; 52% received pelvic and/or paraaortic nodal irradiation, and the remainder received pelvic-abdominal irradiation. Figure 5 contrasts the OS for the three different groups of RT patients. Group-1 patients had clinically evident disease. Group-2 patients had achieved a CCR
Z, 0.75 .0
0- 0.50 C) 0.25
0
0
2
4
6
8 10 Yearsreassessment (n = 195). faoi l patients Fig a. OS
u ul tI, A:d 14, H V u1 IIUL uIIlCn
t1 ressCsbfflel tt;
su1geIy,
111
U.U4gtU, grIuI-J
1,
patients were also in CCR but had disease found at surgery. In addition, four patients who achieved a histologic CR were irradiated and are includ-
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1565
ADVANCED EPITHELIAL OVARIAN CARCINOMA • A_
"
1.00
.
"'
IV epithelial ovarian cancer. The 10-year OS and FFS were 4% and 8%, respectively. There was an apparent plateau for FFS after 8 years. Our survival figures matched those reported by Sutton et a19 for patients who were treated with cisplatin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclophosphamide in whom the OS at 10 years was 9%; 7% were considered disease-free. Similarly, Hainsworth et al10 using hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin reported that 18% of patients (10 patients) remained disease-free between 7 and 9 years from diagnosis. A meta-analysis of randomized trials reports a 7-year OS of 14%, which was
0.75
Ca
o 0 a 0.50
oJ 0.25
0
0
2
4
6
8
10
Years Fig 5. OS of patients who received irradiation subdivided by treatment group. Group 1, clinically evid ent disease after > 6 cycles chemotherapy (n = 37). No clinically evidlent disease after 2 9 cycles chemotherapy. Group 2, reassessmen t surgery not performed (n = 34). Group 3, reassessment surgery performed (n = 24).
ed in group 3. No significant sisurvival difference was found. Median survivals were 322, 24, and 24 months, respectively. Radiotherapy Toxicity Chronic bowel dysfunction (cr amps, malabsorption, and constipation/diarrhea) occu rred in eight (9%) of the irradiated patients. Three addditional patients developed bowel obstruction that requi red surgery. In none of these patients was the problem caused by tumor recurrence. Prognostic Variables The significance values obtained by the univariate analysis are listed in Table 2. Multivariate analysis identified residual disease of more than 2 cm after primary laparotomy as the only independent adverse prognostic factor for both OS (relative risk, 2.08; 95% confidence interval [CI], 1.22 to 3.54; P = .0033) and FFS (relative risk, 3.41; 95% CI, 1.81 to 6.41; P = .00012). The multivariate analysis was performed only on 128 (66%) of the patients who had complete information available on all the variables that were included in the analysis. DISCUSSION Our multimodality regimen of maximal surgery plus doxorubicin-cisplatin induction chemotherapy and, for selected patients, RT and maintenance chemotherapy was curative in less than 10% of patients with stage III or
2 identical to ours.'1 In contrast, Neijt et a11 achieved a
21% 10-year survival for patients who were treated with cisplatin-based chemotherapy. Patient selection could
well account for the difference between our results and those reported by Neijt et al. In our multivariate analysis, the only independant adverse prognostic factor was residual disease that measured more than 2 cm after
primary laparotomy. Eighty percent of the patients in our study had a greater than 2 cm residual disease, in contrast to the 56% reported by Neijt et al.13,14 Even though our stated aim was to use maximal surgery, this in practice did not happen. Only 24% of our patients had such surgery at diagnosis, and another 28% had tumor reduction surgery after six cycles of chemotherapy. Whether our results would have been better if more patients had such surgery we cannot say. The amount of residual disease after primary laparotomy was a prognostic factor, but whether it was the surgical debulking or whether it was the ability of the cancer to be debulked (ie, the biology of the cancer) that was important was not clear. Only a randomized study that Table 2. Univariate Analysis of Adverse Prognostic Factors
for Survival Factor
Weight loss Karnofsky performance status Residual disease Initial surgery Age, years Stage Ascites Histology Grade
OS
FFS
P
P
> 20v 10-19 v < 101b 1,2,3 v 0
.0032
.0018
.0037
.023
> 2 v < 2 cm Incomplete v complete* > 65 v 56-65 v < 56 IVv 111 Present v absent Serous v other 3v2
.008 .0051 .0063 .22 .69 .066 .96
.001 .0018 .11 .24 .50 .23 .72
Comparison
Abbreviations: OS, overall survival; FFS, failure-free survival. *Complete: total abdominal hysterectomy, bilateral oophoredomy, and omentedomy.
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1566
HOSKINS ET AL
compared chemotherapy alone to chemotherapy and maximal surgery would enable us to delineate the role of the surgery. Until this is settled, we recommend that surgeons experienced in the surgery of ovarian cancer perform the operations with the intent of maximal debulking. Our multivariate analysis of prognostic variables identified the size of the residual cancer as the only independent prognostic factor. This contrasts with two other reports in which long-term follow-up is available. 15 ,16 In both of these, performance status, stage, and the presence of ascites as well as residual tumor were independent predictors. Additionally, grade and treating hospital were important in the Dutch analysis, 15 and cell type, age, measurable disease, tumor volume, and cisplatin chemotherapy were independent predictors. As to why in our study only residual disease was important we cannot explain definitively. However, it was probably a reflection of the lesser power of our analysis because of our smaller patient numbers (n = 126). In addition to providing 10-year survival data, does our experience provide any additional information of value to physicians treating advanced ovarian cancer? We believe that it does. There was no evidence that the addition of RT to platinum-based chemotherapy was beneficial. This conclusion is based on two lines of evidence. First, RT was used in two different situations: in patients with clinically measurable disease that persisted during chemotherapy, and in patients who had entered a CCR after chemotherapy. We would have expected the latter group to have fared better given their lesser apparent tumor burden. However, there was no OS difference, and the median survivals were similar at 32 and 24 months. The group with clinically evident disease had the longer median survival. Second, our survival figures (whether median, 5-year, or 7-year) were similar to those achieved by combination chemotherapy alone.9-14"17 We must stress that our study was not randomized, and thus our data cannot be interpreted as being conclusive. In retrospect, we could be criticized for not administering RT to the group of patients who might be expected to benefit the most, ie, those with a histologic CR, but a review of the literature did not provide supporting evidence for this assumption. Relapses were common (approximately 22%) in such patients who were treated with RT, and this was with a short follow-up.18-20 This was similar to the rate observed in patients who were treated with chemotherapy alone.13 Additionally, RT added substantially to the morbidity of the treatment. Nine percent of our irradiated patients
developed chronic bowel dysfunction, and another 3% needed surgery for bowel obstruction. In all of them it was unrelated to tumor recurrence. Maintenance chemotherapy with cyclophosphamide and hexamethylmelamine did not seem to be beneficial. Our survival figures were similar to those obtained with regimens that did not use such maintenance therapy. For those patients with assessable disease who were given these drugs, the response rate was only 3%, a level of activity that suggests no clinical use. This confirms the low response rate (2%) observed in similarly treated patients in a multicenter Canadian trial. 21 This lack of response to hexamethylmelamine contradicted the results observed in some but not all of the studies of patients with recurrent cancer postcisplatin in which 22 24 response rates from 0% to 25% have been found. We believe that this difference in response rates can be explained by the postulate that hexamethylmelamine and cisplatin are crossresistant agents. Most of our patients were given altretamine because of persistent cancer despite nine or more cycles of cisplatin and doxorubicin, ie, they were truly resistant. In contrast, relapsed patients may still be sensitive to cisplatin and, by inference, hexamethylmelamine. Therefore, response rates will vary depending on the mix of resistant and relapsed patients in the study. Our belief that histologic CRs were durable was not confirmed. Sixty-three percent of our patients who had a histologic CR relapsed during the 10-year period. This confirmed the results of the study by Neijt et al, in which there was a 61% relapse rate. 12 Can we postulate any reasons for our poor long-term results? The concept of dose-intensity is currently in vogue. A meta-analysis that defines dose-intensity as milligrams per meters squared per week of ideal dose has shown a slight improvement in response rates and survival with increased cisplatin intensity. 25 Our target cisplatin dosage of 50 mg/im2 every 3 weeks is not intensive. However, the question whether dose-intensity is important is far from settled. Retrospective metaanalyses (flawed by using ideal and not given doseintensities and insensitive to differences in prognostic characteristics) are not definitive. Those randomized studies that try to define the importance of dose intensity are contradictory in their results with the majority not demonstrating benefit 26-28 and one showing an early survival advantage. 29 Another possible explanation is that we used too few drugs in our combination. Randomized studies so far do not confirm that the use of a larger number of drugs is better,17,30 and cisplatin alone may well be as effective.' 7
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1567
ADVANCED EPITHELIAL OVARIAN CARCINOMA
However, in both of these studies, although not significant, there was a trend for patients on the triple-drug regimens to have improved long-term survival. A metaanalysis that included these two trials has demonstrated a significant survival advantage for the triple-drug regimen of cisplatin, cyclophosphamide, and doxorubicin compared with cisplatin and cyclophosphamide. 31 We believe that our long-term results are disappointing not only because of either too low a dose-intensity or that too few drugs were used but because drug resistance is present, and the currently available drugs are crossresistant. There is no doubt that the advent of cisplatin was a major advance, doubling the median and 5-year
survivals compared with noncisplatin therapy. 14 Unfortunately, anthracyclines and cyclophosphamide are crossresistant with cisplatin, as demonstrated by their ineffectiveness when given to patients who relapse from or are resistant to cisplatin.32-34 The ineffectiveness of the cyclophosphamide-hexamethylmelamine in this study is further evidence for this. We believe that new drugs that are noncrossresistant to cisplatin are needed before any meaningful improvements in the survival of patients with advanced EOC are observed. We must add a caveat to this conclusion. Much of the dogma of the 1970s was wrong. Who is to say that the dogma of the 1990s will fare any better?
REFERENCES 1. Tobias JS, Griffiths CT: Management of ovarian carcinoma. Current concepts and future prospects. N Engl J Med 294:818-823, 1978 2. Wiltshaw E, Kroner T: Phase II study of cis-dichlorodiammineplatinum (II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat Rep 60:55-60, 1976 3. de Palo GM, de Lena M, di Re F, et al: Melphalan versus Adriamycin in the treatment of advanced carcinoma of the ovary. Surg Gynecol Obstet 141:899-902, 1975 4. Young RC, Chabner BA, Hubbard S, et al: Advanced ovarian adenocarcinoma: A prospective clinical trial of melphalan (LPAM) versus combination chemotherapy. N Engl J Med 299:12611266, 1978 5. Rubin P: Understanding the problem of understaging in ovarian cancer. Semin Oncol 2:235-242, 1975 6. Petterson F, Kolstad P, Ludwig H, Ulfeder H (eds): Annual report on the results of treatment in gynecological cancer, vol 19. Stockholm, Sweden, International Federation of Gynecology and Obstetrics, 1985, p 211 7. Oken MM, Cuech RH, Toormey DL, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655 1982 8. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980 9. Sutton GP, Stehman FB, Einhorn LH, et al: Ten-year follow-up of patients receiving cisplatin, doxorubicin, and cyclophosphamide chemotherapy for advanced epithelial ovarian carcinoma. J Clin Oncol 7:223-229, 1989 10. Hainsworth JD, Grosh WW, Burnett LS, et al: Advanced ovarian cancer: Long-term results of treatment with intensive cisplatin-based chemotherapy of brief duration. Ann Int Med 108:165-170, 1988 11. Advanced Ovarian Cancer Trialists Group: Chemotherapy in advanced ovarian cancer: An overview of randomised clinical trials. Br Med J 303:884-893, 1991 12. Neijt JP, ten Bokkel Huinink WW, van der Burg MEL, et al: Long term survival in ovarian cancer. Eur J Cancer 27:1367-1372, 1991 13. Neijt JP, ten Bokkel Huinink WW, van der Burg MEL, et al: Randomized trial comparing two combination chemotherapy regimens (CHAP-5 vCP) in advanced ovarian carcinoma. J Clin Oncol 5:1157-1168, 1987
14. Neijt JP, ten Bokkel Huinink WW, van der Burg MEL, et al: Randomized trial comparing two combination chemotherapy regimens (HEXA-CAF v CHAP-5) in advanced ovarian carcinoma. Lancet 2:594-600, 1984 15. van Houwelingen JC, ten Bokkel Huinink WW, van der Burg MEL, et al: Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol 7:769-773, 1989 16. Omura GA, Brady MF, Homesley HD, et al: Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: The Gynecologic Oncology Group experience. J Clin Oncol 9:1138-1150, 1991 17. Gruppo Interregionale Cooperativo Oncologico Ginecologia: Randomized comparison of cisplatin with cyclophosphamide/ cisplatin and with cyclophosphamide/doxorubicin/cisplatin in advanced ovarian cancer. Lancet 2:353-359, 1987 18. Shelley WE, Starreveld AA, Carmichael JA, et al: Toxicity of abdominopelvic radiation in advanced ovarian carcinoma patients after cisplatin/cyclophosphamide therapy and second-look laparotomy. Obstet Gynecol 71:327-332, 1988 19. Kuten A, Stein M, Stiner M, et al: Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma. Int J Radiat Oncol Biol Phys 14:273-279, 1988 20. Goldhirsch A, Greiner R, Dreher E, et al: Treatment of advanced ovarian cancer with surgery, chemotherapy and consolidation of response by whole abdominal radiotherapy. Cancer 62:40-47, 1988 21. Pater JL, Carmichael JA, Krepart GV, et al: Second-line chemotherapy of stage III-IV ovarian carcinoma. A randomized comparison of melphalan to melphalan and hexamethylmelamine in patients with persistent disease after doxorubicin and cisplatin. Cancer Treat Rep 71:277-281, 1987 22. Stehman FB, Ehrlich CE, Callangan MF: Failure of hexamethylmelamine as salvage therapy in ovarian epithelial adenocarcinoma resistant to combination chemotherapy. Gynecol Oncol 17:189-195, 1984 23. Rosen GF, Lurain JR, Newton M: Hexamethylmelamine in ovarian cancer after failure of cisplatin-based multiple agent chemotherapy. Gynecol Oncol 27:173-179, 1987 24. Moore DH, Fowler WC, Jones CP, et al: Hexamethylmelamine chemotherapy for persistent or recurrent epithelial ovarian cancer. Am J Obstet Gynecol 165:573-576, 1991 25. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 5:756-767, 1987
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1568
HOSKINS ET AL
26. Colombo N, Pittelli MR, Marzola M, et al: Randomized study of two cisplatin(P) dose-intensity regimens in patients with stage III/IV epithelial ovarian cancer (EOC). Proc Am Soc Clin Oncol 9:160, 1990 (abstr 619) 27. Menczer J, Brenner J, Modan M, et al: A comparison of low and high dose cisplatin-based combination chemotherapy as initial postoperative treatment in advanced ovarian adenocarcinoma. Am J Obstet Gynecol 155:974-979, 1986 28. McGuire WP, Hoskins WJ, Brady MS, et al: A phase II trial of dose intense (DI) versus standard dose (DS) cisplatin (CDDP) and cytoxan (CTX) in advanced ovarian cancer (AOC). Proc Am Soc Clin Oncol 11:226, 1992 (abstr 718) 2 29. Kaye SB: High dose cisplatin (100 mg/m ) is more effective 2 than low dose (50 mg/m ) in combination with cyclophosphamide (750 mg/m 2) for the treatment of advanced ovarian cancer. Proc Am Soc Clin Oncol 11:226, 1992 (abstr 717) 30. Conte PF, Bruzzone M, Chiara S, et al: A randomized trial
comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer. J Clin Oncol 4:965-971, 1986 31. The Ovarian Cancer Meta-Analysis Project: Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin and cisplatin chemotherapy of ovarian carcinoma: A meta-analysis. J Clin Oncol 9:1668-1674, 1991 32. Sessa C, D'Incalci M, Colombo N, et al: Lack of activity of cyclophosphamide in ovarian cancer patients refractory to cisdichlorodiammine platinum. Cancer Chemother Pharmacol 11:3334, 1983 33. McGuire WP, Blessing JA, Berman ML: A phase II study of esorubicin (4'deoxydoxorubicin) in advanced epithelial carcinoma of the lung. Invest New Drugs 7:333-336, 1989 34. Hakes TB, Daghestani AN, Dougherty JB, et al: Phase II study of 4-demethoxydaunorubicin in advanced ovarian carcinoma. Cancer Treat Rep 69:559-560, 1985
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
