High-Dose, Short-Duration Cisplatin/

Doxorubicin Combination Chemotherapy

for Advanced Ovarian Epithelial Cancer
Richard E. Hunter, MD,* Thomas W. Griffin, MD,t
Sarah Stevens, MD,t Lynda D. Roman, MD,* Faran Bokhari, PhD,t
Frank R. Reale, MD,$ Won K. Tak, MD,§ T. J. Fitzgerald, MD,§
Michael B. Dillon, MD,* and Peter G. Rose, MD*

Sixty-one patients with epithelial ovarian cancer were treated with intensive high-
dose, short-course chemotherapy that consisted of cisplatin (120mg/m') and
doxorubicin (70 mg/m') every 3 weeks for four cycles. Patients in complete clinical
remission were offered second-look laparotomy (SLL). Patients with minimal or no
residual disease at SLL were randomized to either cyclophosphamide (1000 mg/m2
every 21 days for six cycles) or whole-abdominal radiation therapy. All patients
completed therapy with a median leukocyte nadir 1,3/p1 and platelet nadir of 9O/p1.
Forty-five patients (74%) had a complete clinical response. Results of twenty-two of
36 second-look procedures (64%) showed no evidence of disease (NED). After SLL,
19 patients received six courses of cyclophosphamide and 16 patients received
whole-abdominal radiation. Nine patient who refused SLL and one patient with
negative SLL findings refused additional treatment. The median survival time for
all patients was 51.3 months. High-dose intensive chemotherapy regimens have
high response rates, but survival needs to be compared with traditional low-dose
regimens. Although high-dose cisplatin and doxorubicin were myelosuppressive,
the resulting complications were manageable. There was no significant difference
between the mean survival times of patients receiving Cytoxan, abdominal
radiation, or no treatment as second-line therapy. Cancer 68:1890-1894,1991.

D ESPITE RECENT ADVANCES, epithelial Carcinoma O f

the ovary remains the leading cause of death among
'
gynecologic malignancies. The introduction of cisplatin-
based combination chemotherapy has led to increases in
response rates, complete response rates, and median du-
ration of survival in patients with advanced (Stages I11
and IV) ovarian cancer. However, the number of disease-
From the Departments of *Obstetrics and Gynecology, Division of
Gynecologic Oncology, ?Medicine, Division of Oncology, $Pathology,
and §Radiation Therapy, University of Massachusetts Medical Center.
Worcester, Massachusetts.
The authors thank Joyce Sirois, RN; Janet H. Hagstrom for coordi-
nating and typing the manuscript: JefY Collins for technical assistance;
and all investigators and patients who participated in this study.
Address for reprints: Richard E. Hunter, MD, Department of Obstetrics
and Gynecology, University of Massachusetts Medical Center, 55 Lake
Avenue North, Worcester, MA 01655.
Accepted for publication August I , 1991.
free long-term survivors has remained disappointingly
smalL2 Therefore, new therapeutic strategies for this dis-
ease are urgently needed. The optimal agent or agents,
timing of administration, optimum dose, and optimal
duration of therapy is yet to be determined.
The importance of drug dose in determining tumor
response to chemotherapy has been frequently ~tressed.~-~
Clinical trials have shown a clear dose-response effect with
cisplatin.6 However, few studies have been performed to
determine the effect of high-dose intensity and short-du-
ration chemotherapy as a possible determinant of out-
come. To evaluate such a dose-response in advanced
ovarian cancer, this study was designed to investigate high-
dose, short-duration cisplatin/doxorubicin combination
chemotherapy with early second-look laparotomy (SLL).
The patients with minimal or no residual disease after
SLL were randomized to high-dose cyclophosphamide or
whole-abdominal radiation.

1890
No. 9 HIGH-DOSE
ClSPLATIN/DOXORUBlCININ OVARIAN CA - Hwzter 6't d. 1891

Materials and Methods TABLEI. Patient Profle

From 1985 to 1988,6 I patients with epithelial ovarian No. of patients 61

cancer Stages IC to IV who treated at the University of
Massachusetts and affiliated hospitals were entered in a
prospective study. All patients initially had maximum cy-
toreductive surgery. After pathologic confirmation of an
invasive epithelial ovarian carcinoma, patients were in-
vited to participate in this institutionally approved study.
Within 14 days of surgery, chemotherapy consisting of
cisplatin ( I20 mg/m2) and doxorubicin (70 mg/m') was
administered every 2 1 days for four cycles. Because of the
dose-intensity of cisplatin, patients were carefully hy-
drated. Patients were prehydrated with 6 1 of normal saline
over 24 hours. Cisplatin was then administered in 6 1 of
normal saline over the second 24-hour period. Patients
then received an additional 6 1 of normal saline posthy-
dration over the third 24-hour period. Doxorubicin was
given as a bolus injection. Antiemetic coverage was rou-
tinely provided with haloperidol, phenobarbitol, and
dexamethasone. Patients received full supportive care in-
cluding transfusion of blood products, antibiotics, and
nutritional support when appropriate. Doses were not
modified for myelosuppression or gastrointestinal toxicity.
All patients without clinical evidence of disease at the
completion of chemotherapy were offered SLL to deter-
mine the extent of response. Patients with residual disease
less than 2 cm or no disease at SLL were offered random-
ization to either high-dose cyclophosphamide or total-ab-
dominal radiation therapy. Patients with residual disease
of 2 cm or greater at SLL were removed from study. Cy-
clophosphamide was administered as outpatient therapy
at 1 g/m' every 2 I days for six cycles. Patients randomized
to radiation therapy received 3000 cGy to the whole ab-
domen followed by a pelvic boost of an additional 2000
cGy. Figure I outlines the basic scheme of the treatment
plan. Patient survivals were compared by the Mantel-
Cox statistic.
BASIC SCHEMA OF THE TREATMENT PLAN
Maximal Surgery
Age range (yr) 32-73
Mean age (yr) 53
Median age (yr) 56
Stage 1 1
Stage II 6
Stage 111 41
Stage IV 7
Total 61
Results
Putient Prof2le
Sixty-one previously untreated patients with epithelial
ovarian cancer were originally entered in the study. Patient
eligibility required a histologically documented epithelial
carcinoma of the ovary, no previous or concomitant ma-
lignancy, Eastern Cooperative Oncology Group ( ECOG)
performance status of 0 to 2, and informed consent. Pa-
tient profile and and pathologic condition are shown in
Tables 1 and 2, respectively. Two patients were evaluable
only for toxicity because one died of renal failure during
the first course of chemotherapy and the second died of
septicemia after the fourth course of chemotherapy.
The majority of patients had a poorly differentiated
serous cystadenocarcinorna. There were 47 Stage 111 pa-
tients and 7 Stage IV patients. The majority of Stage IV
patients were classified in that stage because of cytologi-
cally malignant pleural effusions. Forty-two patients (69%)
had their tumors cytoreduced to less than 2 cm, and 19
patients ( 3 1%) had residual tumors greater than 2 cni after
the initial operation.
Toxicity
The myelosuppression and toxicity associated with the
cisplatin/doxorubicin regimen is shown in Tables 3 and
4. Thirty-eight patients (60%) experienced nausea and
vomiting. The median nadir leukocyte count was 1.3/pl
for all the cycles administered. A mean nadir leukocyte

4
\
Cycles of Cisplatinum (120 mum2) TABLE2. Pathologic Condition
and Adriamycin (100 mum2)
Histologic grade
\ Second-look Laparotomv
Well differentiated
Moderately differentiated
Poorly differentiated
6
9
46

/ \'
Residual Disease <2 cm Residual Disease >2 cm
Total
T u m o r histologic condition
Mucinous cystadenocarcinoma
61

3
Oft Study Serous cystadenocarcinoma
/\
41
Endometrioid adenocarcinorna 4
Clear cell 4
Cyclophospharnide Total Abdominal Radiation Mixed tumor 2
(1.000 rng/m2 x 6)
Undifferentiated adenocarcinoma 7
Total 61
FIG. 1. Basic scheme of the treatment plan
1892 November 1 1991
CANCER Vol. 68

TABLE3. Myelosuppression and Nephrotoxicity of TABLE5. Long-Term Survivor Characteristics*

the Cisplatin/Doxorubicin Regimen
Initial surgery
Nadirs Mean Medians
No. of patients No. of long-term survivors
Leuk ( ~ 1 ) 1.7 k 1.2 I .3 Residual disease (%) (”/.)
Plt (PI) 122 t 118 90.0
HGB (g/dl) 9.7 i 1.5 9.8 <2cm 42 (69) 23 (54)
HCT (%) 28.8 t 4.7 28.8 >2cm 19 (31) 6 (31)
Peak creat (mg/dl) 1.1 k 0.5 0.9 Total 61 29 (47)

Leuk: leukocyte count X 100 units. Plt: platelet count X 1000 units; Second-look surgervt
HGB: hemoglobin: HCT. hematocrit; Creat: creatinine.
NED$ 22 (61) 16 (73)
Microscopic 3 (8) 0 (0)
count of 1.9/pl or less was associated with 69% of the Macroscopic (cm)
< 2-6
courses. Thirty-two patients were admitted to the hospital > 2-5 1 1 (31) 1 (9)
with documented leukopenia, and seven patients had Total 36 17
documented septicemia. There was one death due to sep-
NED: no evidence of disease.
ticemia. * Survival z 40 months.
Significant thrombocytopenia was seen with a median t Forty-five eligible for second-look laparotomy, 9 refused operations.
nadir platelet count of 9O/pl. Forty-four percent of the $ Two laparoscopies.
courses were associated with nadir platelet counts of less
than 25/p1. The thrombocytopenia was successfully man-
aged with platelet transfusions and was not associated with after initial surgery (Table 5). Of the positive second-look
any mortality. Twenty-six patients were admitted to the results, three were microscopic, six had less than 2 cm of
hospital for packed erythrocyte transfusions. Nephropathy tumor, and five had greater than 2 cm of tumor.
was evident from serum creatinine levels of greater than
1.5 mg/dl associated with 10%ofthe cisplatin/doxorubicir. Patient Survival
courses. One patient died of renal failure.
There were 29 long-term (greater than 40 months) sur-
Peripheral neuropathy was a problem with morbidity.
vivors (49%). One was Stage I (3%), four were Stage I1
Twenty-seven patients (46%)had symptoms of peripheral
(14%), 20 Stage 111 (68%), and 4 Stage IV (1 3%) (Table
neuropathy. The majority were mild to moderate, with
6). The long-term survival rate of Stages I and I1 patients
limitations in buttoning buttons and some limitations of
was 7 1%, and the long-term survival rate of advanced
patient gait. Two patients (3%)were severely affected and
cases (Stages 111 and IV) was 46%. The effect of initial
required a walker or cane.
tumor debulking on patient survival is shown in Figure
2. The median survival time for patients debulked to less
Tumor Response
than 2 cm disease is 46.9 -t 3.7 months compare with
Forty-five patients (74%) had a complete clinical re- 22.5 t- 4.1 months for patients debulked to greater than
sponse. Thirty-six patients underwent second-look pro- 2 cm residual disease at initial surgery. A Mantel-Cox
cedures (34 laparotomies and 2 laparoscopies). Both pa- statistical test shows these survival times to be significant
tients who underwent a second-look laparoscopy showed to P = 0.006. Sixteen of the patients with negative SLL
no evidence of disease (NED). Nine patients refused a findings were long-term survivors, and this constitutes 55%
second-look operation. Twenty-two patients (63%) who of all long-term survivors. The patient survival curve for
underwent second-look procedures showed NED. Of
these, 19 (86%) had their tumors cytoreduced to less than
2 cm and 3 (14%) had residual tumors greater than 2 cm TABLE6. Long-Term* Survivor Characteristics
~~ ~

No. of Refused Neg Mic Mac LTS

TABLE4. Myelosuppression and Nephrotoxicity of the Cisplatin/ Stage patients CCR SLL SLL SLL SLL SLL (%)
__
Doxorubicin Regimen: Patient Distribution
I 1 1 1 0 1 0 0 l(38)
Nadir leukocyte Nadir platelet count Peak creatinine level I1 6 5 4 1 3 0 1 4(14)
111 46 34 28 6 18 2 9 20(68)
count mb) IV 6 5 3 2 1 1 1 4(13)
> 4.0 (8) > 100 (44) > 1.2 (15) Total 59 45 36 9 22 3 11 29(49)
3.0-3.9 (6) 75-99 (12) > 1.5 (10)
2.0-2.9 ( I 8) 50-74 ( 1 4) CCR: complete clinical response; SLL: second-look laparotomy-lap-
1.0-1.9 (35) 25-49 (16) aroscopy; Neg: no evidence of disease; Mic: microscooic disease: Mac:
< 1.0 (33) < 25 (14) macroscopic disease; LTS: long-term survivors.
* Survival 1 40 months.
No. 9 HIGH-DOSE
CISPLATIN/DOXORUBICIN
IN OVARIAN CA Hurztev el a/. 1893

--2cm
---_ >2cm
Median Suwival:51.3 Months p c 0.006
0 , 0 , , , ~ ! ~ 3 - \ ~ 5 ~ ! '
J ' J , J , l ' I ' I ' I ' I
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
Months Months

FIG.2. Patient survival by initial tumor debulking. FIG.4. Patient survival by second-look laparotomy results.

all patients is shown in Figure 3. The median survival months after the start of chemotherapy. Cisplatin/doxo-
time for the patients was 5 1.3 months. Survival as a func- rubicin was chosen for the combination because of our
tion of second-look procedure results are shown in Figure previous successful experience with these drugs and be-
4 (P= 0.0012). cause we wished to reserve cyclophosphamide, an agent
with significant activity in ovarian cancer, for use
Discussion after SLL.
To preserve dose-intensity, the chemotherapeuticdrugs
Levin and Hryniuk7 recently emphasized the impor- were repeated at full doses despite the severe myelosup-
tance of dose-intensity in the outcome of therapy in pa- pression produced (Tables 3 and 4). Thirty-two patients
tients with ovarian cancer. The average relative dose-in- (48%)required at least one hospitalization for leukopenia
tensity (mg/m2/week)correlated significantly with clinical and fever, and seven patients had documented septicemia.
response and median survival time. Our group had pre- One patient died of septicemia after the fourth course of
viously noticed the ability of a high-dose combination of chemotherapy. The degree of myelosuppression seen with
cisplatin and doxorubicin' to induce rapid clinical re- this drug combination (cisplatin [ 120 mg/m2] and doxo-
missions in a large fraction of patients with advanced rubicin [70 g/m2]) exceeded the myelosuppression seen
ovarian cancer. Therefore, in this current trial, we ex- with our previous combination (cisplatin [ 100 mg/m2]
amined the ability of cisplatin/doxorubicin given at high- and doxorubicin [70 g/m2]) despite the minor difference
dose intensity for four cycles to produce surgically con- in platinum dose.* The cisplatin was given as a 24-hour
firmed tumor regression. Tumor response was assessed continuous infusion, sandwiched in 72 hours of aggressive
by an early SLL that was performed approximately 4 saline hydration. Nausea and vomiting, although frequent
(62%), were well controlled with aggressive sedation and
antiemesis during the period of infusion. No patient with-
drew from therapy because of this side effect. Similar to
our previous experience with this drug schedule,' the
nephrotoxicity of high-dose cisplatin given with this degree
of hydration was minimal with the exception of one pa-
.- 0.6- tient who died during her first course of chemotherapy of
r
xe renal failure (Table 4).
In contrast, the greatest morbidity was seen with a sen-
a
p 0.4-
.-c
-3
-
---- NED
sory neuropathy that developed in 46% of patients. Severe
MICRO proprioceptive loss leading to difficulties in ambulation
5 0.2- _.-.- c 2 c m MACRO
0 ..,........ > 2 c m MACRO occurred in a small percentage of patients (3%). In all
p c 0.00005 patients the sensory neuropathy improved over time from
oi I cessation of cisplatin chemotherapy, although recovery
, ' , ' 1 ~ 1 ' 1 , 1 ~ 1 ~ 1 ' 1
0 10 20 30 40 50 60 70 80 90 100 was frequently partial and slow and taking from months
Months to years to improve. The most severely affected patients
FIG.3. Survival of the total patient population. had permanent symptoms.
1894 November 1 199 1
CANCER
In terms of tumor response, this treatment schedule
was extremely effective in the production of pathologic
complete responses (PCR) at the 4 months. For example,
in our previous study,' only six of the 50 entered patients
( I 2%) obtained a PCR confirmed at laparotomy. In the
current study of a comparable patient population in terms
of tumor stage, 22 of the 59 patients (37%) obtained a
PCR at SLL. This increase reflects both an increase in
PCR in patients undergoing SLL (22 of 36 patients versus
6 of 20 patients) and the percentage of entered patients
eligjble for SLL (44 of 59 patients [75%] ver.sus 29 of 50
patients [58%]).
This highly toxic chemotherapeutic regimen was suc-
cessful in increasing the median survival time of all the
patients from 28 months in our previous study' to 40
months in this study. However, it is important to notice
that approximately two-thirds of the patients in the current
study were debulked to less than 2 cm residual disease,
and one-third to greater than 2 cm disease. In our previous
study, two-thirds of the patients were debulked to greater
than 2 cm disease and only one-third to less than 2 cm
of disease. As in other clinical trials of a similar nature,
the increased survival of our patient population may be
partly reflective of the reduced residual disease after initial
surgery.
Complete pathologic remission was induced in 3790 of
patients as opposed to 13% in our previous protocol. These
patients showed a significantly increased mean survival
time of 55.5 k 3.2 months. This confirms the importance
of negative SLL findings as an important predictor of
survival"" because patients with macroscopic second-look
laparotomies showed a mean survival time of only 24
months. This conclusion is corroborated by the obser-
vation that approximately 55% of the long-term survivors
(survival greater than 40 months) had NED at SLL.
Treatment after SLL did not appear to have a major
effect on patient outcome. This is reflected in the prog-
nostic significance of PCR at SLL ( P = 0.001) (Fig. 4).
Because almost 60% of the patients treated after SLL had
minimal (less than 2 cm) or no residual disease, the results
obtained with external beam radiation are disappointing.
'
Dembo' reported excellent tumor control in patients with
this minimal intraabdominal tumor bulk treated de nuvo
with external beam radiation. Our poor results with whole-
abdominal radiation after SLL are consistent with the ex-
perimental data that tumor cells resistant to chemotherapy
are also resistant to irradiation."
No significant differences in survival times were ob-
tained among patients who received either cyclophos-
pharnide or abdominal radiation or no treatment at all.
The varied effects of these treatments on patient survival
may have been masked by the small number of patients
available in each of the subgroups.
Vol. 68
Other groups have recently reported their results with
short-course chemotherapy. Hainsworth et ~ 1 .reported
'~
a response rate of 72% and median survival time of 45
months in patients treated with intensive cisplatin-based
chemotherapy of brief duration. Rothenberg et re-
ported preliminary results with high-dose, short-course
chemotherapy. Their clinical complete response rates were
78% in patients with Stage 111 disease and 29% in patients
with Stage IV disease. The surgically documented com-
plete response rate after chemotherapy was 2490. The tox-
icity of the intensive short-induction approach was sub-
stantial, with peripheral neuropathy being dose limiting.
These results are consistent with the current trial and sug-
gest that prolonged survival may be obtained in advanced
ovarian cancer with only three to four cycles of high-dose
chemotherapy.
In conclusion, the survival time of patients with ad-
vanced epithelial ovarian cancer can be increased to a
median of 5 1.3 months with high-dose cisplatin/doxo-
rubicin chemotherapy with severe, but manageable, my-
elosuppression. NED at SLL may be considered a reliable
predictor of long-term survival.
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