Original Study

Outpatient Intraperitoneal Chemotherapy for

All Stages of Ovarian, Fallopian Tube, and
Peritoneal Cancers: A Pilot Study
David Silver, Nadim Bou Zgheib

Abstract
Purpose: The objective of this pilot study was to evaluate a 2-day, outpatient intraperitoneal (I.P.) chemotherapy
regimen for all stages of ovarian, fallopian tube, and peritoneal cancers. Methods: All stages were included
except low-risk, stage I. The I.P. regimen was the following: day 1, I.P. paclitaxel 60 mg/m2; day 2, I.P. cisplatin
75 mg/m2 plus intravenous (I.V.) paclitaxel at escalating doses. The treatment plan included 3 I.P. cycles for all
stages. Optimal stage III was treated with 3 additional cycles of I.V. paclitaxel/carboplatin. Optimal stage IV was
treated with 6 additional cycles of I.V. chemotherapy. Stages I grade 3 and IC, and optimal stage II received no
further treatment. Follow-up included serial cancer antigen 125 and computer tomographies. Results: From
June 1, 2007, to December 31, 2009, 31 patients were accrued. Fourteen patients had stage III disease. Eight
of 14 were alive and had no evidence of disease (NED). Three of 14 are alive with disease. Three of 14 died, 2
with progressive disease. Median follow-up for stage III was 28 months. Six patients had stage IV. Four of 6
patients are alive and NED. Two of 6 died with progressive disease. The median follow-up for stage IV was 16
months. Eleven patients had early, high-risk disease. Eleven of 11 patients are alive and NED, with a median
follow-up of 21 months. There were no I.P. chemotherapy delays. Grade 3-4 hematologic and nonhematologic
toxicities were rare.Conclusion: Preliminary data revealed tolerance of this 2-day outpatient I.P. chemotherapy
regimen, with promising response and survival. With continued accrual and follow-up, this I.P. chemotherapy
schedule may demonstrate usefulness in all stages of ovarian cancer.

Clinical Ovarian Cancer, Vol. 4, No. 1, 7-11 2011 Elsevier Inc. All rights reserved.
Keywords: Fallopian tube cancer, Intraperitoneal chemotherapy, Ovarian cancer, Primary peritoneal cancer

Introduction therapy. Despite the National Cancer Institutes endorsement of I.P.

Ovarian cancer results in the highest mortality of all gynecologic
malignancies. Because of the lack of adequate screening tests or reli-
able early signs and symptoms, 70% of patients with ovarian cancer
present with stage III disease. Since the 1980s, the hallmarks of
standard treatment for advanced ovarian cancer have been cytore-
ductive surgery followed by adjuvant platinum-based chemotherapy.
In 2006, Armstrong et al1 described the results of a randomized
Gynecologic Oncology Group (GOG) trial (GOG 172), which
demonstrated the superiority of intraperitoneal (I.P.) paclitaxel and
cisplatin over standard intravenous (I.V.) taxane/platinum chemo-
The Womens Institute for Gynecologic Cancer & Special Pelvic Surgery, Phillipsburg, NJ
Submitted: Aug 9, 2010; Accepted: Oct 6, 2011
Address for correspondence: Nadim Bou Zgheib, MD, The Womens Institute for
Gynecologic Cancer & Special Pelvic Surgery, 775 Memorial Parkway, Phillipsburg,
NJ 08865
E-mail contact: bouzgheibn@hotmail.com
chemotherapy for the treatment of advanced ovarian cancer,2 the I.P.
route of administration of chemotherapy has not been widely accepted
in the oncology community at large. The most common reasons for the
lack of acceptance of the GOG 172 regimen are1 the perceived intoler-
able toxicities, and2 inconvenient inpatient schedules.
Although GOG 172 demonstrated a 16-month survival advantage
for patients with stage III ovarian cancer who were optimally cytore-
duced, the efficacy of I.P. chemotherapy for patients with stage IV
disease remains unknown. In addition, in the United States, patients
with high-risk, early ovarian cancer who are routinely treated with
3-6 cycles of IV chemotherapy are perhaps a subset of patients with
disease who may benefit most from I.P. chemotherapy because their
disease is most likely to be confined to the peritoneal cavity.
The aim of this pilot study was to evaluate the tolerability of a
2-day outpatient schedule of I.P. chemotherapy. Furthermore, pre-
liminary data on the efficacy of this I.P. regimen were evaluated in
patients with1 high-risk stage I and II,2 optimal stage III, and3 opti-
mal stage IV ovarian cancer.

1941-4390/$ - see frontmatter 2011 Elsevier Inc. All rights reserved.

doi: 10.1016/j.cloc.2011.04.002 Clinical Ovarian Cancer June 2011 7
 Outpatient Intraperitoneal Chemotherapy
Table 1 TWI-001 Chemotherapy Schedule Compared With GOG 172

Day
Protocol
1 2 3 4 5 6 7 8
2 2
GOG 172 I.V. Taxol, 175 mg/m I.P. cisplatin, 100 mg/m IP Taxol, 60 mg/m2
TWI-001 I.P. Taxol, 60 mg/m2 I.P. cisplatin 75 mg/m2
2a
IV Taxol, 75, 85, 100 mg/m

Abbreviations: GOG Gynecologic Oncology Group; I.P. intraperitoneal; I.V. intravenous; TWI-001 The Womens Institute protocol 001.
a
Escalating doses of I.V. Taxol in cycles 13.

Table 2 Demographic and Pathologic Characteristics

Patients and Methods
After institutional review board approval of this pilot study, The Patients IP Chemotherapy
Womens Institute protocol 001 (TWI-001) was initiated. Patients Characteristics (n 31)
were included in the trial if they were diagnosed with non clear-cell, Age at Diagnosis 63 (range, 46-78)
epithelial ovarian, fallopian tube, or peritoneal cancer, and if they GOG PS
were between the ages of 18 and 80 years old. Patients with stage IA
0 17 (54%)
or IB, grades 1 or 2 were excluded from the protocol, as were any
patients with suboptimal residual disease. 1 14 (46%)
The I.P. portion of the protocol was given by using the following Primary Site
schedule: day 1, I.P. paclitaxel 60 mg/m2; day 2, I.P. cisplatin 75 Ovarian 25 (84%)
mg/m2; and day 2, I.V. paclitaxel at escalating doses (cycle 1, 75 Fallopian tube 1 (3%)
mg/m2; cycle 2, 85 mg/m2; cycle 3, 100 mg/m2). On day 3, all the Primary peritoneal 5 (18%)
patients were offered additional I.V. hydration (1000 mL of saline
Stage
solution with 40 meq KCl infused over 1-2 hours). The TWI-001
schedule is summarized in Table 1 and is compared with the GOG IA grade 3 2 (6%)
172. The patients with diverting loop ileostomies were offered IV IC 2 (6%)
hydration on days 3, 4, and 5 to avoid dehydration and electrolyte IIA 1 (3%)
derangements as described in our previous experience with I.P. che- IIB 6 (19%)
motherapy after extensive colon resection.3 IIIB 1 (3%)
The treatment schedule included 3 cycles of I.P. chemotherapy for
IIIC 13 (42%)
all stages of disease. The patients with stage III disease received 3
additional cycles of standard IV paclitaxel at 175 mg/m2 and carbo- IVB 6 (19%)
platin with an area under the curve (AUC) of 6, for a total of 6 cycles Gross Residual Disease
of chemotherapy. The patients with stage IV disease received 6 ad- Optimal (1 cm) 2 (6%)
ditional cycles of standard IV paclitaxel-carboplatin for a total of 9 Complete 29 (94%)
cycles. Stages I grade 3, IC, and stage II received no additional treat-
ment after the 3 cycles of I.P. chemotherapy as described above. Abbreviations: GOG Gynecologic Oncology Group; IP intraperitoneal; PS performance
status.
The patients with stage III or IV disease underwent peritoneal
port placements at the time of their cytoreductive surgeries. Pa-
tients with high-risk, early staged cancer had ports placed as a to 78 years. The demographic and the pathologic characteristics of
short outpatient procedure via laparoscopy or minilaparotomy our cohort are summarized in Table 2.
after final pathology was obtained 2-3 weeks after their staging Fourteen patients had stage III (13 with IIIC, 1 with IIIB). Nor-
surgeries. malization of the CA-125 level after the first 3 cycles occurred in 14
After completion of the scheduled treatments, the patients were of 14 (the patient with stage IIIB disease had a CA-125 17
followed up with monthly physical examinations and cancer an- units/ml before surgery). Fourteen of 14 patients had no evidence of
tigen (CA)-125 levels and with quarterly computed tomographies disease (NED) by CT after cycle 3. Fourteen of 14 had NED by CTs
(CT) for the first year. CA-125 levels were subsequently followed and CA-125 after cycle 6. Eight of 14 were alive and had NED.
up quarterly, and CTs were obtained as indicated by CA-125 Three of 14 were alive with disease at 12, 14, and 19 months; and 3
elevations or signs and symptoms. All data were prospectively of 3 responded to platinum-based second-line therapy. Three of 14
recorded. died: 2 of progressive disease, and 1 of a late diagnosis of nadir sepsis
after cycle #6 at an outside hospital. She had NED. The median
Results follow-up for stage III disease was 28 months.
From June 1, 2007, to December 31, 2009, 31 patients were Six patients had stage IV (4/6 visible pleural metastases, 2/6
enrolled. The mean age at diagnosis was 63 years, with a range of 46 visible pleural metastasis and liver parenchymal lesion). All CA-

8 Clinical Ovarian Cancer June 2011

 David Silver, Nadim Bou Zgheib
125 levels after cycle 3 had at least a partial response (4/6) (2/6
Table 3 Grade 3-4 Toxicity of TWI-001 Compared With GOG
complete response). Six of 6 patients had NED on CTs after cycle 172
3. Five of 6 had NED by CT and CA-125 levels after cycle 6. Six
of 6 had NED by CT and CA-125 after cycle 9. Four of 6 were WI-001 (n 31),
Adverse Event GOG 172, %
alive and disease free. Two of 6 died of progressive disease in the No. (%)
liver parenchyma. The median follow-up for patients with stage Neutropenia NR 76
IV disease was 16 months. Febrile Neutropenia 4 (13) NR
Eleven patients had early, high-risk disease: 2 stage IA grade 3,
Thrombocytopenia 2 (6) 12
2 stage IC (grades 2 and 3), 1 stage IIA grade 3, 4 stage IIB (2 with
Gastrointestinal 0 46
grade 1, 2 with grade 3), and 2 stage IIC, grade 3. Five of 11 had
CA-125 elevations above the normal range before surgery. Five of Renal 1 (3) 7
5 had normal CA-125 levels after cycle 3. Eleven of 11 CTs after Metabolic NR 27
cycle #3 demonstrated NED. Eleven of 11 patients with early, Neurologic 0 19
high-risk disease were alive and NED, with a median follow-up of Port Infection 1 (3) 16
21 months. Abdominal Pain 0 NR
Prospective recording of toxicities demonstrated the following.
Fatigue NR 18
Three of 31 individuals developed low hemoglobin: 2 of 3 had
stage IV disease, and 1 of 3 had stage III. Among the 3 who Treatment-Related a
1 (3) 2
Death
developed anemia, in 2 patients, this occurred during the first 3
cycles of chemotherapy. Two of 31 individuals developed grade Abbreviations: IP intraperitoneal; GOG Gynecologic Oncology Group; NR not recorded;
TWI-001 The Womens Institute protocol 001.
3-4 thrombocytopenia both of these patients had stage IV disease. a
Neutropenic sepsis inadequately treated at a local community hospital.
Both required a single 1-week delay during the I.V. portion of
their regimen, and both had dose reductions of I.V. carboplatin to cisplatin as well as available data on the pharmacokinetics of I.P.
an AUC of 5. No grade 3-4 thrombocytopenia occurred during chemotherapy and the clinical outcomes of GOG 172.
cycles 1-3. Four of 31 individuals developed febrile neutropenia: In our protocol (TWI-001), all the patients received 3 cycles of
1 of 4 had stage III, 3 of 4 had stage IV. Three patients had a single I.P. paclitaxel/cisplatin. In GOG 172, 42% of patients tolerated 6
1-week delay, and 3 patients had added growth factor support on cycles. Despite this, there was a 16-month survival advantage for the
subsequent cycles. No febrile neutropenia was observed within group that received I.P. chemotherapy, which suggests that thera-
the first 3 cycles of chemotherapy. One patient with stage IIIC peutic benefits are derived from fewer than 6 cycles. It is not unrea-
died of neutropenic sepsis after completing her sixth cycle of sonable to assume that the first several I.P. cycles of chemotherapy are
chemotherapy. She was admitted to a local community hospital the most effective, because the peritoneal surfaces are less likely to
and was inadequately treated, with IV hydration, antibiotics, have developed a fibrotic reaction or adhesions due to previous I.P.
growth factor and appropriate consultations were not obtained. cycles and radical surgery.
One patient at stage IV developed an elevated creatinine level, to Although only 3 cycles of I.P. chemotherapy were given to pa-
2 mg/dl after cycle 7. She required a 2-week delay followed by a tients enrolled in TWI-001, 3 additional cycles of standard pacli-
dose reduction of carboplatin to AUC of 5 and additional I.V. hy- taxel-carboplatin were provided to those with stage III disease, and 6
dration in cycles 8 and 9. No patient developed grade 3-4 neuropa- additional cycles of standard IV chemotherapy were provided to
thy. Thirty-one of 31 completed all 3 I.P. cycles on time, without those with stage IV. In patients with early, high-risk ovarian cancer,
delays. One of 31 I.P. ports was removed due to infection after cycle no subsequent IV chemotherapy was given after the completion of 3
3. Two of 31 patients developed abdominal pain while on cycle 1, cycles of the I.P. regimen.
which resolved in subsequent cycles, with a decrease in the I.P. vol- Although I.P. chemotherapy has established itself as part of the
ume infused, from 2 L to 1 L. The adverse events of TWI-001 to armamentarium for upfront treatment of advanced ovarian cancer
those of GOG 172 are compared in Table 3. limited to the peritoneal cavity, there is little known about its efficacy
on stage IV disease and even less known about its use for early,
Discussion high-risk disease confined to the pelvis (stages I and II). Standard
The controversy over the use of I.P. chemotherapy in ovarian recommendations for patients with early, high-risk ovarian cancer
cancer has persisted for decades despite 3 large, randomized, coop- include IV paclitaxel/carboplatin given over 3 to 6 cycles. Therefore,
erative group trials that each demonstrated its survival advantage offering only 3 total cycles of chemotherapy on our protocol did not
compared with standard IV chemotherapy.1,4,5 The most recent trial deter enrollment. However, because there are little clinical data to
(GOG 172) reported by Armstrong et al1 demonstrated a 16-month support I.P. chemotherapy for stage IV disease, it was thought that 6
overall survival benefit of I.P. paclitaxel/cisplatin over IV paclitaxel/ additional IV cycles had to be offered to patients at stage IV on our
platinum for stage III ovarian cancer. Critics of I.P. chemotherapy protocol so to enhance enrollment.
continue to focus on increased toxicities and inconvenient inpatient I.P. chemotherapy demonstrates variable diffusion rates through
scheduling of I.P. treatments. Our pilot study evaluated a 2-day the peritoneum into the systemic circulation based on a variety of
outpatient I.P. chemotherapy regimen. The development of this reg- molecular factors. Although cisplatin diffuses rapidly, paclitaxels
imen used current knowledge about the interactions of paclitaxel and large molecular size results in a less-efficient transfer across the

Clinical Ovarian Cancer June 2011 9

 Outpatient Intraperitoneal Chemotherapy
peritoneal membrane. The direct tumor effect of I.P. chemother-
apy is maximized by the high concentrations at the tumors sur-
face. In addition, its diffusion into the systemic circulation allows
for the return of I.P. chemotherapy to the tumor via the blood
stream.
Because plasma concentrations of cisplatin are equal whether ad-
ministered via the I.P. route or by I.V. infusion, it is not unreasonable
to predict that I.P. regimens will be effective against metastatic dis-
ease remote from the peritoneal cavity. This also is addressed by
adding an IV dose of paclitaxel on day 2 to supplement the I.P.
paclitaxel, which crosses the peritoneum less efficiently. Six patients
in our study had stage IV disease, with pleural nodules and with or
without parenchymal liver lesions. All 6 developed complete clinical
remission at the end of their prescribed chemotherapy, and 66.7%
remained alive and disease free, with a median follow-up of 16
months. Although it could be argued that the complete responses are
due to the use of 9 total cycles in patients at stage IV enrolled in our
protocol, it is unlikely that 3 additional cycles of IV chemotherapy
would result in this degree of durable disease-free status. Further-
more, 5 of the 6 complete responses were documented by CA-125
and CTs after the sixth cycle of chemotherapy. Only one patient
required all 9 cycles to achieve complete remission. Not surprisingly,
that individual was one of the two who subsequently died of progres-
sive disease. When taking this into consideration, it may not have
been necessary to give all 9 cycles for stage IV disease. Currently at
our institution, patients with stage IV disease are given 6 total cycles
of chemotherapy when using this regimen.
Eleven patients in our cohort had early, high-risk disease that
would warrant 3-6 cycles of I.V. chemotherapy if standard recom-
mendations were followed.6 Because early-stage disease is the most
likely to remain in the peritoneal cavity and 3 cycles of I.P. chemo-
therapy are tolerated by most patients, logic would say that I.P.
chemotherapy is ideal for early-stage disease. After 3 cycles of I.P.
chemotherapy, 11 of 11 patients developed complete clinical remis-
sions and remained disease free, with a median follow-up of 21
months. Furthermore, no significant treatment-related toxicity was
observed. Continued follow-up of this cohort will elucidate long-
term outcomes important in establishing I.P. chemotherapy as a
reasonable treatment plan for early, high-risk disease.
In our protocol, paclitaxel and cisplatin were delivered intraperi-
toneally on 2 consecutive days rather than separating the I.P. doses of
paclitaxel and cisplatin by 7 days as scheduled in GOG 172. In vitro
studies have demonstrated a synergistic effect between paclitaxel and
cisplatin.7-9 By allowing paclitaxel and cisplatin to dwell together
within the peritoneal cavity on consecutive days, our schedule takes
advantage of the synergism demonstrated in petri dishes. In the fu-
ture, we intend to evaluate the use of simultaneous infusions of pa-
clitaxel and cisplatin to capitalize upon this synergism and to add to
the convenience of our protocol.
Paclitaxel was administered on days 1 and 8 on the GOG protocol.
Not only was this schedule somewhat inconvenient for the patients,
but, more importantly, it resulted in a high rate of grade 3-4 periph-
eral neuropathy (19%). Day 8 was omitted from our protocol. In-
stead, I.P. paclitaxel was delivered on day 1, and a relatively low dose
of I.V. paclitaxel was infused on day 2 to supplement the slow rate of
diffusion of I.P. Taxol from the peritoneal cavity to the systemic
10 Clinical Ovarian Cancer June 2011
circulation. The IV dose was administered with a planned dose esca-
lation that was well tolerated in all of our patients up to the maxi-
mum dose of 100 mg/m2. No grade 3-4 neurotoxicity was observed
in our cohort of patients. The changes made to the dose and schedule
of paclitaxel in our study also resulted in a significant decrease in the
hematologic toxicities observed in GOG 172. Although our initial
plan was to increase the IV paclitaxel dose on cycle 1 if the lower
doses were tolerated by 3 consecutive patients, our hospitals institu-
tional review board was more comfortable with observing the pre-
scribed dose escalation on 30 consecutive patients before allowing for
higher doses to be given on the first cycle. The results of our pilot
study suggest that an I.V. dose of 100 mg/m2 paclitaxel on day 2 of
the I.P. portion of our regimen could be prescribed safely in subse-
quent patients.
When comparing TWI-001 with GOG 172, both hematologic
and nonhematologic toxicities were much improved. To prevent
renal toxicity, the dose of I.P. cisplatin was reduced from 100
mg/m2 in GOG 172 to 75 mg/m2 in TWI-001. Although there
are no data in the literature to support this dose change, it has
been adopted as an appropriate alteration from the GOG 172 I.P.
protocol by many in our community who administer chemother-
apy for ovarian cancer. Only 1 patient in our cohort demonstrated
significant renal toxicity, which was prevented on subsequent
cycles with added IV hydration. No significant gastrointestinal
toxicity or electrolyte disturbances were observed. It should be
noted that all of our patients received at least 1 day of postche-
motherapy IV hydration as described in the methods. Further-
more, our antiemetic regimen for I.P. chemotherapy includes
prechemotherapy ondansetron and aprepitant as well as postche-
motherapy metoclopramide, ondansetron, and aprepitant. It is
conceivable that the dose reduction of cisplatin also helped to
prevent the severe neurotoxicity observed in GOG 172. Mild
abdominal pain only occurred in 2 patients due to distention
from large volumes of I.P. infusions, which was easily prevented
on subsequent cycles by decreasing the volume infused to 1 L
instead of 2 L.
Unfortunately, 1 patient with stage IIIC disease died of neu-
tropenic sepsis in a local community hospital after her sixth cycle
of chemotherapy. On review of the hospital records, she was in-
adequately hydrated, did not receive appropriate broad-spectrum
antibiotics, and did not receive growth factors for the first 48
hours of her admission. She died 72 hours after she arrived to the
hospital. Notably, grade 3-4 anemia was observed in 3 individuals
with advanced disease. Two of the 3 occurred during the first
cycle of chemotherapy and were more likely related to their ex-
tensive surgical resection because it is our policy to deliver the first
cycle of chemotherapy just before discharge from the hospital
during the surgical admission. No anemia was encountered in our
early-stage group. One port was removed due to infection after
receiving the third cycle of I.P. chemotherapy and did not delay
subsequent cycles.
Conclusion
I.P. paclitaxel/cisplatin given on a 2-day outpatient schedule was
well tolerated and with acceptable response rates. Although this pilot
study was limited due to its relative small number of subjects and its

single-armed design, the data gleaned from it support the use of I.P.
chemotherapy for all stages of disease, excluding low-risk, stage I.
Further clinical evaluation and follow-up to substantiate these find-
ings is ongoing.
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David Silver, Nadim Bou Zgheib
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