Download Phase II Study of Oxaliplatin in Platinum-Resistant and

Phase II Study of Oxaliplatin in Platinum-Resistant and
Refractory Ovarian Cancer: A Gynecologic Group Study
By Paula M. Fracasso, John A. Blessing, Mark A. Morgan, Anil K. Sood, and James S. Hoffman
Purpose: A phase II study was conducted to determine
the efficacy of oxaliplatin therapy in patients with platinumresistant or refractory epithelial ovarian carcinoma.
Materials and Methods: Eligible patients were to receive
oxaliplatin 130 mg/m2 intravenously over 2 hours, every
21 days, until progression of disease or adverse effects
prohibited further therapy.
Results: Of 25 patients entered onto the study, 23 were
eligible and assessable. There were no patients with complete response. One patient (4.3%) achieved a partial response, with a response duration of 6.4 months. Nine
patients (39.1%) experienced stable disease, with a median
duration of 5.6ⴙ months (range, 1.8 to 13.1months). The
most frequently reported drug-related toxicities were hematologic, gastrointestinal, and neurologic.
Conclusion: Oxaliplatin as a single agent has minimal
activity in patients with platinum-resistant or refractory
ovarian cancer at the dosage and schedule tested. However, future studies of oxaliplatin combined with other
active agents in women with platinum-naı̈ve or platinumsensitive epithelial ovarian carcinoma may be indicated.
J Clin Oncol 21:2856-2859. © 2003 by American
Society of Clinical Oncology.
E
this has limited the use of carboplatin in combination with
other myelosuppressive drugs.
Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatin;
Eloxatine, Sanofi, Paris, France) is a novel diaminocyclohexane platinum derivative with a wide range of activity against
human and murine tumor cell lines, including cisplatinresistant cell lines.5 The mechanism of action of oxaliplatin is
thought to be similar to that of other platinum derivatives that
exert cytotoxic effects through the formation of DNA adducts,
with subsequent impairment of DNA replication and transcription and resultant cell death. Preclinical data indicate,
however, that the platinum-DNA adducts formed by oxaliplatin may be responsible for its unique cytotoxic activity as
compared with that of cisplatin. In particular, the 1,2diaminocyclohexane-platinum (dach-PT) adducts formed
from oxaliplatin may be more effective in DNA synthesis
inhibition than the cis-diamine-PT adducts formed from
cisplatin, and DNA mismatch-repair complexes do not recognize dach-PT adducts.5
Phase I studies of oxaliplatin have demonstrated a favorable
safety profile.6 The dose-limiting toxicity was a cumulative
peripheral sensory neuropathy often exacerbated by cold. Nausea
and vomiting were noted but, unlike cisplatin or carboplatin,
renal toxicity, ototoxicity, and significant hematologic toxicity
were absent for oxaliplatin. The recommended phase II dosage
was 125 to 130 mg/m2 every 3 weeks or 85 m/m2 every 2 weeks.
Efficacy was noted in phase II and III studies using oxaliplatin
for treatment of advanced colon cancer, both as a single agent
and in combination with fluorouracil and leucovorin. As a result,
oxaliplatin in combination with fluorouracil and leucovorin has
been approved for the treatment of colon cancer in Asia, Latin
America, and Europe. Recently, the United States Food and
Drug Administration approved oxaliplatin in combination with
fluorouracil and leucovorin as second-line treatment of patients
with advanced colorectal carcinoma.
PITHELIAL OVARIAN carcinoma is the fifth most frequent type of cancer in American women, accounting for
23,300 new diagnoses and 13,900 deaths in 2002.1 Most patients
present with advanced disease and are treated with cytoreductive
surgery, followed by platinum-based combination chemotherapy. Although most of these women initially respond to treatment, most patients with advanced disease experience its recurrence and eventually die as a result of resistant disease.2
cis-Diamminedichloroplatinum (cisplatin), one of the most
active single agents in ovarian carcinoma, has been widely used
in combination with paclitaxel for the treatment of advanced
disease.3 Despite the activity of cisplatin in ovarian cancer, its
continued use may be limited by acute dose-related renal
toxicity and chronic neurotoxicity.4 Different analogs have
been prepared to combat these toxicities. Carboplatin, a
bidentate dicarboxylate analog of cisplatin, has a therapeutic
spectrum similar to cisplatin and is less nephrotoxic. However, carboplatin is more myelosuppressive than cisplatin, and
From the Washington University School of Medicine, St Louis, MO;
Gynecologic Oncology Group Statistical and Data Cancer; Roswell Park
Cancer Institute, Buffalo, NY; Department of Gynecologic Oncology, University of Pennsylvania Cancer Center, Philadelphia, PA; Division of
Gynecologic Oncology, University of Iowa Hospitals and Clinics, Iowa City,
IA; and Division of Gynecologic Oncology, University of Connecticut School
of Medicine, Farmington, CT.
Submitted March 12, 2003; accepted May 5, 2003.
Supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology
Group Statistical Office (CA 37517), and a Clinical Oncology Career
Development Award from the American Cancer Society to P.M.F.
Address reprint requests to Paula M. Fracasso, MD, PhD, Washington
University School of Medicine, Campus Box 8056, 660 South Euclid, St
Louis, MO 63130; email: [email protected].
© 2003 by American Society of Clinical Oncology.
0732-183X/03/2115-2856/$20.00
2856
Journal of Clinical Oncology, Vol 21, No 15 (August 1), 2003: pp 2856-2859
DOI: 10.1200/JCO.2003.03.077
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Copyright © 2003 by the American Society of Clinical Oncology. All rights reserved.
2857
OXALIPLATIN FOR OVARIAN CARCINOMA
Phase II studies with oxaliplatin have also demonstrated its
activity in women with previously treated ovarian carcinoma
when oxaliplatin is used as a single agent or in combination.7-15
Given the activity and low levels of renal, hematologic, and
ototoxicity seen with single-agent oxaliplatin for ovarian carcinoma, this phase II study was designed to investigate its activity
and toxicity in women with platinum-resistant and refractory
ovarian carcinoma.
MATERIALS AND METHODS
Eligible patients with epithelial ovarian carcinoma were required to have
had one previous platinum-based chemotherapeutic regimen and be platinum-resistant or refractory. Platinum resistance was defined as having had a
treatment-free interval of less than 6 months after platinum treatment.
Patients who were refractory to treatment with platinum were defined as
having had progressive disease during platinum-based therapy. Patients with
a known allergy to platinum compounds or who had undergone prior therapy
with oxaliplatin were ineligible.
Patients were required to have had measurable disease and a Gynecologic
Oncology Group (GOG) performance status of 0 to 2. Laboratory criteria for
eligibility included absolute neutrophil count ⱖ 1,500/␮L, platelets at least
the institutional lower limit of normal, creatinine ⱕ 1.5 times the institutional
upper limit of normal, bilirubin ⱕ 1.5 times the institutional upper limit of
normal, and AST and alkaline phosphatase ⱕ 2.5 times the institutional
upper limit of normal. No chemotherapy or radiotherapy was permitted
within 3 weeks before study entry. Patients with other malignancies during
the previous 5 years (with the exception of nonmelanoma skin cancers) were
ineligible. Patients with significant comorbid conditions (including active
infection, symptomatic congestive heart failure, unstable angina pectoris, and
cardiac arrhythmias) or brain metastases were ineligible, as were patients
with evidence of preexisting peripheral neuropathy greater than grade 1. All
patients provided signed informed consent consistent with all federal, state,
and local requirements before entering onto the study.
Treatment cycles were every 21 days, with oxaliplatin 130 mg/m2
administered by 2-hour continuous intravenous infusion. Premedication
with dexamethasone and 5-hydroxytryptamine-3 antagonists was recommended before and after each dose of oxaliplatin. Patients were counseled
to avoid cold drinks and exposure to cold water and air to avoid
cold-induced sensory neuropathy.
Subsequent courses of oxaliplatin were administered if hematologic
parameters had returned to the following status: neutrophils ⱖ 1,500/␮L and
platelets ⱖ 100,000/␮L. The oxaliplatin dosage was to be reduced by 25%
if the absolute neutrophil count nadir in the previous course was ⱕ 1,000/␮L,
if the platelet nadir was less than 50,000/␮L, or if the hemoglobin nadir was
less than 8.0 g/dL. Before each course, complete resolution of stomatitis or
pharyngitis and diarrhea was required. The oxaliplatin dosage was to be
reduced by 25% for grade 3 or 4 stomatitis or pharyngitis, as well as for
grade 3 or 4 diarrhea.
Patients were monitored for neurotoxicity before each course, with
treatment given only if paresthesia or dysesthesia was grade 2 or less. In the
event grade 2 paresthesia or dysesthesia had not resolved by the beginning of
the next course, the dose of oxaliplatin was to be reduced by 25%. Grade 3
paresthesia ordysesthesia that had not resolved by the beginning of the next
course required discontinuation of treatment. A 25% dosage reduction was
allowed for grade 3 paresthesia or dysesthesia that resolved before the start
of the next course. Any grade 4 paresthesia or dysesthesia required
discontinuation of oxaliplatin treatment. If the patient had pharyngolaryngeal
dysesthesia with prior cycles, the duration of the oxaliplatin infusion was to
be increased from 2 to 6 hours.
Eligible patients were to receive six courses of oxaliplatin, unless evidence
of disease progression or toxicity prohibited further therapy. Those still
receiving clinical benefit after six courses of treatment could continue
therapy for an additional three courses. Response to therapy was evaluated
after the second course of therapy. Patients who received one or more
course(s) of drug were assessable for toxicity, and those who received one or
more course(s) and whose disease was reassessed were assessable for
response. Response was defined according to standard GOG criteria, as
follows: complete response is the disappearance of all gross evidence of
disease for a duration of at least 4 weeks; partial response is a 50% or greater
reduction in the product obtained from measurement of each lesion for at
least 4 weeks and no appearance of new lesions; increasing disease is a 50%
or greater increase in the product from any lesion documented within 2
months of study entry or the appearance of any new lesion within 8 weeks
of study entry; and stable disease is any condition not meeting those criteria.
This study used a two-stage accrual design with an early stopping rule in
the event that the treatment demonstrated insufficient activity. During the
first stage of accrual, 22 to 29 patients were to be entered and evaluated. If
at least four responses were observed among the first 22 to 24 patients, or five
responses were observed among 25 to 29 patients, a second phase of accrual
was to be initiated, which would increase accrual to 53 to 60 patients. The
regimen would be considered active if at least 11 responses were observed
among 53 patients, at least 12 responses were observed among 54 to 57
patients, or at least 13 responses were observed among 58 to 60 patients. If
the true probability of response was only 15%, the study design provided a
90% chance of correctly classifying the treatment as inactive. Conversely, if
the true response rate was 30%, then the probability of correctly classifying
the treatment as active was 90%.
RESULTS
Between February and June 2000, member institutions of the
GOG entered 25 patients with ovarian carcinoma onto GOG
Protocol 126-K to evaluate the efficacy of oxaliplatin. Two
patients were found, on central pathology review, not to have
epithelial ovarian carcinoma and were thus ineligible. The
characteristics of the 23 eligible patients are presented in Table
1. All patients had epithelial ovarian carcinoma and were
resistant or refractory to platinum chemotherapy as defined
above. The median age was 60 years, and the majority of patients
had GOG performance status of 0.
Table 1.
Patient Characteristics (n ⴝ 23)
Characteristic
Age, years
Median
Range
GOG performance status
0
1
Histology
Serous adenocarcinoma
Endometrial adenocarcinoma
Clear-cell carcinoma
Transitional-cell carcinoma
Mixed epithelial carcinoma
Grade
1
2
3
Unspecified
Site of disease
Pelvic
Extrapelvic
Prior chemotherapy
Prior platinum therapy
Prior radiotherapy
No. of Patients
60
43 to 78
Abbreviation: GOG, Gynecologic Oncology Group.
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14
9
17
2
2
1
1
1
8
13
1
12
11
23
23
2
2858
FRACASSO ET AL
Table 2.
Adverse Effects Associated With Oxaliplatin (n ⴝ 23)
Table 3.
No. of Patients by Grade
Adverse Effect
Hematologic
Neutropenia
Leukopenia
Anemia
Thrombocytopenia
Other
Neurotoxicity
Sensory
Pharyngolaryngeal dysesthesia
Gastrointestinal
Nausea or vomiting
Other
Allergy
Cardiovascular
Constitutional
Dermatologic
Genitourinary or renal
Hepatic
Infection
Metabolic
Myalgia or arthralgia
Ocular
Pain
Pulmonary
1
2
3
4
3
7
9
7
1
1
2
9
0
1
3
0
0
6
4
0
0
0
0
0
10
7
6
0
1
0
0
0
8
8
0
2
7
0
2
5
2
2
0
1
5
3
5
3
0
3
9
1
0
1
0
1
1
1
7
3
3
1
1
0
2
1
0
1
1
1
1
0
3
1
0
3
0
0
0
0
0
0
0
2
0
0
0
0
All eligible patients were assessable for response. A total of 97
courses of oxaliplatin were administered, with a median of three
courses (range, 1 to 13 courses) per patient. Five patients
received dosage reductions because of hematologic toxicity;
none had the oxaliplatin dosage reduced because of paresthesia
or dysesthesia, and study therapy was not discontinued because
of neurotoxicity.
Adverse effects associated with oxaliplatin are displayed in
Table 2. Neurotoxicity was the most frequent adverse effect and
could be divided into sensory neurotoxicity (paresthesia or
dysesthesia) and pharyngolaryngeal dysesthesia. Paresthesia or
dysesthesia was most common and occurred in 17 patients,
although grade 3 toxicity occurred in only one patient (4.3%).
Similarly, pharyngolaryngeal dysesthesia occurred in seven patients. There was no grade 4 neurotoxicity reported.
Gastrointestinal toxicity, including nausea and vomiting, was
common, and required intravenous hydration in two patients.
Grade 4 disease-related ileus occurred in three patients. Three
patients had grade 3 or 4 metabolic adverse effects: In two
patients, hyponatremia was due to dehydration; in the third
patient, hypokalemia was secondary to diuretics. One patient
experienced grade 3 infection, and two patients had grade 1
infection, all without neutropenia. Grade 3 myelosuppression
was infrequent and occurred in 13% of patients. RBC transfusions were required in three patients. There were no treatmentrelated deaths.
Response to treatment is summarized in Table 3. One of 23
patients (4.3%) achieved a partial response, with a response
duration of 6.4 months. Nine patients (39.1%) had stable disease,
with a median duration of 5.6⫹ months (range, 1.8 to 13.1
months). Thirteen patients experienced increasing disease.
Response to Treatment With Oxaliplatin (n ⴝ 23)
Clinical Response
No. of Patients
%
Partial response
Stable disease
Increasing disease
1
9
13
4.3
39.1
56.6
DISCUSSION
Oxaliplatin, a novel platinum derivative, is more potent
than cisplatin in vitro, and requires fewer platinum adducts to
achieve an equal level of cytotoxicity.5 In addition, oxaliplatin demonstrated greater efficacy in preclinical studies against
many tumor cell lines, including a cisplatin-resistant ovarian
cancer cell line.16 As a result, oxaliplatin has been evaluated
as a single agent and in combination regimens in women with
ovarian carcinoma.
Several trials have evaluated the activity of oxaliplatin in
women with ovarian carcinoma who had been previously treated
with platinum. In 1991, a trial of 15 women resistant to platinum
compounds revealed activity of oxaliplatin in four patients.7
Four larger trials confirmed this activity. In the first of these
trials, 35 women were treated with varying doses of oxaliplatin
(58 to 130 mg/m2) every 3 weeks.8 An overall response rate of
29% was observed in 34 assessable patients. Partial responses
were noted in six of 13 women (46%) and in three of 18 women
(17%) who were platinum-sensitive and platinum-refractory
(defined as having had platinum-free, progression-free intervals
of ⬍ 6 months), respectively. A second study, conducted by the
European Organization for Research and Treatment of Cancer,
involved patients with advanced ovarian cancer who were
previously treated with platinum therapy and then randomly
assigned to receive either paclitaxel or oxaliplatin.9 A total of 86
patients were enrolled; 45 patients received oxaliplatin and 41
patients received paclitaxel. The overall response rate was 16%
in the oxaliplatin arm and 17% in the paclitaxel arm. In women
treated with oxaliplatin, response was seen in five of 13 patients
(38%) and in two of 32 patients (6%) with platinum-free,
progression-free intervals of 6 to 12 months, versus less than 6
months, respectively. Among the platinum-refractory women
treated with paclitaxel, only five of 31 (16%) responded. In a
third study, 42 assessable women were treated with oxaliplatin
130 mg/m2 every 3 weeks. An overall response rate of 26% was
reported, with responses observed in seven of 17 patients (41%),
three of nine patients (33%), and one of 14 patients (7%) with
platinum-free, progression-free intervals of more than 12
months, 6 to 12 months, and less than 6 months, respectively.10
Finally, a fourth study was reported at the 37th Annual Meeting
of the American Society of Clinical Oncology. One hundred
fifty-six women were enrolled onto this study, with 78 patients
receiving either single-agent oxaliplatin or topotecan. The overall response rate was 11.4% in the oxaliplatin arm and 8.9% in
the topotecan arm. In women with platinum-free, progressionfree intervals of less than 6 months, the response rate was 3.9%
(two of 51 patients) and 5.7% (three of 53 patients) for those
treated with oxaliplatin and topotecan, respectively.11 The tox-
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2859
OXALIPLATIN FOR OVARIAN CARCINOMA
icity profile for oxaliplatin in these four studies was acceptable,
with infrequent incidence of grade 3 or 4 hematologic toxicity.
Nausea, vomiting, and peripheral neuropathy occurred at tolerable levels.
Given that single-agent oxaliplatin has demonstrated activity in
advanced ovarian cancer with little hematologic and no renal
toxicity, we proposed a phase II study of this agent in women with
advanced ovarian carcinoma who were previously treated with
platinum. The majority of patients enrolled onto this trial developed
peripheral sensory neuropathy, although only one had grade 3
toxicity that interfered with daily activities. Acute, self-limited
pharyngolaryngeal dysesthesia was also reported within hours after
the oxaliplatin infusion and was observed in approximately one
third of patients on this trial. Other common side effects included
nausea, vomiting, anemia, and constitutional symptoms. Drugrelated renal toxicity was not observed. In addition, no treatmentrelated alopecia or clinical ototoxicity was reported.
In our study, all patients were required to have received at
least one platinum-based chemotherapy and be resistant or
refractory to platinum, as defined by a treatment-free interval of
less than 6 months after platinum treatment, or have documented
progressive disease during platinum-based therapy. Among the
23 assessable women, no complete response occurred. One
woman (4.3%) achieved a partial response to therapy, with a
duration of 6.4 months. Nine patients (39.1%) experienced stable
disease, with a median duration of 5.6 months. This response rate
is consistent with previously published studies of refractory
disease and demonstrates that, in women with platinum-refractory advanced ovarian carcinoma, oxaliplatin has minimal activity as a single agent.8-11 Given its tolerable toxicity profile, future
studies with oxaliplatin in combination with other active agents
in women with platinum-naı̈ve or platinum-sensitive epithelial
ovarian carcinoma may be indicated. The role of oxaliplatin as
an active chemotherapeutic agent has been demonstrated when it
is used alone for treatment of platinum-sensitive disease or is
combined with other medications in women with advanced
ovarian carcinoma.12-15
ACKNOWLEDGMENT
We thank the following individuals for their contributions to this study: S.
Percy Ivy, MD, Cancer Therapy Evaluation Program, Division of Cancer
Treatment, National Cancer Institute, for her assistance in the development
and execution of this study; Teresa J. Vietti, MD, and Sherry A. Goodner,
RN, MA, for editorial assistance; Suzanne Baskerville, GOG Statistical and
Data Center, for data collection and analysis; and Kia Neff and Meg Colahan,
GOG Administrative Office, for their contributions to protocol management.
APPENDIX
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