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NCI CANCERLIT® Search: Therapy of Ovarian Cancer - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
UI - 11735647
AU - Waterhouse D N; Tardi P G; Mayer L D; Bally M B
TI -
A comparison of liposomal formulations of doxorubicin with drug
administered in free form: changing toxicity profiles.
SO - Drug Saf 2001;24(12):903-20
AD - Department of Pathology and Laboratory Medicine, University of British
Columbia, Vancouver, Canada. dsaxon@bccancer.bc.ca
The anthracycline antibiotic doxorubicin has wide activity against a
number of human neoplasms and is used extensively both as a single agent
and in combination regimens. In addition to the use of free,
unencapsulated doxorubicin, there are two US Food and Drug
Administration approved liposomal formulations of doxorubicin currently
available, with several additional liposomal formulations being
researched either in the laboratory or in clinical trials. The two
approved liposomal formulations of doxorubicin have significantly
different lipid compositions and loading techniques, which lead to both
unique pharmacokinetic and toxicity profiles, distinct from those of the
unencapsulated form. This article discusses the toxicities associated
with the free form of doxorubicin, as well as those associated with the
two most common liposomal formulations, namely Doxil and Myocet. One of
the key toxicity issues linked to the use of free doxorubicin is that of
both an acute and a chronic form of cardiomyopathy. This is circumvented
by the use of liposomal formulations, as these systems tend to sequester
the drug away from organs such as the heart, with greater accumulation
in liver, spleen and tumours. However, as will be discussed, the
liposomal formulations of doxorubicin are not without their own related
toxicities, and, in the case of Doxil, may be associated with the unique
toxicity of palmar-plantar erythrodysaesthesia. Overall, the use of
liposomal doxorubicin allows for a greater lifetime cumulative dose of
doxorubicin to be administered, however acute maximal tolerated doses
differ significantly, with that of Myocet being essentially equivalent
to free doxorubicin, while higher doses of Doxil may be safely
administered. This review highlights the differences in both toxicity
and pharmacokinetic properties between free doxorubicin and the
different liposomal formulations, as have been determined in
pre-clinical and clinical testing against a number of different human
neoplasms. The need for further testing of the liposomal formulations
prior to the replacement of free doxorubicin with liposomal doxorubicin
in any established combination therapy regimens, as well as in
combination with the newer therapeutics such as monoclonal antibodies is
also discussed.
2
UI - 11772158
AU - Young M; Plosker GL
TI -
Paclitaxel: a pharmacoeconomic review of its use in the treatment of
ovarian cancer.
SO - Pharmacoeconomics 2001;19(12):1227-59
AD - Adis International Limited, Auckland, New Zealand.
Paclitaxel belongs to the group of antitumour agents called the taxanes.
Its efficacy in advanced ovarian cancer has been established in large,
randomised phase III clinical trials. When used in combination with
cisplatin for first-line treatment of advanced ovarian cancer, it is
superior to cyclophosphamide/cisplatin, with gains in median survival of
around 1 year. Paclitaxel plus carboplatin has similar efficacy to
paclitaxel plus cisplatin. There is now consensus that paclitaxel plus
either carboplatin or cisplatin is the recommended first-line therapy
for patients with advanced ovarian cancer. The particular combination
employed may vary between institutions and geographical regions,
although paclitaxel plus carboplatin is generally better tolerated (i.e.
lower incidence of non-haematological adverse events) than paclitaxel
plus cisplatin and is widely used in many countries. Paclitaxel is also
used as monotherapy in second-line (salvage) treatment of ovarian
cancer. Pharmacoeconomic analyses performed to date have primarily
focused on first-line therapy comparing the combination of
paclitaxel/cisplatin with cyclophosphamide/cisplatin. All studies
incorporated clinical outcomes data, most commonly from the Gynecologic
Oncology Group (GOG) 111 trial, showing a survival advantage for
paclitaxel/cisplatin. These studies report incremental
cost-effectiveness ratios (ICERs) ranging from $US 6395 per additional
life-year gained (LYG) in Spain (1995/96 values) to $US 44,690 per
additional progression-free LYG in France (year of costs not reported).
Five studies were based in the US and Canada and these reported very
similar ICERs of $US 13,135 (year of costs not reported) to $US 25,131
(1993 costs) per additional LYG. In all of these studies the incremental
costs of paclitaxel/cisplatin therapy fall well within the commonly
cited threshold limit of $US 50,000 for new therapies and compare well
with incremental costs reported for other oncological and life-saving
therapies. Patient preferences and quality of life are important issues
due to the short survival of patients with advanced ovarian cancer. Two
cost-utility studies reported similar incremental cost-utility ratios
(ICURs). In the study based on US costs, the ICUR of
paclitaxel/cisplatin treatment was US $18,200 per additional
quality-adjusted life-year (QALY) [1995 drug costs]. In a Canadian study
the ICUR ranged from 11,600 Canadian dollars ($Can) to $Can 24,200 (1996
costs) per additional progression-free QALY depending on the choice of
second-line treatment. CONCLUSIONS: Paclitaxel used in combination with
cisplatin offers survival and utility gains versus cyclophosphamide plus
cisplatin, when used as first-line treatment in patients with stage III
or IV ovarian cancer. The incremental cost for these gains is within the
accepted range for healthcare interventions. However, pharmacoeconomic
analyses of paclitaxel plus carboplatin--a combination widely accepted
for use in women with advanced ovarian cancer and with clinical
advantages over paclitaxel plus cisplatin in terms of ease of
administration and tolerability profile--are currently lacking.
Nevertheless, results of available pharmacoeconomic data support the
clinical use of paclitaxel/platinum combinations, particularly
paclitaxel plus cisplatin, as a first-line chemotherapy treatment option
in patients with advanced ovarian cancer.
3
UI - 11788818
AU - Baum RP; Przetak C
TI -
Evaluation of therapy response in breast and ovarian cancer patients by
positron emission tomography (PET).
SO - Q J Nucl Med 2001 Sep;45(3):257-68
AD - Zentralklinik Bad Berka Clinic of Nuclear Medicine, Center for PET, Bad
Berka, Germany. info@rpbaum.de
Positron emission tomography (PET) has the potential to contribute
significantly to treatment planning and to the evaluation of response to
therapy in patients with cancer. For disease recurrence PET imaging
provides information non-invasively. The final goal is to biologically
characterize an individual patient's tumor and to predict the response
to treatment at the earliest possible time. Since the development of
neoadjuvant chemotherapy, PET has been proved to be the most sensitive
and accurate imaging technique for early therapy response evaluation of
breast tumors. Quantitative and/or semi-quantitative PET studies yield
valuable information in breast cancer regarding prognosis and response
to chemohormontherapy in a timely fashion. In ovarian cancer, up to now
only few studies have been performed applying PET techniques for the
evaluation of treatment response. These preliminary studies indicate
that serial assessment of tumor metabolism by FDG-PET early during
effective chemotherapy may predict subsequent response to such therapy.
PET studies can be repeated without any side-effects and with low
radiation exposure and results can be directly correlated with clinical
laboratory data and histology. The role of PET in the context of patient
management and the cost-effectiveness of this approach needs further
evaluation. Therapy monitoring by PET could help to optimize neoadjuvant
therapy protocols and to avoid ineffective preoperative therapy in
non-responders, but this has to be proven in a larger number of patients
and in different neoadjuvant settings such as chemotherapy, radiation
therapy, hormone therapy or a combination of these.
4
UI - 11781646
AU - Morgan RJ; Doroshow JH; Leong L; Schriber J; Shibata S; Forman S;
TI -
Hamasaki V; Margolin K; Somlo G; Alvarnas J; McNamara M; Longmate J;
Raschko J; Chow W; Vasilev S; McGonigle K; Yen Y
Phase II trial of high-dose intravenous doxorubicin, etoposide, and
cyclophosphamide with autologous stem cell support in patients with
residual or responding recurrent ovarian cancer.
SO - Bone Marrow Transplant 2001 Nov;28(9):859-63
AD - Department of Medical Oncology and Therapeutics Research, City of Hope
National Medical Center, Duarte, CA 91010, USA.
This study was performed in order to evaluate the toxicities,
progression-free and overall survival of patients with responsive
residual or recurrent ovarian cancer treated with high-dose
chemotherapy. Twenty-seven patients were treated. Doxorubicin, 165
mg/m(2) over 96 h (days -12 to -8), etoposide 700 mg/m(2) every day x3
(days -6 to -4), and cyclophosphamide 4.2 g/m(2) on d -3 was followed by
stem cells and granulocyte colony-stimulating factor. The median days of
granulocyte count <500/microl was 14 (range 10-42) and platelets
<20,000/microl was 13 (range 2-80). Median numbers of red cell and
platelet transfusions were 15 (5-16) and 14 (4-103). Toxicity included
mucositis requiring narcotic analgesia in all patients. Asymptomatic
decreases in ejection fraction to values <50% were observed in four
patients. No clinical congestive heart failure was observed. One death
due to sepsis was observed. Median progression-free survival is 7.5
months (1.0-56 months); five patients remain alive, two of whom remain
progression-free at 19.5 and 24.5 months post transplant. Median overall
survival is 14.0 months (1-68 months). We conclude that high-dose
anthracyclines may be safely administered to ovarian cancer patients.
The short overall and progression-free survivals observed in our
population suggest that this combination is not optimal.
5
UI - 11900231
AU - Dimopoulou I; Galani H; Dafni U; Samakovii A; Roussos C; Dimopoulos MA
TI -
A prospective study of pulmonary function in patients treated with
paclitaxel and carboplatin.
SO - Cancer 2002 Jan 15;94(2):452-8
AD - Department of Pulmonary and Critical Care, Evangelismos Hospital,
Medical School, Athens, Greece. idimo@otenet.gr
BACKGROUND: Adverse effects of paclitaxel and carboplatin have been well
described; however, pulmonary toxicity after patients receive this
regimen has not been investigated extensively. METHODS: To clarify this
issue, 33 consecutive patients who were treated with paclitaxel and
carboplatin underwent prospective evaluation of respiratory function,
which included pulmonary symptoms, pulmonary function tests (PFTs),
arterial blood gas levels, and radiographic studies. Assessment was
performed before and after completion of chemotherapy in all patients.
Patients with substantial declines in PFTs, defined as a decline > or =
20 percent in forced expiratory volume in 1 second (FEV1), total lung
capacity (TLC), or diffusion capacity for carbon monoxide (DLCO), were
reassessed 5 months later. RESULTS: After chemotherapy, there were no
significant changes in forced vital capacity (FVC; 111%+/-21% of the
predicted value before chemotherapy vs. 111+/-20% of the predicted value
after chemotherapy), FEV1 (108%+/-24% of the predicted value before
chemotherapy vs. 107%+/-22% of the predicted value after chemotherapy),
FEV1/FVC ratio (79%+/-8% before chemotherapy vs. 78%+/-6% after
chemotherapy), alveolar volume (VA; 95%+/-14% of the predicted value
before chemotherapy vs. 96%+/-14% of the predicted value after
chemotherapy), or TLC (96%+/-14% of the predicted value before
chemotherapy vs. 97%+/-13% of the predicted value after chemotherapy).
In contrast, there was a significant decline in DLCO (101%+/-20% of the
predicted value before chemotherapy vs. 96+/-21% of the predicted value
after chemotherapy; P < 0.05). Arterial blood gas levels did not change
after treatment. No patient had decreased FEV1 or TLC levels by > or =
20%, whereas 4 of 33 patients (12%) exhibited a substantial decline (>
or = 20%) in DLCO that persisted 5 months after treatment (DLCO at
baseline, immediately after chemotherapy, and 5 months after the
completion of chemotherapy, respectively: 99%+/-36% of the predicted
value vs. 75%+/-28% of the predicted value vs. 74%+/-31% of the
predicted value; P < 0.05). None of the 33 patients developed
respiratory symptoms or had radiologic signs suggestive of lung
toxicity. Among the various risk factors examined, baseline DLCO and
FEV1 levels were associated with changes in DLCO post-treatment.
CONCLUSIONS: This prospective analysis showed that the combination of
paclitaxel with carboplatin induced an isolated decrease in DLCO level
in the absence of clinical or radiologic evidence of toxicity. Further
studies are needed to clarify whether this reduction in DLCO is
predictive of subsequent pulmonary impairment.
6
UI - 11870154
AU - Cannistra SA
TI -
Is there a "best" choice of second-line agent in the treatment of
recurrent, potentially platinum-sensitive ovarian cancer?
SO - J Clin Oncol 2002 Mar 1;20(5):1158-60
7
UI - 11870155
AU - Ozols RF
TI -
Recurrent ovarian cancer: evidence-based treatment.
SO - J Clin Oncol 2002 Mar 1;20(5):1161-3
8
UI - 11870165
AU - Cantu MG; Buda A; Parma G; Rossi R; Floriani I; Bonazzi C; Dell'Anna T;
TI -
Torri V; Colombo N
Randomized controlled trial of single-agent paclitaxel versus
cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent
ovarian cancer who responded to first-line platinum-based regimens.
SO - J Clin Oncol 2002 Mar 1;20(5):1232-7
AD - Department of Gynaecology Oncology, Universita degli Studi di
Milano-Bicocca, Ospedale San Gerardo dei Tintori, Monza, Italy.
PURPOSE: To assess the activity, efficacy, and tolerability of
single-agent paclitaxel and a platinum-containing regimen in previously
treated patients with recurrent ovarian cancer. PATIENTS AND METHODS:
Patients who achieved complete remission with platinum-based regimens
and whose disease recurred after a progression-free interval of more
than 12 months were included in the study. Every 21 days, patients
received paclitaxel 175 mg/m(2) intravenously (IV) over 3 hours or
cyclophosphamide 500 mg/m(2), doxorubicin 50 mg/m(2), and cisplatin 50
consecutive patients with assessable or measurable disease were
randomized to paclitaxel (n = 50) or CAP (n = 47). The median number of
cycles on each arm was six. Toxicities included grade 3/4 leukopenia (4%
for paclitaxel v 34% for CAP), grade 3/4 neutropenia (13% v 36%), grade
1/2 myalgia (19% v 4%), allergic reactions (15% v 2%), and grade 2/3
nausea and vomiting (17% v 51%). Complete responses were achieved in 17%
and 30% of patients receiving paclitaxel and CAP, respectively, and
partial responses were achieved in 28% and 25%, respectively (P =.062).
At a median follow-up time of 49 months, median progression-free
intervals were 9 months for paclitaxel and 15.7 months for CAP (Cox
analysis: hazards ratio [HR], 0.60; 95% confidence interval [CI], 0.37
to 0.97; P =.038); median overall survival times were 25.8 months for
paclitaxel and 34.7 months for CAP (Cox analysis: HR, 0.58; 95% CI, 0.34
to 0.98; P =.043). CONCLUSION: Rechallenge with either single-agent
paclitaxel or platinum-based chemotherapy is effective in this patient
population. Preliminary results suggest that single-agent paclitaxel may
not be as active as platinum-based chemotherapy in recurrent ovarian
cancer. Larger randomized trials are needed.
9
UI - 11870166
AU - Dizon DS; Hensley ML; Poynor EA; Sabbatini P; Aghajanian C; Hummer A;
TI -
Venkatraman E; Spriggs DR
Retrospective analysis of carboplatin and paclitaxel as initial
second-line therapy for recurrent epithelial ovarian carcinoma:
application toward a dynamic disease state model of ovarian cancer.
SO - J Clin Oncol 2002 Mar 1;20(5):1238-47
AD - Department of Medicine, Division of Developmental Chemotherapy, and
Department of Gynecologic Oncology, Memorial Sloan-Kettering Cancer
Center, New York, NY.
PURPOSE: The majority of patients with epithelial ovarian cancer (EOC)
who achieve a complete remission with front-line chemotherapy develop
recurrent disease. Carboplatin and paclitaxel are used for patients with
platinum-sensitive recurrent disease, although there is little
information regarding the response and survival in unselected patients
treated with this strategy. We sought to determine the outcomes for
patients with EOC treated with carboplatin and paclitaxel at the time of
first recurrence. In addition, we sought to define a new paradigm for
disease transition in patients with EOC. PATIENTS AND METHODS:
Eighty-nine patients were identified who had a complete response to
front-line platinum-based chemotherapy for EOC, relapsed 6 months after
completion of front-line chemotherapy, and were treated with carboplatin
and paclitaxel as second-line therapy. RESULTS: Eighty-four cases were
available for analysis of survival end points, and 66 were assessable
for response. The median follow-up was 27 months. The overall response
rate was 70%. The median progression-free interval for the cohort was 13
months (95% confidence interval [CI], 10.7 to 13.8 months). The 3-year
survival rate was 72% (95% CI, 59.4 to 86.1%). Toxicity was limited, and
no deaths from treatment were observed. Using this data, it is possible
to construct a disease states model of EOC, which provides risk
estimates for transitions between clinically distinct categories.
CONCLUSION: Re-treatment with carboplatin and paclitaxel is effective as
initial therapy in recurrent EOC. This should form the basis of a
randomized trial to determine the best agents for initial treatment of
relapse from EOC in potentially platinum-sensitive patients.
10
UI - 11870167
AU - Bristow RE; Tomacruz RS; Armstrong DK; Trimble EL; Montz FJ
TI -
Survival effect of maximal cytoreductive surgery for advanced ovarian
carcinoma during the platinum era: a meta-analysis.
SO - J Clin Oncol 2002 Mar 1;20(5):1248-59
AD - Kelly Gynecologic Oncology Service, Department of Gynecology and
Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD
21287-1248, USA. rbristo@jhmi.edu
PURPOSE: To evaluate the relative effect of percent maximal
cytoreductive surgery and other prognostic variables on survival among
cohorts of patients with advanced-stage ovarian carcinoma treated with
platinum-based chemotherapy. MATERIALS AND METHODS: Eighty-one cohorts
of patients with stage III or IV ovarian carcinoma (6,885 patients) were
identified from articles in MEDLINE (1989 through 1998). Linear
regression models, with weighted correlation calculations, were used to
assess the effects on log median survival time of the proportion of each
cohort undergoing maximal cytoreduction, dose-intensity of the platinum
compound administered, proportion of patients with stage IV disease,
median age, and year of publication. RESULTS: There was a statistically
significant positive correlation between percent maximal cytoreduction
and log median survival time, and this correlation remained significant
after controlling for all other variables (P <.001). Each 10% increase
in maximal cytoreduction was associated with a 5.5% increase in median
survival time. When actuarial survival was estimated, cohorts with < or
= 25% maximal cytoreduction had a mean weighted median survival time of
22.7 months, whereas cohorts with more than 75% maximal cytoreduction
had a mean weighted median survival time of 33.9 months--an increase of
50%. The relationship between platinum dose-intensity and log median
survival time was not statistically significant. CONCLUSION: During the
platinum era, maximal cytoreduction was one of the most powerful
determinants of cohort survival among patients with stage III or IV
ovarian carcinoma. Consistent referral of patients with apparent
advanced ovarian cancer to expert centers for primary surgery may be the
best means currently available for improving overall survival.
11
UI - 11870168
AU - Scheuer L; Kauff N; Robson M; Kelly B; Barakat R; Satagopan J; Ellis N;
TI -
Hensley M; Boyd J; Borgen P; Norton L; Offit K
Outcome of preventive surgery and screening for breast and ovarian
cancer in BRCA mutation carriers.
SO - J Clin Oncol 2002 Mar 1;20(5):1260-8
AD - Clinical Genetics, Breast Cancer Medicine, and Developmental
Chemotherapy Services, Department of Medicine, Memorial Sloan-Kettering
Cancer Center, New york, NY 10021, USA.
PURPOSE: To prospectively determine the impact of genetic counseling and
testing on risk-reduction strategies and cancer incidence in a cohort of
individuals at hereditary risk for breast and ovarian cancer. PATIENTS
AND METHODS: Two hundred fifty-one individuals with BRCA mutations were
identified at a single comprehensive cancer center from May 1, 1995,
through October 31, 2000. Uniform recommendations regarding screening
and preventive surgery were provided in the context of genetic
counseling. Patients were followed for a mean of 24.8 months (range, 1.6
to 66.0 months) using standardized questionnaires, chart reviews, and
contact with primary physicians. RESULTS: Frequency of cancer
surveillance by physical examinations and imaging studies increased
after genetic counseling and testing. Twenty-one breast, ovarian,
primary peritoneal, or fallopian tube cancers were detected after
receipt of genetic test results. Among 29 individuals choosing
risk-reducing mastectomy after testing, two were found to have occult
intraductal breast cancers. Among 90 individuals who underwent
risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm
and one early-stage fallopian tube neoplasm were found. Radiographic or
tumor marker-based screening detected six breast cancers, five of which
were stage 0/I, one early-stage primary peritoneal cancer, and three
stage I or II ovarian cancers. Six additional breast cancers were
detected by physical examination between radiographic screening
intervals; four of these six tumors were stage I. No stage III or stage
IV malignancies were detected after genetic testing. CONCLUSION: This
study provides prospective evidence that genetic counseling and testing
increased surveillance and led to risk-reducing operations, which
resulted in diagnosis of early-stage tumors in patients with BRCA1 and
BRCA2 mutations.
12
UI - 11408492
AU - Fracasso PM; Brady MF; Moore DH; Walker JL; Rose PG; Letvak L; Grogan
TI -
TM; McGuire WP
Phase II study of paclitaxel and valspodar (PSC 833) in refractory
ovarian carcinoma: a gynecologic oncology group study.
SO - J Clin Oncol 2001 Jun 15;19(12):2975-82
AD - Department of Medicine, Washington University School of Medicine, St
Louis, MO, USA. fracasso@im.wustl.edu
PURPOSE: A phase II study was conducted to determine the efficacy of
paclitaxel and valspodar (PSC 833) in patients with advanced epithelial
ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D
analogue that reverses P-glycoprotein-mediated multidrug resistance, in
combination with paclitaxel might be active in paclitaxel-resistant and
refractory ovarian cancer. PATIENTS AND METHODS: Patients received
valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m(2)
intravenously for 3 hours) was administered on day 2, 2 hours after the
fifth or sixth dose of valspodar. This treatment was repeated every 21
days. One blood sample was collected before the sixth dose of valspodar
for the first three cycles to evaluate valspodar trough concentration.
Tumor tissue was obtained from patients for immunohistochemical staining
of P-glycoprotein. RESULTS: Of 60 patients entered, 58 were assessable
for response. There were five partial responses (8.6%; 90% confidence
interval [CI], 3.8 to 20.0; median duration of response, 5.0 months
[range, 1.9 to 10.5 months]). Median progression-free survival was 1.5
months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were
neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and
cerebellar ataxia. The trough concentrations of valspodar were > or =
1,000 ng/mL in all but two of 40 patients in the first cycle.
Immunohistochemical staining for P-glycoprotein was positive for one of
two responding patients. CONCLUSION: Valspodar in combination with
paclitaxel has limited activity in patients with paclitaxel-resistant
ovarian carcinoma. An international randomized clinical trial of
paclitaxel and carboplatin with or without valspodar as first-line
therapy in advanced ovarian cancer is underway.
13
UI - 11762813
AU - Misset JL; Vennin P; Chollet PH; Pouillart P; Laplaige PH; Frobert JL;
TI -
Castera D; Fabro M; Langlois D; Cortesi E; Lucas V; Gamelin E; Laadem A;
Otero J
Multicenter phase II-III study of oxaliplatin plus cyclophosphamide vs.
cisplatin plus cyclophosphamide in chemonaive advanced ovarian cancer
patients.
SO - Ann Oncol 2001 Oct;12(10):1411-5
AD - Federation des Services des Maladies Sanguines Immunitaires et
Tumorales, Hjpital Paul Brousse, Villejuif, France.
jean-louis.misset@sls.ap-hop-paris.fr
PURPOSE: A phase II-III randomised study to compare safety and efficacy
of an oxaliplatin/cyclophosphamide (OXAC) combination, vs. the reference
combination of cisplatin/cyclophosphamide (CPC), in untreated advanced
ovarian cancer patients. PATIENTS AND METHODS: 182 patients were
enrolled, of whom 177 were treated: 86 with OXAC (130 mg/m2 oxaliplatin
two-hour intravenous (i.v.) infusion, 1,000 mg/m2 cyclophosphamide
two-hour i.v. infusion), and 91 with CPC (100 mg/m2 cisplatin one-hour
i.v. infusion. 1,000 mg/m2 cyclophosphamide two-hour i.v. infusion).
Treatment cycles were repeated every three weeks (maximum of six
cycles). RESULTS: The main toxicities, which were significantly less
severe in the OXAC arm, were myelosuppression and vomiting, including
(OXAC vs CPC, % patients): grade 3-4 leukopenia (37% vs. 56%), and
anaemia (7% vs. 32%), with blood transfusions in 8% vs. 21%. In the OXAC
arm, 64% of surgically assessable patients and 33% of clinically
assessable patients achieved an objective response. In the CPC arm, 67%
patients achieved a surgical response and 42% achieved an objective
clinical response. In the OXAC and CPC arms, median progression
free-survival was 13.0 and 13.3 months, and overall survival was 36.0
and 25.1 months respectively, without statistically significant
difference. CONCLUSION: The activity and time-related parameters of the
OXAC and CPC combinations in advanced ovarian cancer patients, are
comparable. Combined with the better safety profile of the
oxaliplatin-containing regimen, this confirms the interest of
oxaliplatin combined with active new agents in this indication.
14
UI - 11823045
AU - Bagnis C; Chabannon C; Gravis G; Imbert AM; Maroc C; Bardin F; Ladaique
TI -
P; Viret F; Genre D; Faucher C; Stoppa AM; Vey N; Blaise D; Maraninchi
D; Viens P; Mannoni P
Transient detection of beta-galactosidase activity in hematopoietic
cells, following reinjection of retrovirally marked autologous blood
progenitors in patients with breast or ovarian cancer receiving
high-dose chemotherapy.
SO - Exp Hematol 2002 Feb;30(2):108-15
AD - Institut Paoli-Calmettes, Centre Regional de Lutte Contre le Cancer
Provence-Alpes-Cote d'Azur, Marseille, France.
OBJECTIVE: The aim of this report is to demonstrate the feasibility and
safety of genetically modifying autologous human blood CD34(+) cells in
vitro, with a retroviral vector that encodes a marker gene. The fate of
genetically modified cells and their progeny was followed in vivo, after
reinfusion in patients treated with high-dose chemotherapy for
poor-prognosis breast or ovarian carcinomas. PATIENTS AND METHODS: Six
patients received genetically modified autologous peripheral blood
progenitors, together with unmanipulated aphereses, following high-dose
chemotherapy. CD34(+) cells were immunoselected from aphereses, and
retrovirally transduced by coculture with the retroviral vector
producing cell line, to express a nuclear localized version of E. coli
beta-galactosidase, encoded by a defective Moloney-murine leukemia
virus-derived retroviral vector. Cells were reinfused to the patients
after myeloablation, without prior ex vivo selection. RESULTS: Five out
of six patients showed the transient presence of low numbers of
beta-galactosidase(+) cells, as detected with an immunocytochemical
assay, in the peripheral blood, during the first month following
infusion. One patient had beta-galactosidase(+) clonogenic progenitors
in her marrow at two months after transplantation, including HPP-CFC;
intriguingly, this patient had the lowest percentage of X-gal(+) cells
in her graft. Patients experienced side effects that are often observed
after high-dose chemotherapy. CONCLUSIONS: Feasibility and safety of
genetic modification of human hematopoietic stem and progenitor cells
are demonstrated by this study. Ex vivo or in vivo selection is not
mandatory, even in clinical situations where transduced cells have no
survival advantage over wild-type cells; however, significant
improvements in gene transfer technology are needed to achieve
potentially useful levels of expression in such clinical situations.
15
UI - 11801569
AU - Kanerva A; Mikheeva GV; Krasnykh V; Coolidge CJ; Lam JT; Mahasreshti PJ;
TI -
Barker SD; Straughn M; Barnes MN; Alvarez RD; Hemminki A; Curiel DT
Targeting adenovirus to the serotype 3 receptor increases gene transfer
efficiency to ovarian cancer cells.
SO - Clin Cancer Res 2002 Jan;8(1):275-80
AD - Division of Human Gene Therapy, Departments of Medicine, Pathology, and
Surgery and the Gene Therapy Center, University of Alabama at
Birmingham, 35294-3300, USA.
Gene delivery efficiency in clinical cancer gene therapy trials with
recombinant adenoviruses (Ads) based on serotype 5 (Ad5) has been
limited partly because of variable expression of the primary Ad5
receptor, the coxsackie and adenovirus receptor (CAR), on human primary
cancer cells. As a means of circumventing CAR deficiency, Ad vectors
have been retargeted by creating chimeric fibers possessing knob domains
of alternate Ad serotypes. In this study, we have constructed an
Ad5-based vector, Ad5/3luc1, with a chimeric fiber protein featuring a
knob domain derived from Ad3. This virus is retargeted to the Ad3
receptor and, therefore, has different tissue tropism. A novel knob
binding assay was used to measure expression of CAR and the Ad3
receptor. Further, to evaluate the correlation of receptor expression
and infectivity by Ad, a panel of ovarian cancer cell lines and purified
primary cancer cells were infected with Ad5luc1 and Ad5/3luc1 at 50,
200, and 1000 viral particles/cell. Our results confirm that Ad5/3luc1
is retargeted to the Ad3 receptor. Furthermore, the Ad3 receptor is
present at higher levels than CAR on ovarian adenocarcinoma cells. Also,
the amount of binding to primary receptor appears to be the major factor
determining the efficiency of transgene expression. The Ad5/3 chimera
displays enhanced infectivity for ovarian cancer cell lines and purified
primary tumor cells, which could translate into increased efficacy in
clinical trials.
16
UI - 11801533
AU - Mills GB
TI -
Mechanisms underlying chemoprevention of ovarian cancer.
SO - Clin Cancer Res 2002 Jan;8(1):7-10
17
UI - 11697814
AU - Distefano M; Ferlini C; De Vincenzo R; Gaggini C; Mancuso S; Scambia G
TI -
Antagonistic effect of the combination gemcitabine/topotecan in ovarian
cancer cells.
SO - Oncol Res 2001;12(9-10):355-9
AD - Department of Obstetrics and Gynecology, Catholic University of the
Sacred Heart, Rome, Italy.
The in vitro interaction between the new antimetabolite gemcitabine
(GEM) and topotecan (TPT) was analyzed in A2780 ovarian cancer cells.
The growth inhibitory effect was assessed after 3 days of drug exposure.
GEM and TPT obtained in vitro IC50 values of 2.1 +/- 0.9 and 33.7 +/-
10.2 nM, respectively. The interaction between GEM and TPT was evaluated
by exposing cancer cells at increasing doses of GEM (0.1, 1, and 10 nM)
and TPT (1, 10, 100, and 1000 nM). Analysis of data about the
interaction between GEM and TPT was performed by applying the isobole
method. An antagonistic effect was noticed when GEM was combined with
TPT in the tested concentration range. DNA analysis was also performed
and showed an augmentation of cells blocked in the G2/M phase during TPT
exposure, while an increase of blocked cells in the G0/1, phase was
observed after GEM treatment. This latter effect was predominant when
the two drugs were used in combination. We also investigated the effect
of sequential exposure to drugs, pretreating A2780 cells for 24 h with
TPT and then for 48 h with GEM, and, conversely, pretreating A2780 cells
with GEM for 24 h and thereafter with TPT for 48 h. Both these combined
sequential treatments showed an antagonist effect of the drugs'
combination. Long-term growth inhibition effect was established by
clonogenic assay performed after 10 days of culture after drug
treatment. Also these data confirmed the antagonistic effect between GEM
and TPT in A2780 ovarian cancer cells.
18
UI - 11898145
AU - Mahon SM; Williams MT; Spies MA
TI -
Screening for second cancers and osteoporosis in long-term survivors.
SO - Cancer Pract 2000 Nov-Dec;8(6):282-90
AD - Saint Louis University, Division of Hematology/Oncology, P.O. Box 15250,
St. Louis, MO 63110-0250, USA.
PURPOSE: The purpose of this preliminary study was to describe the
extent to which healthcare providers recommend the screening strategies
for early detection described by the American Cancer Society (ACS), for
breast, gynecologic, and colorectal cancer, and by the National
Osteoporosis Foundation (NOF), for osteoporosis, to women who are
long-term survivors of breast, ovarian, or endometrial cancer.
DESCRIPTION OF THE STUDY: A four-part survey was developed for this
study, with the first three parts based on the ACS guidelines for
breast, gynecologic, and colorectal cancer screening and the NOF
guidelines for osteoporosis screening. The fourth part related to
personal characteristics, setting, knowledge, and perceptions of the
nurses surveyed. A random sample of outpatient nurses was obtained from
the Oncology Nursing Society. Of 668 nurses, 321 (48%) responded
(Oncology Certified Nurse (OCN) 68.1%; Advanced Oncology Certified Nurse
(AOCN) 16.6%). RESULTS: The most consistently performed screenings that
were reported were mammogram (range 74.2-87.7%), professional breast
examination (range 73.9-83.7%), and Pap test and pelvic examination
(range 61.8-85.2%). The least frequently performed screenings are
flexible sigmoidoscopy/colonoscopy (range 20.2-27.7%), bone mineral
density testing (range 16.9-19.0%), and height measurement (range
22.5-28.3%). Less than one third of survivors are offered counseling on
strategies to promote bone health. CLINICAL IMPLICATIONS: Knowledge of
factors associated with osteoporosis and the use of screening strategies
for second malignancies in survivors of breast, ovarian, and endometrial
cancers can be used to implement activities such as patient education
and clinical practice protocols that will increase the use of current
screening recommendations.
19
UI - 11896105
AU - Vasey PA; Shulman LN; Campos S; Davis J; Gore M; Johnston S; Kirn DH;
TI -
O'Neill V; Siddiqui N; Seiden MV; Kaye SB
Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted
adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in
patients with recurrent/refractory epithelial ovarian cancer.
SO - J Clin Oncol 2002 Mar 15;20(6):1562-9
AD - Beatson Oncology Centre and Stobhill Hospital, Glasgow, United Kingdom.
pav1y@clinmed.gla.ac.uk
PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently
associated with mutations in the p53 gene. The adenovirus dl1520
(ONYX-015) with the E1B 55-kd gene deleted, allowing selective
replication in and lysis of p53-deficient tumor cells, has shown
preclinical efficacy against p53-deficient nude mouse-human ovarian
carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I
trial of intraperitoneal dl1520 in patients with recurrent ovarian
cancer. Sixteen women with recurrent/refractory ovarian cancer received
35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5
in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10)
pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common
significant toxicities related to virus administration were flu-like
symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10)
pfu developed common toxicity criteria grade 3 abdominal pain and
diarrhea, which was dose-limiting. The maximum-tolerated dose was not
reached at 10(11) pfu, and at this dose level patients did not
experience significant toxicity. There was no clear-cut evidence of
clinical or radiologic response in any patient. Blood samples were taken
for adenovirus DNA and neutralizing antibodies. Polymerase chain
reaction data indicating presence of virus up to 10 days after the final
(day 5) infusion of dl1520 are suggestive of continuing viral
replication. CONCLUSION: This article therefore describes the first
clinical experience with the intraperitoneal delivery of any
replication-competent/-selective virus in cancer patients.
20
UI - 11822989
AU - Paley PJ
TI -
Angiogenesis in ovarian cancer: molecular pathology and therapeutic
strategies.
SO - Curr Oncol Rep 2002 Mar;4(2):165-74
AD - Department of Obstetrics and Gynecology, University of Washington School
of Medicine, Box 356460, Seattle, WA 98195, USA. ppaley@u.washington.edu
Ovarian cancer claims the lives of more women in North America each year
than all other gynecologic malignancies combined. Despite the high
initial response rates of patients with advanced ovarian cancer to
aggressive primary surgical debulking followed by combination
chemotherapy, the majority of patients will ultimately develop disease
recurrence. The high risk of relapse and nearly guaranteed incurability
after relapse is due to genetic instability and a high mutation rate of
neoplastic cells that together allow for a high risk of selection for
drug resistance. Given the seemingly insurmountable obstacle that
acquired drug resistance presents in a setting of minimal, often
undetectable, residual tumor burden in women with ovarian cancer,
antiangiogenic-targeted therapies offer an attractive strategy for
enhanced long-term disease-free survival. The past decade has witnessed
a substantial proliferation in our knowledge regarding tumor
angiogenesis, which has spurred interest in antiangiogenesis drug
development. Current clinical trials are evaluating these agents in a
variety of solid tumors, including ovarian cancer. Preliminary work has
provided hope that the addition of antiangiogenic therapies may be
incorporated into the treatment of women afflicted with ovarian cancer
and may translate into enhanced survival.
21
UI - 1960550
AU - Pai LH; Bookman MA; Ozols RF; Young RC; Smith JW 2nd; Longo DL; Gould B;
TI -
Frankel A; McClay EF; Howell S; et al
Clinical evaluation of intraperitoneal Pseudomonas exotoxin
immunoconjugate OVB3-PE in patients with ovarian cancer.
SO - J Clin Oncol 1991 Dec;9(12):2095-103
AD - Laboratory of Molecular Biology, National Cancer Institute, National
Institutes of Health, Bethesda, MD 20892.
OVB3-PE is an immunotoxin composed of a murine monoclonal antibody
reactive with human ovarian cancer and conjugated to Pseudomonas
exotoxin (PE). Twenty-three patients with refractory ovarian cancer were
treated intraperitoneally (IP) with escalating doses of OVB3-PE to study
toxicity, pharmacokinetics, antiimmunotoxin antibody formation, and
antitumor response. Dose-limiting CNS toxicity occurred after repeated
doses at 5 and 10 micrograms/kg. Other non-dose-limiting toxicities
included transient elevation of liver enzymes, fever, and
gastrointestinal toxicity. Pharmacokinetics of IP and serum OVB3-PE were
determined in 16 patients. Peak peritoneal fluid levels exceeded the in
vitro median effective dose at all doses tested. At doses of 1 to 2
micrograms/kg, the immunotoxin concentration in the peritoneal fluid
remained constant for up to 8 hours and dropped to negligible levels
after 12 hours. At the 5 and 10 micrograms/kg doses, levels remained
high for up to 24 hours (greater than 100 ng/mL) and then gradually
decreased and became undetectable (less than 4 ng/mL) after 72 hours.
Serum levels of OVB3-PE were also analyzed in 16 patients. At doses of 1
micrograms/kg and 2 micrograms/kg, serum levels were not detectable
(less than 5 ng/mL). However, after doses of 5 or 10 micrograms/kg, peak
serum level occurred at 24 hours after each dose and dropped to
negligible levels by 72 hours. Sera from 12 patients were analyzed for
anti-PE antibodies and antibodies to mouse immunoglobulin (HAMA). All
patients developed antibodies against PE within 14 days of therapy.
Domain II of PE appeared to be the most immunogenic portion of the PE
molecule. HAMA was detected on day 14 of therapy in nine patients, on
day 21 in two, and on day 28 in one patient. No clinical antitumor
responses were observed. We conclude that IP OVB3-PE at dose levels of 5
micrograms/kg (x 3) and 10 micrograms/kg (x 2) is accompanied by
dose-limiting toxic encephalopathy. Neurologic toxicity is likely to be
due to crossreactivity of OVB3 to normal human brain tissue, which was
not appreciated during preclinical screening.
22
UI - 2981613
AU - Pirker R; FitzGerald DJ; Hamilton TC; Ozols RF; Willingham MC; Pastan I
TI -
Anti-transferrin receptor antibody linked to Pseudomonas exotoxin as a
model immunotoxin in human ovarian carcinoma cell lines.
SO - Cancer Res 1985 Feb;45(2):751-7
The present in vitro study was performed to evaluate the potential
usefulness of immunotoxins in treating human ovarian carcinomas. A
monoclonal antibody against the human transferrin receptor was
covalently linked to Pseudomonas exotoxin. The activity of this
immunotoxin (anti-TFR-PE) was studied in five ovarian carcinoma cell
lines, a breast carcinoma cell line (MCF-7), and in KB cells. The
ovarian carcinoma cell lines included one previously established cell
line (A1847) and four recent isolates obtained from the malignant
ascites of patients with metastatic ovarian carcinoma (OVCAR cell
lines). While all cell lines showed inhibition of protein synthesis by
anti-TFR-PE, there were quantitative differences when the level of
protein synthesis was assayed after a 12-hr incubation with the
immunotoxin. These differences resulted from different kinetics of
anti-TFR-PE activity in the various cell lines. Higher levels of
cellular binding and internalization of anti-TFR were shown to
contribute to increased toxicity of anti-TFR-PE. Verapamil increased the
rate of protein synthesis inhibition and thus enhanced the toxicity of
anti-TFR-PE in the OVCAR cell lines.
23
UI - 3930572
AU - Pirker R; FitzGerald DJ; Hamilton TC; Ozols RF; Laird W; Frankel AE;
TI -
Willingham MC; Pastan I
Characterization of immunotoxins active against ovarian cancer cell
lines.
SO - J Clin Invest 1985 Sep;76(3):1261-7
The purpose of the present study was to develop immunotoxins directed
against human ovarian carcinoma cells. Four monoclonal antibodies
(260F9, 454C11, 280D11, and 245E7) were chosen because they were found
to bind to various ovarian carcinoma cell lines. These antibodies were
covalently linked to either Pseudomonas exotoxin (PE) or ricin A chain
(RTA), and the conjugates were tested against five ovarian cancer cell
lines (OVCAR-2, -3, -4, -5; A1847). The ability of the immunotoxins to
inhibit both protein synthesis and colony formation was evaluated.
Qualitatively similar results were obtained for both types of assays.
Usually, PE conjugates were more toxic than their corresponding RTA
conjugates. 454C11-PE was very toxic for all ovarian carcinoma lines,
whereas 454C11-RTA had low activity. Both 260F9-PE and 260F9-RTA were
active in all OVCAR cell lines but not in A1847 cells. 280D11-PE was
toxic for OVCAR-4; otherwise, 280D11-PE and RTA conjugates of both
280D11 and 245E7 had little activity. Specificity of immunotoxin action
was shown by competition by excess antibody, nontoxicity in nontarget
cells, and inactivity of an irrelevant immunotoxin. To investigate the
basis of antibody-dependent differences in activity of the various
immunotoxins, antibody uptake was studied in OVCAR-2 cells, and the
results indicate that antibody internalization is one important factor
in the activity of immunotoxins.
24
UI - 9170525
AU - Kimura E; Niimi S; Watanabe A; Tanaka T
TI -
[Clinical effect of two azasetron treatment methods against nausea and
vomiting induced by anticancer drugs including CDDP]
SO - Gan To Kagaku Ryoho 1997 May;24(7):855-9
AD - Dept. of Obstetrics and Gynecology, Jikei University School of Medicine.
Azasetron, a selective 5-HT3 receptor antagonist, has been previously
shown to be highly effective in the prophylaxis of nausea and vomiting
induced by anticancer drugs, and is widely used in the clinical setting
in Japan. In order to improve the antiemetic effect of azasetron, we
designed two treatment methods using this drug and compared the
antiemetic effect of this method with that of standard bolus intravenous
injection on nausea and vomiting associated with anticancer drug
including 75 mg/m cisplatin (CDDP). The two-treatment group received an
intravenous bolus injection of 5 mg azasetron before and 8 hours after
the start of chemotherapy, and a standard group was given an intravenous
bolus injection of 10 mg azasetron only once a day. The inhibitory
effect on vomiting in the two-treatment group was significantly greater
than those of the standard group on day 1 and 2 (p = 0.0458, p =
0.0273), and the inhibitory effect on nausea of the two-treatment group
tended to be superior those of the bolus group on day 2 (p = 0.0533). No
adverse effects were observed in either group of this study. From these
data, the two-treatment approach was considered to be highly effective
in prophylaxis of nausea and vomiting induced by anticancer drug.
25
UI - 9233776
AU - Brown R; Hirst GL; Gallagher WM; McIlwrath AJ; Margison GP; van der Zee
TI -
AG; Anthoney DA
hMLH1 expression and cellular responses of ovarian tumour cells to
treatment with cytotoxic anticancer agents.
SO - Oncogene 1997 Jul 3;15(1):45-52
AD - Department Medical Oncology, CRC Beatson Laboratories, Glasgow
University, UK.
Loss of expression of the hMLH1 and hPMS2 subunits of the MutL
alpha-mismatch repair complex is a frequent event (9/10) in independent
cisplatin resistant derivatives of a human ovarian carcinoma cell line.
However, only hMLH1 mRNA is decreased in these MutL alpha-deficient
lines. No alterations in the levels of the hMSH2 and hMSH6 (GTBP)
subunits of the MutS alpha-complex are observed. An increase in the
proportion of ovarian tumours negative for the hMLH1 subunit is observed
in samples taken at second look laparotomy after chemotherapy (36%:
4/11), compared to untreated tumours (10%: 4/39). No significant
difference is observed for hMSH2, hMS
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