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Abramson Cancer CenterNCI CANCERLIT® Search: Therapy of Ovarian Cancer - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
UI - 11148564
AU - Safra T; Groshen S; Jeffers S; Tsao-Wei DD; Zhou L; Muderspach L; Roman
TI -
L; Morrow CP; Burnett A; Muggia FM
Treatment of patients with ovarian carcinoma with pegylated liposomal
doxorubicin: analysis of toxicities and predictors of outcome.
SO - Cancer 2001 Jan 1;91(1):90-100
AD - Department of Medical Oncology, Kenneth Norris Jr. Comprehensive Cancer
Center, University of Southern California, Los Angeles, California, USA.
BACKGROUND: Pegylated liposomal doxorubicin is a new formulation with
activity against epithelial ovarian carcinoma (EOC). The authors sought
to determine patient characteristics that may predict for response to
this treatment and favorable time to failure as well as survival.
METHODS: Eight patients in a Phase I study and 44 patients in two
consecutive Phase II studies who were treated with pegylated liposomal
doxorubicin (40-60 mg/m2 every 3 weeks for the first two cycles and 40
mg/m2 every 4 weeks thereafter) after failing initial platinum-based
chemotherapies for ovarian carcinoma were analyzed. Associations were
sought for response, time to failure (TTF), and survival after the
treatment and various pretreatment characteristics. RESULTS: Treatment
with pegylated liposomal doxorubicin yielded 23% objective responses in
measurable disease and 31% overall responses, including serum CA
125-defined responses. The median TTF was 5.2 months (95% confidence
interval, 4.1-6.9 months) in all patients, and the median response
duration in all responders was 13.2 months (95% confidence interval,
11.9-18.5 months). The overall median survival was 15 months (95%
confidence interval, 11-40 months). The main predictive factors were
tumor size and baseline hemoglobin level for TTF, and these plus
Karnofsky performance status were the main predictive factors for
survival. CONCLUSIONS: Pegylated liposomal doxorubicin is an effective
drug when it is given as secondary therapy to patients with EOC. Lack of
bulky disease is the major predictor for a favorable response, TTF, and
survival. The role of this treatment in combination with other effective
drugs should be explored in both previously treated and untreated
patients with ovarian carcinoma. Copyright 2001 American Cancer Society.
2
UI - 11369252
AU - Markman M
TI -
Intraperitoneal chemotherapy is appropriate first line therapy for
patients with optimally debulked ovarian cancer.
SO - Crit Rev Oncol Hematol 2001 Jun;38(3):171-5
AD - Department of Hematology/Medical Oncology, The Cleveland Clinic
Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
markmam@ccf.org
The intraperitoneal administration of antineoplastic agents in the
front-line treatment of advanced ovarian cancer is a rational strategy,
based on anatomic and pharmacokinetic considerations, as well as an
understanding of the natural history of the malignancy. Phase 1 and 2
clinical trial data have supported the potential role for this unique
method of drug delivery as a safe and effective management approach in
this clinical setting. Two randomized phase 3 trials have demonstrated a
favorable impact of cisplatin-based front-line intraperitoneal therapy
on survival for patients with 'optimal residual' advanced ovarian
cancer. However, for several reasons, additional investigative efforts
are required to convince oncologists the time, effort and potential
toxicity of intraperitoneal therapy justify its routine use as initial
therapy of this malignancy.
3
UI - 11432612
AU - Aebi S; Castiglione-Gertsch M
TI -
High-dose chemotherapy for ovarian cancer: are we ready to go?
SO - Ann Oncol 2001 May;12(5):583-4
4
UI - 11432630
AU - Ledermann JA; Herd R; Maraninchi D; Viens P; Buclon M; Philip T; Cure H;
TI -
Lotz JP; Chauvin F; Ferrante P; Rosti G
High-dose chemotherapy for ovarian carcinoma: long-term results from the
Solid Tumour Registry of the European Group for Blood and Marrow
Transplantation (EBMT).
SO - Ann Oncol 2001 May;12(5):693-9
AD - Department of Oncology, Royal Free & University College Medical School,
UCL, London, UK. j.ledermann@ucl.ac.uk
PURPOSE: to determine the outcome of epithelial ovarian cancer in
patients registered with the European Group for Blood and Marrow
Transplantation (EBMT). PATIENTS AND METHODS: A retrospective analysis
was performed on 254 patients with advanced or recurrent disease, median
age 46 years (14-63) from 39 centres treated between 1982 and 1996. Only
25% of patients were known to have no or microscopic disease after
initial surgery; in approximately 20% the disease status was unknown,
the remainder had macroscopic disease. RESULTS: One hundred five
patients received high-dose chemotherapy in complete or very good
partial remission, twenty-seven in second remission and the remainder in
the presence of residual disease. Most received melphalan or
carboplatin, or a combination (86%) supported by autologous bone marrow
or peripheral blood stem cells. The survival of patients treated in
remission was significantly better than in other groups (median 33 vs.
14 months; P = 0.0001). The durability of remission was longer after
transplantation in first remission than in second remission (median
disease-free survival 18 vs. 9 months; P = 0.005). With a median
follow-up of 76 months from diagnosis the median disease-free and
overall survival in stage III disease transplanted in remission is 42
and 59 months and for stage IV disease 26 and 40 months. CONCLUSIONS:
High-dose chemotherapy has a potential benefit for patients in
remission. The results support the conduct of randomised studies to
determine whether there is a real value from this treatment.
5
UI - 11446487
AU - Boardman CH; Webb MJ
TI -
Surgery in ovarian cancer.
SO - Eur J Gynaecol Oncol 2001;22(2):89-95
AD - Section of Gynecologic Surgery, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota 55905, USA.
The role of surgery in the management of primary and recurrent ovarian
cancer is reviewed. The data to support primary and secondary
cytoreduction are summarized. The role of second-look surgery and of
surgery in the palliation of ovarian cancer is also discussed.
6
UI - 11465869
AU - Markman M
TI -
Intraperitoneal drug delivery of antineoplastics.
SO - Drugs 2001;61(8):1057-65
AD - The Cleveland Clinic Taussig Cancer Center, Department of
Hematology/Medical Oncology, The Cleveland Clinic Foundation, Ohio
44195, USA. markmam@ccf.org
The administration of antineoplastic agents directly into the peritoneal
cavity as treatment of localised cancer is based on sound
pharmacokinetic principles. This unique technique has to the potential
to optimise outcome in settings where preclinical and clinical data
suggest that cytotoxicity of a specific drug against a particular tumour
type is enhanced by either increasing the drug concentration or duration
of exposure. Phase I trials have confirmed the safety and
pharmacokinetic advantage for a number of agents delivered by the
intraperitoneal relative to the systemic route, including cisplatin (10-
to 20-fold advantage for regional delivery), carboplatin (10- to 20-fold
advantage), and paclitaxel (1,000-fold advantage). In phase II trials,
performed mostly in patients with ovarian cancer, this approach has
achieved objective responses in settings where intravenous drug delivery
has not achieved the desired effect (e.g. surgically documented complete
response using intraperitoneal cisplatin as second-line therapy of
ovarian cancer). Phase III trials employing intraperitoneal cisplatin as
initial treatment of small volume advanced ovarian cancer have
demonstrated that regional therapy results in a modest, but
statistically significant, improvement in both progression-free and
overall survival compared to intravenous cisplatin. Further exploration
of this novel method of treatment, including the conduct of definitive
randomised phase III clinical trials, is indicated in ovarian cancer and
in other tumour types where clinical manifestations are principally
localised to the peritoneal cavity.
7
UI - 11465872
AU - Gibbs DD; Gore ME
TI -
Pursuit of optimum outcomes in ovarian cancer: methodological approaches
to therapy.
SO - Drugs 2001;61(8):1103-20
AD - Department of Medicine, The Royal Marsden Hospital, London, England.
The treatment of ovarian cancer is an evolving area and important
clinical questions remain unanswered at all stages from early disease to
relapse. This review outlines current practice at each disease stage,
some of the current unanswered questions and issues surrounding the
design of clinical trials to answer these questions. The gold standard
test for new treatments must remain the randomised controlled trial with
survival as the major endpoint because other outcome measures such as
radiological response do not bear a strong relationship to survival.
Patient factors greatly influence the likelihood of response to
treatment and subsequent survival, hence failure to control for these in
trial design may lead to spurious results. Quality of life is an
important endpoint but quality-of-life measures in clinical trials
should be interpreted carefully. The introduction of novel, target
directed anticancer therapies will require new study designs as the
phase I/II/III paradigm may not be relevant. It is current practice to
offer adjuvant chemotherapy to women with early stage disease who are
considered at high risk of relapse despite conflicting evidence from
clinical trials. Current questions include the optimal choice of regimen
and the duration of treatment. However, the relative rarity of early
stage disease and the likely small difference between treatments makes
evaluations difficult. Advanced disease is currently treated using a
combination of surgical cytoreduction and platinum-paclitaxel
chemotherapy. Women with poor risk disease are unlikely to be cured of
their disease and the investigation of strategies to minimise treatment
may be appropriate. Conversely, women with good risk disease may be
better candidates for experimental treatment to increase cure rate.
Strategies that have been tried include dose-intensification, high-dose
therapy and intraperitoneal therapy. Whereas there is some evidence to
support the latter, there is no current evidence for
dose-intensification or high-dose therapy, and these must remain areas
of investigation. Most current trials investigate the addition of agents
to platinum-paclitaxel. Relapsed disease is an important area. Despite
this, only 9 randomised controlled trials have been undertaken.
Uncertainties exist in the role of surgery, both surgical cytoreduction
and palliative surgery. The mainstay of treatment at disease relapse is
chemotherapy and the choice of agent revolves around the concept of
platinum sensitivity. Many agents are active in platinum-resistant
disease, but uncertainties remain about the relative efficacies of each
and the place of combination therapy.
8
UI - 11499692
AU - Anonymous
TI -
Docetaxel/carboplatin combination produces impressive response in
ovarian cancer patients.
SO - Oncology (Huntingt) 2001 Jul;15(7):920
9
UI - 11489506
AU - Tijerina M; Kopeckova P; Kopecek J
TI -
The effects of subcellular localization of
N-(2-hydroxypropyl)methacrylamide copolymer-Mce(6) conjugates in a human
ovarian carcinoma.
SO - J Control Release 2001 Jul 6;74(1-3):269-73
AD - Department of Pharmaceutics and Pharmaceutical Chemistry, University of
Utah, 30 South 2000 East, Room 301, Salt Lake City, UT 84112, USA.
Photosensitizers, light-sensitive compounds, become activated upon
illumination with a specific wavelength of light generating cytotoxic
oxygen species. Due to the short half-life of singlet oxygen, the
subcellular site of localization and excitation affects the type of
cellular damage produced as well as cellular responses to different
types of photodamage created within the cell. Here, we investigated the
effects of N-(2-hydroxypropyl)methacrylamide (HPMA)
copolymer-mesochlorin e(6) monoethylenediamine (Mce(6)) conjugates
localized to different subcellular compartments. Temperature was
utilized to achieve subcellular localization of conjugates and
subcellular fractionation was performed to confirm localization patterns
of HPMA copolymer-Mce(6) conjugates. Cytotoxicity studies suggest plasma
membrane and late endosomes were more sensitive to photodamage than
lysosomal compartments as observed by an approximate 2-fold decrease in
the IC(50) compared to lysosomally accumulated conjugate. Releasing
Mce(6) from the polymer backbone within lysosomal compartments
significantly lowered the IC(50) when compared to HPMA copolymer
conjugates with Mce6 bound via a nondegradable linkage. These
differences will prove useful in the future design of HPMA
copolymer-Mce(6) conjugates for the treatment of ovarian cancer.
10
UI - 11501778
AU - Trope C; Kristensen G; Kisic J; Kaern J
TI -
Long-term results from a phase II study of paclitaxel combined with
doxorubicin in recurrent platinum refractory ovarian cancer.
SO - Eur J Gynaecol Oncol 2001;22(3):223-7
AD - Department of Gynecologic Oncology, The Norwegian Radium Hospital,
Montebello, Oslo.
BACKGROUND: There is still a need for newer non-cross-resistant agents
and combinations to be tried in cases of failure after first line
platinum-based therapy. Several agents have demonstrated activity after
failure of platinum-containing regimens. Response rate in true platinum
refractory disease up to 20% but with poor long-term survival, has been
reported by single drug paclitaxel. In an effort to improve response
rate and survival duration obtainable with single drug paclitaxel, we
have combined paclitaxel with doxorubicin for the treatment of patients
refractory to cisplatin-cyclophosphamide. PATIENTS AND METHODS: Between
cisplatin-cyclophosphamide were enrolled for toxicity and survival
analysis after receiving the combination doxorubicin 50 mg/m2 and
paclitaxel 135 mg/m2 every third week for four courses. Responding
patients continued on single drug paclitaxel 175 mg/m2 every third week
until unacceptable toxicity or tumor progression occurred. RESULTS: The
objective response rate (CR + PR) was 33%, 95% CI (14.6-57). The median
duration of response was 8.5 months (range 4.0-62.5+) and the median
overall survival was 15.5 months (range 4.0-63.5+). No serious toxicity
was registered. CONCLUSION: Doxorubicin combined with paclitaxel could
safely be administered using this schedule. This study shows that some
patients obtaining CR can be rendered disease-free for a substantial
period of time, sometimes five years or more. A median overall survival
of 15.5 months with a 5-year survival probability of 15% is impressive.
However, although responses can be induced in a significant number of
patients, the survival figures remain poor.
11
UI - 11501784
AU - Elsheikh A; Milingos S; Kallipolitis G; Loutradis D; Vlachos G; Liapi A;
TI -
Michalas S
Ovarian tumors in young females. A laparoscopic approach.
SO - Eur J Gynaecol Oncol 2001;22(3):243-4
AD - 1st Department of Obstetrics & Gynecology, University of Athens,
Alexandra Hospital, Greece.
Ovarian tumors are one of the major preoccupations in the everyday
2000, 54 cases of ovarian tumors in young females aged 14-20 years were
diagnosed and managed laparoscopically in our institution. Twenty-two
cases of mature cystic teratoma, 12 cases of endometriosis, eight cases
of serous cystadenoma, five cases of mucinous cystadenoma, three cases
of fibroma-thecoma, two cases of serous low-malignant tumors and one
case of mucinous low-malignant tumor were found. The management of
ovarian tumors during this age by laparoscopic techniques represents an
efficient and safe procedure.
12
UI - 11499181
AU - Memarzadeh S; Berek JS
TI -
Advances in the management of epithelial ovarian cancer.
SO - J Reprod Med 2001 Jul;46(7):621-9; discussion 629-30
AD - Division of Gynecologic Oncology, University of California-Los Angeles
School of Medicine, 27-136 CNS, 10833 Le Conte Avenue, Los Angeles, CA
90095-1740, USA.
More than 23,400 new cases of ovarian cancer and 13,900 deaths are
expected in the United States this year. Epithelial ovarian cancer is
the most common histologic type of ovarian malignancy. Although there
have been advances in the chemotherapeutic treatment of ovarian cancer,
the five year survival of women with advanced-stage disease is 25-30%.
Because the disease is typically asymptomatic until the disease has
metastasized and because effective screening strategies are not
unavailable, 70-75% of women present with advanced-stage disease. Of
ovarian cancer cases, 90-95% are sporadic and 5-10% associated with
germ-line mutations, including BRCA1 and BRCA2. Known risk factors for
ovarian cancer include nulliparity and a strong family history of
ovarian cancer. The use of oral contraceptives is known to decrease the
risk of ovarian cancer: five years of use will decrease the risk by 50%.
The staging of ovarian cancer (according to the International Federation
of Obstetrics and Gynecology) requires surgical exploration. Determining
the extent of disease is essential to appropriate management. Survival
in patients with metastatic disease is improved in those who undergo
optimal primary cytoreductive surgery. Adjuvant chemotherapy is
recommended in patients with high-risk, early-stage disease and all
patients with advanced-stage disease. Standard chemotherapy is a
combination of paclitaxel and carboplatin. Selected patients with
recurrent disease can undergo secondary cytoreductive surgery.
Second-line chemotherapy for patients who initially respond to
paclitaxel and carboplatin and who have a prolonged disease
progression-free intervals (longer than 12 months) can be re-treated
with either drug or both. Those whose responses to initial therapy were
less successful can be treated with other chemotherapeutic agents--e.g.,
liposomal doxorubicin, topotecan, etoposide, gemcitabine or taxotere.
13
UI - 11562749
AU - Yunmbam MK; Li QQ; Mimnaugh EG; Kayastha GL; Yu JJ; Jones LN; Neckers L;
TI -
Reed E
Effect of the proteasome inhibitor ALLnL on cisplatin sensitivity in
human ovarian tumor cells.
SO - Int J Oncol 2001 Oct;19(4):741-8
AD - Medical Ovarian Cancer Section, Developmental Therapeutics Department,
National Cancer Institute, National Institutes of Health, Bethesda, MD
20892, USA.
Small molecules suppressing proteasome function inhibit the
post-translational ubiquitination of selected proteins. Ubiquitin H2A is
an example of an abundant chromatin-associated protein that is known to
be ubiquitinated, which is important for several proteins involved in
the repair of DNA damage. We therefore studied the effect of the
proteasome inhibitor, N-acetyl leucyl-leucyl norlucinal (ALLnL), on
cisplatin sensitivity in three human ovarian tumor cell lines. The
proteasome inhibitor ALLnL was administered for 4 h before cells were
subsequently exposed to cisplatin for 1 h. Our results showed that
ALLnL, at its respective IC20 concentration, increased cellular
sensitivity to cisplatin in an additive manner in human ovarian cancer
A2780, A2780/CP70, and OVCAR3 cells. We also demonstrated that ALLnL
caused a 50% increase in total cellular accumulation of cisplatin, and
reduced the rate of cisplatin efflux by about 50%. In addition, DNA
damage levels were increased after ALLnL treatment. By contrast, DNA
repair was inhibited 2 to 3-fold in ALLnL-pretreated cells, as compared
to the controls. Furthermore, our study showed that ALLnL
deubiquitinated nucleosomal histone H2A in these cells in a
concentration-dependent fashion, as assessed by Western blot analysis.
These data suggest that sublethal levels of exposure to agents that
inhibit proteasome function may alter the subcellular pharmacology of
platinum in human ovarian carcinoma cells.
14
UI - 11585973
AU - Twelves C
TI -
Vision of the future: capecitabine.
SO - Oncologist 2001;6 Suppl 4():35-9
AD - Cancer Research Campaign Department of Medical Oncology, University of
Glasgow, and Beatson Oncology Centre, Glasgow, United Kingdom.
c.twelves@beatson.gla.ac.uk
Capecitabine is a thymidine phosphorylase (TP)-activated oral
fluoropyrimidine, rationally designed to generate 5-fluorouracil (5-FU)
preferentially within tumors. This tumor selectivity is achieved through
exploitation of the significantly higher activity of TP in tumor
compared with healthy tissue. The high single-agent activity of
capecitabine in breast and colorectal cancer suggests that capecitabine
may have a role in the treatment of other tumor types that are sensitive
to 5-FU, such as pancreatic cancer. Tumor types known to have a high
level of TP activity, such as renal cancer, are especially attractive
targets for capecitabine therapy. Capecitabine has potential as
monotherapy in these tumor types, or as a combination partner for other
cytotoxic agents with different mechanisms of action and little overlap
of key toxicities. In particular, some cytotoxic drugs, such as the
taxanes and cyclophosphamide, are known to upregulate TP activity in
tumor tissue, offering the potential for synergistic action. The
combination of capecitabine and docetaxel has demonstrated significant
activity in women with anthracycline-pretreated breast cancer, and is
the only cytotoxic combination to significantly increase survival
compared with standard therapy in this setting. In addition,
capecitabine as monotherapy or in combination with other cytotoxic
agents has shown encouraging activity in pancreatic, ovarian, and renal
cell cancers. This article discusses recent data from clinical trials
investigating capecitabine in a range of tumor types, highlighting the
potential future role of capecitabine as an alternative to traditional
i.v. chemotherapy.
15
UI - 11593052
AU - Wilailak S; Linasmita V; Srisupundit S
TI -
Phase II study of high-dose megestrol acetate in platinum-refractory
epithelial ovarian cancer.
SO - Anticancer Drugs 2001 Oct;12(9):719-24
AD - Department of Obstetrics & Gynaecology, Ramathibodi Hospital, Mahidol
University, Rama VI Road, Bangkok 10400, Thailand. raswl@mahidol.ac.th
Our objective was to determine the efficacy of megestrol acetate in the
treatment of platinum-refractory epithelial ovarian cancer (EOC), and to
evaluate the toxicities and quality of life (QOL) associated with this
therapy. Patients with platinum-resistant epithelial ovarian cancer were
treated with megestrol acetate (800 mg/day) orally for 28 days and then
400 mg/day for a minimum of 28 days before being assessed ready for
evaluation of response to therapy. Patients who demonstrated a complete
response (CR), partial response (PR) or stable disease were continued in
the study until there was objective evidence of disease progression. All
patients who went off study were followed up at regular intervals, every
2 months, to assess overall survival. Thirty-six patients were enrolled.
Response was observed in seven of 36 patients (three CR and four PR).
The response rate was 19.4% (95% CI 9-36). Four of the responders had
the endometrioid cell type, while two were clear cell carcinoma and one
was serouscystadenocarcinoma. All three CR patients had the histology of
endometrioid carcinoma with the tumors located in the pelvis. Median
survival of the study population was 5.8 months. Median survival in the
responders was 12 months, while median survival in the non-responders
was 5.5 months. Median progression-free survival in the responders was
8.3 months, while median progression-free survival in the non-responders
was only 2 months. The majority of patients gained weight and had a fair
quality of life score during treatment. The only toxicity observed was
alopecia (grade 1) in four patients. We conclude that megestrol acetate
has modest but definite activity in patients with platinum-refractory
EOC, particularly in a small subset of the endometrioid subtype with
limited disease in the pelvis. Only minimal toxicity was observed and
the patients had a fair QOL score during the treatment.
16
UI - 11604551
AU - Underhill CR; Parnis FX; Highley MS; Ahern J; Harper PG; Hansen H; Lund
TI -
B; Dombernowsky P; Hirsch F; Hansen M; Carmichael J; Williams C
Multicenter phase II study of gemcitabine in previously untreated
patients with advanced epithelial ovarian cancer.
SO - Anticancer Drugs 2001 Sep;12(8):647-52
AD - Guys Hospital, London, UK. underhills@hotmail.com
Gemcitabine has activity in advanced ovarian cancer, with responses in
platinum-resistant disease. This study assessed the activity of
gemcitabine in previously untreated patients with advanced epithelial
ovarian cancer. All patients had histologically verified invasive
epithelial ovarian cancer, International Federation of Gynecology and
Obstetrics (FIGO) stage III/IV disease and no prior chemotherapy.
Patients received gemcitabine 1250 mg/m(2) on days 1, 8 and 15 of a
28-day cycle. Radiological response was assessed after two cycles.
evaluable patients, there was one complete response and five partial
responses, for an overall response rate of 18% (95% confidence interval
7-36%). Forty-two percent of patients had a greater than 50% decrease in
their CA-125 levels. Of the 25 patients who received platinum-based
chemotherapy following treatment with gemcitabine, 12 achieved an
overall response rate of 48%. Toxicity was mild, with two episodes of
WHO grade 4 neutropenia (not associated with fever) and two episodes of
grade 4 thrombocytopenia (not associated with bleeding). Gemcitabine has
single-agent activity for poor-prognosis patients with advanced ovarian
cancer. Similar results with subsequent platinum-based therapy indicate
a lack of cross-resistance. This, combined with gemcitabine's favorable
toxicity profile, warrants testing in comparative trials.
17
UI - 11606393
AU - Kumar A; Soprano DR; Parekh HK
TI -
Cross-resistance to the synthetic retinoid CD437 in a
paclitaxel-resistant human ovarian carcinoma cell line is independent of
the overexpression of retinoic acid receptor-gamma.
SO - Cancer Res 2001 Oct 15;61(20):7552-5
AD - Department of Pathology and Laboratory Medicine, Temple University
School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Treatment of ovarian carcinomas with the antimitotic antitumor drug
paclitaxel is highly efficacious. However, development of drug
resistance presents a major obstacle. The common cellular phenotypes
associated with paclitaxel resistance are an increased expression of the
drug transport protein P-glycoprotein (P-gp), an alteration in the
levels of beta-tubulin isotypes, and/or changes in the drug binding
affinity of the microtubules. We established two paclitaxel-resistant
human ovarian carcinoma cell lines. The 2008/17/4 cells exhibited a
"classic" multidrug-resistant phenotype (overexpression of P-gp
associated with cross-resistance to natural product drugs), whereas the
2008/13/4 cells were an atypical multidrug-resistant subline (no
overexpression of P-gp). In addition to being paclitaxel resistant
(250-fold), the 2008/13/4 cells were also cross-resistant to etoposide
(39-fold) and vincristine (460-fold). To identify the alterations in the
gene expression profile associated with the development of atypical
paclitaxel resistance, we used the Clontech Atlas Human Cancer cDNA
Microarray (spotted with 588 genes). The expression of retinoic acid
receptor (RAR)-gamma was significantly higher in the
paclitaxel-resistant (2008/13/4 and 2008/17/4) cells than in the
parental (2008) cells. Northern blotting analysis demonstrated that the
expression of RAR-gamma was 7-fold higher in the 2008/13/4 and 2008/17/4
cells than in the 2008 cells, whereas the expression of RAR-alpha and
RAR-beta was not observed in any cell line. Whereas the 2008, 2008/13/4,
and 2008/17/4 cells were found to resist the antiproliferative effects
of all-trans-retinoic acid, the paclitaxel-resistant cells were 6- to
7-fold cross-resistant to the antiproliferative effects of CD437 (a
synthetic RAR-gamma-selective agonist;
6-[-(1-admantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid) compared
with the sensitivity of the parental cells. To further understand the
association of paclitaxel and CD437 resistance with the observed
RAR-gamma overexpression, we transfected the 2008 cells with a
full-length RAR-gamma cDNA construct. Two transfectants with increased
expression of the RAR-gamma mRNA and protein were isolated and subjected
to growth inhibition assays in the presence of various concentrations of
paclitaxel, etoposide, vincristine, and CD437. The sensitivity of the
2008 transfected clones (displaying increased expression of RAR-gamma)
to the cytotoxic effects of paclitaxel, etoposide, vincristine, and
CD437 was similar to that observed in the parental 2008 cells. These
results suggest that the overexpression of RAR-gamma (observed in the
2008/13/4 and 2008/17/4 cells) by itself is not capable of inducing
paclitaxel and CD437 resistance (or resistance to etoposide and
vincristine).
18
UI - 11606072
AU - Tournigand C; Louvet C; Molitor JL; Dehni N; Lejeune V; Sezeur A; Pigne
TI -
A; Marpeau L; Cady J; de Gramont A
Intravenous chemotherapy, early debulking surgery, and consolidation
intraperitoneal chemotherapy in advanced ovarian carcinoma.
SO - Gynecol Oncol 2001 Nov;83(2):198-204
AD - Service d'Oncologie Medicale, Hopital Saint Antoine, Paris, France.
christophe.tournigand@sat.ap-hop-paris.fr
OBJECTIVE: The efficacy of a cisplatin-anthracycline combination, early
debulking surgery, and intraperitoneal chemotherapy has been
demonstrated through separate studies. We evaluated a multimodal
treatment strategy integrating these therapeutic options. METHODS: Women
with stage III or IV ovarian carcinoma received six cycles of
cisplatin/epirubicin alternating with leucovorin and 5-fluorouracil.
Patients with a residual disease (RD) measuring more than 2 cm after the
initial laparotomy underwent an early debulking surgery after the first
three cycles of chemotherapy. A second-look laparotomy (SLL) was
performed after six cycles of intravenous chemotherapy. Intraperitoneal
chemotherapy with cisplatin, VP16, and mitoxantrone was then
administered in patients with no or RD < 2 cm after SLL. RESULTS: A
total of 87 patients were included. After initial laparotomy, 11
patients (12%) had no macroscopic residual disease, 38 (44%) had a RD <
or =2 cm, and 38 (44%) had a RD > 2 cm. After early debulking surgery,
an additional 18 patients (21%) had a RD < 2 cm. Seventy-five patients
were evaluable for response to intravenous chemotherapy: the overall
response rate was 80%, and 30 patients achieved a pathological complete
response (40%). Eight percent of the patients had stable disease and 12%
had a progression. Sixty-eight patients received intraperitoneal
chemotherapy after second-look laparotomy. With a 72-month median
follow-up, median overall survival and progression-free survival were,
respectively, 37 and 19 months. Five-year survival was 41%. CONCLUSION:
The prognosis of patients with advanced ovarian carcinoma may be
improved by a sequential treatment strategy including intravenous
chemotherapy, early debulking surgery, and intraperitoneal chemotherapy.
Copyright 2001 Academic Press.
19
UI - 11606080
AU - Rodriguez M; Rose PG
TI -
Improved therapeutic index of lower dose topotecan chemotherapy in
recurrent ovarian cancer.
SO - Gynecol Oncol 2001 Nov;83(2):257-62
AD - Michiana Hematology and Oncology, Northern Indiana Cancer Research
Consortium, South Bend, Indiana 46617, USA. mrodriguez@mhopc.com
OBJECTIVE: Topotecan (1.5 mg/m(2)) administered daily for 5 consecutive
days of a 21-day cycle is an established chemotherapeutic regimen in
recurrent ovarian cancer. However, noncumulative myelosuppression has
limited its use by many clinicians. We sought to determine whether a
lower dose of topotecan could provide comparable tumor activity and
higher tolerability in pretreated ovarian cancer patients. METHODS: A
retrospective chart review was conducted on recurrent ovarian,
peritoneal, or fallopian tube cancer patients with measurable disease or
elevated cancer antigen 125 levels (evaluable disease). Patients were
treated with topotecan (1.0 mg/m(2)) given by 30-min intravenous
infusion for 5 consecutive days every 21 days until disease progression
or unacceptable toxicity. RESULTS: Treatment records from 37 women who
had been treated with a median of 3 courses (range, 1 to 17) of lower
dose topotecan were evaluated; all were evaluable for tolerability and
36 were evaluable for response. Patients had received a median of 3
(range, 1 to 6) previous treatments. The overall response rate was 22%
(8/36); the response rates for patients with evaluable disease and
measurable disease were 35.7 (5/14) and 13.6% (3/22), respectively. An
additional 8 patients (22%) achieved stable disease. Grade 4
neutropenia, thrombocytopenia, and anemia occurred in 48.6, 5.4, and
5.4% of patients, respectively. Granulocyte colony-stimulating factor
support was used in 37% of patients, including 5 who experienced febrile
neutropenia. CONCLUSION: Topotecan at 1.0 mg/m(2) x 5 days every 21 days
is active in platinum- and paclitaxel-resistant ovarian cancer, with
significant improvements in hematologic toxicity. In heavily pretreated
patients-topotecan can be safely given at reduced doses without apparent
loss of efficacy. Copyright 2001 Academic Press.
20
UI - 11606086
AU - Jaeger W; Ackermann S; Kessler H; Katalinic A; Lang N
TI -
The effect of bowel resection on survival in advanced epithelial ovarian
cancer.
SO - Gynecol Oncol 2001 Nov;83(2):286-91
AD - Department of Obstetrics and Gynecology, University of
Erlangen-Nuremberg, Erlangen, Germany.
wolfram.jaeger@gyn.med.uni-erlangen.de
OBJECTIVE: FIGO stage III ovarian cancer is further categorized
according to the size of tumor, but not according to the organs
affected. In this study we evaluated the outcome of patients with and
without macroscopic bowel involvement in stage III ovarian cancer.
METHODS: This retrospective study analyzed the outcome of 194 ovarian
cancer patients with FIGO III with and without bowel involvement who
were operated on in our institution between 1985 and 1994. RESULTS: The
study demonstrated that maximum tumor reduction without remaining
macroscopic cancer offered the best overall survival times in FIGO III
ovarian cancer patients. However, whenever the bowel was involved, even
maximum bowel resections did not prolong survival compared to patients
with remaining tumor after surgery. CONCLUSIONS: This retrospective
study demonstrated that bowel involvement in ovarian cancer had a bad
prognosis and that survival in these patients could not substantially be
prolonged when the affected parts of bowel were resected. To further
substantiate these findings, future studies on advanced ovarian cancer
should differentiate between patients with and without bowel
involvement. Copyright 2001 Academic Press.
21
UI - 11606094
AU - O'Meara AT; Sevin BU
TI -
Predictive value of the ATP chemosensitivity assay in epithelial ovarian
cancer.
SO - Gynecol Oncol 2001 Nov;83(2):334-42
AD - Division of Gynecologic Oncology, University of Southern California,
Keck School of Medicine, 1240 N. Mission Road, Room 1L4, Los Angeles,
California 90033, USA. aomeara@usc.edu
OBJECTIVE: The aims of this study were to define the specific parameters
of the ATP chemosensitivity assay which most accurately predict a
patient's clinical response to chemotherapeutic agents in epithelial
ovarian cancer and to assess the clinical utility of the ATP assay.
METHODS: In our laboratory from 1992 to 1994, fresh tumor specimens from
patients with epithelial ovarian carcinomas were assayed with the ATP
chemosensitivity assay (ATP-CSA) for their in vitro responses to several
chemotherapeutic agents including cisplatin, paclitaxel, and
cyclophosphamide. Clinical data on 161 of those patients including all
follow-up assessments were then collected, and an investigator blinded
to the in vitro assay results determined the patients' responses to
chemotherapy. In order to determine which parameter of the assay was the
best predictor of clinical response for each drug, receiver-operator
characteristic (ROC) curves were constructed for several parameters,
including the amount of cell kill at particular dosage levels of drug,
the slope of the dose-response curve, and the IC50, or the average
concentration of drug at which 50% of the cells were nonviable. RESULTS:
The specific parameter of the ATP-CSA which was most predictive of
clinical response differed for each drug tested. The resulting positive
predictive values for cisplatin, cyclophosphamide, and paclitaxel ranged
from 70.0 to 78.3% and negative predictive values from 46.2 to 60.9%,
with overall ATP-CSA positive and negative predictive values of 83.0 and
56.5%. Overall, patients whose tumors tested sensitive to an agent in
vitro were almost twice as likely (83% versus 43%) to show a clinical
response (RR 1.91, 95% CI 1.34-2.71). CONCLUSION: Analysis of the ROC
curves in this study shows that different parameters of the ATP-CSA need
to be utilized for each drug tested in order to give the best prediction
of clinical chemosensitivity. Although the ATP-CSA shows predictive
ability, routine use of the ATP-CSA for clinical selection of drug
therapy in patients with epithelial ovarian cancer would not be
warranted without a prospective study comparing chemotherapy treatment
based on assay results versus clinician selection of drug. Copyright
2001 Academic Press.
22
UI - 11606100
AU - Ghosh K; Downs LS; Padilla LA; Murray KP; Twiggs LB; Letourneau CM;
TI -
Carson LF
The implementation of critical pathways in gynecologic oncology in a
managed care setting: a cost analysis.
SO - Gynecol Oncol 2001 Nov;83(2):378-82
AD - Division of Gynecologic Oncology, University of Minnesota Medical
Center, Minneapolis, Minnesota 55455, USA.
OBJECTIVES: The aim of the study is to determine whether critical
pathways can be implemented at an academic institution to limit cost,
without compromising patient satisfaction and quality of care. PATIENTS
AND METHODS: Patients undergoing a hysterectomy with either cervical or
endometrial cancer were placed on specific critical pathways
consecutively for an 18-month study period. Preoperative teaching was
intensified to educate the patient regarding expectations during the
postoperative period. All patients were started on early feeding and
patients were also placed on separate care pathways addressing pain and
deep vein thrombosis prophylaxis. Total direct costs and patient
satisfaction were obtained throughout the study period. During the year
prior to care pathway implementation, patient data and direct costs were
obtained for the preintervention group utilized for comparison.
Postintervention groups were summarized every 6 months during the study
cervical carcinoma undergoing a radical hysterectomy (DRG 353) and 21
patients with endometrial cancer who underwent a hysterectomy and lymph
node sampling (DRG 355) were utilized as the preintervention group.
(DRG 353) and 25 patients (DRG 355) were accrued. The average length of
stay was reduced from 5.2 (DRG 353) and 4.7 days (DRG 355) prior to
implementation of pathways to 3.4 days in both groups. In addition,
total direct costs were reduced by 29 (DRG 353) and 32% (DRG 355) after
implementation of care pathways. Patient satisfaction data recorded
during the study did not demonstrate any change throughout the study
period nor were there any higher rates of readmission after
implementation of the care pathways. CONCLUSIONS: Critical pathways in
gynecologic oncology can be implemented in a managed care environment in
order to maintain high quality of care, maintain outcomes, and help
reduce costs. Copyright 2001 Academic Press.
23
UI - 11606103
AU - Homesley HD; Hall DJ; Martin DA; Lewandowski GS; Vaccarello L; Nahhas
TI -
WA; Suggs CL; Penley RG
A dose-escalating study of weekly bolus topotecan in previously treated
ovarian cancer patients.
SO - Gynecol Oncol 2001 Nov;83(2):394-9
AD - Brookview Research, Inc., Nashville, Tennessee 37203, USA.
hdh@us.inter.net
OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the
treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal
patient convenience associated with daily topotecan, however, have
prompted investigators to explore alternate regimens, including a weekly
regimen of topotecan. The objective of this study was to determine the
maximum tolerated dose (MTD) of topotecan given as a weekly bolus in
previously treated ovarian cancer patients. METHODS: Second- and
third-line ovarian cancer patients with measurable disease or elevated
cancer antigen 125 received weekly bolus topotecan intravenously
starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of
0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting
toxicity was defined as grade 3/4 neutropenia or thrombocytopenia.
RESULTS: Thirty-two of 35 patients were evaluable for safety and
tolerability. No notable toxicity was observed with weekly topotecan
doses < 4 mg/m(2). Additionally, there was an absence of dose-limiting
myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of
weekly topotecan without the use of granulocyte colony-stimulating
factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and
grade 2 gastrointestinal toxicity limiting further dose escalation.
Weekly topotecan also demonstrated antitumor activity at doses >2
mg/m(2). CONCLUSIONS: The establishment of a well-tolerated, weekly
regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6
mg/m(2)) provides the basis for further investigation in phase II
studies of single-agent and combination regimens in previously treated
ovarian cancer patients. Copyright 2001 Academic Press.
24
UI - 11677705
AU - Watson E; Clements A; Yudkin P; Rose P; Bukach C; Mackay J; Lucassen A;
TI -
Austoker J
Evaluation of the impact of two educational interventions on GP
management of familial breast/ovarian cancer cases: a cluster randomised
controlled trial.
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