Platinum Resistance is in the Eye of the Beholder « Dr. Robert A. Nagourney – Rational Therapeutics – Blog including comments from Liz Mane +

Blogger's Note: pls read the whole article including comments for an accurate view of the opinions expressed
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Platinum Resistance is in the Eye of the Beholder « Dr. Robert A. Nagourney – Rational Therapeutics – Blog

 "I was recently apprised of an online conversation surrounding the treatment of platinum refractory and platinum resistant ovarian cancer. To clarify our terminology, platinum refractory disease refers to cancer that progresses during platinum therapy. This would be considered the most platinum resistant of the ovarian patients. The term “platinum resistant” developed over the last two decades, by Markman and others, is used to describe patients who initially respond to platinum-based chemotherapy and then relapse within six months of treatment.
While platinum refractory seems intuitively obvious, it has been suggested that platinum resistance is somewhat more arbitrary........ 
included comment from 
Liz Mane says:

March 30, 2012 at 7:24 pm

"Dr. N.
I am the one who opined on a chat room that most oncologists won’t redeploy carbo to platinum refractory patients right after unsuccessful front line platinum therapy. However, whoever alerted this comment to you omitted a crucial qualifying aspect of my argument.
...........(I have a Ph.D. in research science though not in bio medical field). My conclusion was,.......

Expert Opinion on Investigational Drugs -Investigational antibody drug conjugates for solid tumors Summary (Pfizer)

Note: access to the full article is payer-per-view ($$$)

"Despite the progress made in the past 20 years in understanding the molecular events leading to the formation of cancer, the success of targeted antitumor agents in solid tumors has lagged behind the scientific discoveries. The most difficult to treat patient segments are those with refractory solid tumors, resistant to standard chemotherapy, and novel therapeutic compounds with improved therapeutic indexes are needed. Antibody drug conjugates (ADCs) are poised to become an important class of cancer therapeutics, as evidenced by the promising objective response rates when administered as single agents to chemorefractory cancer patients..........Herein, we review ADCs (Antibody drug conjugates) targeting solid tumors, with the focus on 11 programs currently undergoing clinical development....)

Correlation of extreme drug resistant assay results and progression-free survival following intraperitoneal chemotherapy for advanced ovarian cancer (Oncotech assay)

Abstract

The aim of this study was to determine if in vitro extreme drug resistance (EDR) to platinum and/or taxane chemotherapy was predictive of patient response to intraperitoneal (I.P.) chemotherapy in patients with stage III or recurrent epithelial ovarian cancer (EOC).

Fifty-six patients were retrospectively identified who underwent optimal cytoreductive surgery for primary or recurrent eOC and then received at least three cycles of either intravenous (I.V.) or I.P. chemotherapy with platinum and paclitaxel-based chemotherapy. EDR to platinum and/or paclitaxel was determined using a commercially available assay (Oncotech, Inc., Tustin, CA).

The primary outcome measure was progression-free survival (PFS).

Twenty-nine (52%) patients received I.P. chemotherapy and 27 (48%) received I.V. chemotherapy. The patients were well matched in terms of age, stage, grade and histology. Ten (35%) patients in the I.OP. arm and ten (37%) patients in the I.V. arm showed EDR to either platinum and/or paclitaxel. Median PFS for all I.P. chemotherapy patients was 23 months, compared with 13 months for those receiving I.V. chemotherapy (p = 0.04).

Patients with EDR to platinum and/or taxane who underwent I.V. chemotherapy had a median PFS of 13.5 months, whereas those who underwent I.P. treatment had a median PFS of 15 months (p = 0.69). Median overall survival had not been reached at the time of analysis. No significant difference in PFS was noted between patients who underwent I.P. and those who underwent I.V. chemotherapy when EDR was predicted to either platinum or paclitaxel or both. These data suggest that the decision to offer I.P. chemotherapy, with the attendant increase in morbidity, in the setting of EDR to platinum and/or taxane chemotherapy, may not be beneficial. 

Prospective studies, preferably analyzing platinum or taxane EDR individually, are required to validate these observations.

Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit From Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer

ABSTRACT

Purpose
The prevalence of BRCA1/2 mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA1/2 changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.

Conclusion
BRCA1/2 somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.

Chemotherapy use and risk of bone marrow suppression in a large population-based cohort of older women with breast and ovarian cancer.

Med Oncol. 2010 Apr 2

Nurgalieva Z, Liu CC, Du XL.

Division of Epidemiology and Disease Control, University of Texas School of Public Health, 1200 Herman Pressler Drive, RAS-E631, Houston, TX, USA.

We studied 65,521 women with breast cancer and 7,420 women with ovarian cancer aged >/= 65 identified from the 16 areas of the Surveillance, Epidemiology and End Results program linked with Medicare data during 1991-2002. Bone marrow toxicity associated with chemotherapy was defined using diagnosis codes from Medicare inpatient, outpatient and physician claims. The time to event Cox regression was utilized to estimate the risk of bone marrow toxicity. Use of anthracyclines, taxanes or platinums was associated with increased risks of short- (3 months) anemia and neutropenia in patients with breast cancer. Alkylating agents or antimetabolites were additional significant predictors of anemia in women with ovarian cancer. Patients who received chemotherapy (irrespective of regimens) were twice (breast cancer) or three times (ovarian cancer) as likely to develop thrombocytopenia compared to those not receiving chemotherapy. Among women with breast cancer, patients receiving cyclophosphamide, methotrexate and fluorouracil regimens (hazard ratio = 19.0, 95% CI = 11.2-32.5), platinum/taxane therapy (21.9, 11.9-40.4) or the cyclophosphamide, adriamycin and fluorouracil regimen (32.5, 19.6-53.9) were strongly associated with risk of aplastic anemia. There was a dose-response relationship between the use of taxane or platinum and the risk of bone marrow suppression, whereas the increased risk of bone marrow toxicity was consistently higher in those with use of alkylating agents or anthracycline-based regimens irrespective of the increasing number of cycles received. In conclusion, there was an association between chemotherapy use and clinical manifestations of bone marrow toxicities in a population-based setting.

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

Abstract/full free pdf: published March 11, 2010


Patients:
Women who were at least 18 years old with recurrent, histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube cancer; measurable disease as defined
by RECIST; had received at least 1 but fewer than 4 prior platinum-containing chemotherapy regimens; at least 1 prior paclitaxel-containing regimen; and considered platinum refractory or resistant disease according to the standard GOG criteria (had progressed during or had persistent disease after completion of platinum-based therapy or had a platinum-free interval of < 6 months) were enrolled. There were no additional limits to lines of therapy.