To evaluate the safety and efficacy of cisplatin plus gemcitabine in persistent or recurrent platinum-resistant ovarian and primary peritoneal cancer.
Eligible, consenting subjects with measurable disease and one prior platinum-based regimen, but no prior gemcitabine, were to receive intravenous cisplatin followed by gemcitabine on days 1 and 8 every 28 days.
Between December 2000 and March 2003, 59 patients were enrolled from 24 institutions; two were ineligible. During the first stage of accrual, 27 subjects received cisplatin 30 mg/m2 and gemcitabine 750 mg/m2. In the second stage, gemcitabine was reduced to 600 mg/m2 because of hematologic toxicity at the higher dose. There were 4 complete and 5 partial responses for an overall response rate of 16% (9/57). Thirty-one women (54%) had stable disease. Median time to progression was 5.4 months. Overall survival was 14.9+ months. Grade 4 toxicities were hematologic, except one cutaneous reaction.
Cisplatin plus gemcitabine, in the doses and schedule employed, has modest activity in this patient population.
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"When toxicity is used as a measure of radiochemotherapeutic activity and/or efficacy, responses in phase I radiochemotherapy studies may occur at a fraction of an investigational anticancer agent’s own active phase II dose and schedule. To illustrate this point in uterine cervix cancer treatment, gemcitabine given for radiosensitization [125 mg/m2 (Chavez-Blanco et al., 2005)] is a fraction (16%) of when gemcitabine is administered as a single agent [800 mg/m2 (Schilder et al., 2005)] or combined in a gemcitabine (800 mg/m2)-cisplatin (30 mg/m2) regimen (Brewer et al., 2006). As another example in uterine cervix cancer radiochemotherapy, much less (−75%) triapine (25 mg/m2) is administered for cisplatin radiochemosensitization (Kunos et al., 2010) than when used as a single agent [96 mg/m2 (Nutting et al., 2009)]. "
[Show abstract][Hide abstract] ABSTRACT: The architects of phase I radiochemotherapy development programs impose a semblance of structured radiation "intensity" and adverse event predictability upon radiation-anticancer agent interactions whose natural complexity and improper mixing would otherwise lead to dire health consequences. It is incumbent upon radiation oncology investigators to pledge radiation quality and safety to the participants of radiochemotherapy trials. Measures of radiation quality and safety may be tools to scrutinize radiation-anticancer agent dose and schedule, as well as, radiation field design among diverse radiation delivery platforms. In this article, the merits and demerits of phase I radiochemotherapy quality and safety policies are critiqued considering the current era of rapidly evolving radiation technologies.
Full-text · Article · Jul 2013 · Frontiers in Oncology
"Ribonucleotide reductase (RNR) inhibitors such as hydroxyurea, gemcitabine, and 3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) have gained new-found importance as anticancer agents in management of ovarian and cervical cancers [5-9]. RNR catalyzes the rate-limiting step in the de novo production of deoxyribonucleoside triphosphates (dNTP) used in DNA synthesis and repair . "
[Show abstract][Hide abstract] ABSTRACT: The potent ribonucleotide reductase (RNR) inhibitor 3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) was tested as a chemosensitizer for restored cisplatin-mediated cytotoxicity in platinum-resistant ovarian cancer.
Preclinical in vitro platinum-resistant ovarian cancer cell survival, RNR activity, and DNA damage assays were done after cisplatin or cisplatin plus 3-AP treatments. Six women with platinum-resistant ovarian cancer underwent four-day 3-AP (96 mg/m(2), day one to four) and cisplatin (25 mg/m(2), day two and three) infusions every 21 days until disease progression or adverse effects prohibited further therapy. Pre-therapy ovarian cancer tissues were analyzed by immunohistochemistry for RNR subunit expression as an indicator of cisplatin plus 3-AP treatment response.
3-AP preceding cisplatin exposure in platinum-resistant ovarian cancer cells was not as effective as sequencing cisplatin plus 3-AP together in cell survival assays. Platinum-mediated DNA damage (i.e., γH2AX foci) resolved quickly after cisplatin-alone or 3-AP preceding cisplatin exposure, but persisted after a cisplatin plus 3-AP sequence. On trial, 25 four-day overlapping 3-AP and cisplatin cycles were administered to six women (median 4.2 cycles per patient). 3-AP-related methemoglobinemia (range seven to 10%) occurred in two (33%) of six women, halting trial accrual.
When sequenced cisplatin plus 3-AP, RNR inhibition restored platinum-sensitivity in platinum-resistant ovarian cancers. 3-AP (96 mg/m(2)) infusions produced modest methemoglobinemia, the expected consequence of ribonucleotide reductase inhibitors disrupting collateral proteins containing iron.
Full-text · Article · Apr 2012 · Journal of Translational Medicine
"The ORR was 39.4%, the median PFS was 7.1 months and the median survival 18.6 months. These results compared favorably with those obtained with the combination of GEM and PLD   and were comparable with those achieved with CDDP and GEM     and similar to those obtained in our previous study using the alternating regimen of GEM/PLD and CDDP/CTX . The combination of PLD, CTX and oxaliplatin was administered in recurrent EOC as second-line treatment . "
[Show abstract][Hide abstract] ABSTRACT: In this phase II study the efficacy and toxicity of an alternating chemotherapy regimen was examined in platinum-resistant relapsed epithelial ovarian cancer (EOC) patients.
Forty-five patients with platinum-refractory/resistant relapsed EOC, previously treated with carboplatin+paclitaxel+/-epirubicin were included. The regimen was consisted of gemcitabine 800 mg/m(2) (days 1+8) and carboplatin AUC 5, alternating with pegylated liposomal doxorubicin 30 mg/m(2) and carboplatin AUC 5, alternating with carboplatin AUC 5 and cyclophosphamide 600 mg/m(2), every 3 weeks for a total of 9 cycles.
Among 38 patients with measurable disease, 39.4% (95% CI: 23.2-55.7) responded (five complete response and 10 partial response), while 30 out of 40 (75%) patients assessable by CA125 criteria had a serological response. Responses were more frequent in patients with platinum-free interval (PFI) 3-6 months than in those with PFI 0-3 months, but this was not statistically-significant. After a median follow-up of 19.5 months (range, 1.0-37+ months) the median progression-free survival was 7.1 months (95% CI: 3.4-10.8) and the median survival (OS) was 18.8 months (95% CI: 15.6-22.0). For patients with PFI 0-3 months PFS was 4.3 (95% CI: 0.8-7.8) months, while for those with PFI 3-6 months PFS was 8.9 (95% CI: 5.3-12.4) months (p=0.062). The regimen was well-tolerated and the main grade 3-4 toxicity was myelosuppression, palmar-plantar erythrodysesthesia, allergy and fatigue.
This alternating regimen, including carboplatin, gemcitabine, liposomal doxorubicin and cyclophosphamide, is an active and well-tolerated treatment in platinum relapsed/refractory EOC patients.