Role For Gemcitabine As Second-line Chemotherapy in Recurrent Clear Cell Ovarian Cancer

In a recent 2014 retrospective analysis involving 72 recurrent ovarian clear cell patients who underwent second-line therapy at one of 20 Italian centers over a 16-year period, the researchers noted that a small subgroup of patients who received the drug gemcitabine (Gemzar®) appeared to have a higher rate of tumor response, as compared to women who were treated with topotecan (Hycamtin®) or pegylated liposomal doxorubicin (Doxil®).

Clear Cell Carcinoma of the Ovary

Clear Cell Carcinoma of the Ovary

In the July 2014 issue of Oncology, Italian researchers present an interesting retrospective analysis of patients with recurrent clear-cell ovarian cancer [1], a fairly chemoresistant subtype of ovarian cancer that can be difficult to treat.

This retrospective analysis included 72 recurrent ovarian clear cell patients (OCCC), who underwent second-line therapy at one of 20 Italian centers over a 16-year period (as part of the “Multicenter Italian Trial in Ovarian Cancer” or “MITO-9”).

In 56% of the OCCC patients, the clear cell histology was “pure,” meaning the predominant cell type identified within the primary tumor was classified as clear cell (i.e., a subtype of epithelial ovarian cancer) by a molecular pathologist. Twenty-five patients were platinum-resistant, 18 patients were platinum-sensitive with a platinum-free interval (PFI) of 6-to-12 months, and 29 patients had a PFI >12 months. Upon disease recurrence, 47% of patients were treated with platinum chemotherapy (e.g., carboplatin or cisplatin) based upon PFI.

The overall tumor response rate (RR) to the use of platinum drugs was 80%, with 55%, 100%, and 80% RRs in patients with PFIs of 6-to-12 months, >12 months, and >24 months, respectively. The RR to non-platinum drugs in resistant OCCC patients was 33%. Among the non-platinum drugs used in primary and secondary resistant cases, gemcitabine (Gemzar®), administered to 12 OCCC patients, produced higher anti-cancer activity (RR = 66%), as compared to topotecan (Hycamtin®) or liposomal doxorubicin (Doxil®) (number of patients = 31; RRs = 33% and 10%, respectively).

The Italian researchers concluded that the overall study results suggest that the treatment of recurrent OCCC, in general, should be based upon the duration of the patient’s PFI, as is customary in the treatment of other epithelial ovarian cancer subtypes. However, the data relating to the platinum-resistant OCCC patients evaluated in the Italian study suggest that gemcitabine (Gemzar®) was the drug that produced the greatest anti-cancer activity.

Notably, the results reported by the Italian researchers are consistent with the similar findings reported in a small number of previous studies involving an equally small number of recurrent OCCC patients. [2 – 5]

Maurie Markman, M.D.

Also appearing in the July 2014 Oncology issue is a commentary written by Maurie Markman, M.D., the President of the Medicine and Science unit of the Cancer Treatment Centers of America (CTCA).[6] Dr. Markman oversees the CTCA national clinical team, with a focus on the application of all clinical and translational research to patient care. In his commentary, Dr. Markman notes the importance of retrospective studies as a “long-established tradition in clinical cancer investigation.” Dr. Markman highlights the potential inportance of retrospective studies as noted below.

  • Single institutional data or large multicenter efforts examining past experiences can serve both as “hypothesis-generating” elements for a future prospective clinical study, an idea to be explored in a translational laboratory research project, and even as confirmation of the results of a reported study in a more heterogeneous patient population.
  • Retrospective analyses can provide critically relevant data in populations known to be poorly represented in cancer clinical trials and may identify adverse events potentially not recognized in the often highly homogenous groups of study participants.
  • The safety and the efficacy associated with longer observation periods and a more prolonged therapy than reported in many prospective clinical trials can be revealed through retrospective examinations of previously treated patients.

Within this context, Dr. Markman addresses the limitations of the Italian recurrent OCCC retrospective analyses cited above, but he also emphasizes the potential benefit of that study, as follows:

“Of course, it must be emphasized that the very limited sample size does not permit any definitive conclusions regarding the relative utility of any individual strategy, including providing a truly meaningful ‘objective response rate’. However, recognizing the rarity of this specific malignant condition (72 total [OCCC] patients identified in a period of 16 years at 20 centers), this retrospective experience will likely be of some value to individual oncologists needing to consider potential therapeutic options for a patient with recurrent clear-cell ovarian cancer. Further, in the event a multi-institutional prospective trial is ultimately undertaken in this most uncommon clinical setting, the results of this retrospective analysis should surely help to inform the planned study design.” [emphasis added]

At Libby’s H*O*P*E*, we generally recommend that recurrent OCCC patients speak to their doctor about the potential benefits (and limitations) associated with (i) molecular/genomic tumor profiling,  and (ii) chemosensistivity and resistance assay (CSRA) testing. The use of both forms of tumor testing may provide a recurrent OCCC patient and her doctor(s) with additional insights related to specific treatment options. In the event that neither form of tumor testing is possible, the results from the Italian study discussed above suggest that the use of gemcitabine (Gemzar®) to treat recurrent OCCC should be, at a minimum, considered by a recurrent OCCC patient and her doctor.

In addition, we strongly recommend that a newly-diagnosed or recurrent OCCC patient should consider the drugs being currently evaluated, as of this writing, in open OCCC patient-dedicated clinical trials, including as temsirolimus (Torisel®) [7], sunitinib (Sutent®) [8], ENMD-2076 [9], and dasatinib (Sprycel®) [10].

References:

1./ Esposito F et al. Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the Multicenter Italian Trials in Ovarian Cancer (MITO-9). Oncology 2014;86:351-358. PubMed PMID:24942520.

2./ Yoshino K, et al. Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: a single-institution experience for a series of 20 patients. Int J Clin Oncol. 2013 Feb;18(1):148-53. doi: 10.1007/s10147-011-0357-5. Epub 2011 Dec 10. PubMed PMID: 22160560.

3./ Komiyama S et al. A heavily pretreated patient with recurrent clear cell adenocarcinoma of the ovary in whom carcinomatous peritonitis was controlled successfully by salvage therapy with gemcitabine. Arch Gynecol Obstet. 2008 Dec;278(6):565-8. Epub 2007 Jun 19. Erratum in: Arch Gynecol Obstet. 2009 Feb;279(2):271. Komiyama, Shin [corrected to Komiyama, Shin-ichi]. PubMed PMID: 17576588.

4./ Ferrandina G et al. A case of drug resistant clear cell ovarian cancer showing responsiveness to gemcitabine at first administration and at re-challenge. Cancer Chemother Pharmacol. 2007 Aug;60(3):459-61. Epub 2007 Apr 11. PubMed PMID: 17429624.

5./ Crotzer DR et al. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 2007 May;105(2):404-8. Epub 2007 Feb 9. PubMed PMID: 17292461.

6./ Markman M. A Unique Role for Retrospective Studies in Clinical Oncology. Oncology. 2014;86(5-6):350. doi: 10.1159/000360911. Epub 2014 Jun 12. PubMed PMID:24942408.

7./ A Phase II Evaluation of Temsirolimus (CCI-779) (NCI Supplied Agent: NSC# 683864,) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus (CCI-779) Consolidation as First-Line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary. ClinicalTrials.gov Identifier: NCT01196429.

8./ A Phase II Evaluation of the Efficacy of Sunitinib® in Patients With Recurrent Ovarian Clear Cell Carcinoma. ClinicalTrials.gov Identifier: NCT01824615.

9./ A Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas. ClinicalTrials.gov Identifier: NCT01914510.

10./ A Phase II Trial of DCTD-Sponsored Dasatinib (NSC #732517) in Recurrent/Persistent Ovary, Fallopian Tube, Primary Peritoneal, and Endometrial Clear Cell Carcinoma Characterized for the Retention or Loss of BAF250a Expression. ClinicalTrials.gov Identifier: NCT02059265.

 

 

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