Regimen in Recurrent Endometrial Cancer Challenged: TAP Not Superior to Less-Toxic, Two-Drug Therapy

OncologyLive, June 2012, Volume 13, Issue 6

A summary of findings from the 43rd Annual Meeting on Women's Cancer with the potential to impact routine management of women with pelvic malignancies.

Harald zur Hausen, MD, who won a Nobel Prize in 2008 for elucidating the human papilloma viruses that cause cervical cancer, calls for vaccinating young males and females in a speech at the Society of Gynecologic Oncology conference.

Without question, the most important study discussed at the SGO meeting was the long and eagerly awaited results of the phase III randomized Gynecologic Oncology Group (GOG) trial that compared the GOG standard of paclitaxel, doxorubicin, and cisplatin (TAP) with the widely recognized clinical community standard of carboplatin plus paclitaxel as primary chemotherapeutic management of metastatic or recurrent endometrial cancer.1

A total of 1381 patients were treated on this trial from 2003 to 2009. The study revealed the equivalence (or in statistical terminology, the noninferiority) in outcome for the carboplatin/paclitaxel regimen compared with the three-drug combination. The median progression-free survival in this study was 14 months in both trial arms, with median overall survival found to be 32 months for carboplatin/ paclitaxel versus 38 months for TAP, respectively (hazard ratio, 1.01). As anticipated, the two- drug combination was associated with a more favorable toxicity profile (less thrombocytopenia, vomiting, diarrhea, metabolic side effects) compared with the TAP program.

While the intent of this commentary is to highlight study results presented at the annual SGO meeting, it is appropriate to acknowledge the controversy surrounding the conduct of this trial, specifically the complex decision-making process that led the GOG to consider this three-drug combination to be its standard treatment regimen in this clinical setting. Hopefully, the study outcome will result in the discontinuation of the use of this more toxic strategy in the routine management of metastatic or recurrent endometrial cancer.

Here are several other studies with noteworthy findings:

Cervical

Tirapazamine Fails to Enhance Standard

A GOG phase III trial compared the standard-of-care program of weekly cisplatin plus external beam radiation (chemoradiation) with cisplatin plus tirapazamine and external beam radiation as primary therapy for stages IB2, IIA, IIIB, and IVA cervical carcinoma.2 It had been hypothesized that tirapazamine might sensitize hypoxic cells to the effects of the cisplatin and radiation. While the study was discontinued slightly early (after 402 patients were randomized) due to an issue with drug supply, the trial failed to reveal any impact of the experimental regimen on either progression-free or overall survival, compared with the control arm. Of relevance, this study failed to support the concept that sensitization of the hypoxic cell population can favorably impact outcome in cervical cancer.

Illustration courtesy of Alan Hoofring/Don Bliss/National Cancer Institute

Erlotinib Combination Shows Promise

A provocative phase II trial from the Brazilian National Cancer Institute examined the combination of erlotinib plus cisplatin and radiation in the treatment of previously untreated locally advanced cervical cancer.3 Previous preclinical work had revealed that the epidermal growth factor receptor (EGFR) is commonly expressed in cervical cancer, and frequently overexpressed. In this noncomparative study, 34 of the 36 evaluable patients (94%) achieved a clinical complete response. This regimen appears worthy of future investigation in a phase III randomized trial compared with the gold standard of concurrent cisplatin plus radiation in this clinical setting.

Endometrial

Bevacizumab Therapy Draws Responses

In a phase II trial examining the novel combination of bevacizumab plus temsirolimus as therapy for recurrent or persistent endometrial cancer, investigators in the GOG treated a total of 53 patients, of whom 12 experienced a response, including one complete response.4 The median progression-free survival of the population was 5.6 months, with a median overall survival of 17 months. This study was based on preclinical data revealing that the PTEN tumor suppressor gene is commonly inactivated in endometrial cancer. Further, prior studies had demonstrated clinical activity for bevacizumab in this clinical setting. The objective response rate observed in this population of fairly heavily pretreated patients suggests this regimen is worthy of further investigation in endometrial cancer.

Ovarian

Results Support Use of Bevacizumab

A GOG study examined the activity of single-agent bevacizumab as a treatment strategy for recurrent sex cord or stromal ovarian tumors.5 The antiangiogenic agent was delivered at the standard dose as employed in other clinical settings (15 mg/kg every 21 days). Of 36 patients entered into the trial, six achieved a partial response (17%). The median progression-free survival in the entire group was 8.6 months. Of note, several patients have remained on study for quite extended periods of time ( >1 year). These data provide support for the conclusion that bevacizumab is a clinically active drug in recurrent sex cord and stromal ovarian tumors and should be considered an acceptable management strategy in this setting.

Dose Intensity Strategies Clarified

Finally, in an interesting retrospective analysis of the question of whether maintaining dose intensity in patients receiving primary chemotherapy for advanced ovarian cancer improves survival, investigators in the GOG study failed to demonstrate a favorable impact of such a strategy on outcome.6 In a population of 591 individuals treated in a previously reported phase III trial (GOG 182) who completed the eight scheduled cycles, 263 required a dose modification. There was no difference in the hazard ratio for time to disease progression or overall survival (median 49.4 months vs 50 months for patients requiring or not requiring a dose modification, respectively). Further, the use of a granulocyte colony-stimulating factor to maintain dose intensity did not appear to impact outcome. These data provide strong support for the conclusion that dose modifications, if required due to the development of excessive toxicity, do not negatively impact survival in ovarian cancer.

Maurie Markman, MD, editor-in-chief of OncologyLive, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, Pennsylvania.

References

  1. Miller D, Filiaci V, Fleming G, et al. Late-breaking abstract 1: randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study [published online ahead of print May 17, 2012]. Gynecol Oncol. 2012;125(3):771. doi: 10.1016/j.ygyno.2012.03.034.
  2. DiSilvestro D, Ali S, Peter C, et al. A Gynecologic Oncology Gr oup phase III randomized trial of weekly cisplatin and radiation versus cisplatin and tirapazamine and radiation in stage IB2, IIA, IIIB and IVA cervical carcinoma limited to the pelvis [published online ahead of print March 6, 2012]. Gynecol Oncol. 2012; 125(suppl 1):S3-S4. doi:10.1016/j.ygyno.2011.12.003.
  3. Rodrigues A, Alves F, Carmo C, et al. INCA-GYN001: erlotinib added to cisplatin and definitive radiotherapy in untreated patients with locally advanced squamous cell cervical carcinoma—a phase II trial and correlative tumor molecular profiling [published online ahead of print March 6, 2012]. Gynecol Oncol. 2012;125(suppl 1):S3. doi:10.1016/j. ygyno.2011.12.002.
  4. Alvarez E, Brady W, Walker J, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study [published online ahead of print March 6, 2012]. Gynecol Oncol. 2012;125(suppl 1):S17. doi:10.1016/j.ygyno.2011.12.041.
  5. Brown J, Brady W, Schink J, et al. Late-breaking abstract 2: bevacizumab shows activity in treating recurrent sex cord-stromal ovarian tumors: results of a phase II trial of the Gynecologic Oncology Group [published online ahead of print May 17, 2012]. Gynecol Oncol. 2012;125(3):771- 772. doi:10.1016/j.ygyno.2012.03.03.
  6. Olawaiye A, Java J, Krivak T, et al. Does maintaining adjuvant chemotherapy dose intensity have an impact on the outcome of treatment in ovarian cancer patients?: a Gynecologic Oncology Group study [published online ahead of print March 6, 2012]. Gynecol Oncol. 2012;125(suppl 1):S25. doi:10.1016/j.ygyno.2011.12.058.

maurie.markman@ctca-hope.com