Home > News > First-line Chemotherapy in Patients with Advanced Ovarian Cancer
Gynaecological Oncology, Ovarian Cancer
Read Time: 4 mins

First-line Chemotherapy in Patients with Advanced Ovarian Cancer

Published Online: August 15th 2011 US Oncological Disease, 2007;1(2):71-2 DOI: https://doi.org/10.17925/OHR.2007.00.2.71
Authors: Dirk Olaf Bauerschlag, Felix Hilpert, Ivo Meinhold-Heerlein, Walter Jonat, Jacobus Pfisterer
Quick Links:
Article
Article Information
Article:

Ovarian cancer is the fifth most common malignancy in women. In the US, approximately 22,000 new cases occur each year.1 In Germany, about 8,000 new cases are diagnosed each year. About 80% of patients suffer from advanced-stage disease (International Federation of Gynaecology and Obstetrics [FIGO] III/IV) with an unfavorable prognosis. Due to the lack of early specific symptoms, most patients are diagnosed at an advanced stage when the cancer has spread beyond the pelvis. Consequently, only 20% of patients are diagnosed at a stage where the malignancy is still confined to the ovary or lower pelvis. These cases, which carry a good prognosis with a five-year survival of about 90%, are often accidentally diagnosed when the ovaries are removed due to cystic changes.

At present, there is no valid screening tool available for ovarian cancer. Sequential vaginal ultrasound is not reliable, even in high-risk patients, because of breast cancer (BRCA) I or II mutations. Also, no blood test, whether the cancer antigen (CA)-1252 or any other protein profiling,3 displayed sufficient specificity or sensitivity to be used as a routine screening marker for ovarian cancer. We have recently shown that the combination of several secreted markers (osteopontin, kallikrein, or matrix metalloproteinase [MMP]7) in combination with CA-125 can accurately distinguish sera of ovarian cancer patients from those of healthy women. Although this blood test was also able to detect early-stage disease, further validation is still necessary.4 The most important prognostic marker for survival in advanced ovarian cancer patients remains the post-operative tumor burden.5 No medical therapy is able to compensate for an inadequate surgical procedure; therefore, patients suspected of ovarian cancer should be referred to a specialized hospital site.

In 1996, the Gynecology Oncology Group (GOG) study 1116 showed that cisplatin in combination with paclitaxel was superior to cisplatin and cyclophosphomide with respect to disease-free survival (DFS) and overall survival (OS). This study was conducted in patients who had received a suboptimal tumor reduction surgery. DFS and OS were significantly prolonged in those patients who received cisplatin and paclitaxel comparedwith patients who received cisplatin and cyclophosphomide (18 versus 12.9 months and 37 versus 24 months, respectively). Based on these results, three prospective randomized trials proved the efficacy of paclitaxel in combination with platin derivates.7–9 The combination of cisplatin, paclitaxel, carboplatin, and paclitaxel showed similar values for time to progression and OS. In contrast, the latter combination was less neurotoxic than the cisplatin-based regimen. Therefore, quality of life is significantly improved by using carboplatin instead of cisplatin.10 Another advantage in favor of the carboplatin/paclitaxel combination is that this regimen can be administeredin an outpatient setting. Therefore, today’s standard primary chemotherapy in ovarian cancer treatment is the combination of carboplatin and paclitaxel, providing the best ratio of benefits to side effects.11

Although this gold standard has been improving OS significantly, the prognosis of ovarian cancer remains poor due the occurrence of chemotherapy resistance. One option to improve the efficacy of the standard treatment is the incorporation of non-cross-resistant cytotoxic drugs in addition to carboplatin and paclitaxel. Several attempts have been undertaken over the past few years with different drugs. The addition of epirubicine did not prolong progression-free survival (PFS) or OS, but did increase hematological and non-hematological toxicities.12,13 Also, the combination of carboplatin, paclitaxel, and topotecan as sequential single agents did not improve outcome.14,15 Incorporating liposomal pegylated doxorubicine and gemcitabine did not benefit patient survival.16 So far, all attempts to further improve efficacy by adding a third non-cross-resistant conventional cytotoxic agent (e.g. topotecan, etoposide, pegylated liposomal doxorubicine, or gemcitabine) have failed.

Using an alternative method to administer the chemotherapeutic agents may optimize treatment. In one recently published study (GOG172),17 patients were treated with chemotherapy administered intravenously (IV) and intraperitonealy (IP). Patients treated in the standard arm received the combination cisplatin 75mg/m2 and paclitaxel 135mg/m2 IV. In contrast, patients treated in the experimental arm received paclitaxel 135mg/m2 on day one IV, cisplatin 100mg/m2 IP on day two, and paclitaxel 60mg/m2 IP on day eight. The authors report a significantly higher median survival for the ‘IP group’: 65.6 versus 49.7 months in the ‘IV group.’ No significant difference was found in PFS, but the patients treated in the IP arm did have a significant disadvantage with respect to quality of life (e.g. abdominal pain, neurotoxicity). Even in experienced cancer centers, only 42% received the IP regimen as planned. Eight percent of the patients did not receive IP chemotherapy at all, and in 34% of the patients only one to two cycles of IP chemotherapy were given. However, interpretation of the results is difficult. One point of criticism is that different dosages of cisplatin wereused (75 versus 100mg/m2). Also, the additional application of paclitaxel on day eight raises the question of whether it would be useful to employ a dose-dense schema rather than giving chemotherapy IP. Additionally, it was not an intention-to-treat analysis. No data about second-line treatment are published; this fact seems to be very important since it is well known that second-line treatment has an impact on survival. Thus, this regimen has not been adopted as standard of care.

Future Perspectives
The future of cancer therapy may lie in identifying biological dependenciesof cancer cells that can be specifically targeted. Within the last few years, more and more specific antibodies and small molecules have become available for targeted therapy. For ovarian cancer patients, the correct therapeutic intervention could be a combination of carboplatin and paclitaxel plus a small-molecule drug. Targeting tumor-induced neoangiogenesis may be one option.

The humanized vascular endolethial growth factor (VEGF) antibody bevacizumab shows clinical responses in heavily pre-treated ovarian cancer patients.18–21 The NCT00129727 trial, in which patients will receive carboplatin, paclitaxel, and bevacizumab, is currently recruiting. In this trial, bevacizumab will be given every three weeks for one year. In a phase II study, erlotinib showed marginal activity but was well tolerated. Interestingly, the survival rate correlated significantly with the skin rush grade induced by erlotinib; patients with higher grades of skin rushes survived for a longer time.22

Erlotinib will also be investigated in a phase III clinical trial, given as maintenance therapy after primary chemotherapy. In phase I clinical trials, the anti-idiotypic antibody abagovomab (CA-125 antigen) in patients withrecurrent ovarian cancer was found to be safe to be administered and was also well tolerated.23,24 Imatinib is a small-molecule drug that inhibits tyrosine kinases. It is used in hematological malignancies and in patients suffering from gastrointestinal stromal tumors (GIST). The recently conducted Southwest Oncology Group (SWOG) S0211 trial using imatinib in recurrent platinum-resistant ovarian cancer did not show a markedly improved response rate.25 Using the small-molecule drug gefitinib in epithelial ovarian cancer also did not show a clinical response. However, at the molecular level a decrease in target phosphorylation was observed.26 Although these data are preliminary, they suggest that the combination of conventional chemotherapy and targeted therapy may increase chemotherapy responses, prolong DFS, and, therefore, improve the prognosis of ovarian cancer.

Conclusion
Today, the combination of radical cytoreductive surgery and chemotherapy with carboplatin and paclitaxel is the standard treatment for advanced ovarian cancer patients. Much hope is pinned on targeted therapies utilizing novel molecular drugs, and several phase III trials with these substances have already begun worldwide.

Article Information:

References

  1. Jemal A, et al., Cancer statistics, CA-Cancer J Clin, 2007;57: 43–66.
  2. Jacobs IJ, et al., Screening for ovarian cancer: a pilot randomised controlled trial, Lancet, 1999;353(9160):1207–10.
  3. Petricoin EF, et al., Use of proteomic patterns in serum to identify ovarian cancer, Lancet, 2002;359(9306):572–7.
  4. Meinhold-Heerlein I, et al., An integrated clinical-genomicsapproach identifies a candidate multi-analyte blood test for serous ovarian carcinoma, Clin Cancer Res, 2007;13(2.1): 458–66.
  5. Bristow RE, et al., Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis, J Clin Oncol, 2002;20(5):1248–59.
  6. McGuire WP, et al., Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer, N Engl J Med, 1996;334(1):1–6.
  7. Ozols RF, et al., Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynaecologic Oncology Group study, J Clin Oncol, 2003;21(17):3194–3200.
  8. du Bois A, et al., A randomised clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer, J Natl Cancer Inst, 2003;95(17): 1320–29.
  9. Neijt JP, et al., Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer, J Clin Oncol, 2000;18(17):3084–92.
  10. Greimel ER, et al., Randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group comparing quality of life in patients with ovarian cancer treated with cisplatin/paclitaxel versus carboplatin/paclitaxel, J Clin Oncol, 2006;24(4):579–86.
  11. du Bois A, et al., 2004 consensus statements on the management of ovarian cancer: final document of the third International Gynaecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004), Ann Oncol,2005,16(Suppl. 8):viii7–12.
  12. du Bois A, et al., Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomised gynaecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, J Clin Oncol, 2006;24(7):1127–35.
  13. Kristensen GB, et al., First-line treatment of ovarian cancer FIGO stages IIb–IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin, Int J Gynecol Cancer, 2003;13(Suppl. 2): 172–7.
  14. De Placido S, et al., Topotecan compared with no therapy after response to surgery and carboplatin/paclitaxel in patients with ovarian cancer: Multicentre Italian Trials in Ovarian Cancer (MITO-1) randomised study, J Clin Oncol, 2004;22(13):2635–42.
  15. Pfisterer J, et al., Randomised phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynaecologic cancer intergroup trial of the AGO-OVAR and GINECO, J Natl Cancer Inst, 2006,98(15):1036–45.
  16. Bookman MA, McMeekin DS, Fracasso PM, Sequence dependence of haematologic toxicity using carboplatin and topotecan for primary therapy of advanced epithelial ovarian cancer: a phase I study of the Gynaecologic Oncology Group, Gynecol Oncol, 2006;103(2):473–8.
  17. Armstrong DK, et al., Intraperitoneal cisplatin and paclitaxel in ovarian cancer, N Engl J Med, 2006;354(1):34–43.
  18. Monk BJ, et al., Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advancedrefractory epithelial ovarian cancer, Gynecol Oncol, 2006;102(2):140–44.
  19. Numnum TM, et al., The use of bevacizumab to palliate symptomatic ascites in patients with refractory ovarian carcinoma, Gynecol Oncol, 2006;102(3):425–8.
  20. Wright JD, et al., Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer, Gynecol Oncol, 2006;103(2):489–93.
  21. Wright JD, et al., Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis, Cancer, 2006;107(1):83–9.
  22. Gordon AN, et al., Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicentre study, Int J Gynecol Cancer, 2005;15(5):785–92.
  23. Pfisterer J, et al., The anti-idiotypic antibody abagovomab in patients with recurrent ovarian cancer. A phase I trial of theAGO-OVAR, Ann Oncol, 2006;17(10):1568–77.
  24. Sabbatini P, et al., Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritonealcancer, Clin Cancer Res, 2006;12(18):5503–10.
  25. Alberts DS, et al., Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211), Int J Gynecol Cancer, 2007.
  26. Posadas EM, et al., A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer, Cancer, 2007.

Further Resources

Share this Article
Related Content In Ovarian Cancer
  • Copied to clipboard!
    accredited arrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-whiteticktimetranscriptup-arrowwebinar Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72