2011 NCCN Conference: New Treatment Options Lead to Steady Progress Against Ovarian Cancer

Recommendations stemming from recent clinical trials highlight notable updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Ovarian Cancer at the National Comprehensive Cancer Network® (NCCN®) 16th Annual Conference.

Robert J. Morgan, Jr., M.D., Professor of Medical Oncology, City of Hope Comprehensive Cancer Center; Chair, NCCN Guidelines Panel for Ovarian Cancer

Although finding effective screening tools remains a priority, new treatment options for women with ovarian cancer, such as the ones outlined in the updated NCCN Guidelines for Ovarian Cancer,[1] are vital to making steady progress against the disease according to Robert J. Morgan, Jr., M.D., of City of Hope Comprehensive Cancer Center and chair of the NCCN Guidelines Panel for Ovarian Cancer. Dr. Morgan outlined significant updates to the NCCN Guidelines during a recent presentation at the NCCN 16th Annual Conference.

The NCCN Guidelines address epithelial ovarian cancer (including borderline or low malignant potential) and less common histopathologies, including malignant germ neoplasms, carcinosarcomas, and sex cord-stromal tumors. They also discuss fallopian tube cancer and primary peritoneal cancer, which are less common neoplasms that are managed in a similar manner to epithelial ovarian cancer.

“Regardless of the type of cancer, the NCCN Guidelines for Ovarian Cancer reflect the importance of stage and grade of disease on prognosis and treatment recommendations,” said Dr. Morgan.

The NCCN Guidelines continue to recommend that women with borderline epithelial ovarian cancer of low malignant potential be primarily surgically managed. In contrast to patients with frankly invasive ovarian carcinoma, women with borderline disease tend to be younger and are often diagnosed with stage I disease.

“The benefits of postoperative chemotherapy has not been demonstrated for patients who have no microscopically demonstrable invasive implants, said Dr. Morgan. “Even patients with advanced stage disease at presentation have an excellent prognosis and chemotherapy should be avoided.”

The NCCN Guidelines recommend surgery limited to a unilateral salpingo-oophorectomy (USO) (preserving the uterus and contralateral ovary) for women who wish to maintain their fertility, and standard ovarian cancer debulking surgery is recommended for those not concerned about fertility preservation.

On the contrary, in women diagnosed with stage II, III, or IV epithelial ovarian cancer, the NCCN Guidelines recommend intraperitoneal chemotherapy for first-line therapy and have been updated to include dose-dense paclitaxel (Taxol®:, Bristol-Myers Squibb) as a possible treatment option.

Dr. Morgan noted that in a recent clinical trial, dose-dense weekly paclitaxel with carboplatin (Paraplatin®:, Bristol-Myers Squibb) showed an increase in both progression-free survival and overall survival when compared with conventional intraperitoneal chemotherapy of weekly carboplatin/paclitaxel.[2]

“However, the dose-dense regimen is more toxic, and patients discontinued dose-dense paclitaxel therapy more often than those receiving standard therapy,” stated Dr. Morgan. “As with all treatment decisions, the patient needs to weigh the potential benefits and risks and discuss them thoroughly with their physician.”

Dr. Morgan discussed two additional phase 3 trials assessing bevacizumab (Avastin®:, Genentech/Roche) combined with carboplatin/paclitaxel in the upfront setting compared to carboplatin/paclitaxel alone.[3-4] Although data regarding overall survival and quality of life have not been reported yet, the studies did indicate that the median progression-free survival increased in patients receiving bevacizumab as a first line and maintenance therapy.

“Only modest improvements in progression-free survival were observed in both of these trials. The NCCN Guidelines Panel prefers to await mature results of these trials prior to recommending the routine addition of bevacizumab to carboplatin/paclitaxel,” said Dr. Morgan.

As such, the updated NCCN Guidelines includes new language detailing the Panel’s view on bevacizumab encouraging participation in ongoing clinical trials that are further investigating the role of anti-angiogenesis agents in the treatment of ovarian cancer, both in the upfront and recurrence settings.

Biomarkers continue to emerge as an area of interest in predicting future patterns of the disease. In patients with ovarian cancer, Dr. Morgan discussed the value of monitoring CA-125 levels in regards to a recent study[5] comparing early versus delayed treatment of relapsed ovarian cancer.

“Often, levels of CA-125 have been shown to rise prior to a clinical or symptomatic relapse in women with ovarian cancer. This trial looked at whether there was a benefit of early treatment on the basis of increased CA-125 concentrations compared with delayed treatment on the basis of clinical recurrence,” said Dr. Morgan.

The study, which was published in The Lancet, found that there was no survival benefit to early institution of treatment based on increased CA-125 levels and that the quality of life was superior in patients in the late treatment arm.

“The results of the trial suggest that the utility of the routine monitoring of CA-125 levels in limited,” said Dr. Morgan. “The NCCN Guidelines Panel encourages patients and their physicians to actively discuss the pros and cons of CA-125 monitoring based upon these findings and have updated the NCCN Guidelines to include language supporting this recommendation.”

Virtually all drugs used in oncology have the potential to cause adverse drug reactions while being infused, which can be classified as either infusion or allergic reactions. Recently, hypersensitivity to platinum compounds has been recognized as a potential issue for patients being administered these compounds.

“Platinum compounds remain very important in the treatment of ovarian cancer in both the upfront and recurrence settings, so it was important to design strategies to allow for the safe desensitization of these agents in patients who develop allergies,” said Dr. Morgan.

Standard desensitization regimens include slowly increasing infusion concentrations over several hours. However, Dr. Morgan noted that these procedures must be done in a specific manner in order to be safely administered and pointed to the recommendations within the updated NCCN Guidelines discussing the management of drug reactions.

In conclusion, Dr. Morgan emphasized that although steady progress is being made in the treatment of ovarian cancer, further trials are necessary to investigate the role of targeted agents alone and in combination in newly diagnosed and recurrent ovarian cancer. In addition, enrollment of patients with ovarian cancer must be encouraged.

The NCCN Guidelines are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of expert physicians from NCCN Member Institutions. The most recent version of this and all NCCN Guidelines are available free of charge at NCCN.org. The NCCN Guidelines for Patients™: Ovarian Cancer is available at NCCN.com.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit NCCN.org.

The NCCN Member Institutions are:

  • City of Hope Comprehensive Cancer Center
  • Dana-Farber/Brigham and Women’s Cancer Center
  • Massachusetts General Hospital Cancer Center
  • Duke Cancer Institute
  • Fox Chase Cancer Center
  • Huntsman Cancer Institute at the University of Utah
  • Fred Hutchinson Cancer Research Center / Seattle Cancer Care Alliance
  • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Robert H. Lurie Comprehensive Cancer Center of Northwestern University
  • Memorial Sloan-Kettering Cancer Center
  • H. Lee Moffitt Cancer Center & Research Institute
  • The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute
  • Roswell Park Cancer Institute
  • Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
  • St. Jude Children’s Research Hospital / University of Tennessee Cancer Institute
  • Stanford Comprehensive Cancer Center
  • University of Alabama at Birmingham Comprehensive Cancer Center
  • UCSF Helen Diller Family Comprehensive Cancer Center
  • University of Michigan Comprehensive Cancer Center
  • UNMC Eppley Cancer Center at The Nebraska Medical Center
  • The University of Texas MD Anderson Cancer Center
  • Vanderbilt-Ingram Cancer Center

References:

1/ Ovarian Cancer Including Fallopian Tube Cancer & Primary Peritoneal Cancer, Version 2.2011, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™), National Comprehensive Cancer Network. [PDF Adobe Reader Document – requires free registration and log-in at NCCN.org]

2/ Katsumata N, Yasuda M, Takahashi F, et. alJapanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trialLancet. 2009 Oct 17;374(9698):1331-8. Epub 2009 Sep 18. PubMed PMID: 19767092.

3/ Burger RA, Brady MF, Bookman MA, et. al.  Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC):  a Gynecologic Oncology Group study.  J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1).

4/ Perren T, Swart AM, Pfisterer J, et. alICON7: A phase III randomized gynecologic cancer intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC).Ann Oncol 21;viii2, 2010 (suppl 8; abstr LBA4).

5/Rustin G, van der Burg M, Griffin C, et. al. Early versus delayed treatment of relapsed ovarian cancer. Lancet. 2011 Jan 29;377(9763):380-1. PubMed PMID: 21277438.

Source:

Additional 2011 NCCN Annual Meeting Information

Modified Chemo Regime Increases Survival In Advanced Ovarian Cancer Patients But Adds Toxicity

Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol®) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up.

Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol®) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up. The results were published online September 18 in The Lancet.

Although the toxicities of this dose-dense regimen were greater than they were in women who received the standard combination, survival benefits of this magnitude “have been rare in women with advanced ovarian cancer,” wrote Dr. Noriyuki Katsumata and colleagues from the Japanese Gynecologic Oncology Group (JGOG).

trimble

Edward L. Trimble, MD, MPH; Head - Gynecologic Cancer Therapeutics and Quality of Cancer Care Therapeutics, Clinical Investigation Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis.

The results, explained Dr. Ted Trimble, from NCI’s Division of Cancer Treatment and Diagnosis, are consistent with what has been seen in breast cancer using a dose-dense chemotherapy regimen. The idea, he continued, is “to balance efficacy and toxicity by using a weekly schedule rather than every 3 weeks.”

Although the findings are important, “they won’t change practice overnight,” Dr. Trimble said. There are still several significant unknowns, including whether a lower dose of paclitaxel might be as effective but less toxic; the optimal timing of surgery; and where intraperitoneal chemotherapy fits into the treatment mix. The JGOG trial results, however, will influence the design of a number of phase III clinical trials, all of which include dose-dense chemotherapy, he added.

More than 630 women at 85 hospitals across Japan enrolled in the trial. Patients were randomly assigned to either of the two treatment groups. After 3 years of follow-up, women who received the dose-dense treatment had a median progression-free survival of 28 months, compared with 17 months for those who received the standard treatment.

bookman

Michael A. Bookman, M.D., Chief, Hematology/Oncology Section, Arizona Cancer Center

Not enough time has passed to determine with statistical confidence whether the overall survival advantage will be maintained. However, in ovarian cancer, improvements in progression-free survival tend to predict overall survival, said Dr. Michael A. Bookman, chief of the Hematology/Oncology Section at the Arizona Cancer Center, in an accompanying editorial in The Lancet.

The dose-dense chemotherapy regimen used in the trial was also dose-intense, meaning the total dose of paclitaxel patients received was actually higher than in those who received standard treatment. This was associated with some toxic side effects that caused treatment delays and modifications and also led to patients receiving less caboplatin than intended. In fact, more than half of the women in the dose-dense group discontinued treatment early, and most of them did so because of the toxicity.

Although it’s possible that the dose intensity was responsible for the survival improvements, Dr. Bookman wrote, the more frequent, lower-dose treatment schedule is the most “plausible explanation.” As a result, “similar results might be achieved” with a lower dose, he concluded, “with improved tolerability.”

As for why the dose-dense approach is more effective than the standard approach, the Japanese researchers suggested that it hampers the formation of blood vessels that feed tumors. In animal model studies, dose-dense chemotherapy, like a similar treatment also under active investigation called metronomic chemotherapy, has been shown to have such an antiangiogenic effect. And in the JGOG trial, the researchers noted, tumor shrinkage following treatment did not differ between those receiving dose-dense chemotherapy and standard chemotherapy. This suggests that the dose-dense treatment “might promote tumor dormancy by maintaining tumor size and preventing outgrowth,” they wrote.

alvarez

Ronald Alvarez, M.D., Director, Division of Gynecologic Oncology, University of Alabama at Birmingham

The U.S.-based Gynecologic Oncology Group is planning to launch a phase III clinical trial in advanced ovarian cancer combining the dose-dense approach with the targeted antiangiogenic drug bevacizumab (Avastin), said Dr. Ronald Alvarez, director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham. This should help to confirm the Japanese trial’s results.

In the meantime, “Given the potential toxicity, clinicians should discuss with their patients the risks versus the benefits of this approach in comparison with other treatment strategies,” Dr. Alvarez said, particularly with those patients who have advanced disease and whose tumors could not be mostly eradicated by surgery.

Source: Modified Chemo Regimen Effective in Advanced Ovarian Cancer, by Carmen Phillips, NCI Cancer Bulletin Volume 6 / Number 18, National Cancer Institute, September 22, 2009.

References:

Evaluation of Neoadjuvant Chemotherapy and Debulking Followed by Intraperitoneal Chemotherapy in Women with Stage III and IV Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

It is well known that intraperitoneal (IP) chemotherapy prolongs survival in optimally cytoreduced (or debulked) ovarian cancer patients.  For patients who can not be optimally debulked, it is possible to administer neoadjuvant chemotherapy to place that patient in a position to be optimally debulked (i.e., 1 cm or less of residual disease post surgery) , thereby allowing the use of post-surgery IP chemotherapy (assuming optimal cytoreduction is achieved through surgery). This theory was tested in a Phase II clinical study (S0009) conducted by the Southwest Oncology Group (SOG). …

It is well known that intraperitoneal (IP) chemotherapy prolongs survival in optimally cytoreduced (or debulked) ovarian cancer patients.  For patients who can not be optimally debulked, it is possible to administer neoadjuvant chemotherapy to place that patient in a position to be optimally debulked (i.e., 1 cm or less of residual disease post surgery) , thereby allowing the use of post-surgery IP chemotherapy (assuming optimal cytoreduction is achieved through surgery). This theory was tested in a Phase II clinical study (S0009) conducted by the Southwest Oncology Group (SOG).

In SOG Study S009, researchers sought to evaluate overall survival (OS), progression-free survival (PFS), percentage of patients optimally debulked, and toxicity in Stage III/IV ovarian cancer patients treated with this strategy.

As part of the study, women with stage III/IV (pleural effusions only in stage IV) epithelial ovarian cancer, and fallopian tube or primary peritoneal carcinoma that presented with bulky disease were treated with neoadjuvant intravenous (IV) paclitaxel and carboplatin.  If, after neoadjuvant IV chemotherapy, the patient experienced a 50% or greater decrease in her CA125 tumor marker, cytoreduction surgery was performed.  If optimal debulking was achieved, the patient received IV paclitaxel, IP carboplatin and IP paclitaxel post-surgery.

The results of the study are set forth below.

  • 62 patients were registered for the study, of which four were ineligible.
  • 56 patients were evaluated for neoadjuvant chemotherapy toxicities. One patient died of pneumonia. Five patients had grade 4 toxicity, including neutropenia, anemia, leukopenia, anorexia, fatigue, muscle weakness, respiratory infection, and cardiac ischemia.
  • 36 patients received debulking surgery, and two patients had grade 4 hemorrhage.
  • 26 patients received post-cytoreduction chemotherapy. Four had grade 4 neutropenia.
  • At a median follow-up of 21 months, median PFS is 21 months and median OS is 32 months for all 58 patients.
  • PFS and OS for the 26 patients who received IV/IP chemotherapy is 29 and 34 months, respectively

The researchers performing the study concluded that the results compare favorably with other studies of sub-optimally debulked (i.e., >1 cm of residual disease post surgery) patients.

Primary SourcePhase II evaluation of neoadjuvant chemotherapy and debulking followed by intraperitoneal chemotherapy in women with stage III and IV epithelial ovarian, fallopian tube or primary peritoneal cancer: Southwest Oncology Group Study S0009; Tiersten AD, Liu PY, Smith HO et. al., Gynecol Oncol. 2009 Mar;112(3):444-9. Epub 2009 Jan 12.

2009 Society of Gynecologic Oncologists Annual Meeting Ovarian Cancer Highlights

From February 5th through 8th, 2009, the Society of Gynecologic Oncologists’ (SGO) held its 40th Annual Meeting on Women’s Cancer in San Antonio, Texas. The meeting, viewed as the preeminent scientific and educational conference for women’s cancer care specialists, featured more than 350 scientific oral and poster presentations as well as educational sessions dealing with advances in the care and treatment of women’s cancers.

40thsgobanner2

From February 5th through 8th, 2009, the Society of Gynecologic Oncologists‘ (SGO)  held its 40th Annual Meeting on Women’s Cancer in San Antonio, Texas.  The meeting, viewed as the preeminent scientific and educational conference for women’s cancer care specialists, featured more than 350 scientific oral and poster presentations as well as educational sessions dealing with advances in the care and treatment of women’s cancers.  Several important presentations relating to ovarian cancer were made during the meeting and are highlighted below:

  • SGO: IVF Confers Slight Long-Term Risk of Ovarian Cancer, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 6, 2009 [Presentation Source:  Burger C, et al; The risk of borderline and invasive ovarian tumors after ovarian stimulation for in vitro fertilization in a large Dutch cohort after 15 years of follow-up, SGO 2009; 112(Suppl 1): Abstract 6].
  • SGO: Optimal Surgery Holds Benefits in Ovarian Cancer with Upper Abdominal Disease, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 6, 2009 [Presentation Source:  Zivanovic O, et al; Upper abdominal disease cephalad to the greater omentum and the impact on progression-free survival in patients with stage IIIC ovarian cancer;  SGO 2009; 112(Suppl 1): Abstract 1].
  • SGO: Rectovaginal Nodules Predict Bowel Perforation Risk with Bevacizumab, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 9, 2009 [Presentation Source:  Richardson DL, et al; Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab? SGO 2009; 112(Suppl 1): Abstract 41].
  • Low Completion Rates for GOG 172 Intraperitoneal Chemotherapy Regimen: See Aletti G, et al Intraperitoneal chemotherapy for ovarian cancer: Exploring the “dark side” of the moon” SGO 2009; 112(Suppl 1): Abstract 40 (Source:  SGO: Few Ovarian Cancer Patients Tolerate Intraperitoneal Regimen, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 11, 2009).
  • Vermillion Presents Critical Data From Its OVA1 Clinical Trial, Vermillion Inc. News Release, February 10, 2009 [Presentation based upon a study entitled, A biomarker panel for distinguishing between malignant and benign ovarian tumors, which was co-authored by Fred Ueland, MD, Associate Professor of Gynecologic Oncology at the University of Kentucky and Principal Investigator of the OVA1 clinical trial, and Zhen Zhang, PhD, Associate Professor of Pathology at the Johns Hopkins University School of Medicine as well as Vermillion scientists].

About the Society of Gynecologic Oncologists

The SGO is a national medical specialty organization of physicians who are trained in the comprehensive management of women with malignancies of the reproductive tract. Its purpose is to improve the care of women with gynecologic cancer by encouraging research, disseminating knowledge which will raise the standards of practice in the prevention and treatment of gynecologic malignancies, and cooperating with other organizations interested in women’s health care, oncology and related fields. The Society’s membership, totaling more than 1280, is primarily comprised of gynecologic oncologists, as well as other related medical specialists including medical oncologists, radiation oncologists and pathologists. SGO members provide multidisciplinary cancer treatment including chemotherapy, radiation therapy, surgery and supportive care. More information on the SGO can be found at http://www.sgo.org.