Early Detection Remains Key in Updated National Comprehensive Cancer Network (NCCN) Guidelines for Ovarian Cancer

New updates to the NCCN Clinical Practice Guidelines in Oncology™ for Ovarian Cancer were presented at the NCCN 14th Annual Conference on March 14. Notable additions to the NCCN Guidelines are a section on managing allergic reactions to chemotherapy agents and new agents for recurrence therapy. Robert J. Morgan Jr., M.D., F.A.C.P. of  the City of Hope Comprehensive Cancer Center presented the updated NCCN Guidelines that continue to stress early detection of ovarian cancer and the enrollment of patients in clinical trials.

“Early Detection Remains Key in Updated NCCN Guidelines for Ovarian Cancer


New updates to the NCCN Clinical Practice Guidelines in Oncology™ for Ovarian Cancer were presented at the NCCN 14th Annual Conference on March 14. Notable additions to the NCCN Guidelines are a section on managing allergic reactions to chemotherapy agents and new agents for recurrence therapy. Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center presented the updated NCCN Guidelines that continue to stress early detection of ovarian cancer and the enrollment of patients in clinical trials.


March 16, 2009

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Robert J. Morgan Jr., M.D., F.A.C.P., Professor of Medical Oncology, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA & Chair of the NCCN Guidelines Panel for Ovarian Cancer

HOLLYWOOD, FL — Improvements in screening and early detection remains the key for women with ovarian cancer according to Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center and chair of the NCCN Guidelines Panel for Ovarian Cancer. Dr. Morgan discussed the future of ovarian cancer and notable changes to the recently updated NCCN Ovarian Cancer Guidelines at the NCCN Annual Conference on Saturday, March 14.

Dr. Morgan began by explaining that the major challenge in treating ovarian cancer is that by the time the majority of patients (70 percent) are diagnosed with the disease, it has already progressed to stage III or IV. ‘We have not yet found a good way to screen the general population or even the high-risk population of women for ovarian cancer,’ he said.

New to the NCCN Guidelines is a section on the management of allergic reactions in patients receiving chemotherapy for ovarian cancer. Dr. Morgan explained the need for this section as ovarian cancer tends to respond to the same treatment repeatedly. Combined with the fact that recurrence rates of ovarian cancer are high, this can result in patients often being retreated with the same chemotherapeutic agent. Given that virtually all chemotherapy drugs have the potential to cause infusion reactions, including agents commonly used in ovarian cancer, the NCCN Guidelines Panel felt it was important to provide information on allergic reactions and recommendations on desensitization regimens.

‘Most patients experiencing allergic reactions are able to be desensitized allowing for continued chemotherapeutic treatment, which is vital to the management of ovarian cancer,’ said Dr. Morgan.

Also new to the updated NCCN Guidelines is the addition of new agents for recurrence therapy, most notably pemetrexed (Alimta®, Eli Lilly and Company) as well as recommendations for therapies based on the timing of recurrence.

‘Seventy-five to 80 percent of patients with stage III or IV ovarian cancer will experience recurrence and this recurrence can occur at any time – during treatment, within 6 months of completing treatment, or more than a year after completing treatment,’ Dr. Morgan noted. ‘In the updated NCCN Guidelines, we differentiated appropriate therapy for recurrence based upon the time frame on which it occurs.’

Additionally, Dr. Morgan referred to a clinical trial suggesting that pemetrexed is active in recurrent ovarian cancer, to support the new recommendation in the updated NCCN Guidelines.

Dr. Morgan described new updates to the Principles of Primary Surgery section in the updated NCCN Guidelines that included the recommendation to consider completion surgery for patients responsive to chemotherapy with initially unresectable residual disease, as well as recommendations relating to special circumstances including minimally-invasive procedures, and fertility sparing procedures.

Dr. Morgan also discussed recent clinical studies conducted abroad that studied the effect of chemotherapy as an up-front therapy in patients with ovarian cancer, and concluded that ‘in the United States, up-front debulking surgery remains the recommendation for the best overall survival.’

Another addition to the updated NCCN Guidelines is a section on the Principles of Chemotherapy. This section emphasizes the encouragement of patients participating in clinical trials during all aspects of their treatment course as well as noting that patients with newly diagnosed tumors should be informed about the different options available, particularly IV [intravenous] vs. IV/IP chemotherapy and the risks and benefits of each regimen.

‘The future of ovarian cancer lies in early detection and improvements in screening,’ Dr. Morgan noted as he discussed potential biomarkers for the detection, prediction and prognostication of ovarian cancer.

He concluded that steady progress is being made in the treatment of ovarian cancer, but further trials are necessary to investigate the role of targeted agents alone and in combination in newly diagnosed and recurrent ovarian cancer. Finally, he again stressed the need for physicians to encourage their patients to participate in clinical trials.

For questions about NCCN or for interview information, please contact Megan Martin 215.690.0576.

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 www.nccn.org.

The NCCN Member Institutions are

Cited SourceEarly Detection Remains Key in Updated NCCN Guidelines for Ovarian Cancer, News, National Comprehensive Cancer Network (NCCN), March 16, 2009.

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.

Sometimes More Is Less: Evaluation of Experimental Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer; A Phase III Trial of the Gynecologic Cancer InterGroup

“… Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent [gemcitibine, liposomal doxorubicin or topotecan] provided no benefit in PFS [progression-free survival] or OS [overall survival] after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.”

“Michael A. Bookman,* Mark F. Brady, William P. McGuire, Peter G. Harper, David S. Alberts, Michael Friedlander, Nicoletta Colombo, Jeffrey M. Fowler, Peter A. Argenta, Koen De Geest, David G. Mutch, Robert A. Burger, Ann Marie Swart, Edward L. Trimble, Chrisann Accario-Winslow, and Lawrence M. Roth

From the Fox Chase Cancer Center, Philadelphia, PA; Gynecologic Oncology Group Statistical and Data Center, Buffalo, NY; Franklin Square Hospital; Baltimore, MD; Guy’s Hospital, London, United Kingdom; Arizona Cancer Center, Tucson, AZ; Australia New Zealand Gynaecological Oncology Group, Camperdown, Australia; European Institute of Cancer Research, Milano, Italy; Ohio State University, Columbus, OH; University of Minnesota School of Medicine, Minneapolis, MN; University of Iowa Hospitals and Clinics, Iowa City, IA; Washington University School of Medicine, St. Louis, MO; University of California, Irvine Medical Center, Orange, CA; University College London and Medical Research Council Clinical Trials Unit, London, United Kingdom; National Cancer Institute, Bethesda, MD; and Indiana University School of Medicine, Indianapolis, IN.

* To whom correspondence should be addressed. E-mail: michael.bookman@fccc.edu

Purpose: To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel.

Patients and Methods: Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons.

Results: Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup.

Conclusion: Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.”

Quoted Source Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup; Bookman MA et. al., J Clin Oncol. 2009 Feb 17. [Epub ahead of print].

Encouraging Survival Data Associated With Maximal Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Using Pegylated Liposomal Doxorubicin

A recent Phase I clinical trial reported encouraging survival data with respect to the use of maximal cytoreduction combined with hyperthermic intraperitoneal chemotherapy (HIPEC) using pegylated liposomal doxorubicin (PLD)(e.g., Doxil™) to treat patients with advanced intra-abdominal, gastrointestinal and gynecological malignancies.

HIPEC is used in conjunction with surgery and chemotherapy to treat patients with gastrointestinal tract and gynecological cancers and sarcomas that have spread to the lining of the abdomen. Even after surgical removal, cancer often recurs in the abdomen. So when the tumor spreads, it is difficult for doctors to treat with standard chemotherapy.

HIPEC involves using a using a heated sterile solution that is circulated throughout the abdominal cavity. With HIPEC treatment, patients are connected to a series of tubes and a pumping device that bathes the abdominal cavity for two hours with a heated sterile solution containing anticancer (chemotherapeutic) drugs. The high temperature of the chemotherapy increases the effect of the drug. The fluid goes through the abdomen to treat tumor cells that may remain after surgery. Both heat and direct contact with chemotherapy drugs kills the cancer cells.

Twenty-one patients were enrolled in this Phase I clinical trial. The maximum PLD dose evaluated in this trial was 100 mg/m² and was well tolerated. The most common grade 3/4 complications were superficial wound infection and prolonged ileus. One patient developed an anastomotic leak in the postoperative period, requiring re-exploration. The length of the median postoperative hospital stay was 7 days (range, 4-29 days), three patients required readmissions within 30 days, and there were no operative deaths.

The median follow-up time for was 13.7 months (range, 3-38 months). The median overall survival was 30.6 months with a median progression free survival (PFS) of 25 months. Based on these findings, the trial investigators concluded that HIPEC with PLD following maximal cytoreduction in patients with advanced abdominal-only, gastrointestinal or gynecologic malignancies is well tolerated. Moreover, the investigators stated that the encouraging survival period after cytoreduction and HIPEC with PLD suggests that a verification Phase II clinical trial is warranted.

For more information regarding the HIPEC procedure, go to HIPECTREATMENT.org. For a list of open clinical trials testing the HIPEC procedure using various chemotherapeutic agents, click here.

Sources:

Who? Where? Two of the Most Important Choices When Facing An Ovarian Cancer Diagnosis.

Robert Bristow, M.D., Director of the Kelly Gynecologic Oncology Service and the Johns Hopkins Ovarian Cancer Center of Excellence, and colleagues highlight the importance of referring patients with suspected ovarian cancer to expert centers for their first surgery. By combining multiple studies of patients with stage III or IV ovarian carcinoma (6,885 patients) Bristow et al showed that consistent referral of patients with apparent advanced ovarian cancer to expert centers for primary surgery may be the best means currently available for improving overall survival. Even with the use of platinum based chemotherapy, maximal (or optimal or complete) cytoreduction was one of the most powerful determinants of cohort survival among patients with stage III or IV ovarian carcinoma. While the influence of platinum dose-intensity upon survival was not statistically significant, maximal cytoreduction was associated with a 50% increase of actuarial survival.

PubMed medical study abstract: “Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis,”Bristow, R.E., Tomacruz, R.S., Armstrong, D.K., Trimble, E.L., Montz, F.J., Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287-1248, USA. rbristo@jhmi.edu, J. Clin. Oncol. 2002 Mar 1;20(5):1248-59.

Full Text of medical study: Journal of Clinical Oncology, Vol. 20, Issue 5 (March), 2002: pp.1248-1259.

Additional medical studies:

COMMENT: If you were recently diagnosed with ovarian cancer, these studies suggest that you should seek treatment from a medical institution(s) that (i) utilizes Gynecologic Oncologists as an essential part of the cancer diagnosis and treatment process, (ii) utilizes surgeons that possess high-end expertise with respect to gynecologic oncology surgical procedures such as maximum cytoreduction (e.g., gynecologic oncology surgeons), and (iii) conducts a high volume of gynecologic oncology surgeries and procedures resulting in best outcome. Refer to the resources below.