Most ovarian cancers have spread beyond the ovary by the time they are diagnosed, and they often recur even after responding to primary treatment. Researchers at The University of Texas MD Anderson Cancer Center aim to improve patient outcomes by changing the standard approach to newly diagnosed advanced ovarian cancer.
“There are several areas of opportunity to improve the up-front management of advanced ovarian cancer. If we can identify the patients who need surgery first and those who need chemotherapy first, that can change our practice. We’re also conducting trials that will help us identify new agents of interest for these patients in the up-front setting,” said Shannon Westin, M.D., an assistant professor in the Department of Gynecologic Oncology and Reproductive Medicine.
Need for macroscopically complete resection
Patients with newly diagnosed advanced ovarian cancer with no evidence of extra-abdominal metastases typically undergo a combination of chemotherapy and surgery to debulk or completely remove the primary and metastatic tumors, but whether chemotherapy or surgery should be given first remains a matter of debate. Although a recent clinical trial suggested that the chemotherapy-first and surgery-first approaches lead to similar survival times in patients with advanced ovarian cancer, the broad applicability of those results has been questioned. And some ovarian cancer specialists maintain that the choice of up-front treatment can influence survival. “Selecting the subgroup of patients that will likely benefit from up-front surgery remains a diagnostic dilemma,” said Alpa Nick, M.D., an assistant professor in the Department of Gynecologic Oncology and Reproductive Medicine.
Dr. Nick explained that several studies showed that patients in whom macroscopically (grossly) complete resection of the ovarian cancer was achieved by cytoreductive surgery survived longer than those with macroscopically evident disease remaining after the surgery. Therefore, increasing the rate of complete resection is expected to lengthen survival.
If the likelihood of achieving grossly complete resection through up-front surgery could be predicted before treatment begins, then the overall treatment approach could be personalized. Patients for whom up-front surgery is likely to eradicate all grossly visible cancer could receive surgery first, and patients unlikely to attain a grossly complete resection with up-front surgery could receive chemotherapy first to increase the likelihood of a complete resection later.
Predicting which patients will have a grossly complete resection before surgery is performed can be difficult. Imaging-based predictors, such as whether a patient has liver or lung metastases on computed tomography, can reliably reveal unresectable disease but cannot accurately predict which ovarian tumors can be completely resected. To date, the most accurate method for assessing the resectability of advanced ovarian cancer has been laparoscopy. Hence, researchers at MD Anderson have implemented a new algorithm that uses laparoscopic findings to determine the best course of treatment for patients with advanced ovarian cancer.
As part of an MD Anderson program to accelerate the discovery and implementation of new treatments for breast and ovarian cancers, clinicians have focused on improving the rate of cytoreductive surgeries that result in grossly complete resections in patients with advanced ovarian cancer. In April 2013, the Gynecologic Oncology Clinic at MD Anderson implemented a quality improvement initiative in which all surgeons agreed to perform diagnostic laparoscopy before attempting cytoreductive surgery in all patients believed to have advanced ovarian cancer on the basis of clinical assessment and computed tomography.
During the laparoscopy, two surgeons independently score the extent of metastatic cancer using an index for disease distribution in the abdomen. The index, created by Anna Fagotti, M.D., and colleagues at Catholic University of the Sacred Heart in Italy, assigns a score of 0 (absent) or 2 (present) for each of seven parameters: unresectable peritoneal carcinomatosis, widespread diaphragmatic disease, infiltrating mesenteric disease, need for potential bowel resection, liver surface involvement, obvious neoplastic involvement of the gastric wall, and supracolic omental disease. According to the Anderson algorithm, a total score below 8 means the disease is resectable, and a score of 8 or higher means the disease is not currently resectable.
If both surgeons score the cancer as resectable during the laparoscopy, then the patient receives surgery followed by chemotherapy. If both surgeons score the cancer as unresectable, then the patient receives three cycles of neoadjuvant chemotherapy followed by surgery. If the surgeons disagree, then a third surgeon is consulted.
This algorithm differs from previous practice in a few notable ways. Although laparoscopy has been used to determine resectability before, its use before cytoreductive surgery is not currently a standard practice in the United States; instead, the decision of whether to use surgery or chemotherapy first might be made on the basis of clinical assessment. The use of two surgeons to assess the extent of disease during the laparoscopy helps maximize the success rate of the surgery by ensuring that no patient whose disease is too extensive undergoes up-front surgery. Finally, the use of grossly complete resection as an endpoint, in keeping with evidence suggesting that grossly complete resection significantly contributes to longer survival, contrasts with previous definitions of optimal cytoreduction as resecting all nodules that are larger than 1 cm or larger than 2 cm.
So far, the new algorithm has, as predicted, improved rates of macroscopically complete resection in patients treated for advanced ovarian cancer. In the patients treated with surgery before chemotherapy, the rate of complete resection dramatically increased, from 20% before April 2013 to almost 90% after the implementation of the algorithm. Similarly, the complete resection rate increased from 60% to almost 80% in patients treated with chemotherapy before surgery. Although it is too soon to tell whether these patients also survive longer, their high rates of complete resection are expected to improve their survival times.
Furthermore, the use of the new algorithm has not affected the patients’ time to chemotherapy, a quality measure for ovarian cancer care. Dr. Nick said, “We closely track patient outcomes to ensure that patients are able to begin postoperative treatment in a timely fashion. Thus far, we have not seen any delay in the start of chemotherapy. In fact, the time to chemotherapy has actually decreased in the patients treated with chemotherapy first.”
Clinical trials with the Anderson algorithm
Researchers at MD Anderson are also using the Anderson algorithm along with new systemic treatments in patients with advanced ovarian cancer. Dr. Westin is leading a series of clinical trials using a novel trial design called the “window of opportunity,” which refers to the time between laparoscopic evaluation and cytoreductive surgery in patients scheduled to undergo surgery before chemotherapy. “We’re using the time between the laparoscopy and the surgery to add new therapies,” Dr. Westin said. “Standard chemotherapy for ovarian cancer, with paclitaxel and carboplatin, frequently leads to complete responses, but the cancer often recurs later. So we’re adding different agents into that up-front setting to maximize the early response and keep the cancer from coming back.”
In the window-of-opportunity trials, patients whose laparoscopy shows advanced ovarian cancer that can be completely resected with up-front surgery are given novel agents during the 7–10 days before the surgery. The first such trial will give these patients a short course of the poly(ADP-ribose) polymerase (PARP) inhibitor BMN 673 before surgery. Researchers will then compare tumor tissue taken at the time of the laparoscopy with tumor tissue taken at the time of the cytoreductive surgery, immediately after the short treatment. Dr. Westin said, “These trials are very information rich because they show us the effects these drugs have on tumor tissue that has never been treated before. Once we identify drugs that seem to produce a response in patients with specific characteristics, we can treat those patients and subsequent patients who have those characteristics with those new agents combined with standard chemotherapy after their surgery and possibly get better outcomes than what we’re currently achieving.”
In another line of trials, patients with advanced ovarian cancer who will receive neoadjuvant chemotherapy will be given experimental agents along with the cytotoxic chemotherapy drugs. Dr. Nick is developing one such trial, in which patients will receive neoadjuvant chemotherapy combined with the immune checkpoint inhibitor MK-3475. To assess the effects of these combination treatments on tumor tissue, the tissue taken before treatment during the laparoscopy will be compared with tissue taken at the time of the cytoreductive surgery.
Another area of interest for researchers is maintenance therapy. “Advanced ovarian cancer tends to recur. If there’s a drug that these patients could take after primary treatment that would keep the cancer away, that would be a huge benefit,” said Dr. Westin. “We are considering certain targeted agents, like PARP inhibitors and antiangiogenic agents, that may work as maintenance therapy. Some of our trials in this area are looking at which drugs to give which patients as maintenance and at what dosages those drugs should be given.”
Clinicians in the Department of Gynecologic Oncology and Reproductive Medicine think the Anderson algorithm could change the standard approach to advanced ovarian cancer. Dr. Nick and Anil Sood, M.D., a professor in the Department of Gynecologic Oncology and Reproductive Medicine, have presented the algorithm at institutions in the MD Anderson Network, at other tertiary care centers in the United States, and at institutions worldwide throughout MD Anderson’s Global Academic Programs Sister Institution Network. Dr. Nick said that these other groups are highly interested in implementing the algorithm in their practices.
MD Anderson researchers also hope to gain knowledge of the molecular and genomic profiles of ovarian cancer over the course of treatment. Tissue changes after neoadjuvant or window-of-opportunity treatment with new systemic agents should help reveal which tumors respond best to which drugs, and molecular changes between the primary tumor and metastatic sites throughout the abdomen are expected to shed light on ovarian cancer biology and evolution.
For more information, contact Dr. Alpa Nick at 713-563-6658 or Dr. Shannon Westin at 713-794-4314. To learn more about ongoing clinical trials for ovarian cancer treatment, visit www.clinicaltrials.org.
Nick AM, Coleman RL, Ramirez PT, et al. A framework for a personalized surgical approach to ovarian cancer. Nat Rev Clin Oncol. 2015;12:239–245.
OncoLog, May 2015, Volume 60, Issue 5
Genetic Testing in High-Grade Ovarian Cancer
Because close to 20% of patients with high-grade serous ovarian cancer—with or without a family history of cancer—have oncogenic mutations, current National Comprehensive Cancer Network guidelines recommend that all patients with high-grade serous ovarian cancer undergo genetic testing for BRCA1 and BRCA2 mutations. Therefore, the MD Anderson “moon shot” program for breast and ovarian cancer aims to offer universal testing for patients with high-grade ovarian cancer and to identify at-risk family members. Since patients with germline BRCA mutations are more likely than other patient populations to respond to PARP inhibitors, Dr. Westin will be leading several clinical trials in which patients with ovarian cancer and BRCA mutations will be treated with PARP inhibitors.
For more information about MD Anderson’s moon shot programs, visit www.cancermoonshots.org.