NEW YORK CITY—Canadian oncologists have begun using a new two-drug carboplatin-paclitaxel chemotherapy regimen for research in advanced endometrial cancer instead of the gold standard of cisplatin-doxorubicin. In a report here at the 9th International Symposium on Platinum Coordination Compounds in Cancer Chemotherapy, researchers said the new doublet offers reduced toxicity and greater convenience of administration without loss of efficacy.
It is somewhat novel that chemotherapy is the preferred treatment for endometrial cancer at all, and it has taken numerous studies to show the efficacy of chemotherapy in advanced endometrial cancer.
The cancer most responsive to platinum-based chemotherapy is still ovarian, but recent experience shows that the drug is also potent against endometrial cancers not cured by surgery (with or without radiotherapy), researchers said at the meeting, which was sponsored by New York University.
“New studies, particularly from the Gynecologic Oncology Group (GOG), are persuading oncologists that chemotherapy plays a major role in the treatment of endometrial cancer in patients at high risk of recurrence,” said Symposium Co-chair Franco M. Muggia, MD, Professor of Oncology at NYU's Kaplan Comprehensive Cancer Center.
Platinum's strong suit in gynecologic cancers is still in treatment of ovarian cancer. “But endometrial cancer is a new target and it is clear that chemotherapy plays a role that was not so clear a couple of years ago,” Dr. Muggia said. “Platinum is adding to survival [in advanced endometrial cancer] and may also play a role in the earlier stages.”
A British Columbian oncologist described the evolution of platinum-based chemotherapy in Canada leading to the decision by the National Cancer Institute of Canada to use the carboplatin-paclitaxel regimen in future chemotherapy trials, bypassing Phase III studies comparing it with a three-drug regimen of cisplatin, paclitaxel, and doxorubicin
Paul J. Hoskins, MA, FRCPC, of the British Columbia Cancer Agency said the gold standard in Canada for advanced endometrial cancer has been cisplatin at 50 mg/m2 and doxorubicin at 60 mg/m2. Radiotherapy can be added to improve local control after surgery.
But the doxorubicin-cisplatin regimen is a toxic regimen, Dr. Hoskins said.
“Cisplatin has nasty side effects and a ho-hum response. Carboplatin is much easier to take.”
Meanwhile, paclitaxel was demonstrating efficacy as a single agent in this setting, and a cisplatin-paclitaxel combination without doxorubicin was found to be at least as effective as a regimen of all three.
And carboplatin-paclitaxel is relatively convenient to deliver, he said.
“The NCIC will use carboplatin-paclitaxel as its standard arm in future studies with no need to perform a Phase III study comparing it to a three-drug regimen containing doxorubicin,” Dr. Hoskins said.
The two-drug regimen for advanced or recurrent endometrial cancer consists of paclitaxel at 175 mg/m2over three hours followed by carboplatin (at an area under the curve [AUC] of 5–7), every four weeks.
If the tumor can be covered by radiation, radiotherapy to the pelvis and possibly to the para-aortics is given after three chemotherapy cycles. Radiotherapy is given at 4,500 cGy for the whole abdomen in 32 fractions, or 2,250 cGy to the abdomen in 22 fractions. For the pelvis and/or para-aortics, the dosage is 4,000 to 6000 cGy in 25 to 33 fractions.
If the tumor is non “radio-encompassable,” six cycles of chemotherapy are given, Dr. Hoskins said.
“But we decided not to use hormones because for the great majority of women with advanced disease or recurrent Grade III tumors, the chance of getting better with hormones—any one you care to name—is less than 10%,” he said.
If the tumor is encompassable with radiation, radiotherapy is known to improve local control post-surgery.
But whole abdominal radiation is of limited value, he added, because a safe dose is not as effective as chemotherapy.
Dr. Hoskins said patterns of relapse suggest what treatment to use. For a purely local pelvic relapse, radiotherapy or chemotherapy alone would work. For more widespread disease, a systemic treatment such as chemotherapy or targeted therapy is appropriate.
Dr. Hoskins described a small study in Vancouver using the carboplatin-paclitaxel regimen with or without radiotherapy in 62 patients, median age of 64.
Among nine patients with newly diagnosed advanced non-papillary-serous disease evaluable for response, seven responded (78%). Their median failure-free survival time was 23 months, and overall survival has not been reached.
There were 15 patients with newly diagnosed advanced papillary serous endometrial cancer. Nine had a response (60%).
Failure-free survival was 18 months; overall survival was 26 months. Among 18 patients with recurrent non-papillary serous disease (none receiving radiation), 10 responded to therapy (56%); failure-free and overall survival were six and 15 months, respectively.
And two of four patients (50%) with recurrent papillary disease responded to treatment.
“With 50 to 60 percent of patients alive and well out past five years, we may be curing some of these patients,” Dr. Hoskins said.
The regimen appeared safe. Of 62 patients, 58 received more than one cycle of chemotherapy, only 13 (22%) needed dose reductions, and none of the cycles were delayed.
Thirty patients received radiotherapy, and only two had delay and two received a diminished dose, Dr. Hoskins reported.
The rate of febrile neutropenia was 3%, and the hospitalization rate 4%.
Dr. Muggia, in his presentation, said gynecologic cancer researchers must now decide whether a new gold standard should include carboplatin or cisplatin, and whether it should include a taxane or doxorubicin.
It must also be determined which regimen is more easily integrated with radiation, and whether hormone therapy might play a role before or after chemotherapy-induced remissions.
He touched on the question of chemotherapy versus radiotherapy by describing the GOG 122 trial, presented at the most recent ASCO annual meeting (by Marcus Randall et al), in which adjuvant cisplatin-doxorubicin chemotherapy for locally confined unresectable Stages III and IVa advanced endometrial cancer was compared with whole abdominal radiation after surgery.
“The surprising results were that progression-free survival at 24 months was significantly in favor of the chemotherapy regimen—59% versus 46% for the radiation,” Dr. Muggia said.
The survival rate was 70% versus 59%, again favoring doxorubicin-cisplatin over whole abdominal radiation.
“GOG122 proved that doxorubicin-cisplatin chemotherapy proved more effective than whole abdominal radiation in preventing recurrences,” Dr. Muggia said.
The implications from GOG 122 are that platinum-based chemotherapy needs to be tested in early stages of endometrial cancer, and that drug substitutions need to be explored to make chemotherapy less toxic.
“The evolution of GOG therapeutic strategies against advanced or recurrent endometrial cancer clearly demonstrate a major role for platinum based-chemotherapy in the treatment of patients not cured by surgery,” Dr. Muggia said.