CHICAGO – Maintenance immunotherapy with low-dose interleukin-2 and 13-cis-retinoic acid demonstrated an "unexpected" survival benefit in a phase II trial among 500 patients who had derived clinical benefit from chemotherapy for a variety of stage IV cancers, investigators from Italy reported.
The 15-year disease-free survival and overall survival rates reached 32.6% and 36.8%, respectively, in the open, nonrandomized trial, and a breakdown by tumor type showed better outcomes than seen in historic controls, Dr. Francesco Recchia reported at the annual meeting of the American Association for Cancer Research.
©AACR/Phil McCarten
Dr. Francesco Recchia
Comparing their data with outcomes for the most commonly treated metastatic cancers in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the investigators found their 5-year overall survival rates were 42.7% vs. 23.3% for breast cancer, 26.4% vs. 3.6% for lung cancer, 43.6% vs. 11.7% for colorectal cancer, and 23% vs. 11% for renal cancer.
"The good and unexpected results of this immunotherapy regimen were seen in all types of cancer: ovarian cancer and recurrent ovarian cancer, non–small cell lung cancer, cardiac metastases of sarcoma, colorectal cancer, gastric cancer, renal cell carcinoma, melanoma, head and neck cancer, breast cancer, and pancreatic cancer," said Dr. Recchia, director of oncology at the Civilian Hospital in Avezzano (Italy).
"The best merit of our research is the low cost of this therapy," he added.
The impetus for the phase II trial was an observation, in 1995, that a patient, who could not tolerate standard high-dose (18 x 106 IU/m2) IL-2 therapy for metastatic melanoma, experienced a long-lasting response to low-dose subcutaneous IL-2. Dr. Recchia and his colleagues conducted a series of phase I and II randomized studies of low-dose IL-2 with and without retinoic acid, ultimately determining that the combination of the two agents was most effective in increasing natural killer (NK) cell populations and decreasing vascular endothelial growth factor (VEGF) expression.
In the current study, after a median follow-up of 60 months, Dr. Recchia and his colleagues observed a statistically significant increase in the number of NK cells – mediators of lytic activity against cancer cell lines – from a baseline mean of 309/mm3 to a mean of 579/mm3. They also found a statistically significant decrease in VEGF expression, from a baseline mean of 520 pg/mm3 to a mean of 150 pg/mm3 in the study participants.
"Both of these mechanisms are associated with slowing cancer growth," he said in an interview.
All of the patients enrolled in the study were in chemotherapy-induced remission, with good performance status, from stage IV cancer, and all (median age 61 years) were treated for 1 year with self-administered subcutaneous IL-2 (1.8 x 106 IU) and oral 13-cis-retinoic acid (0.5 mg/kg) 5 days per week for two consecutive 3-week cycles, with a 1-week rest. This was followed by continued intermittently scheduled therapy for 5 years or until disease progression, with assessment of NK cells, serum VEGF, tumor response, and toxicity every 4 months, Dr. Recchia said.
The study’s primary end point was NK cell and VEGF response, he added, noting that disease-free survival, overall survival, and toxicity in various tumor types were secondary end points.
The treatment was not associated with any World Health Organization grade 3 or 4 toxicities, Dr. Recchia reported. Grade 2 cutaneous toxicity (20%), fever (13%), mild hypothyroidism (5%), and triglyceride elevation (15%) were observed, he said; one patient discontinued treatment because of grade 2 urticaria.
Prior to using the maintenance regimen in clinical practice, the findings of the current study have to be validated in a blinded, controlled, randomized trial, said Dr. Recchia, noting that a phase III study is underway in patients with advanced breast cancer.
Dr. Recchia reported having no relevant financial conflicts of interest.