Silvia C. Formenti, MD

In Part 2 of this two-part series, we review the clinical evidence in support of combining immunotherapy with stereotactic radiosurgery for the treatment of brain metastases; examine controversies regarding radiation dose and fractionation, as well as temporal sequencing of multimodality treatment; and discuss future directions in combined therapy.

In this review, we highlight preclinical and clinical data to support the rationale for combination of stereotactic radiosurgery with immunotherapy for the treatment of brain metastases; describe some areas of controversy, especially with regard to radiation fractionation and the timing of combination therapy; and discuss ongoing research into multimodality treatment of CNS tumors.

During the past decade, scientific evidence has emerged that shows that radiotherapy can induce: A) immunogenic cell death, a form of cancer cell death that is effectively signaling to the immune system; and B) a series of “danger” and pro-immunogenic signals that are sensed by the host’s immune system, and can be harnessed to reject the tumor.

It is only recently that the radiation oncology community has acknowledged the immunogenic effect of ionizing radiation and started exploiting its clinical potential.

The field of cancer immunotherapy, once the sole purview of immunology, has evolved toward the harnessing of newly described properties of ionizing radiation (IR). Cancer immunotherapy now includes the combination of established cytotoxic modalities with immune manipulations, as vaccines alone are unlikely to succeed at curing bulky, established tumors.

After pegylated liposomal doxorubicin (PEG-LD) (Doxil) was shown to be active in ovarian tumors, several trials were developed at the University of Southern California to determine its safety and efficacy in a variety of gynecologic and peritoneal malignancies. Completed phase I and phase II trials have found PEG-LD to be safe and effective in the treatment of platinum- and paclitaxel-refractory epithelial ovarian carcinoma. A new phase II trial is currently underway in similarly refractory patients with ovarian and other related cancers and various degrees of pretreatment. In addition, the efficacy of PEG-LD is being explored in combination with paclitaxel (Taxol), with cisplatin, and with hyperthermia. [ONCOLOGY 11(Suppl 11):38-44, 1997]