Introduction: The Challenge of Platinum-Resistant Ovarian Cancer
Ovarian cancer, particularly in its platinum-resistant form, remains one of the most challenging gynecologic cancers to treat. Typically diagnosed at advanced stages, ovarian cancer’s treatment protocol largely revolves around platinum-based chemotherapy. However, as resistance develops, particularly to platinum, survival rates significantly decrease, with limited therapeutic options available. Most standard therapies, such as non-platinum chemotherapy, yield poor responses. In addition, while immunotherapy shows promise, its efficacy remains minimal for platinum-resistant cases. This case report highlights an innovative treatment combination—interstitial implantation radiotherapy, immunotherapy, and granulocyte-macrophage colony-stimulating factor (GM-CSF)—that resulted in a remarkable partial response in a patient with oligometastatic platinum-resistant ovarian cancer, showcasing a potential new pathway for treatment.
Ovarian Cancer Treatment Landscape: Limited Options in Platinum-Resistance
Ovarian cancer is the second leading cause of death among women with gynecologic cancers worldwide. The disease is often diagnosed at an advanced stage, with most patients undergoing a combination of tumor cytoreduction surgery and chemotherapy. The standard chemotherapy treatment for advanced ovarian cancer typically involves platinum-based drugs like carboplatin and paclitaxel. However, as ovarian cancer progresses, particularly in the case of platinum resistance, survival rates become dismal, and patients often experience rapid disease recurrence within months of completing chemotherapy. In fact, nearly 20% of patients become resistant to platinum at first recurrence, and almost all eventually develop platinum resistance. While non-platinum single-agent chemotherapy offers some relief, it only achieves a response rate of 10-15% and limited progression-free survival (PFS) of around four months.
Recent attempts to incorporate immunotherapy have yielded disappointing results, with programmed cell death protein-1 (PD-1)/PD-1 ligand (PD-L1) antibodies showing response rates of only 8% in platinum-resistant ovarian cancer. With the challenges of immunotherapy monotherapy in this setting, combining different therapeutic strategies—such as radiation, chemotherapy, and GM-CSF—has emerged as a promising approach to enhancing the immune system’s response to cancer cells.
Case Description: Triple Therapy with PRaG Approach
The patient in this case is a 66-year-old woman diagnosed with ovarian adenocarcinoma in June 2017. After completing six cycles of platinum-based chemotherapy, she initially showed a complete response (CR) with no signs of recurrence for over two years. However, in February 2020, the patient experienced vaginal bleeding, and diagnostic imaging revealed the return of ovarian cancer. Despite undergoing another round of chemotherapy and bevacizumab, the tumor continued to progress, and by May 2021, it became evident that the patient had developed platinum resistance. Subsequently, in June 2022, a large mass in the pelvis was identified, and the patient’s condition worsened.
Faced with these recurring tumors and limited options, the patient opted for a novel approach consisting of interstitial implantation radiotherapy combined with a PD-1 inhibitor (tirilizumab) and GM-CSF. The treatment began in November 2022, with interstitial radiotherapy administered at a dose of 10 Gy, followed by subcutaneous GM-CSF injections for one week. The patient received tirilizumab immunotherapy in December 2022. Within a short time, follow-up imaging showed a remarkable partial response (PR) in the pelvic mass. By June 2023, the mass had significantly reduced, and tumor markers (CA125) continued to decrease, marking a sustained benefit over six months.
Mechanism Behind the Triple-Therapy Approach
The triple-combination therapy employed in this case leverages the complementary effects of radiation, immunotherapy, and GM-CSF to enhance tumor control. Interstitial implantation radiotherapy works by delivering high doses of radiation directly to the tumor, which causes DNA damage and cell death. This radiation therapy also triggers immune responses through the activation of dendritic cells and T-cells, potentially converting irradiated tumor sites into “in situ vaccines.” Radiation has been shown to upregulate the expression of molecules necessary for immune activation and stimulate systemic immune responses, making it an ideal partner for immunotherapy.
Immunotherapy with PD-1 inhibitors, such as tirilizumab, works by blocking the PD-1 receptor, allowing T-cells to recognize and attack tumor cells. The addition of GM-CSF further enhances the immune response by stimulating the production and activation of dendritic cells, which are crucial for antigen presentation and initiating a broader immune attack on cancer cells. Together, these therapies work synergistically to attack the tumor both locally and systemically, providing a more robust and sustained anti-cancer effect.
Clinical Results: Significant Tumor Reduction and Long-Term Benefits
The results of the triple-combination therapy in this case were promising. The patient demonstrated a partial response (PR) after just one cycle of therapy, with a significant reduction in the size of the pelvic mass. Imaging studies confirmed the tumor shrinkage, and the patient’s CA125 levels continued to decrease, providing evidence of the efficacy of this novel approach. Remarkably, the patient sustained these benefits for over six months, marking an encouraging outcome for a disease typically resistant to conventional treatments.
Safety and Side Effects: Manageable and Well-Tolerated
Throughout the treatment, the patient experienced only mild adverse effects, including localized erythema from radiation and mild skin pigmentation changes. There were no significant immune-related adverse events, such as severe hematologic, thyroid, or liver dysfunction, which are commonly seen with other treatments. This suggests that the combination therapy used in this case was not only effective but also well-tolerated by the patient, a crucial consideration in the management of platinum-resistant ovarian cancer.
Conclusion: A Promising Strategy for Ovarian Cancer
This case highlights the potential of combining interstitial implantation radiotherapy with immunotherapy and GM-CSF for the treatment of platinum-resistant ovarian cancer. Despite the poor prognosis typically associated with platinum-resistant cases, the patient in this case experienced a significant tumor response and prolonged benefit, demonstrating the effectiveness of the PRaG approach. While further studies and clinical trials are necessary to confirm the long-term efficacy and safety of this strategy, the combination of radiation and immunotherapy represents a promising avenue for enhancing treatment outcomes in challenging cases of ovarian cancer.
