Ovarian cancer is a significant health challenge. Chemotherapy is a primary treatment approach, but “platinum resistance” can emerge, altering the course of treatment. This article clarifies what platinum-resistant ovarian cancer means and explores current and developing management strategies.
Defining Platinum Resistance in Ovarian Cancer
Platinum-based chemotherapy drugs, such as cisplatin and carboplatin, are initial treatments for many ovarian cancer patients. These medications damage cancer cell DNA, preventing growth and leading to cell death. This approach is a standard first-line therapy, often combined with other agents like paclitaxel, to control cancer after surgery.
Platinum resistance is defined by the timeframe of cancer recurrence after treatment. A tumor is platinum-resistant if the cancer returns less than six months after completing the most recent platinum-based chemotherapy. This differs from platinum-sensitive disease, where cancer recurs more than six months after treatment, and refractory disease, where cancer progresses during platinum therapy.
Doctors monitor patients after initial treatment to determine platinum sensitivity. This surveillance involves physical examinations, imaging scans like CT or PET scans, and blood tests for tumor markers such as CA-125. While CA-125 levels track tumor volume, rising levels can precede other recurrence signs. The platinum-free interval, or time without platinum-based therapy, guides subsequent treatment decisions.
Biological Mechanisms of Resistance
Cancer cells develop resistance to platinum-based chemotherapy through several biological mechanisms. One way is by reducing the drug amount that reaches the DNA inside the cell. Cancer cells may decrease platinum compound uptake by downregulating influx transporters like copper transporter 1 (CTR1).
Cells can also actively pump chemotherapy drugs out, a process known as increased efflux, mediated by transporters like ATPase copper-transporting alpha and beta (ATP7A and ATP7B). Internal cellular components such as glutathione (GSH) and metallothionein (MT) can bind to and inactivate platinum compounds, neutralizing the drug before it causes damage.
Another mechanism involves enhanced DNA repair pathways within cancer cells. Platinum drugs damage DNA by forming crosslinks, but resistant cells become more efficient at repairing these lesions. Pathways such as nucleotide excision repair (NER), homologous recombination (HR), and non-homologous end-joining (NHEJ) can be upregulated, counteracting chemotherapy’s effect. Mutations in genes like BRCA1 or BRCA2, normally involved in DNA repair, can undergo “reversion mutations” that restore their function, leading to resistance to platinum agents and PARP inhibitors. The surrounding tumor microenvironment, including various cell types and signaling molecules, also contributes to drug resistance and protecting cancer stem cells that evade treatment.
Standard Treatment Approaches
Once ovarian cancer is diagnosed as platinum-resistant, treatment shifts from platinum-based drugs to alternative therapies. Single-agent non-platinum chemotherapy drugs are employed in this setting. Options include pegylated liposomal doxorubicin (PLD), paclitaxel, topotecan, and gemcitabine. These agents offer objective response rates ranging from 10% to 15%, with a median progression-free survival of 3 to 4 months.
Targeted therapies focus on specific molecular pathways involved in cancer growth. Bevacizumab (Avastin) is an anti-angiogenesis agent that blocks vascular endothelial growth factor (VEGF). VEGF promotes new blood vessel formation that tumors need to grow and spread. By inhibiting VEGF, bevacizumab can reduce the tumor’s blood supply, slowing its growth and enhancing other chemotherapy drugs. When added to non-platinum chemotherapy, bevacizumab improves progression-free survival in patients with platinum-resistant ovarian cancer.
Poly (ADP-ribose) polymerase (PARP) inhibitors are another class of targeted therapy, effective for patients with specific genetic alterations. These drugs, such as olaparib, rucaparib, and niraparib, exploit synthetic lethality by blocking DNA repair pathways in cancer cells. They are beneficial for patients whose tumors have mutations in BRCA1 or BRCA2 genes, or other homologous recombination deficiencies (HRD). Genetic testing is important to identify eligible patients likely to respond to PARP inhibitors.
Emerging Therapies and Clinical Trials
The treatment landscape for platinum-resistant ovarian cancer continuously evolves with novel therapies. Antibody-drug conjugates (ADCs) are an emerging class of treatments. These drugs combine a chemotherapy agent with an antibody that targets a protein on cancer cells, allowing precise delivery to the tumor while minimizing damage to healthy cells.
Mirvetuximab soravtansine is an example, targeting the folate receptor alpha (FRα) protein, often overexpressed in ovarian cancers. It has received FDA approval for FRα-positive, platinum-resistant ovarian cancer, demonstrating improved overall and progression-free survival in clinical trials.
Immunotherapy, particularly immune checkpoint inhibitors, harnesses the body’s immune system to fight cancer. Agents like pembrolizumab block proteins such as PD-1 that prevent immune cells (T cells) from attacking cancer. While immunotherapy succeeds in other cancers, its single-agent effectiveness in ovarian cancer is limited, making combination strategies an active research area. Clear cell ovarian carcinoma, a subtype, shows increased sensitivity to immunotherapy.
Clinical trials offer access to innovative treatments and advance medical knowledge. Participation provides potential access to new therapies and contributes valuable data to research. Patients can discuss clinical trial options with their healthcare team. Resources like ClinicalTrials.gov and CenterWatch.com provide searchable databases for ongoing studies.
Prognosis and Managing Quality of Life
A diagnosis of platinum-resistant ovarian cancer is a challenge, and individual outcomes vary considerably. Median overall survival for patients with platinum-resistant disease has been reported as 9 to 12 months, extending to 12 to 18 months for those with secondary resistance. Factors like BRCA1/2 mutations can influence survival rates, with some studies showing improved outcomes.
For many, platinum-resistant ovarian cancer is managed as a chronic condition, focusing on long-term well-being alongside active treatment. Palliative care plays a role in this approach, providing specialized medical care to relieve symptoms, pain, and stress associated with the illness. This care aims to improve the overall quality of life for the patient and their family.
Palliative care can be integrated at any illness stage, even during active anti-cancer treatments. It addresses common symptoms like pain, fatigue, nausea, vomiting, bloating, and constipation. It also offers support for emotional concerns such as stress, anxiety, and depression. The goal is to balance treatment effectiveness with maintaining the best possible quality of life, ensuring comprehensive support for physical and emotional needs.