Cancer treatment historically relied on single-agent approaches, but the complexity of the disease often makes one therapy inadequate. Cancer cells are highly adaptable, capable of evading single-drug treatments and developing resistance over time. This challenge has driven a shift toward multi-pronged strategies to achieve better long-term outcomes. Combination therapy, using multiple therapeutic agents or methods simultaneously or sequentially, is now a widely adopted strategy to overcome the resilience of malignant cells.
Defining Combination Therapy
Combination therapy in oncology involves the planned use of two or more distinct treatment modalities to fight cancer. These combined approaches can involve drugs, radiation, or surgical procedures, often tailored to the specific type and stage of the tumor. The treatments may be delivered in different temporal schedules, which are broadly categorized as concurrent or sequential.
A concurrent approach administers two or more treatments at the same time, such as combining chemotherapy with radiation therapy. In contrast, sequential therapy involves treatments given one after the other in a specific order to maximize their effect. The modalities combined can include traditional treatments like surgery and chemotherapy, as well as newer agents like targeted therapies, hormone therapy, and immunotherapy.
Rationale for Combining Treatments
The necessity for using combined therapies stems directly from the complex biology of cancer, particularly two features: tumor heterogeneity and drug resistance. Tumors are not uniform masses of identical cells; they are composed of diverse subpopulations, each with unique genetic mutations and vulnerabilities. A single drug might eliminate one subpopulation but leave others untouched, allowing the resistant cells to multiply and cause relapse.
Combining drugs with different mechanisms of action helps to address this heterogeneity by targeting multiple cell populations simultaneously. This multi-target approach is designed to prevent or significantly delay the development of drug resistance. When a cancer cell attempts to bypass the effect of one drug, a second agent is already in place to block the cell’s alternative survival pathway. This simultaneous blockade creates a synergistic effect, where the combined impact is greater than the sum of the individual treatments.
Combining Local and Systemic Approaches
Many cancer treatment plans integrate therapies that act locally with those that work systemically throughout the body. Local treatments, such as surgery and radiation therapy, aim to destroy or remove the tumor mass in a specific area. Systemic treatments, like drug therapies, travel through the bloodstream to target cancer cells that may have spread to distant sites or are circulating in the body.
This integration is often sequenced using neoadjuvant or adjuvant strategies. Neoadjuvant therapy is administered before the primary local treatment, typically surgery, with the goal of shrinking the tumor to make the surgical removal easier or less invasive. For example, neoadjuvant chemoradiation for locally advanced rectal cancer can significantly reduce the tumor size, increasing the likelihood of a complete surgical removal.
Adjuvant therapy, conversely, is given after the primary local treatment, such as following surgical removal of the tumor. The purpose of this approach is to eliminate any microscopic residual disease, or micrometastases, that may have been left behind and could potentially cause a recurrence. In breast cancer, for instance, adjuvant chemotherapy or hormone therapy is commonly used after a lumpectomy or mastectomy to reduce the risk of the cancer returning.
Examples of Drug-Drug Combinations
Systemic drug-drug combinations are designed to attack cancer on a molecular level by hitting multiple targets within the malignant cells or their microenvironment. One of the most established forms is the combination of different cytotoxic chemotherapy agents, such as the FOLFIRI or FOLFOX regimens used for colorectal cancer. The FOLFOX regimen, for example, combines the DNA-damaging agent oxaliplatin with the cell-cycle inhibitor 5-fluorouracil, which is potentiated by leucovorin.
Newer combinations involve pairing targeted agents with immunotherapy, designed to unmask the cancer to the patient’s immune system. In hepatocellular carcinoma, combining an anti-PD-L1 immune checkpoint inhibitor with an anti-VEGF monoclonal antibody has become a standard first-line treatment. The anti-VEGF agent works by inhibiting the growth of new blood vessels that tumors rely on, but it also reduces the immunosuppressive environment that the tumor creates, making the anti-PD-L1 agent more effective at activating T-cells to attack the cancer.
A third major strategy is the dual checkpoint blockade, which uses two different immunotherapy drugs to remove distinct “brakes” on the immune response. The combination of a PD-1 inhibitor (which targets the programmed cell death protein 1 pathway) and a CTLA-4 inhibitor (which targets the cytotoxic T-lymphocyte-associated protein 4 pathway) is used in cancers like melanoma or in certain types of microsatellite instability-high colorectal cancer. By blocking two separate inhibitory signals, this combination leads to a more robust and sustained activation of the immune system against the tumor cells.