Immunotherapy uses specialized drugs to activate the body’s own defense system to recognize and attack cancer cells, unlike traditional chemotherapy. This article addresses the serious concern of whether this powerful treatment can lead to outcomes that appear to be, or truly are, a worsening of the disease or a patient’s health. Understanding these specific risks is paramount for anyone considering or undergoing this form of cancer treatment.
How Immunotherapy Works
Immune checkpoint inhibition removes natural “brakes” the immune system uses to prevent attacking healthy tissue. Cancer cells often exploit these checkpoints, such as the PD-1/PD-L1 or CTLA-4 pathways, to hide from the body’s T-cells, which kill tumors.
Immune checkpoint inhibitor drugs block the interaction between these checkpoint proteins, releasing the T-cells from the cancer’s control. This blockade allows T-cells to become fully activated and launch a targeted attack on the tumor. The goal is to unleash a sustained anti-cancer response leading to durable remission.
However, this mechanism is a double-edged sword because the activation is systemic, not localized. An overactive or misdirected immune response leads to the risks associated with this therapy. The unleashed immune system may struggle to distinguish between cancer cells and healthy, normal cells throughout the body.
Distinguishing True Progression from Pseudo-Progression
When initial scans suggest the cancer is worsening, this is often pseudo-progression. This phenomenon is an apparent increase in tumor size or the development of new lesions on imaging that is actually a temporary effect of the treatment working.
This radiographic worsening is caused by a massive infiltration of activated immune cells, specifically T-cells, into the tumor site. This influx of cells and associated swelling creates a larger mass that mimics true tumor growth. Despite the concerning scan results, the patient’s overall clinical condition often remains stable or even improves.
To avoid prematurely stopping effective treatment, doctors use modified assessment tools like immune-related Response Evaluation Criteria in Solid Tumors (irRECIST or iRECIST). These criteria allow the physician to continue therapy following initial apparent progression to see if a delayed response or tumor shrinkage occurs.
Pseudo-progression is uncommon, occurring in less than 10% of patients across various cancers. True progression, in contrast, involves cancer cells multiplying rapidly despite treatment, leading to a noticeable decline in the patient’s health.
Hyperprogression The Mechanism of Rapid Worsening
Hyperprogressive Disease (HPD) is a distinct and more severe scenario than pseudo-progression. HPD is a rare pattern where immunotherapy directly accelerates tumor growth. It is characterized by an unusually rapid and dramatic increase in tumor burden following the initiation of checkpoint inhibitors, far exceeding the pace of the cancer’s natural growth before treatment.
The incidence of HPD varies significantly across studies and cancer types, with reported ranges spanning from 4% to 30% of patients treated with immune checkpoint inhibitors. Diagnosis relies on comparing the rate of tumor growth after starting immunotherapy with the rate measured in the months before treatment began.
While the precise mechanism is not fully understood, one hypothesis suggests that immunotherapy may inadvertently activate tumor-promoting cells within the tumor microenvironment. Specific molecular changes, such as the amplification of genes like MDM2 or MDM4, have been linked to a higher risk of HPD in small patient subsets.
Another theory points to the activation of suppressive immune cells, like certain types of M2-like macrophages. These cells can be unintentionally stimulated by the drug and promote tumor growth instead of fighting it. Because HPD is associated with poor outcomes and rapid decline, identifying reliable predictive markers remains a high priority for researchers.
Severe Immune-Related Adverse Events
The most common way immunotherapy can worsen a patient’s health, even if the cancer is responding, is through severe immune-related adverse events (irAEs). These are autoimmune-like side effects that occur when the hyper-activated immune system attacks healthy organs and tissues throughout the body.
The effects can be systemic and involve virtually any organ. The most commonly affected areas are the gastrointestinal tract, lungs, and endocrine glands. Specific severe irAEs include colitis (inflammation of the colon), pneumonitis (inflammation of the lungs), and endocrinopathies (inflammation leading to dysfunction of glands like the thyroid or pituitary).
Myocarditis, inflammation of the heart muscle, is a rare but life-threatening irAE that demands immediate medical attention. Management of severe irAEs typically involves temporarily holding the immunotherapy treatment and initiating high-dose immunosuppressive medication, such as corticosteroids (e.g., prednisone at 1 to 2 mg/kg per day).
If the adverse event is refractory to steroid treatment, other immunosuppressants may be necessary. While this treatment is often successful, the use of immunosuppressive drugs can necessitate the permanent discontinuation of the cancer treatment, compromising the long-term cancer control and patient prognosis.