What are the complications and expectations of chemotherapy and immunotherapy in cancer treatment?

Chemotherapy and Immunotherapy Combinations: Complications and Expectations

When combining chemotherapy with immunotherapy in cancer treatment, expect a modest 16% increase in all-grade adverse events compared to chemotherapy alone, but importantly, no increase in treatment-related mortality, with significantly improved survival outcomes across multiple tumor types. 1

Overall Toxicity Profile

The combination of chemotherapy plus immunotherapy increases overall adverse events modestly (RR 1.16 [1.10-1.24]) compared to chemotherapy alone, but this does not translate to increased treatment-related deaths (RR 1.08 [0.88-1.32]). 1 This analysis included nearly 15,000 patients across 20 randomized controlled trials spanning lung, digestive, breast, head and neck, and cervical cancers. 1

Key Point on Mortality

• Treatment-related death rates remain statistically similar between combination therapy and chemotherapy alone, providing reassurance about the safety of this approach despite increased toxicity. 1

Specific Complications to Anticipate

Most Significantly Increased Toxicities (All Grades)

Pneumonitis represents the most dramatically increased risk with combination therapy (RR 2.79 [2.09-3.74]), nearly tripling compared to chemotherapy alone, and is one of the most common treatment-related causes of death despite being rare overall. 1

Thyroid dysfunction more than doubles with combination therapy (RR 2.13 [1.90-2.40]), making routine thyroid monitoring essential. 1

Other significantly elevated toxicities include:

• Rash: 56% increase (RR 1.56 [1.44-1.70]) 1
• Creatinine elevation: 34% increase (RR 1.34 [1.21-1.48]) 1
• Diarrhea: 19% increase (RR 1.19 [1.13-1.26]) 1
• Dyspnea: 19% increase (RR 1.19 [1.07-1.33]) 1

Moderately Increased Toxicities

• Peripheral neuropathy: 14% increase (RR 1.14 [1.07-1.21]) 1
• Elevated liver enzymes: 13% increase (RR 1.13 [1.06-1.21]) 1
• Vomiting: 12% increase (RR 1.12 [1.05-1.19]) 1
• Neutropenia: 11% increase (RR 1.11 [1.07-1.15]) 1
• Fatigue: 8% increase (RR 1.08 [1.04-1.13]) 1

Grade 3-4 Severe Toxicities

For severe adverse events, the most concerning increases are:

• Dyspnea: 87% increase (RR 1.87 [1.37-2.55]) 1
• Rash: 158% increase (RR 2.58 [1.21-5.52]) 1
• Elevated liver enzymes: 56% increase (RR 1.56 [1.22-2.01]) 1
• Diarrhea: 42% increase (RR 1.42 [1.09-1.87]) 1
• Fatigue: 32% increase (RR 1.32 [1.05-1.66]) 1

Immunotherapy-Specific Complications

Immune-related adverse events (irAEs) unique to or predominantly seen with immunotherapy include: 1

• Uveitis
• Endocrinopathies (thyroid, pituitary, adrenal)
• Myocarditis 2
• Pneumonitis
• Hepatitis
• Arthralgia
• Enterocolitis

Critical Diagnostic Challenge

Clinical manifestations of irAEs can mimic chemotherapy toxicity, particularly for diarrhea, hepatotoxicity, skin eruptions, and fatigue, yet require completely different management approaches. 1 Currently, no biomarkers exist in routine practice to distinguish cytotoxic side effects from immune-related adverse events. 1

Mechanistic Understanding

The increased diarrhea likely results from both chemotherapy-induced and immunotherapy-induced colitis, potentially compounded by gut microbiome disturbances from both therapies. 1

The elevated dyspnea and pneumonitis risk reflects that pneumonitis is the most common serious adverse event with anti-PD-1 treatments, layered onto chemotherapy-related pulmonary toxicity. 1

Hepatotoxicity increases because both cytotoxic agents (especially taxanes, anthracyclines, 5-FU, cyclophosphamide, oxaliplatin) and immune checkpoint inhibitors independently cause liver injury, though with different microscopic patterns. 1

Clinical Expectations and Outcomes

Survival Benefits Justify Toxicity Risk

Despite increased toxicity, combination therapy demonstrates substantial survival improvements across multiple cancer types: 1

• NSCLC (non-squamous): OS 22.0 vs 10.7 months (HR 0.56) with pembrolizumab + pemetrexed + platinum 1
• Triple-negative breast cancer: OS 23.0 vs 16.1 months (HR 0.73) with pembrolizumab + chemotherapy 1
• Esophageal cancer: OS 12.4 vs 9.8 months (HR 0.73) with pembrolizumab + 5-FU + platinum 1
• Gastric/GEJ cancer: OS 14.4 vs 11.1 months (HR 0.71) with nivolumab + chemotherapy 1

Treatment Discontinuation Rates

In neoadjuvant NSCLC treatment, 18% of patients permanently discontinued any study drug due to adverse reactions with combination therapy, with the most common reasons being acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). 2

In adjuvant NSCLC treatment with single-agent pembrolizumab, 12% discontinued due to adverse reactions, most frequently diarrhea (1.7%), interstitial lung disease (1.4%), AST elevation (1%), and musculoskeletal pain (1%). 2

Age-Related Considerations

Patients aged 75 or older experience higher discontinuation rates (29-38% depending on regimen) compared to all patients (18-23%), though overall safety profiles remain similar. 3 Serious adverse reaction rates also increase in this age group (68% vs 54% overall for nivolumab + ipilimumab in mesothelioma). 3

Comparative Safety: Immunotherapy vs Chemotherapy Alone

When immunotherapy is used as monotherapy (without chemotherapy), it demonstrates superior safety compared to traditional chemotherapy: 4

• Grade ≥3 adverse events: 16.5% with immunotherapy vs 41.09% with chemotherapy (OR 0.26) 4
• Treatment discontinuation due to AEs: significantly lower with immunotherapy (OR 0.55) 4
• Deaths from treatment-related AEs: lower with immunotherapy (OR 0.67) 4

Critical Management Pitfalls

The absence of additive toxicity for most adverse events suggests the mechanisms are not simply cumulative, but the hypothesis of synergistic toxic effects cannot be eliminated. 1 This means clinicians cannot predict toxicity by simply adding expected rates from each therapy independently.

Distinguishing between chemotherapy-induced toxicity and immune-related adverse events is critical because management differs fundamentally: immunotherapy toxicity typically requires immunosuppression (corticosteroids), while chemotherapy toxicity requires supportive care and dose modifications. 1, 5

Pneumonitis, though rare, demands immediate attention as it represents one of the most common treatment-related causes of death and shows the highest relative risk increase (nearly 3-fold) with combination therapy. 1