Mesothelioma Chemotherapy: Drugs and Response

First-Line Chemotherapy: Pemetrexed Plus Cisplatin

Pemetrexed combined with cisplatin is the established first-line chemotherapy for advanced malignant pleural mesothelioma. This combination was approved based on the phase III EMPHASIS trial (Vogelzang et al., 2003) and remains the standard backbone of treatment.

Survival Data from Clinical Trials

Treatment	Median Overall Survival	Response Rate
Pemetrexed + Cisplatin	12.1 months	41.3%
Cisplatin alone	9.3 months	16.7%

The hazard ratio of 0.77 (p=0.020) represents a statistically significant survival benefit for the combination therapy.

How Chemotherapy Works

Pemetrexed is an antifolate that disrupts cancer cell DNA synthesis. Cisplatin is a platinum compound that damages DNA and triggers cell death. Together, they:

• Slow tumor growth
• Reduce pleural fluid accumulation
• Improve breathing and reduce chest pain
• Extend survival compared to best supportive care

Carboplatin as Alternative

For patients who cannot tolerate cisplatin due to kidney impairment or other toxicity, carboplatin may substitute. Both platinum agents show similar efficacy, though cisplatin remains preferred when tolerable.

Response Rates by Cell Type

Chemotherapy effectiveness varies significantly based on mesothelioma histology. The CheckMate-743 trial provides the clearest data:

Cell Type	Chemotherapy Median Survival	Notes
Epithelioid	16.5 months	Best response to chemotherapy
Sarcomatoid/Biphasic	8.8 months	Chemoresistant

Why Cell Type Matters

Epithelioid mesothelioma (60–70% of cases) responds better to chemotherapy:

• Response rates of 30–40%
• More predictable tumor behavior
• Better surgical outcomes when combined

Sarcomatoid mesothelioma (10–20% of cases) is notably chemoresistant:

• Response rates under 20%
• Aggressive tumor behavior
• Immunotherapy may offer greater benefit

Biphasic mesothelioma contains both cell types, with outcomes depending on the proportion of each.

Managing Side Effects

Chemotherapy affects fast-growing healthy cells, causing predictable side effects. Most can be managed with supportive care.

Common Side Effects

Blood-related:

• Low white blood cells (increased infection risk)
• Low red blood cells (fatigue, anemia)
• Low platelets (bleeding risk)

Gastrointestinal:

• Nausea and vomiting
• Loss of appetite
• Constipation or diarrhea
• Mouth sores

Neurological:

• Neuropathy (numbness, tingling in hands/feet)
• “Chemo brain” (cognitive changes)
• Fatigue

Other:

• Hair thinning (less common with this regimen)
• Kidney changes
• Weight loss

Supportive Care Strategies

Side Effect	Management
Nausea/vomiting	Ondansetron, aprepitant, dietary changes
Infection risk	Filgrastim (growth factor), avoiding crowds
Neuropathy	Gabapentin, duloxetine
Mouth sores	Saline rinses, avoiding spicy foods
Loss of appetite	Megestrol acetate, nutritional counseling
Fatigue	Gentle exercise, energy conservation

Chemotherapy Combined with Surgery

Multimodal treatment, combining chemotherapy with surgery, can significantly extend survival in appropriate candidates.

Neoadjuvant Chemotherapy

Given before surgery to:

• Shrink tumors for easier removal
• Test tumor response to treatment
• Identify patients likely to benefit from surgery

Adjuvant Chemotherapy

Given after surgery to:

• Target microscopic residual disease
• Reduce recurrence risk
• Extend disease-free survival

HIPEC Outcomes

Cytoreductive surgery combined with HIPEC:

Outcome	Result
Median survival with CRS + HIPEC	28–34 months
5-year survival (complete cytoreduction)	Up to 50%
Median survival (synchronous disease with neoadjuvant)	28 months

A 2025 study by Framarini et al. found neoadjuvant chemotherapy showed a protective effect (HR=0.09) in peritoneal mesothelioma patients undergoing CRS + HIPEC.

Second-Line Options After Progression

When first-line pemetrexed-cisplatin stops working, several options exist:

Gemcitabine

Gemcitabine (Gemzar) is the primary second-line chemotherapy option:

• Can significantly improve survival in late-stage disease
• Different mechanism than first-line drugs
• May be combined with other agents

Vinorelbine

Sometimes used as second-line therapy, particularly in:

• Patients who cannot tolerate gemcitabine
• Clinical trial settings
• Combination regimens

Retreatment with Pemetrexed

For patients who responded well initially and had a prolonged treatment-free interval, rechallenge with pemetrexed-platinum may be considered.

Chemotherapy Plus Immunotherapy

Combining chemotherapy with immunotherapy is an active area of research showing promising results.

KEYNOTE-483 Trial (Pembrolizumab + Chemotherapy)

Outcome	Combination	Chemotherapy Alone
Median survival	17.3 months	16.1 months
3-year survival	25%	17%

CheckMate-743 (Dual Immunotherapy vs Chemotherapy)

The landmark CheckMate-743 trial compared nivolumab plus ipilimumab to chemotherapy:

Outcome	Immunotherapy	Chemotherapy
Median survival	18.1 months	14.1 months
2-year survival	41%	27%
3-year survival	23%	15%

This led to FDA approval of nivolumab-ipilimumab as first-line treatment.

Choosing Between Options

The decision depends on:

• Cell type: Sarcomatoid may benefit more from immunotherapy
• PD-L1 status: May predict immunotherapy response
• Patient factors: Age, performance status, preferences
• Side effect profile: Immunotherapy often better tolerated

Treatment Timeline

Typical Chemotherapy Schedule

• Cycle length: 21 days
• Administration: Day 1 of each cycle
• Duration: 4–6 cycles initially
• Maintenance: May continue if responding

What to Expect

Before each cycle:

• Blood tests to check counts
• Kidney function assessment
• Symptom review

On treatment day:

• Vitamin supplementation
• Anti-nausea pre-medication
• IV infusion (approximately 10 minutes for pemetrexed, longer for cisplatin)
• Hydration to protect kidneys

Between cycles:

• Report fevers or infections immediately
• Manage side effects as directed
• Maintain nutrition and hydration

Emerging Research

ATOMIC-MESO Trial

Pegargiminase (ADI-PEG20) combined with pemetrexed-cisplatin quadrupled 3-year survival rates versus chemotherapy alone in this phase III trial, representing a potential paradigm shift.

Biomarker Development

Researchers are working to identify:

• Predictive markers for chemotherapy response
• Tumor characteristics guiding treatment selection
• Gene expression profiles for personalized therapy