What Is Multimodal Treatment?
Multimodal therapy combines two or more treatment types to improve survival outcomes. For mesothelioma, this typically means:
- Surgery (tumor removal)
- Chemotherapy (systemic or regional)
- Radiation therapy (targeted radiation)
- Immunotherapy (increasingly incorporated)
Multimodal treatment can nearly double survival rates compared to single-modality approaches. About half of mesothelioma patients survive at least two years after receiving surgery followed by chemotherapy and radiation.
Survival by Treatment Approach
| Treatment Regimen | Median Survival |
|---|---|
| No treatment | 4–12 months |
| Chemotherapy alone | 11.7 months |
| Immunotherapy ± chemo | 18.2 months |
| Surgery + chemotherapy | 20.7 months |
| Surgery + immunotherapy + chemo | 22.6 months |
| Trimodal therapy (epithelioid) | 42–66 months |
Treatment approach is one of the most influential factors in mesothelioma survival.
Trimodal Therapy for Pleural Mesothelioma
Trimodal therapy, combining surgery, chemotherapy, and radiation, produces the longest survival rates for pleural mesothelioma.
Surgical Options
Pleurectomy/Decortication (P/D):
- Lung-sparing surgery removing the pleura
- Operative mortality: ~4%
- Median survival: 58.2 months in some studies
- Better preserved lung function
- Increasingly preferred over EPP
Extrapleural Pneumonectomy (EPP):
- Removes lung, pleura, pericardium, and diaphragm
- Operative mortality: ~7%
- More aggressive but higher morbidity
- Decreasing in use due to complication rates
The SMART Protocol
The SMART (Surgery for Mesothelioma After Radiation Therapy) protocol, developed at Princess Margaret Cancer Centre, delivers radiation before surgery:
Protocol:
- 25 Gy radiation in five daily fractions to the hemithorax
- Surgery within one week of completing radiation
- Chemotherapy post-operatively
Outcomes:
- Median survival: 42.8 months (epithelioid)
- 3-year survival: 84% for epithelioid subtype
- Survival more than doubled compared to surgery-first approaches
Protocol variations:
- SMARTER: Uses P/D instead of EPP (broader patient eligibility)
- SMARTEST: Adds immunotherapy (tremelimumab + durvalumab)
Treatment Sequencing
Neoadjuvant approach (chemo first):
- Pemetrexed 500 mg/m² + cisplatin 75 mg/m² every 21 days × 3 cycles
- Surgery 3–8 weeks after chemotherapy
- Radiation 4–8 weeks post-surgery
Adjuvant approach (surgery first):
- Surgery followed by chemotherapy
- Radiation after chemotherapy
- Order varies by center and patient factors
Both approaches show similar outcomes in studies. The choice depends on patient condition, tumor characteristics, and center expertise.
HIPEC for Peritoneal Mesothelioma
Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard of care for peritoneal mesothelioma.
The Procedure
- Cytoreductive surgery: Removes all visible tumor from the peritoneal cavity
- HIPEC: Heated chemotherapy (41–43°C) circulated directly in the abdomen for 60–90 minutes to kill microscopic remaining cancer cells
Survival Outcomes
| Treatment | Median Survival | 5-Year Survival |
|---|---|---|
| Untreated | 6–12 months | Less than 5% |
| Systemic chemo alone | 12–28 months | ~10% |
| CRS/HIPEC | 53 months | 49–69% |
Patients with complete cytoreduction (no visible residual disease) have median survival of 104 months, nearly 9 years.
Key Prognostic Factors
Peritoneal Cancer Index (PCI):
- PCI 0–20: Median survival 103 months
- PCI 21–39: Median survival 33 months
Completeness of Cytoreduction:
- CC0 (no residual): Median survival 104 months
- CC1 (under 2.5mm residual): Median survival 30 months
- CC2 (>2.5mm residual): Median survival 2.7 months
Histology:
- Papillary: 70.3 months
- Epithelioid: 38.1 months
- Sarcomatoid: 2.0 months
A March 2025 consensus established CRS-HIPEC as standard-of-care for resectable peritoneal mesothelioma.
Patient Selection Criteria
Not all patients are candidates for aggressive multimodal treatment. Selection criteria include:
Required Factors
| Factor | Requirement |
|---|---|
| Performance status | ECOG 0–1 |
| Tumor stage | T1–T3, no distant metastasis |
| Node status | N0–N2 (varies by protocol) |
| Histology | Epithelioid preferred |
| Pulmonary function (EPP) | FEV1 >2 L |
Exclusion Criteria
- Sarcomatoid or sarcomatoid-predominant histology
- Stage IV disease (distant metastasis)
- Poor performance status
- Significant cardiac or pulmonary comorbidities
- Tumor spread through diaphragm
Multimodality Prognostic Score (MMPS)
Validated scoring system considering:
- Tumor volume before chemotherapy
- Histological subtype
- C-reactive protein levels
- Response to chemotherapy
Patients should be evaluated at specialized mesothelioma centers for multimodal treatment candidacy. Not everyone qualifies, but for eligible patients, outcomes are dramatically better.
Adding Immunotherapy
Modern protocols increasingly incorporate immunotherapy into multimodal treatment.
Perioperative Immunotherapy
A 2025 Johns Hopkins trial tested:
- Preoperative: Nivolumab ± ipilimumab
- Surgery
- Postoperative: Nivolumab maintenance
Results:
- Median survival: 28.6 months
- 36% alive and recurrence-free at follow-up
Current Combinations
| Protocol | Components |
|---|---|
| Standard trimodal + IO | Surgery + chemo + radiation + checkpoint inhibitor |
| SMARTEST | SMART protocol + durvalumab + tremelimumab |
| Maintenance | Surgery + chemo → maintenance nivolumab |
CheckMate-743 established that nivolumab plus ipilimumab significantly improves survival in unresectable disease (18.1 vs 14.1 months). Integration with surgery is being actively studied.
Major Treatment Centers
Multimodal treatment requires specialized expertise. Leading centers include:
Memorial Sloan Kettering Cancer Center (New York)
- 400+ mesothelioma cases annually
- Pioneered P/D techniques
- Developed IMPRINT radiation technique
MD Anderson Cancer Center (Houston)
- 30+ mesothelioma specialists
- Multiple exclusive clinical trials
- All disease stages covered
Brigham and Women’s Hospital / Dana-Farber (Boston)
- International Mesothelioma Program
- Harvard Medical School teaching hospital
- $500M+ annual NIH research funding
Princess Margaret Cancer Centre (Toronto)
- Developed SMART, SMARTER, SMARTEST protocols
- Leading radiation-first expertise
Moffitt Cancer Center (Tampa)
- Mesothelioma Research and Treatment Center
- Thoracic oncology focus
University of Maryland
- Peritoneal mesothelioma / HIPEC expertise
- 69% 5-year survival with CRS/HIPEC
What to Expect
Treatment Timeline
| Phase | Duration |
|---|---|
| Evaluation and staging | 2–4 weeks |
| Neoadjuvant therapy (if used) | 9–12 weeks |
| Surgery | 1 day (4–12 hour procedure) |
| Hospital recovery | 5–14 days |
| Post-surgical recovery | 4–8 weeks |
| Adjuvant therapy | 6–12 weeks |
| Total initial treatment | 3–6 months |
Some patients continue maintenance immunotherapy for months to years after initial treatment.
Side Effects Management
Multimodal treatment involves significant side effects from each modality:
- Surgery: Pain, fatigue, reduced lung capacity, wound healing
- Chemotherapy: Nausea, fatigue, low blood counts, neuropathy
- Radiation: Skin irritation, fatigue, esophagitis
Palliative care teams help manage symptoms throughout treatment.
Am I a candidate for multimodal treatment?▼
Candidates typically have ECOG 0-1 performance status, T1-T3 stage without distant metastasis, epithelioid histology, and adequate pulmonary function. Evaluation at a specialized center is essential.
What is the recommended treatment sequence for my case?▼
Sequence depends on tumor characteristics and center expertise. Neoadjuvant (chemo first) and surgery-first approaches show similar outcomes. Some protocols like SMART use radiation first.
Does this center have experience with mesothelioma multimodal protocols?▼
Volume matters. Leading centers include Memorial Sloan Kettering, MD Anderson, Brigham/Dana-Farber, Princess Margaret, and Moffitt. Ask about their annual mesothelioma case volume.
Are there clinical trials I should consider?▼
Trials incorporating immunotherapy (SMARTEST protocol, perioperative nivolumab) are actively enrolling. These may offer even better outcomes than current standard multimodal approaches.
References
The Lancet Oncology. (2014). SMART Protocol for Malignant Pleural Mesothelioma.
https://pubmed.ncbi.nlm.nih.gov/24239211/
Annals of Surgical Oncology. (2023). Cytoreductive surgery and HIPEC for peritoneal mesothelioma.
https://pubmed.ncbi.nlm.nih.gov/36754945/
Annals of Thoracic Surgery. (2021). Multimodal treatment for malignant pleural mesothelioma.
https://pubmed.ncbi.nlm.nih.gov/32650066/