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Dr Sumit Kumar
Assistant professor
NEIGRIHMS
Pleural mesothelioma is the most common form, comprising about 70-80% of all
mesothelioma cases, and primarily affects the lining of the lungs.
Pleural mesothelioma is often diagnosed at advanced stages (Stage III or IV), which can
limit treatment options and prognosis.
The 5-year survival rate for pleural mesothelioma is typically around 5% to 10%,
highlighting its aggressive nature and the challenges in treating this form of cancer.
Treatment approaches for pleural mesothelioma often involve a combination of surgery,
chemotherapy, radiation therapy, and emerging targeted therapies, tailored to the stage
of the disease.
Preventing asbestos exposure is crucial in reducing the risk of pleural mesothelioma, with
workplace safety measures and asbestos removal being important preventive strategies.
Mesothelioma is an insidious neoplasm arising from the mesothelial
surfaces of the pleural and peritoneal cavities, the tunica vaginalis, or
the pericardium.
The predominant cause of malignant mesothelioma is inhalational
exposure to asbestos, with approximately 70 %.
Mesothelioma incidence rates are predicted to increase dramatically in
resource-limited settings :-
Secondary to poor regulation of asbestos mining and
The proliferation of industrial and
Household utilization of asbestos.
1
4 5
2 3
Asbestos exposure
Genetic factors
Viral oncogenes
Carbon nanotubes
Radiation exposure
Lifetime risk: as high as 10 %
Latency period: Approx. 30 to
40 yrs
Supradiaphragmatic fields in
the treatment of malignancy
(hodgkin lymphoma, non-
hodgkin lymphoma,
testicular cancer
Simian virus 40 (SV40)
polyomavirus
Elevated risk for
mesothelioma among those
whose parents or siblings
were diagnosed with the
disease of 3.9- and 12.4-fold,
respectively
Epithelioid Sarcomatoid Biphasic(mixed)
Most common: 60 percent
Subtype : Tubulopapillary,
Acinar
(glandular),
Adenomatoid
and
Solid epithelioid
pattern
Composed of malignant
spindle cells which may
mimic malignant
mesenchymal tumors
Have epithelioid and
sarcomatoid features
• No single marker that has sufficiently high sensitivity and specificity for malignant
mesothelioma
• Pancytokeratin stains are very useful in the diagnosis of mesothelioma and will stain the vast
majority of mesotheliomas.
• BAP-1 and MTAP improve sensitivity and specificity for mesothelioma
 Useful IHC marker (Mesothalioma)
Positive
 WT1
 Calretinin
 D2-40
 CK 5/6
Negative
 CEA
 TTF-1
 Claudin-4
 To estabilish diagnosis
Atleast 2 mesothelial& 2 Carcinoma marker to be check
 Sarcomatoid Mesothalioma
Shows focal to absent expression for most mesothelial markers, with the most sensitive marker being
D2-40/Podoplanin
 GATA3 :-Potential diagnostic for sarcomatoid as it expressed in only 10-20%sarcomatoid
carcinoma.
(claudin-4,
TTF-1,
CEA)
(Calretinin,
WT1,
D2-40)
FISH to detect p16 deletion use for benign versus malignant mesothelial
proliferations.
Detection of loss of (BRCA1)-associated protein (BAP1) by IHC used to
distinguish malignant mesothelioma from reactive mesothelial
proliferation
A. Localised mesothelioma
B. Well-differentiated papillary mesothelioma
C. Adenomatoid tumor
D. Benign multicystic mesothelioma
E. Mesothelioma in situ
Most mesothelioma patients initially experience pulmonary symptoms like dyspnea, cough,
and chest pain, typically indicating advanced intrathoracic disease.
Diagnosis involves clinical suspicion arising from respiratory symptoms in the context of
pleural changes and a history of asbestos exposure, with biopsy confirmation being
necessary.
A multidisciplinary approach is employed, considering disease extent, patient health, and
their treatment preferences.
Surgical candidates with resectable disease undergo combined-modality treatment,
including surgery aimed at macroscopic complete resection (MCR), chemotherapy, and
radiation therapy.
Nonsurgical candidates with unresectable disease or medical contraindications receive
systemic chemotherapy and symptom-directed treatment.
T Primary Tumor
TX Primary tumor cannot be assessed
T0 no evidence of primary tumor
T1 Tumor limited to the ipsilateral parietal pleura with or without involvement of:
Visceral pleura
Mediastinal pleura
Diaphragmatic pleura
T2 Tumor involving each of the ipsilateral pleural surfaces ( parietal, mediastinal, diaphragmatic and
visceral pleura) with at least one of the following feature:
Involvement of diaphragmatic muscle
Extension of tumor from visceral pleura into the underlying pulmonary parenchyma
T3 Locally advanced but potentially resectable tumor.
Tumor involving all ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura),
with at least one of the following features;
Involvement of the endothoracic fascia
Extension into the mediastinal fat
Solitary, completely resettable focus of tumor extending into the soft tissue of the chest wall
Non transmural involvement of the pericardium
T4 locally advanced technically unresectable tumor.
Tumor involving all ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura)
with atleast one of the following features:
Diffuse extension of multifocal masses of tumor in the chest wall ,with or without associated rib
destruction
Direct transdiaphragmatic extension of the tumor to the peritoneal
Direct extension of tumor to the contralateral pleura
Direct extension of tumor mediastinal organs
Direct extension of tumor into the spine
Direct extending through to the internal surface of the pericardium or without a pericardial effusion;
or tumor involving the myocardum
N Regional lymph nodes
NX Lymph nodes canot be assessed
N0 No regional lymph node metastases
N1 Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal
(including the internal mammary , peridiapharagamtic, pericardial fat pad
of intercostal lymph nodes
N2 Metastases in the contralateral mediastinal , ipsilateral or contralateral
supraclavicular lymph nodes
M Distant metastasis
M0 No distant metastases
M1 Distant metastases present
Recurrent pleural effusion and/ or
pleural thickening
CECT-thorax
Thoracentesis for cytologic
assessment
Pleural biopsy
Pleural mesothelioma confirmed
Clinical stage I-IIIA &
epitheloid histology
Clinical stage IIIB or IV, Sarcomatoid or
biphasic histology, or medically
inoperable
CECT abdomen
PS 0-2 PS 3-4
Systemic therapy BST
NACT with pem.
& cisplatin
Systemic therapy or
observation
Resectable
P/D or EPP
Unresectabl
e
Surgical
exploration
Hemithoracic
IMRT
RT
Resectable
P/D or EPP
Unresectable
Systemic therapy and consider
RT
A combined-modality approach is employed for surgically resectable mesothelioma
patients.
Components of this approach include definitive surgery EPP or P/D, radiation therapy
(RT), and chemotherapy (systemic, preoperative/postoperative, or intraoperative).
While randomized trials haven't demonstrated an overall survival advantage, this
approach offers relatively prolonged survival compared to chemotherapy alone.
Surgery not standard, but beneficial for select MPM patients.
Requires expertise; active research on surgical candidates.
Histologic subtype is a critical selection criterion, with a preference for epithelial subtype
confirmed by biopsy.
Negative factors: age >50, male gender, high platelet/WBC count, chest wall pain, and large tumor
volume.
Surgeons should aim for complete resection and consider pleural effusion drainage.
Individual assessment by experienced surgeons, avoiding "palliative" explorations.
Criteria for patient-specific selection: no disseminated disease, good cardiopulmonary function,
and no severe comorbidities.
Emphasize the absence of a uniform MPM treatment; recommend expert consultation.
EPP
En bloc resection of the
parietal and visceral
pleura with the
ipsilateral lung,
pericardium, and
diaphragm.
Extended P/D
Parietal and visceral
pleurectomy to remove all
gross tumor with resection of
the diaphragm and/or
pericardium.
1
2
P/D
Parietal and visceral
pleurectomy to remove all
gross tumor without
diaphragm or pericardial
resection.
Partial Pleurectomy
Partial removal of parietal and/or
visceral pleura for diagnostic or
palliative purposes but leaving
gross tumor behind when an R0
or R1 resection does not prove
to be feasible.
3
4
Surgical Morbidity and Mortality:
• Earliar EPP reports had mortality rates as high as 31%.
• Improved patient selection and techniques reduced mortality rates to less than 5%.
• Difficult to predict which patients will benefit from surgery.
Surgery Combined with Chemotherapy and Radiation:
• EPP feasible in 70-90% of cases after induction chemotherapy.
• Low operative mortality rates (0-7%).
• Chemotherapy administered both before and after surgery.
• Lung-sparing procedures like P/D also combined with chemotherapy and radiation
therapy.
Optimal Procedure and Integration:
• No data from randomized trials to determine the best surgical approach (EPP vs. P/D).
• Lack of randomized trials defining the optimal integration of modalities
(chemotherapy, radiation) before and after surgery.
EPP has seen a decrease in morbidity and mortality with improved patient selection and expertise in high-
volume centers.
The extent to which improved results are due to patient selection, reduced procedure-related
mortality, or the benefits of surgery is unclear.
EPP, when used in combination with other treatment methods for MPM, has shown a median
survival of around 18 months in contemporary studies.
However, long-term survival rates are relatively low, with only 14% and 4% of patients surviving
at 5 and 10 years, respectively.
Perioperative mortality and morbidity rates vary but have improved due to advancements in
various aspects of the procedure.
Large Single
Institution
Over 300 cases
Survival data not
specified
Mortality rate 3.4%
Atrial fibrillation,
myocardial infarction,
pulmonary
complications,
herniation of heart or
abdominal contents,
vocal cord
dysfunction,
bronchopleural
fistula, empyema,
prolonged
respiratory failure
Pleurectomy/decortication (P/D) is an alternative surgical procedure to EPP for the management MPM.
Unlike EPP, P/D aims to preserve lung parenchyma while achieving macroscopic complete resection (MCR) of the tumor.
Benefits of P/D:
• Lung Preservation: P/D is chosen to preserve as much lung tissue as possible, making it suitable for carefully selected patients
with MPM.
• Achieving MCR: P/D, when performed successfully, removes the visible tumor and involved pleura.
Table: Comparative Results and Side Effects of P/D vs. EPP
Aspect Pleurectomy/Decortication (P/D) Extrapleural Pneumonectomy (EPP)
Mortality Lower (4%) Higher (7%)
Operative Mortality Less than EPP Greater than P/D
Overall Survival (OS) Better OS compared to palliative P/D Worse OS (median 12 vs. 16 months)
Stage Comparison
No statistically significant difference
at any stage
No statistically significant difference
at any stage
Morbidity Lower morbidity Higher morbidity
Contemporary Data
Shows satisfactory morbidity and
mortality with EPP
-
Adjuvant Therapy: Radiation is used after surgery (P/D or EPP) to target remaining
cancer cells and enhance local disease control.
Local Recurrence Prevention: It helps reduce the risk of cancer recurrence in the chest
cavity.
Customized Approach: Treatment decisions are tailored to individual factors and extent
of the disease. It ensures that the radiation therapy plan is flexible and adaptable,
optimizing the chances of success while minimizing unnecessary side effects.
RT before EPP — NART also investigated. Patients receive 25 to 30 Gy of IMRT to the entire
hemithorax one week prior to EPP. Treatment has been well tolerated with only one treatment-
related death amongst 62 patients, and median survival of 36 months.
RT following EPP for MPM has evolved with the use of highly conformal techniques like IMRT.
Historically, conventional RT covered the entire involved hemithorax, but it had limitations,
such as potential radiation underdosing and difficulties in sparing critical organs.
Conventional RT had limitations, with around 10 to 15 % of patients at risk of local failure due
to radiation underdosing.
IMRT, a more precise and conformal radiation technique, offers the potential for safer, more
effective treatments with improved dosimetric control.
Nonetheless, IMRT introduces a risk of radiation pneumonitis due to higher doses to the
contralateral lung.
Experience with IMRT has improved target coverage and reduced toxicity rates
A phase II trial exploring high-dose hemithoracic RT to 54 Gy following EPP demonstrated
high rates of local control, with only two isolated locoregional failures in 54 patients and a
median survival of 17 months (stage I and II tumors, 33.8 months; stage III or IV, 10 months).
•Modern Techniques: Contemporary radiation therapy (RT) such as IMRT is increasingly used
with P/D to enhance local control while minimizing toxicity.
•Historical Limitations: Older 2D RT techniques post-P/D were challenged in effectively sparing
the lung, resulting in limited success with a one-year local control rate of 42% and a median
survival of 13.5 months.
Study Effect Reported Toxicities
Memorial Sloan Kettering Cancer Center
67 patient(2004-2013) [50..4 Gy/1.8 Gy]
42 patients (63%) underwent P/D prior to
RT, while 25 (37 %) were unresectable
- One-year OS: 85% - Two-year OS: 50%
Median follow up: 24 months
Not specified
- Majority of local failures at sites of gross
disease - In-field failure in 64% of cases,
74% at sites of previous gross disease -
Significantly prolonged time to in-field
recurrence (P/D followed by IMRT: 14
months, IMRT alone: 6 months)
Two-center Phase II Study (Pleural IMRT
with chemotherapy)
- Median progression-free survival: 12.4
months - Overall Survival: 23.7 months -
Two-year OS: 59% in resectable tumors,
25% in unresectable tumors
- Eight patients experienced grade 2 or 3
pneumonitis - Suggested better outcomes
with pleural IMRT compared to
conventional techniques
Here's a table summarizing the studies, their effects, and reported toxicities for the use of IMRT and
contemporary radiation techniques following P/D in pleural mesothelioma:
Combinations of active agents, such as cisplatin plus pemetrexed, have demonstrated improved overall survival (OS) in
patients with unresectable disease.
Chemotherapy regimens are also integrated into combined-modality approaches for patients with resectable
disease.
The choice of chemotherapy typically includes pemetrexed and a platinum agent.
Study Key Findings
Multicenter Phase II Study (Neoadjuvant
Chemo)
77 patients
- Neoadjuvant pemetrexed plus cisplatin
followed by EPP and adjuvant RT - Median
OS for the entire cohort: 17 months -
Median survival for those who completed
all treatments: 29 months - Two-year
survival rate: 61%
Intraoperative Intracavitary
Chemotherapy( 92 patients)
- Hyperthermic intracavitary perfusion
with cisplatin (225 mg/m2) following EPP -
Recurrence in 51% of patients, with 17%
I/L recurrence.
Considered experimental and limited to
clinical studies
Lack of definitive randomized trials for combined-modality therapy in
localized MPM.
The Mesothelioma and Radical Surgery trial, originally designed to
assess the role of EPP, faced accrual difficulties and transformed into a
feasibility study.
• In this study, 112 patients received induction chemotherapy, and 50 were randomly assigned
to EPP or no EPP followed by radiation therapy (RT).
• No statistically significant survival differences at 6, 12, or 18 months; median survivals were
14.4 months for EPP and 19.5 months for no EPP.
• The trial was severely underpowered and had methodological issues, including an 18%
operative mortality rate.
New trials are in development to further investigate combined-modality
approaches for MPM.
In malignant pleural mesothelioma (MPM), pleural effusions often
lead to debilitating symptoms like persistent dyspnea and pain.
1.Pleurodesis with Talc:
• Pleurodesis is a procedure that can provide symptom relief in MPM by creating
adhesions between the visceral and parietal pleura, effectively obliterating the
pleural space.
• Sterile, asbestos-free talc is commonly used either in powder form or as a slurry
introduced through a chest tube.
• However, bulky tumor presence in the pleural space or a thick visceral pleural peel
of tumor may limit successful pleurodesis, particularly when the lung cannot fully
expand.
• Talc should not be used as a sclerosant unless full lung expansion is achieved
because it can serve as a permanent foreign body, posing the risk of intractable
empyema if infection occurs in the residual pleural space.
2.Tunneled Catheters: For some MPM patients with entrapped lungs and
sizable pleural effusions, tunneled catheters can alleviate symptoms.
• Although these catheters may not restore full lung expansion, they can relieve
pressure on the diaphragm, leading to improved breathing, reduced pain, and
less early satiety.
• This option provides palliative relief for patients who might not be candidates
for more invasive procedures.
3.VATS Pleurectomy: Video-Assisted Thoracoscopic Subtotal (VATS)
pleurectomy is another palliative approach for managing pleural effusions in
MPM.
• However, it's important to note that VATS pleurectomy does not significantly
extend overall survival.
• In the MesoVATS trial, better control of pleural effusion at 1 and 6 months
when compared to pleurodesis but did not maintain this advantage at 3 and 12
months. Additionally, VATS pleurectomy has not been directly compared to the
use of indwelling valved catheters in MPM patients.
Tumor Seeding at the Instrument Site:
•Prophylactic RT Debate: Prophylactic radiation therapy (RT) for preventing tumor
seeding at the site of diagnostic or therapeutic interventions in malignant pleural
mesothelioma (MPM) remains a contentious issue.
•Lack of Standard Practice: Prophylactic RT is not a universally accepted standard
practice for patients undergoing limited procedures like open surgical biopsies, video-
assisted thoracoscopic surgery biopsies, thoracoscopy, or chest drains in MPM.
•UK Randomized Trial: In a UK randomized trial with 375 MPM patients, those who
received prophylactic RT (21 Gy in 3 fractions within 42 days of the procedure) showed
similar incidence of chest wall metastases at 6 months compared to those without post-
procedure RT (3.2% vs. 5.3%).
•Common Skin Toxicity: The most frequent adverse event in the UK trial was skin toxicity,
occurring in over 50% of patients. However, only one patient experienced severe
dermatitis.
•Previous Small Trial: In an earlier small trial, RT demonstrated a significant reduction in
recurrences for patients who had invasive diagnostic procedures (cytology, needle biopsy,
thoracoscopy, or chest tube placement). Patients receiving 21 Gy in three fractions had no
chest wall recurrences, in contrast to untreated patients who had a 40% recurrence rate.
•Majority of Studies: Most studies do not support the use of RT to decrease seeding at
surgical sites for MPM patients, suggesting that it is not recommended for this purpose.
Dr Sumit Kumar
Assistant professor
NEIGRIHMS
Generally, the majority of MPM cases are diagnosed at an unresectable stage
due to the aggressive nature of the disease.
Symptoms often do not manifest until the cancer has progressed significantly.
Systemic treatment options for unresectable MPM have evolved significantly in
recent years, offering new hope for improved outcomes and enhanced quality
of life for patients.
It often has an extremely poor prognosis the median survival is 4 to 13 months
for untreated patients and 6 to 18 months for treated patients, regardless of
the therapeutic approach.
• The combination of nivolumab plus ipilimumab is approved by the US-FDA for unresectable
mesothelioma as an initial option for patients with nonepithelioid tumors.
Parameter
Nivolumab/Ipili
mumab
Platinum-Based
Chemotherapy
OS
median follow- up
30 ths
18 months 14 months
Two-Year OS Rate 41% 27%
Three-Year OS
Rate
23% 15%
Subgroup
Nivolumab/Ipili
mumab
Platinum-Based
Chemotherapy
Nonepithelioid
Histologies
18 months 9 months
Epithelioid
Histology
19 months 17 months
 Subgroup analysis indicated that the benefits of nivolumab/ipilimumab over chemotherapy were
statistically significant in patients with nonepithelioid histologies, but not in those with epithelioid histology.
Phase III trial
including 605 patients
advanced, treatment-naïve
mesothelioma,
Arm 1 nivolumab (3 mg/kg intravenously once
every two weeks) plus ipilimumab (1 mg/kg
intravenously once every six weeks) for up to two
years
Arm 2:pemetrexed chemotherapy (500 mg/m2 ]
plus cisplatin (75 mg/m2) or carboplatin [AUC-5])
once every 3 weeks for up to 6 cycles
Preffered option:
pemetrexed plus cisplatin
4-6 cycle and then
pemetrexed maintenance till
progression
Alternative option :
Nivolumab plus ipilimumab
continue till progression
ARM 1
Pemetrexed & cisplatin
ARM 2
cisplatin and placebo
After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a
significant reduction in toxicities in the pemetrexed/cisplatin arm.
Parameter Pemetrexed/Cisplatin Cisplatin Alone
Median Survival Time (months) 12.1 9.3
Median Time to Progression
(months)
5.7 3.9
Response Rate (%) 41.3% 16.7%
Hazard Ratio for Survival
(Pemetrexed vs. Cisplatin)
0.77
Addition of Folic Acid and Vitamin
B12
Reduced Toxicity
Parameter Pemetrexed Maintenance Observation
Median Progression-Free
Survival (PFS)
3.4 months 3 months
Median Overall Survival (OS) 16.3 months 11.8 months
Statistical Significance Not statistically significant Not statistically significant
randomized trial of 49 patients
unresectable MPM and at least stable disease after four to six cycles of pemetrexed and
platinum-based chemotherapy,
Compare with maintenance pemetrexed vs placebo
A separate trial suggested a PFS benefit with maintenance gemcitabine, but given the lack of
OS benefit, this is not a recommended approach
• Predictive factors for longer overall survival (OS) in malignant pleural mesothelioma
(MPM) include:
Therapy group, specifically the use of pemetrexed and cisplatin.
Vitamin supplementation along with therapy.
High Karnofsky performance status (90 to 100).
A specific disease stage (likely early stage).
Epithelioid subtype of MPM.
Elevated white blood cell count (≥8200/microL).
Low thymidylate synthase levels, indicating improved response to pemetrexed-
based treatment. Ongoing prospective trials are evaluating thymidylate synthase
as a predictive biomarker.
Aspect MAPS Trial Results
Study Design Phase III
Number of Patients 448
Patient Eligibility Unresectable MPM
Chemotherapy Regimen
- Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) on day 1 of each of
six 21-day cycles
- Bevacizumab (15 mg/kg) on day 1, continued as maintenance every
three weeks after six chemotherapy cycles
Crossover Not allowed
Median Follow-Up 39 months
Progression-Free Survival (PFS)
Increased with bevacizumab combination compared to cisplatin-
pemetrexed alone (median PFS: 9.2 versus 7.3 months)
Overall Survival (OS)
Increased with bevacizumab combination compared to cisplatin-
pemetrexed alone (median OS: 18.8 versus 16.1 months)
Findings and Conclusions
Bevacizumab combination resulted in improved PFS and OS in MPM
patients who were not eligible for radical surgery
 The addition of bevacizumab to the pemetrexed-cisplatin regimen improved both PFS and OS
compared to pemetrexed-cisplatin alone in a large Phase III trial.
 However, results from other trials evaluating antiangiogenic agents have been inconsistent.
Aspect
Cisplatin-Pemetrexed +
Cediranib
Cisplatin-Pemetrexed +
Placebo
Progression-Free Survival
(PFS)
Median PFS: 7.2 months Median PFS: 5.6 months
Hazard Ratio (HR) for PFS HR: 0.71 (80% CI: 0.59-0.95)
Overall Survival (OS) Similar between both groups
Toxicities
Increased with cediranib
(including more severe grade 3and 4
diarrhea, dehydration,
and weight loss)
 Summary of the findings from the separate randomized trial
comparing cisplatin-pemetrexed with cediranib to the same
chemotherapy with a placebo:
Aspect
TTF + Pemetrexed + Platinum-based
Chemo Historic Control
TTF Mechanism
Electric fields at 150 kHz to disrupt
tumor cell division
Treatment in Phase II Trial
Continuous TTF (≥18 hours/day) +
standard dosing of pemetrexed with
cisplatin or carboplatin
Median Overall Survival (OS) 18 months 12 months (historic control)
Median Progression-Free Survival (PFS) 7.6 months 5.7 months (historic control)
TTF-Related Dermatitis
46%
5%
46%
Grade 3 Dermatitis
Grade 3 to 4 Adverse Events
Tumor-Treating Fields (TTF) is an innovative approach for the treatment of MPM.
TTF involves the use of electric fields at specific frequencies to disrupt the division of solid
tumor cancer cells.
Treatment Mechanism: TTF works by applying low-intensity electric fields to the tumor site.
These electric fields inhibiting cancer cell growth.
Pemetrexed plus carboplatin — Carboplatin has been substituted for cisplatin in
conjunction with pemetrexed in an effort to decrease toxicity.
Aspect Carboplatin + Pemetrexed
Study Design Nonrandomized Phase II
Number of Patients 102
Chemotherapy Regimen
Carboplatin (AUC 5) + Pemetrexed (500
mg/m2) every 21 days with folic acid and
vitamin B12 supplementation
Objective Responses 19%
Median Time to Progression
(PFS)
6.5 months
Median Survival (OS) 12.7 months
NO data from bevacizumb in combination with carboplatin
Carboplatin based regimen well tolerated by older patient with age more than 70
years.
1.Gemcitabine plus platinum compounds (e.g., cisplatin,
carboplatin, oxaliplatin).
2.Gemcitabine-plus-cisplatin with or without bevacizumab.
3.Other cisplatin-based combinations, including:
 Anthracyclines (doxorubicin, epirubicin).
 The combination of fluorouracil, mitomycin, plus etoposide.
 The combination of methotrexate plus vinblastine.
NO benefit after adding bevacizumab in combination with gemcitabine
• Response assessment in unresectable malignant mesothelioma involves
routine CT scans of the chest, abdomen, and pelvis.
• Typically performed with any change in clinical status or every two to three
treatment cycles.
• PET/CT imaging may be favoured by some experts for its ability to detect
changes in metabolic activity within the tumor, potentially providing insights
into the time to disease progression.
• Serum mesothelin-related peptide levels, while suggested for recurrence
detection, are not widely used in routine clinical care due to a lack of FDA
approval and inconsistent correlation with treatment responses.
• The decision to change therapy based on :
• Radiographic findings of progression (ie, new or worsening disease) and/or
• Clinical deterioration with more symptoms of pain, shortness of breath, or
weight loss.
• Have significant side effects to treatment may also require a change in
therapy. .
• For those initially treated with immunotherapy —
• For patients treated initially with immunotherapy, second-line treatment
consists of chemotherapy may be in combination or single agent.
1st line immunotherapy 1st line chemotherapy
Use chemotherapy may
be single agent or
combination
Progression >6 months
after platinum
chemotherapy
Rechallenge with same
regimen
Progression <6 months
after platinum
chemotherapy
Immunotherapy:
Pembrolizumab
Nivolumab
Nivolumab and
ipilimumab tremelimumab
Durvalumab
Chemotherapy
single-agent gemcitabine ,
vinca alkaloids, and
anthracyclines.
methotrexate
Parameter Pembrolizumab Chemotherapy
Objective
Response Rate
22% 6%
PFS 2.5 months 3.4 months
Overall Survival 10.7 months 11.7 months
Pembrolizumab
Phase III-144 patients pretreated
Parameter Nivolumab Placebo
PFS 3.0 months 1.8 months
Overall Survival 10.2 months 6.9 months
Grade ≥3 Adverse Events
-Diarrhoea 3% 2%
-Infusion-Related
Rk
3% 0%
Nivolumab
phase III trial, among 332 patients platinum-
refractory mesothelioma
• Nintedanib: Although it showed progression-free survival (PFS) benefit in a
phase II trial when added to chemotherapy, no significant benefit was observed
in a phase III trial.
• Vorinostat: This oral histone deacetylase inhibitor showed some activity in an
initial phase I study, but more extensive evaluation did not confirm a clinically
meaningful benefit. In a phase III trial, PFS was prolonged with vorinostat, but
the increase was not considered clinically significant, and there was no
significant difference in overall survival.
• Agents targeting mesothelin: These include MORAb-009, SS1P, BAY
9409343, and CRS-207. Preliminary efficacy against mesothelioma has been
observed in clinical trials, and several randomized trials are ongoing.
• Angiogenesis Inhibitors: Experimental agents like thalidomide, lurbinectedin,
and tyrosine kinase inhibitors such as sorafenib, sunitinib, imatinib, vatalani, and
cediranib.
• For patients with advanced malignant pleural mesotheliomas (MPM) who are not
candidates for surgery
For those with nonepithelioid histologies, initial treatment with nivolumab plus
ipilimumab .
For those with epithelioid histologies, chemotherapy using a platinum-based
doublet, with or without bevacizumab.
• When using chemotherapy with pemetrexed, also including prophylactic folic acid
and vitamin B12.
• If bevacizumab is considered, patients should be typically <75 years of age, with a
good performance status, and without contraindications
● Subsequent-line treatment
• For those who experience progression on initial treatment with immunotherapy,
next-line treatment is with chemotherapy
• For patients initially treated with chemotherapy who progress at least six months
after completion, rechallenge with the initial chemotherapy regimen.
• For patients initially treated with chemotherapy who progress on or within six
months of their initial regimen, we suggest either immunotherapy or a single-
agent chemotherapy agent .
MESOTHELIOMA (pleural) Management.pptx
MESOTHELIOMA (pleural) Management.pptx
MESOTHELIOMA (pleural) Management.pptx
MESOTHELIOMA (pleural) Management.pptx
MESOTHELIOMA (pleural) Management.pptx
MESOTHELIOMA (pleural) Management.pptx
MESOTHELIOMA (pleural) Management.pptx
MESOTHELIOMA (pleural) Management.pptx
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MESOTHELIOMA (pleural) Management.pptx

  • 1. Dr Sumit Kumar Assistant professor NEIGRIHMS
  • 2. Pleural mesothelioma is the most common form, comprising about 70-80% of all mesothelioma cases, and primarily affects the lining of the lungs. Pleural mesothelioma is often diagnosed at advanced stages (Stage III or IV), which can limit treatment options and prognosis. The 5-year survival rate for pleural mesothelioma is typically around 5% to 10%, highlighting its aggressive nature and the challenges in treating this form of cancer. Treatment approaches for pleural mesothelioma often involve a combination of surgery, chemotherapy, radiation therapy, and emerging targeted therapies, tailored to the stage of the disease. Preventing asbestos exposure is crucial in reducing the risk of pleural mesothelioma, with workplace safety measures and asbestos removal being important preventive strategies.
  • 3. Mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the tunica vaginalis, or the pericardium. The predominant cause of malignant mesothelioma is inhalational exposure to asbestos, with approximately 70 %. Mesothelioma incidence rates are predicted to increase dramatically in resource-limited settings :- Secondary to poor regulation of asbestos mining and The proliferation of industrial and Household utilization of asbestos.
  • 4. 1 4 5 2 3 Asbestos exposure Genetic factors Viral oncogenes Carbon nanotubes Radiation exposure Lifetime risk: as high as 10 % Latency period: Approx. 30 to 40 yrs Supradiaphragmatic fields in the treatment of malignancy (hodgkin lymphoma, non- hodgkin lymphoma, testicular cancer Simian virus 40 (SV40) polyomavirus Elevated risk for mesothelioma among those whose parents or siblings were diagnosed with the disease of 3.9- and 12.4-fold, respectively
  • 5. Epithelioid Sarcomatoid Biphasic(mixed) Most common: 60 percent Subtype : Tubulopapillary, Acinar (glandular), Adenomatoid and Solid epithelioid pattern Composed of malignant spindle cells which may mimic malignant mesenchymal tumors Have epithelioid and sarcomatoid features
  • 6. • No single marker that has sufficiently high sensitivity and specificity for malignant mesothelioma • Pancytokeratin stains are very useful in the diagnosis of mesothelioma and will stain the vast majority of mesotheliomas. • BAP-1 and MTAP improve sensitivity and specificity for mesothelioma  Useful IHC marker (Mesothalioma) Positive  WT1  Calretinin  D2-40  CK 5/6 Negative  CEA  TTF-1  Claudin-4  To estabilish diagnosis Atleast 2 mesothelial& 2 Carcinoma marker to be check  Sarcomatoid Mesothalioma Shows focal to absent expression for most mesothelial markers, with the most sensitive marker being D2-40/Podoplanin  GATA3 :-Potential diagnostic for sarcomatoid as it expressed in only 10-20%sarcomatoid carcinoma. (claudin-4, TTF-1, CEA) (Calretinin, WT1, D2-40)
  • 7. FISH to detect p16 deletion use for benign versus malignant mesothelial proliferations. Detection of loss of (BRCA1)-associated protein (BAP1) by IHC used to distinguish malignant mesothelioma from reactive mesothelial proliferation
  • 8. A. Localised mesothelioma B. Well-differentiated papillary mesothelioma C. Adenomatoid tumor D. Benign multicystic mesothelioma E. Mesothelioma in situ
  • 9. Most mesothelioma patients initially experience pulmonary symptoms like dyspnea, cough, and chest pain, typically indicating advanced intrathoracic disease. Diagnosis involves clinical suspicion arising from respiratory symptoms in the context of pleural changes and a history of asbestos exposure, with biopsy confirmation being necessary. A multidisciplinary approach is employed, considering disease extent, patient health, and their treatment preferences. Surgical candidates with resectable disease undergo combined-modality treatment, including surgery aimed at macroscopic complete resection (MCR), chemotherapy, and radiation therapy. Nonsurgical candidates with unresectable disease or medical contraindications receive systemic chemotherapy and symptom-directed treatment.
  • 10. T Primary Tumor TX Primary tumor cannot be assessed T0 no evidence of primary tumor T1 Tumor limited to the ipsilateral parietal pleura with or without involvement of: Visceral pleura Mediastinal pleura Diaphragmatic pleura T2 Tumor involving each of the ipsilateral pleural surfaces ( parietal, mediastinal, diaphragmatic and visceral pleura) with at least one of the following feature: Involvement of diaphragmatic muscle Extension of tumor from visceral pleura into the underlying pulmonary parenchyma T3 Locally advanced but potentially resectable tumor. Tumor involving all ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura), with at least one of the following features; Involvement of the endothoracic fascia Extension into the mediastinal fat Solitary, completely resettable focus of tumor extending into the soft tissue of the chest wall Non transmural involvement of the pericardium T4 locally advanced technically unresectable tumor. Tumor involving all ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with atleast one of the following features: Diffuse extension of multifocal masses of tumor in the chest wall ,with or without associated rib destruction Direct transdiaphragmatic extension of the tumor to the peritoneal Direct extension of tumor to the contralateral pleura Direct extension of tumor mediastinal organs Direct extension of tumor into the spine Direct extending through to the internal surface of the pericardium or without a pericardial effusion; or tumor involving the myocardum
  • 11. N Regional lymph nodes NX Lymph nodes canot be assessed N0 No regional lymph node metastases N1 Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary , peridiapharagamtic, pericardial fat pad of intercostal lymph nodes N2 Metastases in the contralateral mediastinal , ipsilateral or contralateral supraclavicular lymph nodes M Distant metastasis M0 No distant metastases M1 Distant metastases present
  • 12. Recurrent pleural effusion and/ or pleural thickening CECT-thorax Thoracentesis for cytologic assessment Pleural biopsy Pleural mesothelioma confirmed Clinical stage I-IIIA & epitheloid histology Clinical stage IIIB or IV, Sarcomatoid or biphasic histology, or medically inoperable CECT abdomen PS 0-2 PS 3-4 Systemic therapy BST NACT with pem. & cisplatin Systemic therapy or observation Resectable P/D or EPP Unresectabl e Surgical exploration Hemithoracic IMRT RT Resectable P/D or EPP Unresectable Systemic therapy and consider RT
  • 13. A combined-modality approach is employed for surgically resectable mesothelioma patients. Components of this approach include definitive surgery EPP or P/D, radiation therapy (RT), and chemotherapy (systemic, preoperative/postoperative, or intraoperative). While randomized trials haven't demonstrated an overall survival advantage, this approach offers relatively prolonged survival compared to chemotherapy alone.
  • 14. Surgery not standard, but beneficial for select MPM patients. Requires expertise; active research on surgical candidates. Histologic subtype is a critical selection criterion, with a preference for epithelial subtype confirmed by biopsy. Negative factors: age >50, male gender, high platelet/WBC count, chest wall pain, and large tumor volume. Surgeons should aim for complete resection and consider pleural effusion drainage. Individual assessment by experienced surgeons, avoiding "palliative" explorations. Criteria for patient-specific selection: no disseminated disease, good cardiopulmonary function, and no severe comorbidities. Emphasize the absence of a uniform MPM treatment; recommend expert consultation.
  • 15. EPP En bloc resection of the parietal and visceral pleura with the ipsilateral lung, pericardium, and diaphragm. Extended P/D Parietal and visceral pleurectomy to remove all gross tumor with resection of the diaphragm and/or pericardium. 1 2 P/D Parietal and visceral pleurectomy to remove all gross tumor without diaphragm or pericardial resection. Partial Pleurectomy Partial removal of parietal and/or visceral pleura for diagnostic or palliative purposes but leaving gross tumor behind when an R0 or R1 resection does not prove to be feasible. 3 4
  • 16. Surgical Morbidity and Mortality: • Earliar EPP reports had mortality rates as high as 31%. • Improved patient selection and techniques reduced mortality rates to less than 5%. • Difficult to predict which patients will benefit from surgery. Surgery Combined with Chemotherapy and Radiation: • EPP feasible in 70-90% of cases after induction chemotherapy. • Low operative mortality rates (0-7%). • Chemotherapy administered both before and after surgery. • Lung-sparing procedures like P/D also combined with chemotherapy and radiation therapy. Optimal Procedure and Integration: • No data from randomized trials to determine the best surgical approach (EPP vs. P/D). • Lack of randomized trials defining the optimal integration of modalities (chemotherapy, radiation) before and after surgery.
  • 17. EPP has seen a decrease in morbidity and mortality with improved patient selection and expertise in high- volume centers. The extent to which improved results are due to patient selection, reduced procedure-related mortality, or the benefits of surgery is unclear. EPP, when used in combination with other treatment methods for MPM, has shown a median survival of around 18 months in contemporary studies. However, long-term survival rates are relatively low, with only 14% and 4% of patients surviving at 5 and 10 years, respectively. Perioperative mortality and morbidity rates vary but have improved due to advancements in various aspects of the procedure. Large Single Institution Over 300 cases Survival data not specified Mortality rate 3.4% Atrial fibrillation, myocardial infarction, pulmonary complications, herniation of heart or abdominal contents, vocal cord dysfunction, bronchopleural fistula, empyema, prolonged respiratory failure
  • 18. Pleurectomy/decortication (P/D) is an alternative surgical procedure to EPP for the management MPM. Unlike EPP, P/D aims to preserve lung parenchyma while achieving macroscopic complete resection (MCR) of the tumor. Benefits of P/D: • Lung Preservation: P/D is chosen to preserve as much lung tissue as possible, making it suitable for carefully selected patients with MPM. • Achieving MCR: P/D, when performed successfully, removes the visible tumor and involved pleura. Table: Comparative Results and Side Effects of P/D vs. EPP Aspect Pleurectomy/Decortication (P/D) Extrapleural Pneumonectomy (EPP) Mortality Lower (4%) Higher (7%) Operative Mortality Less than EPP Greater than P/D Overall Survival (OS) Better OS compared to palliative P/D Worse OS (median 12 vs. 16 months) Stage Comparison No statistically significant difference at any stage No statistically significant difference at any stage Morbidity Lower morbidity Higher morbidity Contemporary Data Shows satisfactory morbidity and mortality with EPP -
  • 19. Adjuvant Therapy: Radiation is used after surgery (P/D or EPP) to target remaining cancer cells and enhance local disease control. Local Recurrence Prevention: It helps reduce the risk of cancer recurrence in the chest cavity. Customized Approach: Treatment decisions are tailored to individual factors and extent of the disease. It ensures that the radiation therapy plan is flexible and adaptable, optimizing the chances of success while minimizing unnecessary side effects. RT before EPP — NART also investigated. Patients receive 25 to 30 Gy of IMRT to the entire hemithorax one week prior to EPP. Treatment has been well tolerated with only one treatment- related death amongst 62 patients, and median survival of 36 months.
  • 20. RT following EPP for MPM has evolved with the use of highly conformal techniques like IMRT. Historically, conventional RT covered the entire involved hemithorax, but it had limitations, such as potential radiation underdosing and difficulties in sparing critical organs. Conventional RT had limitations, with around 10 to 15 % of patients at risk of local failure due to radiation underdosing. IMRT, a more precise and conformal radiation technique, offers the potential for safer, more effective treatments with improved dosimetric control. Nonetheless, IMRT introduces a risk of radiation pneumonitis due to higher doses to the contralateral lung. Experience with IMRT has improved target coverage and reduced toxicity rates A phase II trial exploring high-dose hemithoracic RT to 54 Gy following EPP demonstrated high rates of local control, with only two isolated locoregional failures in 54 patients and a median survival of 17 months (stage I and II tumors, 33.8 months; stage III or IV, 10 months).
  • 21. •Modern Techniques: Contemporary radiation therapy (RT) such as IMRT is increasingly used with P/D to enhance local control while minimizing toxicity. •Historical Limitations: Older 2D RT techniques post-P/D were challenged in effectively sparing the lung, resulting in limited success with a one-year local control rate of 42% and a median survival of 13.5 months. Study Effect Reported Toxicities Memorial Sloan Kettering Cancer Center 67 patient(2004-2013) [50..4 Gy/1.8 Gy] 42 patients (63%) underwent P/D prior to RT, while 25 (37 %) were unresectable - One-year OS: 85% - Two-year OS: 50% Median follow up: 24 months Not specified - Majority of local failures at sites of gross disease - In-field failure in 64% of cases, 74% at sites of previous gross disease - Significantly prolonged time to in-field recurrence (P/D followed by IMRT: 14 months, IMRT alone: 6 months) Two-center Phase II Study (Pleural IMRT with chemotherapy) - Median progression-free survival: 12.4 months - Overall Survival: 23.7 months - Two-year OS: 59% in resectable tumors, 25% in unresectable tumors - Eight patients experienced grade 2 or 3 pneumonitis - Suggested better outcomes with pleural IMRT compared to conventional techniques Here's a table summarizing the studies, their effects, and reported toxicities for the use of IMRT and contemporary radiation techniques following P/D in pleural mesothelioma:
  • 22. Combinations of active agents, such as cisplatin plus pemetrexed, have demonstrated improved overall survival (OS) in patients with unresectable disease. Chemotherapy regimens are also integrated into combined-modality approaches for patients with resectable disease. The choice of chemotherapy typically includes pemetrexed and a platinum agent. Study Key Findings Multicenter Phase II Study (Neoadjuvant Chemo) 77 patients - Neoadjuvant pemetrexed plus cisplatin followed by EPP and adjuvant RT - Median OS for the entire cohort: 17 months - Median survival for those who completed all treatments: 29 months - Two-year survival rate: 61% Intraoperative Intracavitary Chemotherapy( 92 patients) - Hyperthermic intracavitary perfusion with cisplatin (225 mg/m2) following EPP - Recurrence in 51% of patients, with 17% I/L recurrence. Considered experimental and limited to clinical studies
  • 23. Lack of definitive randomized trials for combined-modality therapy in localized MPM. The Mesothelioma and Radical Surgery trial, originally designed to assess the role of EPP, faced accrual difficulties and transformed into a feasibility study. • In this study, 112 patients received induction chemotherapy, and 50 were randomly assigned to EPP or no EPP followed by radiation therapy (RT). • No statistically significant survival differences at 6, 12, or 18 months; median survivals were 14.4 months for EPP and 19.5 months for no EPP. • The trial was severely underpowered and had methodological issues, including an 18% operative mortality rate. New trials are in development to further investigate combined-modality approaches for MPM.
  • 24. In malignant pleural mesothelioma (MPM), pleural effusions often lead to debilitating symptoms like persistent dyspnea and pain. 1.Pleurodesis with Talc: • Pleurodesis is a procedure that can provide symptom relief in MPM by creating adhesions between the visceral and parietal pleura, effectively obliterating the pleural space. • Sterile, asbestos-free talc is commonly used either in powder form or as a slurry introduced through a chest tube. • However, bulky tumor presence in the pleural space or a thick visceral pleural peel of tumor may limit successful pleurodesis, particularly when the lung cannot fully expand. • Talc should not be used as a sclerosant unless full lung expansion is achieved because it can serve as a permanent foreign body, posing the risk of intractable empyema if infection occurs in the residual pleural space.
  • 25. 2.Tunneled Catheters: For some MPM patients with entrapped lungs and sizable pleural effusions, tunneled catheters can alleviate symptoms. • Although these catheters may not restore full lung expansion, they can relieve pressure on the diaphragm, leading to improved breathing, reduced pain, and less early satiety. • This option provides palliative relief for patients who might not be candidates for more invasive procedures. 3.VATS Pleurectomy: Video-Assisted Thoracoscopic Subtotal (VATS) pleurectomy is another palliative approach for managing pleural effusions in MPM. • However, it's important to note that VATS pleurectomy does not significantly extend overall survival. • In the MesoVATS trial, better control of pleural effusion at 1 and 6 months when compared to pleurodesis but did not maintain this advantage at 3 and 12 months. Additionally, VATS pleurectomy has not been directly compared to the use of indwelling valved catheters in MPM patients.
  • 26. Tumor Seeding at the Instrument Site: •Prophylactic RT Debate: Prophylactic radiation therapy (RT) for preventing tumor seeding at the site of diagnostic or therapeutic interventions in malignant pleural mesothelioma (MPM) remains a contentious issue. •Lack of Standard Practice: Prophylactic RT is not a universally accepted standard practice for patients undergoing limited procedures like open surgical biopsies, video- assisted thoracoscopic surgery biopsies, thoracoscopy, or chest drains in MPM. •UK Randomized Trial: In a UK randomized trial with 375 MPM patients, those who received prophylactic RT (21 Gy in 3 fractions within 42 days of the procedure) showed similar incidence of chest wall metastases at 6 months compared to those without post- procedure RT (3.2% vs. 5.3%). •Common Skin Toxicity: The most frequent adverse event in the UK trial was skin toxicity, occurring in over 50% of patients. However, only one patient experienced severe dermatitis. •Previous Small Trial: In an earlier small trial, RT demonstrated a significant reduction in recurrences for patients who had invasive diagnostic procedures (cytology, needle biopsy, thoracoscopy, or chest tube placement). Patients receiving 21 Gy in three fractions had no chest wall recurrences, in contrast to untreated patients who had a 40% recurrence rate. •Majority of Studies: Most studies do not support the use of RT to decrease seeding at surgical sites for MPM patients, suggesting that it is not recommended for this purpose.
  • 27. Dr Sumit Kumar Assistant professor NEIGRIHMS
  • 28. Generally, the majority of MPM cases are diagnosed at an unresectable stage due to the aggressive nature of the disease. Symptoms often do not manifest until the cancer has progressed significantly. Systemic treatment options for unresectable MPM have evolved significantly in recent years, offering new hope for improved outcomes and enhanced quality of life for patients. It often has an extremely poor prognosis the median survival is 4 to 13 months for untreated patients and 6 to 18 months for treated patients, regardless of the therapeutic approach.
  • 29.
  • 30. • The combination of nivolumab plus ipilimumab is approved by the US-FDA for unresectable mesothelioma as an initial option for patients with nonepithelioid tumors. Parameter Nivolumab/Ipili mumab Platinum-Based Chemotherapy OS median follow- up 30 ths 18 months 14 months Two-Year OS Rate 41% 27% Three-Year OS Rate 23% 15% Subgroup Nivolumab/Ipili mumab Platinum-Based Chemotherapy Nonepithelioid Histologies 18 months 9 months Epithelioid Histology 19 months 17 months  Subgroup analysis indicated that the benefits of nivolumab/ipilimumab over chemotherapy were statistically significant in patients with nonepithelioid histologies, but not in those with epithelioid histology. Phase III trial including 605 patients advanced, treatment-naïve mesothelioma, Arm 1 nivolumab (3 mg/kg intravenously once every two weeks) plus ipilimumab (1 mg/kg intravenously once every six weeks) for up to two years Arm 2:pemetrexed chemotherapy (500 mg/m2 ] plus cisplatin (75 mg/m2) or carboplatin [AUC-5]) once every 3 weeks for up to 6 cycles
  • 31. Preffered option: pemetrexed plus cisplatin 4-6 cycle and then pemetrexed maintenance till progression Alternative option : Nivolumab plus ipilimumab continue till progression ARM 1 Pemetrexed & cisplatin ARM 2 cisplatin and placebo After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. Parameter Pemetrexed/Cisplatin Cisplatin Alone Median Survival Time (months) 12.1 9.3 Median Time to Progression (months) 5.7 3.9 Response Rate (%) 41.3% 16.7% Hazard Ratio for Survival (Pemetrexed vs. Cisplatin) 0.77 Addition of Folic Acid and Vitamin B12 Reduced Toxicity
  • 32. Parameter Pemetrexed Maintenance Observation Median Progression-Free Survival (PFS) 3.4 months 3 months Median Overall Survival (OS) 16.3 months 11.8 months Statistical Significance Not statistically significant Not statistically significant randomized trial of 49 patients unresectable MPM and at least stable disease after four to six cycles of pemetrexed and platinum-based chemotherapy, Compare with maintenance pemetrexed vs placebo A separate trial suggested a PFS benefit with maintenance gemcitabine, but given the lack of OS benefit, this is not a recommended approach
  • 33. • Predictive factors for longer overall survival (OS) in malignant pleural mesothelioma (MPM) include: Therapy group, specifically the use of pemetrexed and cisplatin. Vitamin supplementation along with therapy. High Karnofsky performance status (90 to 100). A specific disease stage (likely early stage). Epithelioid subtype of MPM. Elevated white blood cell count (≥8200/microL). Low thymidylate synthase levels, indicating improved response to pemetrexed- based treatment. Ongoing prospective trials are evaluating thymidylate synthase as a predictive biomarker.
  • 34. Aspect MAPS Trial Results Study Design Phase III Number of Patients 448 Patient Eligibility Unresectable MPM Chemotherapy Regimen - Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) on day 1 of each of six 21-day cycles - Bevacizumab (15 mg/kg) on day 1, continued as maintenance every three weeks after six chemotherapy cycles Crossover Not allowed Median Follow-Up 39 months Progression-Free Survival (PFS) Increased with bevacizumab combination compared to cisplatin- pemetrexed alone (median PFS: 9.2 versus 7.3 months) Overall Survival (OS) Increased with bevacizumab combination compared to cisplatin- pemetrexed alone (median OS: 18.8 versus 16.1 months) Findings and Conclusions Bevacizumab combination resulted in improved PFS and OS in MPM patients who were not eligible for radical surgery  The addition of bevacizumab to the pemetrexed-cisplatin regimen improved both PFS and OS compared to pemetrexed-cisplatin alone in a large Phase III trial.  However, results from other trials evaluating antiangiogenic agents have been inconsistent.
  • 35. Aspect Cisplatin-Pemetrexed + Cediranib Cisplatin-Pemetrexed + Placebo Progression-Free Survival (PFS) Median PFS: 7.2 months Median PFS: 5.6 months Hazard Ratio (HR) for PFS HR: 0.71 (80% CI: 0.59-0.95) Overall Survival (OS) Similar between both groups Toxicities Increased with cediranib (including more severe grade 3and 4 diarrhea, dehydration, and weight loss)  Summary of the findings from the separate randomized trial comparing cisplatin-pemetrexed with cediranib to the same chemotherapy with a placebo:
  • 36. Aspect TTF + Pemetrexed + Platinum-based Chemo Historic Control TTF Mechanism Electric fields at 150 kHz to disrupt tumor cell division Treatment in Phase II Trial Continuous TTF (≥18 hours/day) + standard dosing of pemetrexed with cisplatin or carboplatin Median Overall Survival (OS) 18 months 12 months (historic control) Median Progression-Free Survival (PFS) 7.6 months 5.7 months (historic control) TTF-Related Dermatitis 46% 5% 46% Grade 3 Dermatitis Grade 3 to 4 Adverse Events Tumor-Treating Fields (TTF) is an innovative approach for the treatment of MPM. TTF involves the use of electric fields at specific frequencies to disrupt the division of solid tumor cancer cells. Treatment Mechanism: TTF works by applying low-intensity electric fields to the tumor site. These electric fields inhibiting cancer cell growth.
  • 37. Pemetrexed plus carboplatin — Carboplatin has been substituted for cisplatin in conjunction with pemetrexed in an effort to decrease toxicity. Aspect Carboplatin + Pemetrexed Study Design Nonrandomized Phase II Number of Patients 102 Chemotherapy Regimen Carboplatin (AUC 5) + Pemetrexed (500 mg/m2) every 21 days with folic acid and vitamin B12 supplementation Objective Responses 19% Median Time to Progression (PFS) 6.5 months Median Survival (OS) 12.7 months NO data from bevacizumb in combination with carboplatin Carboplatin based regimen well tolerated by older patient with age more than 70 years.
  • 38. 1.Gemcitabine plus platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin). 2.Gemcitabine-plus-cisplatin with or without bevacizumab. 3.Other cisplatin-based combinations, including:  Anthracyclines (doxorubicin, epirubicin).  The combination of fluorouracil, mitomycin, plus etoposide.  The combination of methotrexate plus vinblastine. NO benefit after adding bevacizumab in combination with gemcitabine
  • 39. • Response assessment in unresectable malignant mesothelioma involves routine CT scans of the chest, abdomen, and pelvis. • Typically performed with any change in clinical status or every two to three treatment cycles. • PET/CT imaging may be favoured by some experts for its ability to detect changes in metabolic activity within the tumor, potentially providing insights into the time to disease progression. • Serum mesothelin-related peptide levels, while suggested for recurrence detection, are not widely used in routine clinical care due to a lack of FDA approval and inconsistent correlation with treatment responses.
  • 40. • The decision to change therapy based on : • Radiographic findings of progression (ie, new or worsening disease) and/or • Clinical deterioration with more symptoms of pain, shortness of breath, or weight loss. • Have significant side effects to treatment may also require a change in therapy. . • For those initially treated with immunotherapy — • For patients treated initially with immunotherapy, second-line treatment consists of chemotherapy may be in combination or single agent.
  • 41. 1st line immunotherapy 1st line chemotherapy Use chemotherapy may be single agent or combination Progression >6 months after platinum chemotherapy Rechallenge with same regimen Progression <6 months after platinum chemotherapy Immunotherapy: Pembrolizumab Nivolumab Nivolumab and ipilimumab tremelimumab Durvalumab Chemotherapy single-agent gemcitabine , vinca alkaloids, and anthracyclines. methotrexate
  • 42. Parameter Pembrolizumab Chemotherapy Objective Response Rate 22% 6% PFS 2.5 months 3.4 months Overall Survival 10.7 months 11.7 months Pembrolizumab Phase III-144 patients pretreated Parameter Nivolumab Placebo PFS 3.0 months 1.8 months Overall Survival 10.2 months 6.9 months Grade ≥3 Adverse Events -Diarrhoea 3% 2% -Infusion-Related Rk 3% 0% Nivolumab phase III trial, among 332 patients platinum- refractory mesothelioma
  • 43. • Nintedanib: Although it showed progression-free survival (PFS) benefit in a phase II trial when added to chemotherapy, no significant benefit was observed in a phase III trial. • Vorinostat: This oral histone deacetylase inhibitor showed some activity in an initial phase I study, but more extensive evaluation did not confirm a clinically meaningful benefit. In a phase III trial, PFS was prolonged with vorinostat, but the increase was not considered clinically significant, and there was no significant difference in overall survival. • Agents targeting mesothelin: These include MORAb-009, SS1P, BAY 9409343, and CRS-207. Preliminary efficacy against mesothelioma has been observed in clinical trials, and several randomized trials are ongoing. • Angiogenesis Inhibitors: Experimental agents like thalidomide, lurbinectedin, and tyrosine kinase inhibitors such as sorafenib, sunitinib, imatinib, vatalani, and cediranib.
  • 44. • For patients with advanced malignant pleural mesotheliomas (MPM) who are not candidates for surgery For those with nonepithelioid histologies, initial treatment with nivolumab plus ipilimumab . For those with epithelioid histologies, chemotherapy using a platinum-based doublet, with or without bevacizumab. • When using chemotherapy with pemetrexed, also including prophylactic folic acid and vitamin B12. • If bevacizumab is considered, patients should be typically <75 years of age, with a good performance status, and without contraindications
  • 45. ● Subsequent-line treatment • For those who experience progression on initial treatment with immunotherapy, next-line treatment is with chemotherapy • For patients initially treated with chemotherapy who progress at least six months after completion, rechallenge with the initial chemotherapy regimen. • For patients initially treated with chemotherapy who progress on or within six months of their initial regimen, we suggest either immunotherapy or a single- agent chemotherapy agent .