Chapter 26: Mesothelioma

Verna Vanderpuye; Anish Thomas; Nicholas J. Vogelzang

PLEURAL MESOTHELIOMA

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Epidemiology

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Epidemiology

Incidence:

3000 new cases per year

Median age:

60 years

Male to female ratio:

3:1

Peto J et al. Lancet 1995;345:535–539

Vogelzang NJ et al. Cancer 1984;53:377–383

Pathology

H & E staining

Epithelioid: 60% of cases = tubopapillary, granular, solid (occasional 5-year survival)
Sarcomatoid/mixed: 40% of cases (0% 5-year survival)

Immunohistochemical staining: Keratin positive, CEA negative, Leu M negative, calretinin positive

Cytogenetics: Deletion of short arm of chromosome 1 and 3 and long arm of chromosome 22

Chaihinan AP et al. In: Holland JC, Frei E, eds. Cancer Medicine. 5th ed. Hamilton, ON: BC Decker; 2000:1293–1312

Corson JM. Semin Thorac Cardiovasc Surg 1997;9:347–355

Staging

No defined universal staging system

Rusch VW. Chest 1995;108:1122–1128

Additional information

Thoracic lymph node involvement: 20% at presentation/70% at autopsy
Hematogenous metastases: Liver, lung, and bone: usually late in disease course

Curran D et al. J Clin Oncol 1998;16:145–152

Herndon JE et al. Chest 1998;113:723–731

Symanowski JT et al. Proc Am Soc Clin Oncol 2003;22:647 [Abstract 2602]

Work-up

Chest x-ray: Initial tool in diagnosing pleural plaques and effusion
CT scan or MRI: CT scan or MRI can be used to assess extent of disease. Calcifications are not generally visible on CT scan. Furthermore, the CT scan is less sensitive than the MRI in depicting diaphragmatic, pericardial, and chest wall involvement
3. PET scan: Has shown benefit in assessing lymph node involvement but is useful in only 50–70% of cases
Thoracentesis: Used when there is a pleural effusion (30% diagnostic yield)
CT-guided biopsy: Depends on CT findings. If tumor is thick and easily biopsied, do a CT-directed biopsy
Video-assisted thorascopic (VAT) surgery: Do if on CT scan disease is thin or minimal or in a difficult location and thoracentesis is negative (90% diagnostic yield)

Flores RM et al. Proc Am Soc Clin Oncol 2003;22:620 [Abstract 2495]

Patz EF Jr et al. AJR Am J Roentgenol 1992;159: 961–966

Schneider DB et al. J Thorac Cardiovasc Surg 2000;120: 128–133

Steele JPC. Semin Oncol 2002;29:36–40

Survival

Overall survival: 6–18 months

Expert Opinion

Surgical management

Data regarding the choice of surgical procedure are derived mostly from observational studies involving selected patient populations treated with a variety of surgical techniques and adjuvant chemotherapies

Pleurectomy and decortication (lung sparing surgery): Indicated for minimal bulky disease associated with massive or recurrent pleural effusions
Extrapleural pneumonectomy (en bloc resection of ipsilateral lung, pleura [parietal and visceral], pericardium, and hemidiaphragm): Indicated for highly selected patients with early stage epithelioid type disease with extensive involvement of the diaphragm and visceral pleural surfaces, no nodal metastases, good performance status, and no comorbidities

Radiation therapy

Because of the large volume of lung in the radiation field, delivery of tumoricidal doses of radiation is difficult without causing serious toxicities. Hence, radiation is not usually recommended as single-modality treatment. It is, however, recommended for palliating pain and to prevent or treating chest wall masses that are the result of seeding from sites of invasive procedures, such as prior thoracocentesis or thorascopic surgery. It is also used as part of a combined modality approach in patients with surgically resectable disease

Chemotherapy

Chemotherapy is indicated in patients with malignant pleural mesothelioma whose disease is either unresectable or who are not otherwise candidates for curative surgery. Pemetrexed in combination with cisplatin is the standard first-line chemotherapy with vitamin B₁₂ and folic acid given prophylactically to mitigate leukopenia and gastrointestinal adverse effects associated with pemetrexed

Boutin C et al. Chest 1995;108:754–758

Flores RM et al. J Thorac Cardiovasc Surg 2008;135:620–626

Flores RM. Semin Thorac Cardiovasc Surg 2009;2:149–153

Maasilta P et al. Int J Radiat Oncol Biol Phys 1991;20:433–438

Rice D. Ann Diagn Pathol 2009;13:65–72

Vogelzang NJ et al. J Clin Oncol 2003;21:2636–2644

Yanagawa J, Rusch V. Thorac Surg Clin 2013;23:73–78

REGIMEN: PEMETREXED + CISPLATIN

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Regimen: Pemetrexed + Cisplatin

Vogelzang NJ et al. J Clin Oncol 2003;21:2636–2644

Folic acid 350–1000 mcg daily; administer orally, beginning 1–3 weeks before chemotherapy and continuing throughout treatment with pemetrexed + cisplatin, and

Cyanocobalamin (vitamin B₁₂) 1000 mcg; administer intramuscularly every 9 weeks, beginning 1–3 weeks before chemotherapy and continuing throughout treatment with pemetrexed + cisplatin

Dexamethasone 4 mg; administer intravenously or orally twice daily for 3 consecutive days, starting the day before pemetrexed administration to decrease the risk of severe skin rash associated with pemetrexed (total dose/cycle = 24 mg)

Hydration: 0.9% Sodium chloride injection (0.9% NS), ≥1000 mL before and after cisplatin; administer intravenously over a minimum of 2–4 hours. Encourage patients to increase oral nonalcoholic fluid intake. Monitor and replace magnesium/electrolytes as needed

Pemetrexed 500 mg/m²; administer intravenously in 100 mL 0.9% NS over 10 minutes, given before cisplatin on day 1, every 21 days (total dosage/cycle = 500 mg/m²)

Cisplatin 75 mg/m²; administer intravenously in 1000 mL 0.9% NS over 2 hours on day 1, beginning 30 minutes after pemetrexed has been administered, every 21 days (total dosage/cycle = 75 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Additional supportive care

Add a proton pump inhibitor during dexamethasone use to prevent gastritis and duodenitis

Patient Population Studied

A study of 456 patients with advanced measurable pleural mesothelioma

Efficacy

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Efficacy

Response rate

40–45%

Median time to progression

5–6 months

1-Year survival

50%

Median survival

12–13 months

Therapy Monitoring

Before initial and repeated treatments: H&P, CBC with differential, calculated creatinine clearance, serum electrolytes glucose, calcium, LFTs, and vitamin metabolites
Treatment evaluation: Every 2 cycles

Toxicity (N = 168 Fully Supplemented with Vitamins)

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Toxicity (N = 168 Fully Supplemented with Vitamins)

% CTC G3/4

Hematologic

Hemoglobin

4.2

Leukocytes

14.9

Neutrophils

23.2

Platelets

5.4

Febrile neutropenia

0.6

Nonhematologic

Nausea

11.9

Fatigue

10.1

Vomiting

10.7

Diarrhea

3.6

Dehydration

4.2

Stomatitis

Anorexia

1.2

Rash

0.6

Three deaths thought possibly related to pemetrexed + cisplatin occurred before folic acid and vitamin B₁₂ supplementation was added; none occurred thereafter

Treatment Modifications

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Treatment Modifications

Delay cycle until ANC is >1500/mm³ and platelet >100,000/mm³

Adverse Event

Dose Modification

G3 hematologic toxicities

Hold therapy until returns to baseline. Then decrease both drug dosages by 25%

G4 hematologic toxicities (thrombocytopenia)

Hold therapy until returns to baseline. Then decrease both drug dosages by 50%

Serum creatinine 1.6–2 mg/dL (141–177 μmol/L)

Decrease cisplatin dosage by 25%

Serum creatinine ≥2 mg/dL (≥177 μmol/L)

Hold therapy until serum creatinine <2 mg/dL (<177 μmol/L), then decrease cisplatin dosage by 25%

G ≥2 diarrhea

Hold chemotherapy until toxicity resolves to grade <2, then decrease both drug dosages by 25%

G3/4 mucositis

Decrease pemetrexed dosage 50%

Increased liver transaminases

Hold therapy until toxicity resolves, then decrease pemetrexed dosage by 25%

Other G ≥3 nonhematologic toxicities (except N/V, elevated transaminases and alopecia)

Delay treatment until toxicity resolves to baseline, then, decrease both drug dosages by 25% from previous dose levels

Delays of ≤42 days are permitted for recovery from pemetrexed- and cisplatin-related toxicities

Patients requiring 3 dose reductions: discontinue therapy

Notes

G2 neutropenia and anemia secondary to pemetrexed are brief and not cumulative
Anemia is cumulative with cisplatin. Consider using erythropoietin therapy if anemia G <1 occurs
Folate deficiency is best measured with homocysteine levels
Vitamin B₁₂ deficiency can be tested most readily with methylmalonic acid (MMA) levels

REGIMEN: PEMETREXED + CARBOPLATIN

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Regimen: Pemetrexed + Carboplatin

Ceresoli GL et al. J Clin Oncol 2006;24:1443–1448

Folic acid 350–1000 mcg/day orally beginning at least 1 week before the first dose of pemetrexed and continued throughout the duration of treatment

Cyanocobalamin (vitamin B₁₂) 1000 mcg intramuscularly at least 1 week before the first dose of pemetrexed and repeated every 9 weeks (every 3 cycles) throughout treatment

Dexamethasone 4 mg/dose orally twice daily for 3 consecutive days (6 doses), starting the day before pemetrexed administration to decrease the risk of severe skin rash associated with pemetrexed (total dose/cycle = 24 mg)

Pemetrexed 500 mg/m²; administer intravenously in 100 mL 0.9% sodium chloride injection over 10 minutes on day 1, every 21 days (total dosage/cycle = 500 mg/m²), followed 30 minutes later by:

Carboplatin AUC 5 mg/mL per min; administer intravenously in 50–250 mL D5W over 30 minutes on day 1, every 21 days (total dosage/cycle calculated to produce an AUC = 5 mg/mL per min)

Notes:

Salicylates and nonsteroidal antiinflammatory agents (NSAIDs) were not allowed during the 2 days before (5 days for NSAIDs with a long half-life), the day of, and for 2 days after chemotherapy

Carboplatin dose calculation is based on formulas developed to achieve consistent drug exposure within and among patients. In the method that follows, area under the plasma concentration versus time curve (AUC) is the targeted pharmacokinetic endpoint used to obtain consistent exposure

Current product labeling for carboplatin approved by the U.S. Food and Drug Administration describes dose calculation based on a formula described by Calvert et al^✫,†,‡:

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be measured from a 24-hour urine collection or estimated from 1 among several equations, such as the method of Cockcroft and Gault^§:

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. Since the end of 2010, all clinical laboratories in the United States use the standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm228974.htm [last accessed September 4, 2013]

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is at least MODERATE. Potential for delayed emetic symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

Encourage patients to maintain intake of nonalcoholic fluids
Evaluate patients for oral pain and provide analgesic medications
Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain
Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

Patients with intact oral mucosa:

Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultrasoft toothbrush with fluoride toothpaste
Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth
Patients may use saline or commercial brand, nonalcoholic rinses
- Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute
Rinse mouth several times a day to remove debris
- Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in 1 quart (~950 mL) of warm water. Follow with a plain water rinse
- Do not use mouthwashes that contain alcohols
Foam-tipped swabs (eg, Toothettes) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque
Advise patients who develop mucositis to:
- Choose foods that are easy to chew and swallow
- Take small bites of food, chew slowly, and sip liquids with meals
- Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs
- For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids
- Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

ANC <1500/mm³ or platelet count <100,000/mm³

Delay start of cycle up to 42 days until ANC ≥1500/mm³ and platelet count ≥100,000/mm³

ANC nadir <500/mm³ and platelets ≥50,000/mm³

Administer 75% of the previous pemetrexed dose, or carboplatin AUC = 4 mg/mL per min

Platelet nadir count <50,000/mm³ and any ANC

Administer 50% of the previous pemetrexed dose, or carboplatin AUC = 3 mg/mL per min

Recurrence of G3/4 thrombocytopenia or neutropenia after 2 dose reductions

Discontinue therapy

G3/4 nonhematologic toxicities

Delay treatment until there is resolution to G ≤1 then proceed with pemetrexed reduced to 75% of the previous dose and carboplatin at AUC = 4 mg/mL per min

Creatinine clearance^✫ <45 mL/min (<0.75 mL/s)

Delay the next cycle until creatinine clearance ≥45 mL/min (≥0.75 mL/s)

^✫Calculated by the Cockcroft and Gault formula before each dose

Efficacy (N = 102)

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Efficacy (N = 102)

Response Rate^✫,†

Objective response rate

18.6% (95% CI, 11.6–27.5%)

Complete response

1.96% (2 patients) (10+ and 11 months)

Partial response

16.66% (17 patients)

Stable disease

47% (95% CI, 37.1–57.2%) (48 patients)

Progressive disease

34.3% (35 patients)

Response According to Histology

Epithelial MPM

15/80 (18.8%)

Mixed histotype MPM

4/8 (50%)

Sarcomatoid MPM

0/7

Effect on ECOG Performance Status^‡

Patients with OR/baseline PS (N = 19)

0 (3)/1 (16)

Patients with OR/posttreatment PS

0 (10)/1 (9)

Patients with SD/baseline PS (N = 48)

0 (21)/1 (25)/2 (2)

Patients with SD/posttreatment PS

0 (23)/1 (22)/2 (3)

Median Follow-Up Time of 14.2 Months (95% CI, 12.2–15 Months) 26 without any Evidence of Disease Progression

Median TTP^§

6.5 months

Median OS

12.7 months

6-month survival estimates

70.0% (95% CI, 60.0–78.0%)

1-year survival estimates

51.6% (95% CI, 40.7–61.5%)

^✫Best tumor response was assessed according to an intent-to-treat analysis

^†Response to treatment showed a trend that correlated with OS in univariate analysis (P = 0.069) and reached statistical significance in the multivariate model (P = 0.024). When SD patients were grouped with responders, the correlation with OS was much more significant (P <0.001)

^‡Sixty-nine patients (68%) were symptomatic at the time of study enrollment. ECOG PS improved or was stable in the majority of patients who achieved response or SD

^§TTP was significantly related to good PS (P = 0.047) and epithelial histology (P = 0.02) in both univariate and multivariate analyses

Patients' PS was the only factor significantly related to OS in univariate and multivariate analyses (P = 0.04)

Patient Population Studied

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Patient Population Studied

Patients with histologically proven malignant pleural mesothelioma who were not candidates for curative surgery. Eligibility criteria included ages >18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, and an estimated life expectancy of ≥12 weeks. Creatinine clearance ≥45 mL/min. Patients were excluded if they were unable to discontinue administration of aspirin and/or other nonsteroidal antiinflammatory agents for 2 days before (5 days for long-acting agents), the day of, and 2 days after the dose of pemetrexed

Patient Characteristics

Characteristic

Number of Patients (N = 102)

Percent

Sex

Male

74.5

Female

25.5

Age, years

Median

Range

38–79

ECOG performance status

Histologic subtype

Mixed cell

Unspecified

Epithelial

Sarcomatoid

EORTC prognostic score

Good

24.5

Poor

75.5

IMIG stage

III

Relapse after EPP

Toxicity

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Toxicity

Hematologic Toxicity by Cycle (N = 482)

Toxicity

Toxicity Grade (Number of Patients)

% G3/4

Neutropenia

9.7

Thrombocytopenia

7^✫

3^✫

Anemia

166

16^†

1^†

3.5

Hematologic Toxicity by Patient (N = 102)

Neutropenia

11^‡

19.6

Thrombocytopenia

7.8

Anemia

11.7

Nonhematologic Toxicity by Patient (N = 102)^§

Nausea/vomiting

Fatigue

Stomatitis

Conjunctivitis

Diarrhea

Constipation

^✫G3/4 thrombocytopenia occurred after the second cycle in 7/10 (70%) patients

^†G3/4 anemia occurred after the second cycle in 15 (88%) of 17 patients

^‡Febrile neutropenia was reported in 2 patients

^§Other toxicities reported as rare events included G4 rhabdomyolysis (1 patient), G2 hepatotoxicity (1 patient), G2 arthralgia-myalgia (2 patients), G2 genitourinary mucositis (2 patients), and G1 skin rash (2 patients)

Therapy Monitoring

Before initial and repeated treatments: H&P, CBC with differential, calculated or measured creatinine clearance, serum electrolytes, glucose, calcium, LFTs, and vitamin metabolites
Treatment evaluation: Every 2 cycles

REGIMEN: GEMCITABINE + CISPLATIN

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Regimen: Gemcitabine + Cisplatin

Byrne MJ et al. J Clin Oncol 1999;17:25–30

van Haarst JW et al. Br J Cancer 2002;86(3):342–345

Hydration: 0.9% Sodium chloride injection (0.9% NS) ≥1000 mL before and after cisplatin; administer intravenously over a minimum of 2–4 hours. Monitor and replace magnesium/electrolytes as needed

Cisplatin 100 mg/m²; administer intravenously in 100–250 mL 0.9% NS over 60 minutes, given before gemcitabine on day 1, every 28 days for 6 cycles (total dosage/cycle = 100 mg/m²), plus

Gemcitabine 1000 mg/m² per dose; administer intravenously in 50–250 mL 0.9% NS over 30 minutes, given on days 1, 8, and 15, every 28 days for 6 cycles (total dosage/cycle = 3000 mg/m²)

Cisplatin 80 mg/m²; administer intravenously in 100–250 mL 0.9% NS over 60 minutes, on day 1, every 3 weeks for a maximum of 6 cycles (total dosage/cycle = 80 mg/m²), plus

Gemcitabine 1250 mg/m² per dose; administer intravenously in 50–250 mL 0.9% NS over 30 minutes, on days 1 and 8, every 3 weeks for a maximum of 6 cycles (total dosage/cycle = 2500 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is HIGH. Potential for delayed symptoms

Emetogenic potential with gemcitabine alone is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 21 patients with advanced measurable pleural mesothelioma (Byrne MJ et al.)

A study of 25 patients with advanced measurable pleural mesothelioma (van Haarst JW et al.)

Therapy Monitoring

Before chemotherapy on cycle days 1, 8, and 15: CBC with differential, serum electrolytes, creatinine, bilirubin, ALT, and alkaline phosphatase
Treatment evaluation: Every 2 cycles

Byrne MJ et al. J Clin Oncol 1999;17:25–30

Efficacy (N = 46)

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Efficacy (N = 46)

Response rate

18–47%

Duration of response

5–7 months

Estimated median survival

9.5–12 months

Estimated 1-year survival

41%

Nine of 10 responding patients achieved substantial or complete symptomatic improvement. Symptoms decreased significantly in 3 additional patients who achieved disease stabilization

From Byrne MJ et al. J Clin Oncol 1999;17:25–30 van Haarst JW et al. Br J Cancer 2002;86(3):342–345

Treatment Modifications

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Treatment Modifications

Serum creatinine >1.4 mg/dL (>124 μmol/L), but <1.7 mg/dL (<150 μmol/L)

Decrease cisplatin by 50% and gemcitabine by 25%

Serum creatinine >1.7 mg/dL (>150 μmol/L)

Withhold cisplatin and gemcitabine until serum creatinine <1.7 mg/dL (<150 μmol/L), then administer 50% of the previous cisplatin dosage and 75% of the previous gemcitabine dosage

WBC <3000/mm³ or platelet <100,000/mm³ on days 1 and 8 or days 1, 8, and 15 when gemcitabine treatment is planned

Decrease gemcitabine by 25%

WBC <2000/mm³ or platelet <75,000/mm³ when gemcitabine treatment is planned for day 8 or days 8 and 15

Omit gemcitabine

Byrne MJ et al. J Clin Oncol 1999;17:25–30

Toxicity (N = 21)

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Toxicity (N = 21)

Worst Toxicity Grade (%)

Hematologic

Leukopenia

Thrombocytopenia^✫

Anemia

Nonhematologic

Nausea/vomiting^†

Stomatitis

Alopecia

Hearing loss

Neurologic

^✫Thrombocytopenia on days 8 and 15 was the major cause of dose modification

^†One-third of patients had ≥1 episodes of severe nausea and vomiting, and symptoms were worse >24 hours after treatment

From Byrne MJ et al. J Clin Oncol 1999;17:25–30

PERITONEAL MESOTHELIOMA

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Epidemiology

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Epidemiology

Incidence:

10% of all mesothelioma (200–400 new cases per year)

Median age:

53 years

Male to female ratio:

1:1

Expert Opinion

No standard treatment
Resectable disease
1. In women: Treatment is the same as for ovarian cancer because these tumors behave and respond similarly to cytoreduction followed by cisplatin-based chemotherapy. Intraperitoneal (IP) chemotherapy has shown superiority over intravenous chemotherapy for advanced ovarian cancer
2. In men: Treatment is the same as for pleural mesothelioma, or if disease is not related to asbestos exposure, it can be treated with IP chemotherapy
Locally advanced or recurrent disease: Give systemic chemotherapy as for pleural mesothelioma

Alberts DS et al. [Editorial]. J Clin Oncol 2002;20:3944–3949

Eltabbakh GH et al. J Surg Oncol 1999;70:6–12

Markman M, Kelsen D. J Cancer Res Clin Oncol 1992;118:547–550

Markman M et al. J Clin Oncol 2001;19:1001–1007

Survival

Median survival: 1 year

REGIMEN: INTRAPERITONEAL (IP) CISPLATIN + PACLITAXEL

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Regimen: Intraperitoneal (IP) Cisplatin + Paclitaxel

Rothenberg ML et al. J Clin Oncol 2003;21:1313–1319

Dexamethasone 20 mg/dose; administer orally for 2 doses, 12 hours and 6 hours before paclitaxel on days 1 and 8, plus

Diphenhydramine 50 mg; administer by intravenous injection 30–60 minutes before paclitaxel on days 1 and 8, plus

Ranitidine 50 mg or cimetidine 300 mg; administer intravenously in 25–100 mL of a compatible solution; for example, 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 5–30 minutes beginning 30–60 minutes before paclitaxel on days 1 and 8

Paclitaxel 135 mg/m²; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a solution with concentration within the range 0.3–1.2 mg/mL over 24 hours on day 1, every 21 days for 6 cycles (total paclitaxel dosage/cycle given intravenously = 135 mg/m²)

Cisplatin 100 mg/m²; administer intraperitoneally in 2000 mL 0.9% NS warmed to body temperature on day 2, every 21 days for 6 cycles (total dosage/cycle = 100 mg/m²)

Paclitaxel 60 mg/m²; administer intraperitoneally in 2000 mL 0.9% NS, warmed to body temperature on day 8, every 21 days for 6 cycles (total paclitaxel dosage/cycle from IP route = 60 mg/m²)

Additional information: Drug distribution is facilitated by sequentially placing patients R side down, L side down, in Trendelenburg and in reverse Trendelenburg position for 15 minutes each after drugs are instilled IP. Cisplatin- and paclitaxel-containing fluids are not drained after instillation

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1 and 8 is LOW

Emetogenic potential on day 2 is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Toxicity (N = 68)

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Toxicity (N = 68)

% G3

% G4

Hematologic

Neutropenia

Anemia

Thrombocytopenia

Infection with neutropenia

Nonhematologic

Nausea

Vomiting

Abdominal pain

Diarrhea

Fatigue/malaise/lethargy

Sensory neuropathy

Catheter-related infection

% G1

% G2

Alopecia

96% of patients experienced ≥1 G3/4 toxicity

Therapy Monitoring

Before each treatment cycle: PE, CBC with differential, serum creatinine, and serum bilirubin
Weekly: CBC, serum electrolytes, serum creatinine, calcium, magnesium, and LFTs

Patient Population Studied

A study of 68 patients with FIGO stage III epithelial ovarian cancer (tumor extending outside the pelvis and/or positive retroperitoneal or inguinal lymph nodes) with residual peritoneal disease ≤1 cm in largest dimension after surgical staging by GOG standards

Efficacy (N = 68)

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Efficacy (N = 68)

Median disease-free survival

33 months

Median survival

51 months

2-Year survival rate

91%

Treatment Modifications

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Treatment Modifications

ANC ≥3000/mm³ and platelet ≥100,000/mm³ required to start cycle. Delay therapy up to 2 weeks to allow hematologic recovery

Adverse Event

Dose Modification

Hematologic toxicity

No dose modifications. Day 8 paclitaxel given without regard for CBC

G >2 peripheral neuropathy

Delay therapy until toxicity grade ≤2, then decrease all drug dosages by 20%

G2 abdominal pain

Decrease IP drug dosages by 20%

G3/4 abdominal pain

Decrease IP drug dosages by 40%

CrCl <50 mL/min

Hold cisplatin until CrCl >50 mL/min (>0.83 mL/s), then decrease cisplatin dosage to 75 mg/m² during all subsequent cycles

Peritoneal catheter dysfunction or inability to administer therapy IP

Modify regimen schedule and route of administration for all remaining cycles: Paclitaxel 135 mg/m² intravenously over 24 hours on day 1, every 21 days; cisplatin 100 mg/m² intravenously over 60 minutes on day 2, every 21 days

MESOTHELIOMA REGIMEN: BEVACIZUMAB + GEMCITABINE + CISPLATIN

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Mesothelioma Regimen: Bevacizumab + Gemcitabine + Cisplatin

Kindler HL et al. J Clin Oncol 2012;30:2509–2515

Gemcitabine 1250 mg/m² per dose; administer intravenously in 50–250 mL 0.9% sodium chloride injection (0.9% NS) over 30 minutes, on days 1 and 8, every 3 weeks for up to 6 cycles (total dosage/3-week cycle = 2500 mg/m²), followed by:

Hydration before cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 1 hour before commencing cisplatin administration

Cisplatin 75 mg/m²; administer intravenously in 1000 mL 0.9% NS over 1 hour, following gemcitabine administration and prior to bevacizumab administration, on day 1 every 3 weeks for up to 6 cycles (total dosage/3-week cycle = 75 mg/m²), followed by:

Hydration after cisplatin: Administer by intravenous infusion ≥1000 mL 0.9% NS over a minimum of 2 hours. Encourage patients to increase oral intake of nonalcoholic fluids and provide electrolyte replacement as needed (potassium, magnesium, sodium)

Bevacizumab 15 mg/kg; administer intravenously in 100 mL 0.9% NS on day 1, following cisplatin administration, every 3 weeks for up to 6 cycles (total dosage/3-week cycle = 15 mg/kg)

Notes:

Duration of administration for the initial dose of bevacizumab is 90 minutes. If administration is well tolerated, the administration duration may be decreased stepwise during subsequent administrations to 60 minutes and, finally, to a minimum duration of 30 minutes
In the absence of disease progression following completion of 6 cycles of bevacizumab + gemcitabine + cisplatin, maintenance therapy with bevacizumab monotherapy is allowed, thus:
- Bevacizumab 15 mg/kg; administer intravenously in 100 mL 0.9% NS on day 1, every 3 weeks as maintenance therapy (total dosage/3-week cycle = 15 mg/kg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 (of cycles 1–6) is HIGH. Potential for delayed symptoms

Emetogenic potential on day 8 (of cycles 1–6) is LOW

Emetogenic potential on day 1 (during bevacizumab maintenance therapy) is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

This multicenter, double-blind, placebo-controlled, randomized, phase 2 trial included 108 patients with histologically or cytologically confirmed malignant mesothelioma not amenable to curative surgery. Eligible patients were aged >18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤1, and life expectancy >3 months. Patients who had previous systemic cytotoxic chemotherapy, and patients on anticoagulation, were not eligible. On day 1 of a 21-day cycle, all patients received intravenous gemcitabine (1250 mg/m²) and then cisplatin (75 mg/m²), and then either bevacizumab (15 mg/kg) or placebo. All patients also received intravenous gemcitabine (1250 mg/m²) on day 8. Combination therapy was administered for 6 cycles. Bevacizumab or placebo was continued every 21 days after the 6 cycles until disease progression, unacceptable adverse effects, or withdrawal of consent.

Efficacy (N = 108)

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Efficacy (N = 108)

Bevacizumab + Gemcitabine + Cisplatin (N = 53)

Placebo + Gemcitabine + Cisplatin (N = 55)

Estimated median progression-free survival

6.9 months

6.0 months

HR 0.90, 95% CI 0.61–1.34; P = 0.62

Estimated median survival

15.6 months

14.7 months

HR 1.04, 95% CI 0.68–1.59; P = 0.87

Objective response rate^✫

24.5%

21.8%

P = 0.74

^✫Objective response rate is the percentage of patients who experienced a confirmed partial or complete response to the study drug. In this study, no patients experienced a complete response

Therapy Monitoring

Before therapy: History and physical examination. CBC with differential, renal and liver function tests, serum electrolytes
Assess proteinuria by urine dipstick and/or urinary protein-to-creatinine ratio. Patients with a urine dipstick reading ≥2+ should undergo further assessment with 24-hour urine collection
Blood pressure every 2 weeks or more frequently as indicated during treatment
Monitor hepatic function prior to initiation and during therapy with gemcitabine
Pulmonary toxicity and respiratory failure: Discontinue gemcitabine immediately for unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity
Monitor renal function and electrolytes prior to initiation and during therapy with cisplatin and gemcitabine, including hemolytic uremic syndrome (HUS) secondary to gemcitabine
Increased toxicity with infusion time >30 minutes or dosing more frequently than once weekly may occur with gemcitabine; monitor carefully
Response evaluation: CT scan every 8 weeks for 6 months (modified RECIST 1.1 for mesothelioma), then every 12 weeks

Treatment Modifications

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Treatment Modifications

BEVACIZUMAB DOSAGE MODIFICATIONS

Adverse Event

Treatment Modification

Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ

Discontinue bevacizumab permanently

Serious bleeding

Wound dehiscence requiring medical intervention

Nephrotic syndrome

Hypertensive crisis or hypertensive encephalopathy or reversible posterior leukoencephalopathy syndrome (RPLS)

Congestive heart failure

Necrotizing fasciitis

Severe arterial or venous thromboembolic events

Discontinue bevacizumab permanently; the safety of reinitiating bevacizumab after a thromboembolic event is resolved is not known

Moderate to severe proteinuria

Patients with a urine dipstick reading ≥2+ should undergo further assessment, eg, 24-hour urine collection. Suspend bevacizumab administration for ≥2 g of proteinuria/24 h and resume when proteinuria is <2 g/24 h

Severe hypertension not controlled with medical management

Hold bevacizumab pending further evaluation and treatment of hypertension

Mild, clinically insignificant infusion reaction

Decrease the rate of infusion

Clinically significant but not severe infusion reaction

Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution. If decision is made to restart, the infusion may be continued at ≤50% of the rate prior to the reaction and increased in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle

Severe infusion reaction—hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, G3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis)

Stop infusion and administer appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and/or oxygen). Discontinue bevacizumab

Planned elective surgery

Suspend bevacizumab at least 28 days before elective surgery and do not resume for at least 28 days after surgery or until surgical incision is fully healed

Recent hemoptysis

Do not administer bevacizumab

Evidence of rectosigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

CISPLATIN + GEMCITABINE

Dose Levels

Gemcitabine

Cisplatin

Starting dose

1250 mg/m² per dose on days 1 and 8

75 mg/m² on day 1

Dose level −1

1000 mg/m² per dose on days 1 and 8

60 mg/m² on day 1

Dose level −2

800 mg/m² per dose on days 1 and 8

50 mg/m² on day 1

Dose level −3

600 mg/m² per dose on days 1 and 8

40 mg/m² on day 1

Delay cycle until ANC is >1500/mm³ and platelet count is >100,000/mm³

Adverse Event

Treatment Modification

G3 hematologic toxicities (ANC <1000/mm³; platelet count <50,000/mm³)

Hold therapy until ANC and platelets return to baseline. Then decrease both drug dosages by 1 dose level

G4 hematologic toxicities (ANC <500/mm³; platelet count <25,000/mm³)

Hold therapy until ANC and platelets return to baseline. Then decrease both drug dosages by 2 dose levels. Consider use of hematopoietic growth factor (CSF) prophylaxis in subsequent cycles for dose-limiting neutropenia.

Day 8 ANC ≥1500/mm³ and/or platelet count >100,000/mm³

Administer full dose of gemcitabine

Day 8 ANC 1000–1499/mm³ and/or platelet count 75,000–99,999/mm³

Administer 50% of day 1 gemcitabine dose

Day 8 ANC <1000/mm³ and or platelet count <100,000/mm³

Withhold day 8 gemcitabine dose. Consider use of hematopoietic growth factor (CSF) prophylaxis in subsequent cycles for dose-limiting neutropenia

Serum creatinine ≥1.5 mg/dL (≥130 µmol/L) and/or BUN ≥25 mg/dL (≥8.92 mmol/L).

Withhold cisplatin until serum creatinine <1.5 mg/dL (<130 µmol/L) and BUN <25 mg/dL (<8.92 mmol/L). Then decrease cisplatin dosage by 1 dose level; if already reduced then reduce again

≥G2 diarrhea

Hold chemotherapy until toxicity resolves to grade <2, then decrease gemcitabine 1 dose level

G3/4 mucositis

Decrease gemcitabine dosage by 2 dose levels

ALT and AST >1.5× ULN in a patient without liver metastasis

Withhold gemcitabine until ALT and AST ≤1.5× ULN

ALT and AST >2.5× ULN in a patient with liver metastasis with alkaline phosphatase >2.5× ULN

Withhold gemcitabine until ALT and AST ≤2.5× ULN and alkaline phosphatase ≤2.5× ULN

Peripheral neuropathy ≥G3

G4 discontinue cisplatin permanently; G3 may reinstitute if toxicity resolves within 2–3 weeks to ≤G1

Cisplatin induced hearing loss ≥G3

Severe hypersensitivity reaction to gemcitabine or cisplatin is noted

Permanently discontinue gemcitabine or cisplatin

Other ≥G3 nonhematologic toxicities (except nausea, vomiting, elevated transaminases, and alopecia)

Delay treatment until toxicity resolves to baseline, then decrease both drug dosages by 1 dose level from previous levels

Unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity

Discontinue gemcitabine immediately and assess for gemcitabine pulmonary toxicity

HUS

Discontinue gemcitabine for HUS or severe renal impairment

Capillary leak syndrome

Discontinue gemcitabine

PRES

Discontinue gemcitabine

Notes:

Patients who are pregnant or become pregnant should be apprised of the potential hazard to the fetus; women of childbearing potential should be advised to avoid becoming pregnant during therapy
Gemcitabine may cause severe and life-threatening toxicity when administered during or within 7 days of radiation therapy

Adverse Events (N = 108)

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Adverse Events (N = 108)

Bevacizumab + Gemcitabine + Cisplatin (N = 53)

Placebo + Gemcitabine + Cisplatin (N = 55)

Neutropenia

Thrombocytopenia

Hypertension

Venous thrombosis

Epistaxis

Infection without neutropenia

Proteinuria

Anemia

Febrile neutropenia

Cerebrovascular accident

^✫According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Note: G3/4 toxicities are included in the table. No significant differences in G≥3 events were observed

MESOTHELIOMA REGIMEN: BEVACIZUMAB + PEMETREXED + CISPLATIN

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Mesothelioma Regimen: Bevacizumab + Pemetrexed + Cisplatin

Zalcman G et al. Lancet 2016;387:1405–1414

Premedications for Pemetrexed

Folic acid 350–1000 mcg daily; administer orally, beginning 1–3 weeks before chemotherapy and continuing throughout treatment with pemetrexed and for 21 days after the last pemetrexed dose, and

Cyanocobalamin (vitamin B₁₂) 1000 mcg; administer intramuscularly every 9 weeks, beginning 1–3 weeks before chemotherapy and continuing throughout treatment with pemetrexed, and

Bevacizumab 15 mg/kg; administer intravenously in 100 mL 0.9% sodium chloride injection (0.9% NS) on day 1, every 3 weeks for up to 6 cycles (total dosage/3-week cycle = 15 mg/kg)

Notes:

Duration of administration for the initial dose of bevacizumab is 90 minutes. If administration is well tolerated, the administration duration may be decreased stepwise during subsequent administrations to 60 minutes and, finally, to a minimum duration of 30 minutes
In the absence of disease progression following completion of 6 cycles of bevacizumab + pemetrexed + cisplatin, maintenance therapy with bevacizumab monotherapy is allowed, thus:
- Bevacizumab 15 mg/kg; administer intravenously in 100 mL 0.9% NS on day 1, every 3 weeks as maintenance therapy (total dosage/3-week cycle = 15 mg/kg)

Pemetrexed 500 mg/m²; administer intravenously in 100 mL 0.9% NS over 10 minutes, given before cisplatin, on day 1, every 21 days for up to 6 cycles (total dosage/3-week cycle = 500 mg/m²)

Hydration before cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 1 hour before commencing cisplatin administration

Cisplatin 75 mg/m²; administer intravenously in 1000 mL 0.9% NS over 2 hours, beginning 30 minutes after pemetrexed has been administered, on day 1 every 21 days for up to 6 cycles (total dosage/3-week cycle = 75 mg/m²)

Note:

In case of ≥ grade 2 renal toxicity with cisplatin, substitution with carboplatin (AUC = 5) was allowed (Zalcman et al)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 (of cycles 1–6) is HIGH. Potential for delayed symptoms

Emetogenic potential on day 1 (during bevacizumab maintenance therapy) is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Additional supportive care

Add a proton pump inhibitor during dexamethasone use to prevent gastritis and duodenitis

Patient Population Studied

This multicenter, randomized, open-label, phase 3 trial (MAPS) included 448 patients with histologically confirmed malignant pleural mesothelioma who had not previously received chemotherapy. Eligible patients were aged 18–75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤2 and life expectancy >12 weeks. Patients who had central nervous system metastases were not eligible. On day 1 of a 21-day cycle, all patients received intravenous pemetrexed (500 mg/m²) and cisplatin (75 mg/m²), and those randomly assigned to receive triple therapy also received bevacizumab (15 mg/kg). Combination therapy was administered for a maximum of 6 cycles. Patients in the triple-therapy group were allowed to receive maintenance bevacizumab after the 6 cycles until disease progression or toxic effects.

Efficacy (N = 448)

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Efficacy (N = 448)

Bevacizumab + Pemetrexed + Cisplatin (N = 223)

Pemetrexed + Cisplatin (N = 225)

Median survival

18.8 months

16.1 months

HR 0.77, 95% CI 0.62–0.95; P = 0.0167

Median progression-free survival

9.2 months

7.3 months

HR 0.61, 95% CI 0.50–0.75; P < 0.0001

Note: The median duration of follow-up was 39.4 months

Therapy Monitoring

Once per week: CBC with differential and platelet count
Before the start of a cycle: CBC with differential, serum electrolytes, serum bilirubin, AST or ALT, and alkaline phosphatase, BUN, and creatinine
Observe closely for hypersensitivity reactions, especially during the first and second bevacizumab infusions
Blood pressure every 2 weeks or more frequently as indicated during treatment
Assess proteinuria by urine dipstick and/or urinary protein-to-creatinine ratio. Patients with a urine dipstick reading ≥2+ should undergo further assessment with 24-hour urine collection
Response evaluation: CT scan every 8 weeks for 6 months (modified RECIST 1.1 for mesothelioma), then every 12 weeks

Treatment Modifications

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Treatment Modifications

BEVACIZUMAB + PEMETREXED + CISPLATIN

BEVACIZUMAB DOSAGE MODIFICATIONS

Adverse Event

Treatment Modification

Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ

Discontinue bevacizumab permanently

Serious bleeding

Wound dehiscence requiring medical intervention

Nephrotic syndrome

Hypertensive crisis or hypertensive encephalopathy or reversible posterior leukoencephalopathy syndrome (RPLS)

Congestive heart failure

Necrotizing fasciitis

Severe arterial or venous thromboembolic events

Discontinue bevacizumab permanently; the safety of reinitiating bevacizumab after a thromboembolic event is resolved is not known

Moderate to severe proteinuria

Severe hypertension not controlled with medical management

Hold bevacizumab pending further evaluation and treatment of hypertension

Mild, clinically insignificant infusion reaction

Decrease the rate of infusion

Clinically significant but not severe infusion reaction

Stop infusion and administer appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and/or oxygen). Discontinue bevacizumab

Planned elective surgery

Suspend bevacizumab at least 28 days before elective surgery and do not resume for at least 28 days after surgery or until surgical incision is fully healed

Recent hemoptysis

Do not administer bevacizumab

Evidence of rectosigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

CISPLATIN + PEMETREXED

Delay cycle until ANC is >1500/mm³ and platelet count is >100,000/mm³

G3 hematologic toxicities

Hold therapy until values return to baseline. Then decrease both drug dosages by 25%

G4 hematologic toxicities

Hold therapy until values return to baseline. Then decrease both drug dosages by 50%

Serum creatinine ≥1.5 mg/dL (≥130 µmol/L) and/or BUN ≥25 mg/dL (≥8.92 mmol/L)

Withhold cisplatin until serum creatinine <1.5 mg/dL (<130 µmol/L) and BUN <25 mg/dL (<8.92 mmol/L). Then consider a decrease in cisplatin dosage by 25%

≥G2 renal toxicity due to cisplatin

Consider substituting carboplatin (AUC = 5) for cisplatin in subsequent cycles

≥G2 diarrhea

Hold chemotherapy until toxicity resolves to <G2, then decrease both drug dosages by 25%

G3/4 mucositis

Decrease pemetrexed dosage by 50%

ALT and AST >1.5× ULN in a patient without liver metastasis

Withhold cisplatin and pemetrexed until ALT and AST ≤1.5× ULN

ALT and AST >2.5× ULN in a patient with liver metastasis with alkaline phosphatase >2.5× ULN

Withhold cisplatin and pemetrexed until ALT and AST ≤2.5× ULN and alkaline phosphatase ≤2.5× ULN

Peripheral neuropathy of ≥G3

Permanently discontinue cisplatin + pemetrexed

Cisplatin-induced hearing loss ≥G3

Severe hypersensitivity reaction to pemetrexed or cisplatin is noted

Occurrence of an adverse event requiring a third dose reduction

Other ≥G3 nonhematologic toxicities (except nausea, vomiting, and alopecia)

Delay treatment until toxicity resolves to baseline, then decrease both drug dosages by 25% from previous levels

Delays of ≤42 days are permitted for recovery from pemetrexed- and cisplatin-related toxicities

Patients requiring 3 dose reductions: Discontinue therapy

Adverse Events (N = 446)

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Adverse Events (N = 446)

Bevacizumab + Pemetrexed + Cisplatin (N = 222)

Pemetrexed + Cisplatin (N = 224)

Grade (%)^✫

Grade 1/2

Grade 3–5

Grade 1/2

Grade 3–5

Nausea or vomiting

Neutropenia

Anemia

Asthenia or fatigue

Cardiovascular adverse events

Thrombocytopenia

Hypertension

Hemorrhage

Elevated creatinine level

Anorexia

Constipation

Oral mucositis

Diarrhea

Weight loss

Arterial and venous thromboembolic events

Hepatic enzymes

Febrile neutropenia

Sepsis

^✫According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

MESOTHELIOMA REGIMEN: PEMBROLIZUMAB

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Mesothelioma Regimen: Pembrolizumab

Alley EW et al. Lancet Oncol 2017;18:623–630

Kindler H et al. Thorac Oncol 2017;12:S293

ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29. Identifier NCT02628067, Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158); 2015 Dec 11 [cited 2018 May 30]; [about 4 screens]. Available from: https://clinicaltrials.gov/ct2/show/record/NCT02628067

Pembrolizumab 10 mg/kg; administer intravenously over 30 minutes in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W), USP, sufficient to produce a pembrolizumab concentration within the range of 1–10 mg/mL every 2 weeks for up to 24 months (total dosage/2-week cycle = 10 mg/kg)

Administer pembrolizumab with an administration set that contains a sterile, nonpyrogenic, low protein-binding in-line or add-on filter with pore size within the range of 0.2–5 μm

Notes:

Eligibility required PD-L1 expression in ≥1% of tumor cells (Alley et al)
A 200-mg fixed-dose regimen of pembrolizumab is currently under study for malignant mesothelioma (eg, Kindler et al, NCT02628067), thus:
- Pembrolizumab 200 mg; administer intravenously over 30 minutes in a volume of 0.9% NS or D5W sufficient to produce a pembrolizumab concentration within the range of 1–10 mg/mL every 3 weeks for up to 24 months (total dosage/3-week cycle = 200 mg)
  - Administer pembrolizumab with an administration set that contains a sterile, nonpyrogenic, low protein-binding in-line or add-on filter with pore size within the range of 0.2–5 μm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

This ongoing, multicenter, nonrandomized, open-label, multicohort, phase 1b trial (KEYNOTE-028) included 25 patients with incurable, histologically confirmed, locally advanced, or metastatic malignant pleural mesothelioma that was PD-L1-positive. Eligible patients were aged ≥18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤1, and had failed or were unable to receive standard therapy. Patients who had previously received treatment with PD-1 and PD-L1 checkpoint inhibitors were not eligible. All patients received intravenous pembrolizumab (10 mg/kg) every 2 weeks.

Efficacy (N = 25)

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Efficacy (N = 25)

Objective response rate^✫

20%

Median progression-free survival

5.4 months (95% CI 3.4–7.5)

Median survival

18 months (95% CI 9.4–not reached)

Median duration of response

12 months (95% CI 3.7–not reached)

^✫Objective response rate is the percentage of patients who experienced a confirmed partial or complete response to the study drug

Note: The median duration of follow-up was 18.7 months, and the median duration of therapy was 5.1 months

Therapy Monitoring

Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria
Initially at the time of each dose, and eventually every 6–12 weeks, perform a total body skin examination with attention to all mucous membranes as well as a complete review of systems
Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with chest x-ray, CT scan, and pulse oximetry. For toxicity ≥2, may include nasal swab, sputum culture and sensitivity, blood culture and sensitivity, and urine culture and sensitivity
Monitor patients for signs and symptoms of colitis. Encourage patients to report diarrhea immediately to any member of the healthcare team
Draw AST, ALT, and bilirubin prior to each infusion and/or weekly if there are G1 LFT elevations. Note, no treatment is recommended for G1 LFT abnormalities. For toxicity ≥2, work up for other causes of elevated LFTs, including viral hepatitis
Use basic metabolic panel (Na, K, CO₂, glucose) and patient history as screening tools for hypophysitis, including hypopituitarism and adrenal insufficiency. If in doubt, evaluate morning adrenocorticotropic hormone (ACTH) and cortisol levels. Consider ACTH stimulation test for indeterminate results
Assess thyroid function at the start of treatment, periodically during treatment, and, as indicated, based on clinical evaluation and for clinical signs and symptoms of thyroid disorders. Test for TSH and free thyroxine (FT4) every 4–6 weeks as part of routine clinical monitoring on therapy or for case detection in symptomatic patients
Measure glucose at baseline and with each treatment during the first 12 weeks and every 6 weeks thereafter
Obtain a serum creatinine level prior to every dose. If creatinine is found to be newly elevated, consider holding therapy while other potential causes are evaluated. Note: Routine urinalysis is not necessary other than to rule out urinary tract infections, etc
Obtain a complete rheumatologic history and perform an examination of all peripheral joints for tenderness, swelling, and range of motion. Examine the spine. Consider plain x-ray/imaging to exclude metastases and evaluate joint damage (erosions), if appropriate
In patients at high risk for infections and in appropriately selected patients based on an infectious disease evaluation, draw screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients to start infliximab
Response evaluation: CT scan every 8 weeks for 6 months (modified RECIST 1.1 for mesothelioma), then every 12 weeks

Treatment Modifications

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Treatment Modifications

RECOMMENDED DOSAGE MODIFICATIONS FOR PEMBROLIZUMAB

Adverse Event

Grade / Severity

Treatment Modification

Infusion reaction

Clinically significant but not severe infusion reaction

Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution. If decision is made to restart, begin at ≤50% of the rate prior to the reaction and increase in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle

G3/4 (severe infusion reaction—pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria). Not rapidly responsive to brief interruption of infusion

Stop infusion and administer appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and/or oxygen). Discontinue pembrolizumab

Colitis

Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. If G1 diarrhea or colitis persists >14 days, add prednisolone 0.5–1 mg/kg (non–enteric coated) or consider oral budesonide 9 mg daily if no bloody diarrhea

G2/3 diarrhea or colitis

Withhold pembrolizumab. Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G4 diarrhea or colitis

Permanently discontinue pembrolizumab. Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve. If symptoms do not improve over 72 hours or worsen, perform flexible sigmoidoscopy/colonoscopy to document colitis, then begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider addition of tacrolimus or ATG

Pneumonitis

Withhold pembrolizumab. Consider pneumocystis prophylaxis depending on the clinical context and coverage with empiric antibiotics. Administer oral prednisone/prednisolone at a dosage of 1–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate after 48 hours, administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 6 weeks when symptoms improve to G1, titrating to symptoms. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G3/4

Permanently discontinue pembrolizumab. Consider pneumocystis prophylaxis depending on the clinical context; cover with empiric antibiotics. Administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 1–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 8 weeks when symptoms improve to G1, titrating to symptoms. If, when initially treated, improvement does not occur within 48–72 hours, begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response to infliximab, add MMF 500–1000 mg twice daily. Consider MMF especially if concurrent hepatic toxicity

Hepatitis

G2 (AST or ALT >3–5× ULN or total bilirubin >1.5–3× ULN)

Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 1–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G3/4 (AST or ALT >5× ULN or total bilirubin >3× ULN)

Permanently discontinue pembrolizumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 6 weeks when symptoms improve. If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus or ATG

Hypophysitis

G2/3 (moderate symptoms, ie, headache but no visual disturbance or fatigue/mood alteration but hemodynamically stable, no electrolyte disturbance)

Administer analgesia as needed for headache. Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When improves to G1, begin a slow corticosteroid taper over at least 4 weeks. If no improvement in 48 hours, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone/prednisolone or equivalent; do not stop steroids. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G4 (severe mass effect symptoms, ie, severe headache, any visual disturbance or severe hypoadrenalism, ie, hypotension, severe electrolyte disturbance)

Permanently discontinue pembrolizumab. Administer analgesia as needed for headache. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone prednisolone or equivalent; do not stop steroids

Adrenal insufficiency

Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 pm) until recovery of adrenal function is documented. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G3/4

Permanently discontinue pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 pm) until recovery of adrenal function is documented

Type 1 diabetes mellitus

G3 hyperglycemia

Withhold pembrolizumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown, and use is not recommended. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G4 hyperglycemia

Permanently discontinue pembrolizumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown, and use is not recommended.

Nephritis and renal dysfunction

G2/3 (serum creatinine 1.5–6× ULN)

Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G4 (serum creatinine >6× ULN)

Permanently discontinue pembrolizumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1.

Skin

G1/2

Continue pembrolizumab. Avoid skin irritants, avoid sun exposure; topical emollients recommended. Topical steroid (mild strength for G1, moderate/potent strength for G2) cream once or twice daily ± oral or topical antihistamines for itching

G3 rash or suspected SJS or TEN

Withhold pembrolizumab. Avoid skin irritants, avoid sun exposure; topical emollients recommended. Administer oral or topical antihistamines for itching. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg or its equivalent daily for 3 days followed by a slow corticosteroid taper over at least 4 weeks when the rash improves to G1. If rash does not respond adequately, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when the rash improves to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G4 rash or confirmed SJS or TEN

Avoid skin irritants, avoid sun exposure; topical emollients recommended. Administer oral or topical antihistamines for itching. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to oral steroids 0.5–2 mg/kg prednisone/prednisolone each day or its equivalent only after a response. Taper over at least 4 weeks when the rash improves to G1. Permanently discontinue pembrolizumab

Encephalitis

Confusion or altered behavior, headaches, alteration in Glasgow coma scale, motor or sensory deficits, speech abnormality; may or may not be febrile

Initially withhold pembrolizumab, but permanently discontinue pembrolizumab if there is no doubt as to diagnosis. Exclude bacterial and ideally viral infections prior to high-dose steroids. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If symptoms are severe, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Consider concurrent empiric antiviral (intravenous acyclovir) and antibacterial therapy

Aseptic meningitis

Headache, photophobia, neck stiffness with fever, or may be afebrile, vomiting; normal cognition/cerebral function (distinguishes from encephalitis)

Other syndromes include neurosarcoidosis, posterior reversible leukoencephalopathy syndrome (PRES), Vogt-Harada-Koyanagi syndrome, demyelination, vasculitic encephalopathy, and generalized seizures

Transverse myelitis

Acute or subacute neurologic signs/symptoms of motor, sensory, autonomic origin; most have sensory level; often bilateral symptoms

Initially withhold pembrolizumab, but permanently discontinue pembrolizumab if there is no doubt as to diagnosis. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. Plasmapheresis may be required if steroids do not bring about improvement

Myocarditis

Permanently discontinue pembrolizumab. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus

Peripheral neurologic toxicity

Moderate: some interference with ADL, symptoms concerning to patient

Withhold pembrolizumab. Initial observation reasonable or initiate prednisone/prednisolone 0.5–1 mg/kg (if progressing, eg, from mild) and/or pregabalin or duloxetine for pain. When symptoms improve, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

Severe: limits self-care and aids warranted, life-threatening, eg, respiratory problems

Guillain-Barré syndrome

Progressive symmetrical muscle weakness with absent or reduced tendon reflexes—involves extremities; facial, respiratory, and bulbar and oculomotor muscles; dysregulation of autonomic nerves

Permanently discontinue pembrolizumab. Use of steroids not recommended in idiopathic Guillain-Barré syndrome; however, a trial of (methyl)prednisolone 1–2 mg/kg is reasonable, converting to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG is indicated

Myasthenia gravis

Fluctuating muscle weakness (proximal limb, trunk, ocular, eg, ptosis/diplopia or bulbar) with fatigability; respiratory muscles may also be involved

Permanently discontinue pembrolizumab. Administer pyridostigmine at an initial dosage of 30 mg 3 times daily. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone, depending on the severity of symptoms. If treatment begins with intravenous drug, convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG may be considered. Additional immunosuppressants used in myasthenia gravis include azathioprine, cyclosporine, and mycophenolate. Avoid certain medications, eg, ciprofloxacin and beta-blockers, that may precipitate cholinergic crisis

Other syndromes, including motor and sensory peripheral neuropathy, multifocal radicular neuropathy/plexopathy, autonomic neuropathy, phrenic nerve palsy, cranial nerve palsies (eg, facial nerve, optic nerve, hypoglossal nerve)

Permanently discontinue pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone, depending on the severity of symptoms. If treatment begins with intravenous drug, convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response

Arthralgia

G1 (mild pain with inflammation, erythema, or joint swelling)

Continue pembrolizumab. Administer acetaminophen (paracetamol) and ibuprofen

G2 (moderate pain with inflammation, erythema, or joint swelling that limits ADLs)

Withhold pembrolizumab. Administer higher doses of acetaminophen (paracetamol) and ibuprofen and use diclofenac or naproxen or etoricoxib. If inadequately controlled, consider intra-articular steroid injections for large joints or administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

G3 (severe pain; irreversible joint damage; disabling; limits self-care ADLs)

Withhold pembrolizumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. In severe cases, infliximab or another anti-TNF-alpha drug may be required for improvement of arthritis. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg

Other

First occurrence of other G3

Recurrence of same G3

Life-threatening or G4

Requirement for ³10 mg/day prednisone or equivalent for >12 weeks

Permanently discontinue pembrolizumab

Persistent G2/3 adverse reactions lasting ³12 weeks

ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATG, anti-thymocyte globulin; CHF, congestive heart failure; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; NYHA, New York Heart Association; PRES, posterior reversible leukoencephalopathy syndrome; SJS, Stevens-Johnson syndrome; TB, tuberculosis; TEN, toxic epidermal necrolysis; TNF, tumor necrosis factor; ULN, upper limit of normal

Notes on general supportive care:

Steroid taper in most cases will proceed over a minimum of 1 month, but if symptoms improve rapidly, a 2-week taper can be considered. If steroids are administered for >4 weeks, consider PCP prophylaxis (cotrimoxazole 480 mg twice daily M/W/F or inhaled pentamidine if cotrimoxazole allergy), regular random blood glucose, vitamin D level, and starting calcium/vitamin D supplementation as per guidelines

Notes on pregnancy and breastfeeding:

Pembrolizumab can cause fetal harm. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Women of reproductive potential should use highly effective contraception during treatment and for 4 months after the last dose of pembrolizumab
It is not known whether pembrolizumab is excreted in human milk. Therefore, it is recommended that women discontinue nursing during treatment with and for 4 months after the final dose of pembrolizumab

Adverse Events (N = 25)

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Adverse Events (N = 25)

Grade (%)^✫

Grade 1

Grade 2

Grade 3

Nausea

Fatigue

Arthralgia

Pruritus

Decreased appetite

Dry mouth

Dyspnea

Pyrexia

Asthenia

Diarrhea

Headache

Constipation

Dry skin

Mucosal inflammation

Rash maculopapular

Decreased neutrophil count

Elevated ALT level

Iridocyclitis

Thrombocytopenia

Cancer pain

Decreased white blood cell count

Dysgeusia

Elevated AST level

Elevated γ-glutamyltransferase level

Infusion-related reaction

Pleuritic pain

Rash pruritic

Thrombosis

Balance disorder

Burning sensation

Chest pain

Cough

Decreased hemoglobin level

Decreased platelet count

Elevated blood alkaline phosphatase

Hypocalcemia

Irritability

Joint stiffness

Musculoskeletal stiffness

Myalgia

Paresthesia

Rash

Rash generalized

Vitreous floaters

^✫According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

Note: Toxicities are included in the table if the events were deemed to be related to the study treatment. No G4 or G5 treatment-related adverse events occurred. In total, 64% of patients reported treatment-related adverse events. No one discontinued treatment as a result of a treatment-related adverse event

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Chapter 26: Mesothelioma

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PLEURAL MESOTHELIOMA

Expert Opinion

REGIMEN: PEMETREXED + CISPLATIN

REGIMEN: PEMETREXED + CARBOPLATIN

REGIMEN: GEMCITABINE + CISPLATIN

PERITONEAL MESOTHELIOMA

Expert Opinion

REGIMEN: INTRAPERITONEAL (IP) CISPLATIN + PACLITAXEL

MESOTHELIOMA REGIMEN: BEVACIZUMAB + GEMCITABINE + CISPLATIN

MESOTHELIOMA REGIMEN: BEVACIZUMAB + PEMETREXED + CISPLATIN

MESOTHELIOMA REGIMEN: PEMBROLIZUMAB

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