Table 3.
Double and Triple combination outcomes.
| a. Double Combination Outcomes | |||||
| Study | Toxicity ≥ Grade 3 | Main ≥ Grade 3 Hematological Toxicities | Main ≥ Grade 3 Non-Hematological Toxicities | Clinical Outcome | |
| Mehta (2015) [14] | 29.6% (acute) | lymphopenia (5%), anemia (4%) | Fatigue (7%) hyponatremia (6%) dehydration (5%) hyperglycemia (4%) |
6-month OS: 54% | |
| Chabot (2017) [15] | 43% (acute, placebo arm) vs. 28% (50 mg BID arm) vs. 25% (200 mg BID arm) | anemia (3% vs. 1% vs. 2%, for placebo, 50 mg BID and 200 mg BID, resp.); thrombocytopenia (1% vs. 3% vs. 2%). | pulmonary embolism (1% vs. 4% vs. 2% for placebo, 50 mg BID and 200 mg BID resp.); pneumonia (8% vs. 3% vs. 2%) fatigue (4% vs. 2%. vs. 2%) hyperglycemia (1% vs. 2%. vs. 2%) |
OS: 185 d. (placebo) vs. 209 d. (50 mg) vs. 209 d. (200 mg) ORR: 41.2% (placebo) vs. 36.9% (50 mg) vs. 42.2% (200 mg) |
|
| Reiss (2017) [17] | ≥59% (acute) | lymphopenia (59%), thrombocytopenia (12%), anemia (9%), neutropenia (6%) | nausea (6%) diarrhea (6%) anorexia (6%) vomiting (6%) fatigue (6%) |
Median PFS: 3.6 months. Median OS: 9.1 months | |
| Jagsi (2018) [18] | 46.7% (late; at year 3) | no late G3 hematological toxicity | fibrosis (40% at 3 years) lymphoedema (20%) skin induration (13%) chest wall pain (7%) atrial clot (7%) |
3-year disease control: 50% (15 failures) 3-year OS: 56.7% (13/30 deaths). | |
| Loap (2020 and 2021) [12,13] | Acute toxicity ≥50% Late (1-year) toxicity: 0% | Acute: lymphopenia (50%) Late: 0% treatment related |
Acute: Radiodermatitis (8%) pain (4%) Late 0% treatment related |
1-year OS 96% (88%-100%) | |
| b. Triple combination outcomes | |||||
| Study | Drug | Toxicity ≥ Grade 3 |
Main ≥ Grade 3
Hematological Toxicities |
Main ≥ Grade 3
Non-Hematological Toxicities |
Clinical Outcome |
| Czito (2017) [16] | capecitabine 825 mg/m2 twice daily | 25% (acute) | anemia (3%), lymphopenia (3%) | diarrhea (9%) radiation skin injury (3%) hyperglycemia (3%) pulmonary embolism (3%) syncope (3%) vaginal stricture (3%) radiation enteritis (3%) |
pCR: 29%. Tumor downstaging: 71%. CEA response rate: 68% |
| Karam (2018) [19] | Cetuximab 400 mg/m2 (5–7 day before RT) and 250 mg/m2 weekly |
≥69% (acute) | lymphopenia (19%) | mucositis (69%) dermatitis (38%) dysphagia (31%) nausea (13%) dehydration (13%) hypomagnesemia (13%) malnutrition (13%) vomiting (13%) oral pain (6%) weight loss (6%) |
2-year OS: 72% 2-year PFS: 63% 2-year LC: 72% 2-year DC: 79% |
| Tuli (2021) [20] | Gemcitabine 400 mg/m2 | >96% (acute) | lymphopenia (96%) anemia (38%) thrombocytopenia (19%) neutropenia (4%) febrile neutropenia (4%) |
anorexia (19%) abdominal pain (12%) nausea (12%) vomiting (8%) diarrhea (4%) colitis (4%) fatigue (4%) |
median PFS: 9.8 months; median OS: 14.6 months |
| de Haan (2020) [22] |
CDDP 6 mg/m2/daily | 80% in CDDP + Olaparib arm vs. 57% Olaparib BID vs. 45% Olaparib once/day | CDDP + Olaparib arm: Neutropenia (30%, Lymphocytopenia (70% G3, 30% G4 with 1% G3 late), Thrombocytopenia G4 (10%) Olaparib BID Lymphocytopenia (23% G3, 14% G4 with 17% G3 late) Olaparib once daily: Lymphocytopenia (18% G3, 18% G4 with 11% G3 late) |
CDDP + Olaparib arm: Gastro-intestinal (33%) G4 fibrosis (11%), G5 fibrosis (11%) Olaparib BID: gastrointestinal (29% acute,17% late) Pneumonitis (17%) Lung hemorrhage G4 (17%) Olaparib once daily: gastrointestinal (9% acute only). Lung infection (9%), dyspnea (9%), pneumonitis G5 (9%), lung hemorrhage G5 (11%) and fibrosis G5 (11%); spinal fracture (11%) |
2-year LC:84% (with a 95% confidence interval of 58–95%; 89% with cisplatin and 83% without cisplatin Median PFS: 6.5 months (oligometastatic) and 12 months (Locally advanced) Median OS: 23 months (oligometastatic) and 28 months (locally advanced) |
| Baxter (2020) [21] | Temozolomide (135 mg/m2 d1–5/28 d) | ≥50% (acute) | lymphopenia (50%) neutropenia (32.7%) thrombocytopenia (23.1%) |
maculopapular rash (3%) neurological deterioration (2%) |
1-year OS: 37.2% 2-year OS: 5.3% PR: 14% |
| Argiris (2021) [23] | Paclitaxel 45 mg/m2/carboplatin AUC2 (weekly concomitant and in consolidation) | Phase I: 81% (acute), including one treatment-related G5 esophageal perforation. Phase II: 47% (arm Veliparib); 69% (arm placebo) |
Phase I: lymphopenia (57%); neutropenia (38%); Phase II: neutropenia (18%), thrombocytopenia (3%) |
Phase I: esophagitis (19%), fatigue (10%); esophageal perforation (5%) Phase II: anorexia (6%), esophageal pain (6%), fatigue (6%), hyperglycemia (6%), oral mucositis (1%) |
1-year PFS: 43% (Veliparib) vs. 40% (placebo); 1-year OS: 76% (Veliparib) vs. 50% (placebo) |
| Sim (2021) [24] | Temozolomide (75 mg/m2 OD concomitant and 150–200 mg/m2 d1–5/28 d) | 55% (both Veliparib and standard arm) | Veliparib arm: thrombocytopenia (17%); neutropenia (12%). Standard arm: thrombocytopenia (8%), neutropenia (3%) |
Veliparib arm: seizures (11%), fatigue (7%). Standard arm: seizures (5%), hyperglycemia (5%), diarrhea (5%) |
median PFS: 5.7 months (Veliparib) vs. 4.2 months (standard); median OS: 12.7 months (Veliparib) vs. 12.8 months (standard) |
Legend Table 3a,b: for each analyzed study, the percentages are referred to all the patients included.