Controlled, randomized clinical trials or high-powered retrospective trials with high-quality analysis assessing the impact of a retinoid compared to a placebo or other appropriate control
| Intent to treat . | Drug . | Mechanism . | Design . | Population . | Cancer effects . | Cardiometabolic effects . | Trial ID . | Sample size . | CoMed . | Note . |
|---|---|---|---|---|---|---|---|---|---|---|
| Prevention trials | ||||||||||
| β-Carotene | Vitamin A | RCT | High-risk male smokers | 18% increase lung cancer | 11% increase heart disease | ATBC | 29,133 | Tocopherol | ||
| β-Carotene/retinyl palmitate | Vitamin A | RCT | High-risk smokers/asbestos | 28% increase lung cancer, 52% prostate cancer | 26% increase cardiovascular mortality | CARET | 18,314 | None | ||
| β-Carotene/retinol | Vitamin A | Retrospective | Healthy individuals (ages 50–76) | 53% increase lung cancer | Not assessed | VITAL | 77,126 | Lutein | ||
| Fenretinide | RAR agonist | RCT | Healthy women | No overall effect | Not assessed | PMID: 10547391 | 2,972 | None | a | |
| Fenretinide | RAR agonist | RCT | High-grade cervical squamous lesions | 40% decrease in response rate | Not assessed | PMID: 11705848 | 39 | None | ||
| Intervention trials | ||||||||||
| Melanoma | Retinol | Vitamin A | RCT | High-risk resected melanoma | No effect | Not assessed | PMID: 7931474 | 248 | None | b |
| HNSCC | Retinyl palmitate | Vitamin A | RCT | HNSCC | Trend to twofold increase in recurrence | Not assessed | PMID: 9039219 | 106 | None | |
| HNSCC | Retinyl palmitate | Vitamin A | RCT | Early HNSCC and lung cancer | No effect | Low-requency hypercholesterolemia and liver enzyme elevation | EUROSCAN | 2,592 | N-acetylcysteine | c |
| Lung cancer | Retinyl palmitate | Vitamin A | RCT | Stage 1 NSCLC | Trend to improved disease-free survival (P = 0.054) | Hyperlipidemia and GGT elevation | PMID: 8391063 | 307 | None | |
| Lung cancer | Tamibarotene | RAR agonist | RCT | Stage IIIB/IV NSCLC | PFS HR 1.54 (P = 0.088). OS HR 1.48 (P = 0.24) | Grade 3/4 hypertriglyceridemia | NCT01337154 | 137 | Paclitaxel/carboplatin | d |
| Lung cancer | atRA | RAR agonist | RCT | Advanced SCLC | No effect | No effect | NCT00617409 | 69 | Chemo + DC vaccine | |
| Liver cancer | Amsilarotene | RARα agonist | RCT | Advanced HCC | No effect | Deep vein thrombosis | NCT00687596 | 52 | None | |
| Cervical cancer | Alitretinoin | RAR/RXR agonist | RCT | CIN 2/3 cervical dysplasia | No effect | Hyperlipidemia and decreased HDL | PMID: 12582020 | 114 | None | |
| Lung cancer | Bexarotene | RXR agonist | RCT | Advanced NSCLC | Trend to reduced OS/PFS | Hyperlipidemia and hypothyroidism | Spirit I | 623 | Cisplatin/vinorelbine | |
| Lung cancer | Bexarotene | RXR agonist | RCT | Advanced NSCLC | Trend to reduced OS/PFS (P = 0.06) | Hyperlipidemia | Spirit II | 612 | Carboplatin/paclitaxel | |
| Lung cancer | Isotretinoin | Non-nuclear retinoid | RCT | Stage 1 NSCLC | 56% increased death in smokers (P = 0.01) | No significant differences | PMID: 11309437 | 1,166 | None | |
| HNSCC | Isotretinoin | Non-nuclear retinoid | RCT | Stage 1/2 HNSCC | No effect | None | PMID: 16595780 | 1,190 | ||
| Renal cancer | Isotretinoin | Non-nuclear retinoid | RCT | Metastatic RCC | 31% increased survival | None | EORTC 30951 | 320 | Interferon α | |
| Neuroblastoma | Isotretinoin | Non-nuclear retinoid | RCT | Pediatric high-risk neuroblastoma | Trend to improved survival (P = 0.054) | None | CCG-3891 | 379 | ||
| Neuroblastoma | Isotretinoin | Non-nuclear retinoid | RCT | Pediatric stage 3/4 neuroblastoma | No effect | None | PMID: 11027423 | 175 | ||
| Glioblastoma | Isotretinoin | Non-nuclear retinoid | CT | Glioblastoma | Trend to worse outcomes | None | NCT00112502 | 178 | TMZ, thalidomide, celecoxib | |
| Lung cancer | Disulfiram | ALDH1a1/2 inhibitor | RCT | Stage 4 NSCLC | Improved PFS and OS | Not assessed | PMID: 25777347 | 40 | Cisplatin/vinorelbine | |
| Topical gel trials | ||||||||||
| AIDS Kaposi sarcoma | Alitretinoin (topical) | RAR agonist | Within patient trial | Cutaneous Kaposi sarcoma | 16% increased response rate | None | PMID: 11115156 | 115 | ||
| CTCL | Bexarotene (topical) | RXR agonist | Within patient trial | Early CTCL | 46% response rate | None | PMID: 14576658 | 50 | ||
| Keratinocyte carcinoma | Tretinoin (topical) | RAR agonist | RCT | Men with history of KC | No overall effect | Fourfold increase in death due to vascular disease | VATTC | 1,131 | None | e |
| Noncancer trials | ||||||||||
| Immune thrombocytopenia | atRA | RAR agonist | RCT | Steroid-resistant thrombocytopenia | 47% improved response | None | PMID: 28917657 | 96 | Danazol | |
| Intent to treat . | Drug . | Mechanism . | Design . | Population . | Cancer effects . | Cardiometabolic effects . | Trial ID . | Sample size . | CoMed . | Note . |
|---|---|---|---|---|---|---|---|---|---|---|
| Prevention trials | ||||||||||
| β-Carotene | Vitamin A | RCT | High-risk male smokers | 18% increase lung cancer | 11% increase heart disease | ATBC | 29,133 | Tocopherol | ||
| β-Carotene/retinyl palmitate | Vitamin A | RCT | High-risk smokers/asbestos | 28% increase lung cancer, 52% prostate cancer | 26% increase cardiovascular mortality | CARET | 18,314 | None | ||
| β-Carotene/retinol | Vitamin A | Retrospective | Healthy individuals (ages 50–76) | 53% increase lung cancer | Not assessed | VITAL | 77,126 | Lutein | ||
| Fenretinide | RAR agonist | RCT | Healthy women | No overall effect | Not assessed | PMID: 10547391 | 2,972 | None | a | |
| Fenretinide | RAR agonist | RCT | High-grade cervical squamous lesions | 40% decrease in response rate | Not assessed | PMID: 11705848 | 39 | None | ||
| Intervention trials | ||||||||||
| Melanoma | Retinol | Vitamin A | RCT | High-risk resected melanoma | No effect | Not assessed | PMID: 7931474 | 248 | None | b |
| HNSCC | Retinyl palmitate | Vitamin A | RCT | HNSCC | Trend to twofold increase in recurrence | Not assessed | PMID: 9039219 | 106 | None | |
| HNSCC | Retinyl palmitate | Vitamin A | RCT | Early HNSCC and lung cancer | No effect | Low-requency hypercholesterolemia and liver enzyme elevation | EUROSCAN | 2,592 | N-acetylcysteine | c |
| Lung cancer | Retinyl palmitate | Vitamin A | RCT | Stage 1 NSCLC | Trend to improved disease-free survival (P = 0.054) | Hyperlipidemia and GGT elevation | PMID: 8391063 | 307 | None | |
| Lung cancer | Tamibarotene | RAR agonist | RCT | Stage IIIB/IV NSCLC | PFS HR 1.54 (P = 0.088). OS HR 1.48 (P = 0.24) | Grade 3/4 hypertriglyceridemia | NCT01337154 | 137 | Paclitaxel/carboplatin | d |
| Lung cancer | atRA | RAR agonist | RCT | Advanced SCLC | No effect | No effect | NCT00617409 | 69 | Chemo + DC vaccine | |
| Liver cancer | Amsilarotene | RARα agonist | RCT | Advanced HCC | No effect | Deep vein thrombosis | NCT00687596 | 52 | None | |
| Cervical cancer | Alitretinoin | RAR/RXR agonist | RCT | CIN 2/3 cervical dysplasia | No effect | Hyperlipidemia and decreased HDL | PMID: 12582020 | 114 | None | |
| Lung cancer | Bexarotene | RXR agonist | RCT | Advanced NSCLC | Trend to reduced OS/PFS | Hyperlipidemia and hypothyroidism | Spirit I | 623 | Cisplatin/vinorelbine | |
| Lung cancer | Bexarotene | RXR agonist | RCT | Advanced NSCLC | Trend to reduced OS/PFS (P = 0.06) | Hyperlipidemia | Spirit II | 612 | Carboplatin/paclitaxel | |
| Lung cancer | Isotretinoin | Non-nuclear retinoid | RCT | Stage 1 NSCLC | 56% increased death in smokers (P = 0.01) | No significant differences | PMID: 11309437 | 1,166 | None | |
| HNSCC | Isotretinoin | Non-nuclear retinoid | RCT | Stage 1/2 HNSCC | No effect | None | PMID: 16595780 | 1,190 | ||
| Renal cancer | Isotretinoin | Non-nuclear retinoid | RCT | Metastatic RCC | 31% increased survival | None | EORTC 30951 | 320 | Interferon α | |
| Neuroblastoma | Isotretinoin | Non-nuclear retinoid | RCT | Pediatric high-risk neuroblastoma | Trend to improved survival (P = 0.054) | None | CCG-3891 | 379 | ||
| Neuroblastoma | Isotretinoin | Non-nuclear retinoid | RCT | Pediatric stage 3/4 neuroblastoma | No effect | None | PMID: 11027423 | 175 | ||
| Glioblastoma | Isotretinoin | Non-nuclear retinoid | CT | Glioblastoma | Trend to worse outcomes | None | NCT00112502 | 178 | TMZ, thalidomide, celecoxib | |
| Lung cancer | Disulfiram | ALDH1a1/2 inhibitor | RCT | Stage 4 NSCLC | Improved PFS and OS | Not assessed | PMID: 25777347 | 40 | Cisplatin/vinorelbine | |
| Topical gel trials | ||||||||||
| AIDS Kaposi sarcoma | Alitretinoin (topical) | RAR agonist | Within patient trial | Cutaneous Kaposi sarcoma | 16% increased response rate | None | PMID: 11115156 | 115 | ||
| CTCL | Bexarotene (topical) | RXR agonist | Within patient trial | Early CTCL | 46% response rate | None | PMID: 14576658 | 50 | ||
| Keratinocyte carcinoma | Tretinoin (topical) | RAR agonist | RCT | Men with history of KC | No overall effect | Fourfold increase in death due to vascular disease | VATTC | 1,131 | None | e |
| Noncancer trials | ||||||||||
| Immune thrombocytopenia | atRA | RAR agonist | RCT | Steroid-resistant thrombocytopenia | 47% improved response | None | PMID: 28917657 | 96 | Danazol | |
Key trial attributes along with cancer and cardiometabolic effects are listed. Bold indicates significant effects. Orange shading indicates adverse effect. Green shading indicates beneficial effect. HNSCC, head and neck squamous cell carcinoma; RCT, randomized controlled trial; CT, clinical trial; KC, keratinocyte carcinoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; CIN, cervical intraepithelial neoplasia; HCC, hepatocellular carcinoma; SCLC, small cell lung cancer; PFS, progression-free survival; HR, hazard ratio; OS, overall survival; GGT, gamma-glutamyl transferase; VITAL, VITamin D and OmegA-3 TriaL; EUROSCAN, European Study on Chemoprevention with Antioxidants; EORTC, European Organisation for Research and Treatment of Cancer; CoMed, combination medication; TMZ, temozolomide.
Beneficial effect seen in pre-menopausal women. Worse effect in post-menopausal women.
12% grade 3/4 toxicities, lipids not measured.
Possible increase in second primary malignancy.
Increased grade 3/4 anemia, hypertrigyceridemia, and febrile neutropenia.
Significantly increased lung cancer and pulmonary disease in treated patients.