Table 3.
Summary of clinical studies included in review of d-limonene and its derivatives on breast cancer
| Author(s) | Trial Phase | Compound | Cancer type | Dose | Toxicity | Maximum tolerated dose | Effect on breast cancer |
|---|---|---|---|---|---|---|---|
| d-limonene | |||||||
| Vigushin et al. 1998 [22] | Phase 1: Human subjects (n = 32) | Orally administered d-limonene | Phase 1: refractory solid tumorsa | 0.5 to 12 g/m2 per day in 21-day cycles | Gastrointestinal toxicities leading to nausea, vomiting and diarrhea were dose limiting | 8 g/m2 per day | Phase 1: Partial responseb observed in one breast cancer patient. Effect was sustained for 11 months. |
| Phase 2: Human subjects (n = 10) | Phase 2: locally advanced breast cancer | 8 g/m2 per day for 15 cycles | Not indicated | Phase 2: no response | |||
| Miller et al. 2013 [26] | Phase 2: Human subjects (n = 43) | Orally administered d-limonene | Newly diagnosed, operable cancers breast cancer | 2 g d-limonene for 2–6 weeks | Well tolerated | Not indicated | D-limonene concentrated in breast tissue (mean 41.3 μg/g tissue); Small but statistically significant increase in insulin-like growth factor levels; Reduction in tumor cyclin D1 expression |
| Perillyl alcohol | |||||||
| Ripple et al. 1998 [23] | Phase 1: Human subjects (n = 18) | Orally administered perillyl Alcohol | Advanced malignanciesc | Dose escalation: 800, 1200 and 1600 mg/m2/dose administered 3 time a day | Dose- related gastrointestinal toxicities leading to nausea and vomiting; 2 participants experienced severe drug related myelosuppression | Not indicated | No objective tumor response observed in any patients |
| Ripple et al. 2000 [24] | Phase 1: Human subjects (n = 16) | Orally administered perillyl Alcohol | Advanced refractory malignanciesd | Dose escalation: 800, 1600 and 2400 mg/m2/dose administered 4 time a day | Gastrointestinal toxicities, including nausea, vomiting, satiety, and eructation, that were dose limiting | 1200 mg/m2/dose | No anticancer activity observed in breast cancer patient. Tumor regression observed in one patient with metastatic colorectal cancer |
| Bailey et al. 2008 [25] | Phase 2: Women (N = 14) | Orally administered perillyl Alcohol | Advanced treatment-refractory breast cancer | Dose escalation: 1200–1500 mg/m2/dose administered 4 time a day | Poor toleration due to gastrointestinal and fatigue- related toxicities | Not indicated | No partial or complete regression observed in any participant. |
aIncluding breast cancer colorectal carcinoma, metastatic adenocarcinoma, esophagus, pancreas, bronchus, ovary, and soft tissue sarcoma
bPartial response defined as ≥ 50% reduction in tumor size assessed by two measurements conducted ≥ 4 weeks apart
cIncluding prostrate (n = 4), ovarian (n = 3), sarcoma, renal cell (n = 3), breast (n = 2), hepatocellular (n = 2), chronic myelogenous leukemia (n = 1), chronic lymphocytic leukemia (n = 1),adenocarcinoma (n = 1)
dincluding: prostrate (n = 4), ovarian (n = 3), adenocarcinoma (n = 2), colorectal (n = 1), chronic myelogenous leukemia (n = 1), melanoma (n = 1), non-Hodgkin’s lymphoma (n-1), pancreas (n = 1), salivary gland (n = 1), and sarcoma (n = 1)