Table 5.
Clinical trials and studies considering time of day in the treatment of cancer.
| DRUG(S) | CANCER TYPE | STUDY DESIGN; POPULATION | STUDY CONCLUSIONS | SUGGESTED TIME OF DAY | CITATION |
|---|---|---|---|---|---|
| Chemotherapeutics | |||||
| Doxorubicin (DOX) + Cisplatin (CDDP) | Ovarian Cancer | 31 patients with advanced ovarian cancer | DOX treatment at O600 h followed by CDDP treatment 1800 h, compared to DOX treatment at 1600 h followed by CDDP treatment at 0600 h, had fewer dose reductions, treatment delays, and treatment complications. | DOX at 0600 h + CDDP at 1800 h | Hrushesky 1985 |
| Patients with advanced ovarian cancer | 0600 h DOX treatment with 1600 h CDDP treatment is advantageous in reducing adverse side effects; this study demonstrated that this treatment schedule increased the 5 year survival rate from 11% to 44%. | DOX at 0600 h + CDDP at 1800 h | Hrushesky and Bjarnason 1993 | ||
| 4’−0-tetrahydropyranyl doxorubicin (THP) + Cisplatin (CDDP) | Randomized phase II trial; 31 patients with advanced ovarian cancer | Patients receiving a THP intravenous bolus at 0600 h followed by a 4-hour infusion of CDDP at 1600 h, had less neutropenia, thrombocytopenia, anemia, and renal toxicity relative to patients beginning THP treatment at 1800 h, followed by CDDP at 0400 h. | THP at 0600 h + CDDP at 1600 h | Levi, Benavides et al. 1990 | |
| Cisplatin (CDDP) | Advanced non-small cell lung cancer | Patients with advanced non-small cell lung cancer | Evening treatment caused less adverse effects such as leucopenia, neutropenia, and gastrointestinal toxicity relative to a morning treatment group. | Evening | Li, Chen et al. 2015 |
| Etoposide + Cisplatin | Advanced lung cancer, mixture of solid tumors, or metastatic cancer | advanced lung cancer, mixture of solid tumors, or metastatic cancer | Morning (0600 h or 0700 h) etoposide and evening CDDP (1800 h) treatment demonstrated less adverse hematological toxicities relative to patients receiving etoposide at 1800 h and CDDP at 0600 h. | Etopside at 0600 or 0700 h + CDDP at 1800 h | Krakowski, Levi et al. 1988, Krakowski, Levi et al. 1988, Focan 1995 |
| Floxuridine (FUDR) | Advanced Metastatic Cancer | 54 patients with advanced metastatic cancer | Patients receiving chronomodulated variable rate infusions had less frequent and less severe diarrhea, nausea, and vomiting. Additionally, patients receiving variable rate infusions increased their maximally tolerated dose by 45%. | Chronomodulated variable rate infusions | von Roemeling and Hrushesky 1989 |
| Oxaliplatin (1-OHP) + 5-Fluorouracil (5-FU) and Folinic Acid | Metastatic Colorectal Cancer | 92 patients with metastatic colorectal cancer | Chronomodulated variable rate infusions of chemotherapeutics demonstrated five times less severe stomatitis, the dose limiting adverse effect of 5-FU, an increased in the maximal tolerated dose of 5-FU, and an increase in median survival (19 months vs 14.9) relative to constant rate infusions. | Chronomodulated variable rate infusions | Levi, Zidani et al. 1994 |
| 5-FU and 1-OHP | Randomised multicentre trial; 186 patients with untreated metastases from colorectal cancer | Patients receiving chronomodulated variable rate infusions had five time less severe mucosal toxicity and half as much peripheral neuropathy. However, median survival and three year survival were unchanged relative to constant rate infusion. | Chronomodulated variable rate infusions | Levi, Zidani et al. 1997 | |
| 5-FU and cisplatin (CDDP) | Less adverse effects with chronomodulated variable rate infusions. | Chronomodulated variable rate infusions | Levi, Tubiana-Mathieu et al. 2004 | ||
| 5-FU | Failed to demonstrate beneficial effects of chronomodulated variable rate infusions. | No differences | Price, Ross et al. 2004, Garufi, Vanni et al. 2006, Ramanathan, Bjarnason et al. 2008, Huang, Yu et al. 2017 | ||
| 5-FU | Chronomodulation only demonstrated favorable effects on males. | Giacchetti, Bjarnason et al. 2006, Levi, Innominato et al. 2009, Giacchetti, Dugue et al. 2012 | |||
| Docetaxel (DOC) | Advanced Nasopharyngeal Carcinoma | Chronomodulated variable rate infusions of chemotherapeutics resulted in less adverse effects. | Chronomodulated variable rate infusions | Bi, Jin et al. 2015, Mao 2015, Liao 2016, Gou, Jin et al. 2018, Wan 2018, Zhang, Jin et al. 2018 | |
| Cisplatin (CDDP) | |||||
| 5-FU + radiotherapy | Improved cellular immune numbers in virtually all clinical trials. | ||||
| 5-FU without radiotherapy | |||||
| 6-Mercaptopurine and Methotrexate | Childhood Acute Lymphoblastic Leukemia | Evening administration of 6-mercaptopurine and methotrexate increased disease-free survival and reduced the risk of relapse by 2.5 times. | Evening | Rivard, Infante-Rivard et al. 1993 | |
| Phase II clinical trial; | Similar effects of increased event free survival from evening consumption. | Evening | Schmiegelow, Glomstein et al. 1997 | ||
| Capecitabine | Advanced Colorectal cancer | Chronomodulated asymmetrical dose did not significantly reduce toxicity or improve efficacy. | Qvortrup, Jensen et al. 2010 | ||
| Radiotherapeutics | |||||
| Radiotherapy | Breast Cancer | Retrospective study of 878 patients | Examining adverse effects following radiotherapy, the authors conclude that patients receiving radiotherapy in the afternoon (i.e. after 1200) had less adverse reactions. | Afternoon (after 1200 h) | Johnson, Chang-Claude et al. 2019 |
| Radiotherapy | Afternoon (after 1500 h) timed radiotherapy was associated with higher incidences of adverse skin reactions relative to morning-timed. | Morning | Noh, Choi et al. 2014) | ||
| Radiotherapy | Cervical cancer | Inconsistent results in adverse effects. | Inconclusive | Shukla, Gupta et al. 2010, Chang, Li et al. 2016 | |
| Radiotherapy | Head and Neck Carcinoma or Squamous Cell Carcinoma of Oral Cavity/Pharynx/Larynx | No significant differences in adverse effects. | No differences | Bjarnason, Mackenzie et al. 2009, Goyal, Shukla et al. 2009 | |
| Radiotherapy | Advanced Rectal Cancer | Afternoon-timed radiotherapy was associated with a higher incidence of complete or moderate pathological response and improved nodal downstaging in advanced rectal cancer. | Afternoon | Squire, Buchanan et al. 2017 | |
| Radiotherapy | Brain Metastases | Increased overall survival in patients receiving radiotherapy in the morning (before 1200 h). | Morning (before 1200 h) | Rahn, Ray et al. 2011, Badiyan, Ferraro et al. 2013 | |
| Radiotherapy | No difference between morning and afternoon groups. | No differences | Kabolizadeh, Wegner et al. 2011, Chan, Rowbottom et al. 2016 | ||
| Sunitinib | No differences in adverse events or overall survival. | No differences | Escudier, Roigas et al. 2009, George, Blay et al. 2009 | ||