Timing of Therapy

Our assessments of evidence for each medical benefit fall into one of these categories:

• Strong evidence: consistent, significant effects in several large (or at least one very large) well designed clinical studies or at least two meta-analysesa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of clinical studies of moderate or better quality (or one large meta-analysis) finding similar results
• Good evidence: significant effects in one large or several mid-sized and well-designed clinical studies ( randomized controlled trialsa study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects with an appropriate placebo or other strong comparison control or observational studies that control for confounds)
• Modest evidence: significant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies), or several small studies aggregated into a meta-analysis
• Preliminary evidence: significant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect
• Weak evidence: one or more case studies, supported by animal evidence OR small treatment effects of limited clinical significance OR studies with no controls OR weak trends of effects
• Insufficient evidence: preclinical evidence only OR clinical studies with such poor or unclear methodology that no conclusion can be drawn OR conflicting findings across clinical studies with no preponderance of evidence in one direction; conflicting evidence occurs when studies find conflicting effects (positive effect vs no effect or negative effect) with the same treatment and the same general study population (same cancer type, for example)

Learn more about how we research and rate therapies and practices in How We Rate Therapies ›

No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on progression or survival among people with advanced cancer receiving chemotherapy on a schedule that peaked at 4 p.m. in one study.

• No evidence of an effect on progression or survival among people with advanced cancer receiving carboplatin chemotherapy on a circadian-aligned schedule (peaking at 4 p.m.) compared to a flat rate in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹Natoli C, Salini V et al. A phase I study of 5-day continuous venous infusion of carboplatin at circadian rhythm-modulated rate compared with constant rate. Anticancer Research. 1996 May-Jun;16(3A):1275-9.

Weak evidenceone or more case studies, supported by animal evidence OR small treatment effects of limited clinical significance OR studies with no controls OR weak trends of effects (this is the CancerChoices definition; other researchers and studies may define this differently) of a higher tolerated dose among people receiving circadian-modified capecitabine for advanced cancer; however, this does not necessarily mean more effective treatment.

• 20% higher maximum tolerated dose among people with advanced cancer receiving capecitabine chemotherapy with doses at 9 a.m. and midnight in a 3:5 ratio in a small phase 1 uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design²Roosendaal J, Jacobs BAW et al. Phase I pharmacological study of continuous chronomodulated capecitabine treatment. Pharmaceutical Research. 2020 May 7;37(5):89.

Modest evidencesignificant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observational studies), or several small studies aggregated into a meta-analysis (this is the CancerChoices definition; other researchers and studies may define this differently) of longer overall survival among people receiving immunotherapy earlier in the day

• Longer overall survival among people with cancer receiving immunotherapy earlier in the day compared to later in a combined analysis of 13 retrospective studies³Landré T, Karaboué A et al. Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis. ESMO Open. 2024 Feb;9(2):102220.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of longer disease-free survival among people with early breast cancer receiving endocrine therapy with tamoxifen, though not with aromatase inhibitors, in the evening or at night

• Longer disease-free survival among people with breast cancer undergoing endocrine therapy with Tamoxifen, but not aromatase inhibitors (anastrozole, exemestane, or letrozole), who received their therapy in the evening or at night compared to earlier in the day in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁴Giacchetti S, Laas E et al. Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG- UNIRAD trial. EBioMedicine. 2024 Jun;104:105141.

No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on survival among people with metastatic colorectal cancer receiving chronomodulated chemotherapy (5-fluorouracil in the morning and oxaliplatin in the evening) across several studies

• No evidence of an effect on overall survival among people with metastatic colorectal cancer receiving chrono-chemotherapy (earlier in the day, compared to later) in a combined analysis of 6 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁵Huang Y, Yu Q et al. Efficacy and safety of chronomodulated chemotherapy for patients with metastatic colorectal cancer: a systematic review and meta-analysis. Asia Pacific Journal of Clinical Oncology. 2017 Apr;13(2):e171-e178.

A weak trendan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward better overall survival among people with advanced colorectal cancer receiving irinotecan chemotherapy as a six-hour sinusoidal infusion peaking at 5 a.m. compared to a one-hour flat-rate infusion

• A weak trend toward better overall survival among people with advanced colorectal cancer receiving irinotecan chemotherapy as a six-hour sinusoidal infusion peaking at 5 a.m. compared to a one-hour flat-rate infusion in a small RCT⁶Garufi C, Vanni B et al. Randomised phase II study of standard versus chronomodulated CPT-11 plus chronomodulated 5-fluorouracil and folinic acid in advanced colorectal cancer patients. European Journal of Cancer. 2006 Mar;42(5):608-16.

No evidence of an effect on response to treatment among people with locally advanced rectal cancer receiving capecitabine chemotherapy and radiation on a “Brunch” regimen (60% of the capecitabine at 8 a.m., 40% at 12 p.m., and radiation between 2 p.m. and 4 p.m.) in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design

• No evidence of an effect on response to treatment among people with locally advanced rectal cancer receiving capecitabine chemotherapy and radiation on a “Brunch” regimen (60% of the capecitabine at 8 a.m., 40% at 12 p.m., and radiation between 2 p.m. and 4 p.m.) compared to people in other studies receiving capecitabine and radiation on different schedules in a small uncontrolled trial⁷Akgun Z, Saglam S et al. Neoadjuvant chronomodulated capecitabine with radiotherapy in rectal cancer: a phase II brunch regimen study. Cancer Chemotherapy and Pharmacology. 2014 Oct;74(4):751-6.

No evidence of an effect on progression or survival among people with metastatic colorectal cancer receiving cisplatin before 5-fluorouracil compared to after

• No evidence of an effect on response to treatment depending on whether cisplatin was administered before or after 5-fluorouracil among people undergoing chemotherapy for metastatic colorectal cancer in a small RCT⁸Falcone A, Allegrini G et al. 5-fluorouracil administered as a 48-hour chronomodulated infusion in combination with leucovorin and cisplatin: a randomized phase II study in metastatic colorectal cancer. Oncology. 2001;61(1):28-35.

No evidence of an effect on progression or survival among people with liver metastases from colorectal cancer receiving chemotherapy as an intermittent (waxing and waning) infusion rather than a flat-rate infusion

• No evidence of an effect on progression or survival, though fewer side effects, allowing a higher dose, among people with liver metastases from colorectal cancer receiving 5-fluorouracil and 5-fluorodeoxyuridine chemotherapy as an intermittent (waxing and waning) infusion rather than a flat-rate infusion over 5 days every 3 weeks in a small RCT⁹Focan C, Levi F et al. Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion. Anticancer Drugs. 1999 Apr;10(4):385-92.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of a sex difference in response to chronomodulated chemotherapy for colorectal cancer (5-fluorouracil in the morning and oxaliplatin in the evening), with female patients showing shorter overall survival time but male patients showing longer overall survival time

• Sex difference in response to chronomodulated chemotherapy among people with metastatic colorectal cancer: shorter overall survival among females receiving chronomodulated chemotherapy compared to non-time-specified infusions, but longer overall survival among males receiving chronomodulated chemotherapy compared to non-time-specified infusions¹⁰Giacchetti S, Dugué PA et al. Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis. Annals of Oncology. 2012 Dec;23(12):3110-3116.

Preliminary evidence of better survival among people with metastatic colorectal cancer who had worse neutropenia from chronomodulated FOLFOX chronotherapy (5-fluorouracil in the morning and oxaliplatin in the evening)

• Longer survival among people with metastatic colorectal cancer with more neutropenia from circadian-aligned FOLFOX chemotherapy, compared to shorter survival among those with less neutropenia from non-time-specified FOLFOX chemotherapy in a mid-sized RCT¹¹Innominato PF, Giacchetti S et al. Prediction of survival by neutropenia according to delivery schedule of oxaliplatin-5-Fluorouracil-leucovorin for metastatic colorectal cancer in a randomized international trial (EORTC 05963). Chronobiology International. 2011 Aug;28(7):586-600. Note: according to the authors, this result indicates that in chronotherapy, oncologists should not choose the highest possible dose as indicated by neutropenia. (See more under Safety and Precautions ›)

No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on response to treatment among people with metastatic gastrointestinal cancer receiving 5-fluorouracil chemotherapy and leucovorin as intermittent (waxing and waning) infusions over 14 days compared to flat infusions

• No evidence of an effect on response to treatment among people with metastatic gastrointestinal cancer receiving 5-fluorouracil chemotherapy and leucovorin as intermittent (waxing and waning) infusions over 14 days, compared to flat infusions over 14 days, in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹²Falcone A, Allegrini G et al. Infusions of fluorouracil and leucovorin: effects of the timing and semi-intermittency of drug delivery. Oncology. 1999 Oct;57(3):195-201.

Modest evidencesignificant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observational studies), or several small studies aggregated into a meta-analysis (this is the CancerChoices definition; other researchers and studies may define this differently) of better likelihood of a good response to chemotherapy among people with head and neck cancer receiving platinum-based and antimetabolite chemotherapy in the morning, compared to the evening.

• Higher likelihood of good response to chemotherapy among people with head and neck cancer receiving platinum-based and antimetabolite chemotherapy in the morning, compared to the evening, in a combined analysis of 13 retrospective and observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies¹³Abusamak M, Abu-Samak AA et al. Chronotherapy in head and neck cancer: A systematic review and meta-analysis. International Journal of Cancer. 2025 Mar 1;156(5):1015-1032.

Modest evidencesignificant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observational studies), or several small studies aggregated into a meta-analysis (this is the CancerChoices definition; other researchers and studies may define this differently) of better overall survival among people with metastatic renal cell carcinoma receiving immunotherapy earlier in the day

• Better overall survival among people undergoing immunotherapy for metastatic renal cell carcinoma who received their therapy earlier in the day in a combined analysis of four retrospective studies¹⁴Rizzo A, Monteiro FM et al. Impact of time-of-day administration of immunotherapy on survival in metastatic renal cell carcinoma: the MOUSEION-09 meta-analysis. Clinical and Experimental Metastasis. 2024 Dec 16;42(1):3.

Insufficient evidencepreclinical evidence only OR clinical studies with such poor or unclear methodology that no conclusion can be drawn OR conflicting findings across clinical studies with no preponderance of evidence in one direction; conflicting evidence occurs when studies find conflicting effects (positive effect vs no effect or negative effect) with the same treatment and the same general study population (same cancer type, for example) (this is the CancerChoices definition; other researchers and studies may define this differently) of an effect on survival among people with brain metastases from non-small-cell lung cancer who received radiation in the morning compared to the afternoon

• Longer survival among people with brain metastases from non-small-cell lung cancer who received gamma knife radiation before 12:30 in the morning compared to after in a small retrospective study¹⁵Rahn DA 3rd, Ray DK et al. Gamma knife radiosurgery for brain metastasis of nonsmall cell lung cancer: is there a difference in outcome between morning and afternoon treatment? Cancer. 2011 Jan 15;117(2):414-20.
• When controlling for confounding variables, no evidence of an effect on survival among people with brain metastases from non-small-cell lung cancer who received stereotactic radiation in the morning compared to the afternoon in a mid-sized retrospective study¹⁶Badiyan SN, Ferraro DJ et al. Impact of time of day on outcomes after stereotactic radiosurgery for non-small cell lung cancer brain metastases. Cancer. 2013 Oct 1;119(19):3563-9.
• When controlling for confounding variables, no evidence of an effect on survival among people with brain metastases from non-small-cell lung cancer based on the time of day they received radiation in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study¹⁷Kabolizadeh P, Wegner R et al. The effect of treatment time on outcome in non-small cell lung cancer brain metastases treated with stereotactic radiosurgery. International Journal of Radiation Oncology, Biology, Physics. 2011: 81(2), S301.

No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on response to treatment among people with non-small-cell lung cancer receiving cisplatin chemotherapy with docetaxel or gemcitabine who received the cisplatin at 6 p.m. in one study

• No evidence of an effect on response to treatment among people with non-small-cell lung cancer receiving cisplatin chemotherapy with docetaxel or gemcitabine when the cisplatin was administered at 6 p.m. compared to no time specification in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹⁸Li J, Chen R et al. Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis. Cancer Chemotherapy and Pharmacology. 2015 Sep;76(3):651-5.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of lower overall survival among people with melanoma receiving 20% or more of their immune checkpoint inhibitor infusion sessions after 4:30 p.m.

• Lower overall survival among people with melanoma receiving 20% or more of their immune checkpoint inhibitor infusion sessions after 4:30 p.m. compared to those who did not receive at least 20% of these infusions after 4:30 p.m. in a mid-sized observational study¹⁹Qian DC, Kleber T et al. Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncology. 2021 Dec;22(12):1777-1786.

No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on survival among people with nasopharyngeal carcinoma receiving cisplatin chemotherapy on a 12-hour sinusoidal pump, with peak delivery at 4pm, in one study

• No evidence of an effect on survival among people with nasopharyngeal carcinoma receiving cisplatin chemotherapy on a 12-hour sinusoidal pump, with peak delivery at 4pm, compared to a flat rate over 4 hours in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²⁰Zhang PX, Jin F et al. A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy. Chronobiology International. 2018 Feb;35(2):240-248.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of a better short-term response, but no evidence of an effect on long-term survival (1 year or more), among people undergoing chemotherapy and radiotherapy for nasopharyngeal carcinoma who received the chemotherapy on a specified 24-hour schedule (cisplatin during the day, 5-fluorouracil overnight) compared to standard schedule

• Better response rate at one month, but no evidence of an effect at 1, 5, or 10 years, among people receiving chemotherapy and radiotherapy for nasopharyngeal carcinoma who received the chemotherapy on a specified 24-hour schedule (cisplatin during the day, 5-fluorouracil overnight) compared to chemotherapy on a standard schedule (cisplatin in 1 hour, 5-fluorouracil over 24 hours) in a small RCT²¹Gou XX, Jin F et al. Induction chronomodulated chemotherapy plus radiotherapy for nasopharyngeal carcinoma: A Phase II prospective randomized study. Journal of Cancer Research and Therapeutics. 2018;14(7):1613-1619.

Modest evidencesignificant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observational studies), or several small studies aggregated into a meta-analysis (this is the CancerChoices definition; other researchers and studies may define this differently) of less neutropenia among people with metastatic colorectal cancer receiving chrono-chemotherapy (mostly receiving 5-fluorouracil in the morning and oxaliplatin in the afternoon)

• Less neutropenia among people with metastatic colorectal cancer receiving chrono-chemotherapy (mostly receiving 5-fluorouracil in the morning and oxaliplatin in the afternoon) in a combined analysis of 6 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²²Huang Y, Yu Q et al. Efficacy and safety of chronomodulated chemotherapy for patients with metastatic colorectal cancer: a systematic review and meta-analysis. Asia Pacific Journal of Clinical Oncology. 2017 Apr;13(2):e171-e178.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of a sex difference among people undergoing irinotecan chemotherapy for metastatic colorectal cancer, with female patients showing less neutropenia when they received chemotherapy in the afternoon but male patients showing less neutropenia when they received chemotherapy in the morning

• Less neutropenia among females undergoing irinotecan chemotherapy for metastatic colorectal cancer in the afternoon compared to the morning, but the reverse (less neutropenia when receiving chemotherapy in the morning) among males, in a mid-sized RCT²³Innominato PF, Ballesta A et al. Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial. Cancer Medicine. 2020 Jun;9(12):4148-4159.

Preliminary evidence of less leukocytopenia and thrombocytopenia among people undergoing chemotherapy and radiotherapy for nasopharyngeal carcinoma who received cisplatin during the day and 5-fluorouracil overnight

• Less leukocytopenia and thrombocytopenia among people receiving chemotherapy and radiotherapy for nasopharyngeal carcinoma who received the chemotherapy on a specified 24-hour schedule (cisplatin during the day, 5-fluorouracil overnight) compared to chemotherapy on a standard schedule (cisplatin in 1 hour, 5-fluorouracil over 24 hours) in a small RCT²⁴Gou XX, Jin F et al. Induction chronomodulated chemotherapy plus radiotherapy for nasopharyngeal carcinoma: A Phase II prospective randomized study. Journal of Cancer Research and Therapies 2018;14(7):1613-1619.

Preliminary evidence of less neutropenia and leukopenia among people with non-small-cell lung cancer receiving cisplatin chemotherapy with docetaxel or gemcitabine when the cisplatin was administered at 6 p.m.

• Less neutropenia and leukopenia among people with non-small-cell lung cancer receiving cisplatin chemotherapy with docetaxel or gemcitabine when the cisplatin was administered at 6 p.m. compared to no time specification in a small RCT²⁵Li J, Chen R et al. Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis. Cancer Chemotherapy and Pharmacology. 2015 Sep;76(3):651-5.

Preliminary evidence of less leukopenia, but worse levels of gastrointestinal side effects (nausea, diarrhea, and stomach pain), among people with metastatic breast cancer receiving vinorelbine chemotherapy (5-fluorouracil) at 5 p.m. compared to other times of day

• Less leukopenia among people with metastatic breast cancer receiving vinorelbine chemotherapy (5-fluorouracil) at 5 p.m. compared to other times of day in a small RCT; however, 5 p.m. was not the least toxic time for other side effects²⁶Coudert B, Focan C et al. A randomized multicenter study of optimal circadian time of vinorelbine combined with chronomodulated 5-fluorouracil in pretreated metastatic breast cancer patients: EORTC trial 05971. Chronobiology International. 2008 Sep;25(5):680-96.

Preliminary evidence of less neutropenia among people with bone or soft tissue cancer undergoing ifosfamide chemotherapy receiving granulocyte-macrophage colony-stimulating factor (GM-CSF; a medication that prompts the body to produce more white blood cells) in the morning

• Shorter duration of neutropenia among people with bone or soft tissue cancer cancer undergoing ifosfamide chemotherapy who received granulocyte-macrophage colony-stimulating factor (GM-CSF) in the morning compared to at night in a small RCT²⁷Dinçol D, Samur M et al. Prospective randomized comparison of morning versus night daily single subcutaneous administration of granulocyte-macrophage-colony stimulating factor in patients with soft tissue or bone sarcoma. Cancer. 2000 May 1;88(9):2033-6.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of less loss of appetite among female patients undergoing irinotecan chemotherapy for metastatic colorectal cancer in the afternoon, but less loss of appetite when receiving chemotherapy in the morning among male patients

• Less loss of appetite among females undergoing irinotecan chemotherapy for metastatic colorectal cancer in the afternoon compared to the morning, but the reverse (less loss of appetite when receiving chemotherapy in the morning) among males, in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²⁸Innominato PF, Ballesta A et al. Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial. Cancer Medicine. 2020 Jun;9(12):4148-4159.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of fewer gastrointestinal side effects among people with prostate cancer receiving high-dose radiotherapy in the daytime compared to the evening

• Fewer gastrointestinal side effects among people with prostate cancer receiving high-dose radiotherapy in the daytime compared to the evening in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study²⁹Hsu FM, Hou WH et al. Differences in toxicity and outcome associated with circadian variations between patients undergoing daytime and evening radiotherapy for prostate adenocarcinoma. Chronobiology International. 2016;33(2):210-9.

No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on severe nausea and vomiting among people receiving chrono-chemotherapy (mostly 5-fluorouracil in the morning and oxaliplatin in the afternoon) for metastatic colorectal cancer across several studies.

• No evidence of an effect on severe nausea and vomiting among people with metastatic colorectal cancer receiving chrono-chemotherapy (earlier in the day, compared to later) in a combined analysis of 6 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³⁰Huang Y, Yu Q et al. Efficacy and safety of chronomodulated chemotherapy for patients with metastatic colorectal cancer: a systematic review and meta-analysis. Asia Pacific Journal of Clinical Oncology. 2017 Apr;13(2):e171-e178.

Preliminary evidence of less nausea and vomiting among people receiving chemotherapy and radiotherapy for nasopharyngeal carcinoma on a specified 24-hour schedule (cisplatin during the day, 5-fluorouracil overnight)

• Less nausea and vomiting among people receiving chemotherapy and radiotherapy for nasopharyngeal carcinoma who received the chemotherapy on a specified 24-hour schedule (cisplatin during the day, 5-fluorouracil overnight) compared to chemotherapy on a standard schedule (cisplatin in 1 hour, 5-fluorouracil over 24 hours) in a small RCT³¹Gou XX, Jin F et al. Induction chronomodulated chemotherapy plus radiotherapy for nasopharyngeal carcinoma: A Phase II prospective randomized study. Journal of Cancer Research and Therapeutics. 2018;14(7):1613-1619.

Preliminary evidence of less nausea and vomiting among people receiving cisplatin chemotherapy on a 12-hour sinusoidal pump, with peak delivery at 4pm

• Less nausea and vomiting among people with nasopharyngeal carcinoma receiving cisplatin chemotherapy on a 12-hour sinusoidal pump, with peak delivery at 4pm, compared to a flat rate over 4 hours in a mid-sized RCT³²Zhang PX, Jin F et al. A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy. Chronobiology International. 2018 Feb;35(2):240-248.

Preliminary evidence of less severe nausea among people with non-small-cell lung cancer receiving cisplatin chemotherapy with docetaxel or gemcitabine when the cisplatin was administered at 6 p.m.

• Lower incidence of severe nausea among people with non-small-cell lung cancer receiving cisplatin chemotherapy with docetaxel or gemcitabine when the cisplatin was administered at 6 p.m. compared to no time specification in a small RCT³³Li J, Chen R et al. Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis. Cancer Chemotherapy and Pharmacology. 2015 Sep;76(3):651-5.

Preliminary evidence of less diarrhea among people with metastatic gastrointestinal cancer receiving 5-fluorouracil chemotherapy and leucovorin as intermittent (waxing and waning) infusions

• Less diarrhea among people with metastatic gastrointestinal cancer receiving 5-fluorouracil chemotherapy and leucovorin as intermittent (waxing and waning) infusions over 14 days, compared to flat infusions over 14 days, in a mid-sized RCT³⁴Falcone A, Allegrini G et al. Infusions of fluorouracil and leucovorin: effects of the timing and semi-intermittency of drug delivery. Oncology. 1999 Oct;57(3):195-201.

Preliminary evidence of a sex difference among people undergoing irinotecan chemotherapy for metastatic colorectal cancer, with females showing less diarrhea when receiving their infusions in the afternoon but males showing less diarrhea when receiving it in the morning

• Less diarrhea among females undergoing irinotecan chemotherapy for metastatic colorectal cancer in the afternoon compared to the morning, but the reverse (less diarrhea when receiving chemotherapy in the morning) among males, in a mid-sized RCT³⁵Innominato PF, Ballesta A et al. Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial. Cancer Medicine. 2020 Jun;9(12):4148-4159.

Weak evidenceone or more case studies, supported by animal evidence OR small treatment effects of limited clinical significance OR studies with no controls OR weak trends of effects (this is the CancerChoices definition; other researchers and studies may define this differently) of a sex difference in fatigue among people undergoing irinotecan chemotherapy for metastatic colorectal cancer, with females showing less fatigue when their infusions were in the afternoon, but males showing less fatigue when their infusions were in the morning

• A weak trendan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward less fatigue among females undergoing irinotecan chemotherapy for metastatic colorectal cancer in the afternoon compared to the morning, but the reverse (a weak trend toward less fatigue when receiving chemotherapy in the morning) among males, in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³⁶Innominato PF, Ballesta A et al. Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial. Cancer Medicine. 2020 Jun;9(12):4148-4159.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of less impairment from neuropathy among people with metastatic colorectal cancer receiving 5-fluorouracil and oxaliplatin chemotherapy with leucovorin on a waxing-and-waning schedule

• Less impairment from neuropathy among people with metastatic colorectal cancer receiving 5-fluorouracil and oxaliplatin chemotherapy with leucovorin on a waxing-and-waning schedule designed to align with their circadian rhythms, compared to a flat-rate infusion, for 5 days every 3 weeks in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³⁷Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.

No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on peripheral neuropathy among people with metastatic colorectal cancer receiving chrono-chemotherapy (mostly 5-fluorouracil in the morning and oxaliplatin at night) across several studies.

• No evidence of an effect on peripheral neuropathy among people with metastatic colorectal cancer receiving chrono-chemotherapy (earlier in the day, compared to later) in a combined analysis of 6 RCTs³⁸Huang Y, Yu Q et al. Efficacy and safety of chronomodulated chemotherapy for patients with metastatic colorectal cancer: a systematic review and meta-analysis. Asia Pacific Journal of Clinical Oncology. 2017 Apr;13(2):e171-e178.

Radiation:

Modest evidencesignificant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observational studies), or several small studies aggregated into a meta-analysis (this is the CancerChoices definition; other researchers and studies may define this differently) of less severe oral mucositis among people with head and neck cancer undergoing radiation in the morning rather than the evening

• 31% lower risk of developing severe oral mucositis (grade ≥3) among people with head and neck cancer undergoing morning, rather than evening, radiation in a combined analysis of 9 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies³⁹Abusamak M, Abu-Samak AA et al. Chronotherapy in head and neck cancer: A systematic review and meta-analysis. International Journal of Cancer. 2025 Mar 1;156(5):1015-1032.

Chemotherapy:

Modest evidence of less mucositis among people with metastatic colorectal cancer receiving chrono-chemotherapy (mostly 5-fluorouracil in the morning and oxaliplatin at night) across several studies

• Less mucositis among people with metastatic colorectal cancer receiving chrono-chemotherapy (mostly 5-fluorouracil in the morning and oxaliplatin at night) in a combined analysis of 6 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁴⁰Huang Y, Yu Q et al. Efficacy and safety of chronomodulated chemotherapy for patients with metastatic colorectal cancer: a systematic review and meta-analysis. Asia Pacific Journal of Clinical Oncology. 2017 Apr;13(2):e171-e178.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of less mucositis among people with metastatic gastrointestinal cancer receiving 5-fluorouracil chemotherapy and leucovorin as intermittent (waxing and waning) infusions

• Less mucositis among people with metastatic gastrointestinal cancer receiving 5-fluorouracil chemotherapy and leucovorin as intermittent (waxing and waning) infusions over 14 days, compared to flat infusions over 14 days, in a mid-sized RCT⁴¹Falcone A, Allegrini G et al. Infusions of fluorouracil and leucovorin: effects of the timing and semi-intermittency of drug delivery. Oncology. 1999 Oct;57(3):195-201.
• Less mucositis among people with metastatic colorectal cancer receiving 5-fluorouracil and oxaliplatin chemotherapy with leucovorin on a waxing-and-waning schedule designed to align with their circadian rhythms, compared to a flat-rate infusion, for 5 days every 3 weeks in a small RCT⁴²Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.

Preliminary evidence of less mucositis among people with nasopharyngeal carcinoma receiving cisplatin chemotherapy on a 12-hour sinusoidal pump, with peak delivery at 4 p.m.

• Less mucositis among people with nasopharyngeal carcinoma receiving cisplatin chemotherapy on a 12-hour sinusoidal pump, with peak delivery at 4 p.m., compared to a flat rate over 4 hours in a mid-sized RCT⁴³Zhang PX, Jin F et al. A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy. Chronobiology International. 2018 Feb;35(2):240-248.

Preliminary evidence of less mucositis among people with non-small-cell lung cancer receiving 5-fluorouracil and carboplatin chemotherapy with 5-fluorouracil at 4 a.m. and carboplatin at 4 p.m.

• Less mucositis among people with non-small-cell lung cancer receiving combined 5-fluorouracil and carboplatin chemotherapy with leucovorin where the 5-fluorouracil and leucovorin were delivered at 4 a.m. and the carboplatin was delivered at 4 p.m. compared to other timings in a small RCT. This is an older regimen not used currently.⁴⁴Focan C, Kreutz F et al. Etude randomisée évaluant la chronotolérance d’une association de 5-fluorouracile, acide folinique et carboplatine chez des patients porteurs d’un cancer pulmonaire non à petites cellules (CPNPC) [Randomised study to evaluate the chronotolerance of a combination infusional chemotherapy with 5-fluorouracil, folinic acid and carboplatin in non small cell lung cancer (NSCLC) patients]. Pathologie-Biologie (Paris). 2003 Jun;51(4):204-5. French.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of fewer skin reactions among people with breast cancer undergoing radiation in the morning

• Lower incidence of skin reactions among people with breast cancer undergoing radiation in the morning compared to the afternoon in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁴⁵Noh JM, Choi DH et al. Comparison of acute skin reaction following morning versus late afternoon radiotherapy in patients with breast cancer who have undergone curative surgical resection. Journal of Radiation Research. 2014 May;55(3):553-8.

Preliminary evidence of less hand-foot syndrome among people treated with capecitabine chemotherapy on a “brunch” regimen.

• A lower rate of hand-foot syndrome, a skin reaction, among people with locally advanced rectal cancer receiving capecitabine chemotherapy and radiation on a “Brunch” regimen (60% of the capecitabine at 8 a.m., 40% at 12 p.m., and radiation between 2 p.m. and 4 p.m.) compared to people in other studies receiving capecitabine and radiation on different schedules in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁴⁶Akgun Z, Saglam S et al. Neoadjuvant chronomodulated capecitabine with radiotherapy in rectal cancer: a phase II brunch regimen study. Cancer Chemotherapy and Pharmacology. 2014 Oct;74(4):751-6.

Modest evidencesignificant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observational studies), or several small studies aggregated into a meta-analysis (this is the CancerChoices definition; other researchers and studies may define this differently) of lower rate of side effects and adverse events among people with head and neck cancer undergoing chemotherapy in the morning, compared to the evening, in a combined analysis of 13 observational studies

• Lower rate of overall side effects and adverse events among people with head and neck cancer undergoing chemotherapy in the morning, compared to the evening, in a combined analysis of 13 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁴⁷Abusamak M, Abu-Samak AA et al. Chronotherapy in head and neck cancer: A systematic review and meta-analysis. International Journal of Cancer. 2025 Mar 1;156(5):1015-1032.

Preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of more side effects among people with ovarian cancer undergoing doxorubicin and cisplatin chemotherapy who received doxorubicin in the evening and cisplatin in the morning

• More side effects, requiring treatment delays and dose reductions, among people with ovarian cancer undergoing doxorubicin and cisplatin chemotherapy who received doxorubicin in the evening and cisplatin in the morning, compared to the other way round, in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁴⁸Hrushesky WJ. Circadian timing of cancer chemotherapy. Science. 1985 Apr 5;228(4695):73-5.

Weak evidenceone or more case studies, supported by animal evidence OR small treatment effects of limited clinical significance OR studies with no controls OR weak trends of effects (this is the CancerChoices definition; other researchers and studies may define this differently) of lower side effects among people receiving 5-fluorouracil chemotherapy, hyperthermia, and radiation for locally advanced rectal cancer who received their chemotherapy as an overnight infusion

• Low rate (6.9%) of serious side effects among people receiving 5-fluorouracil chemotherapy, hyperthermia, and radiation for locally advanced rectal cancer who received their chemotherapy as an overnight infusion in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁴⁹Asao T, Sakurai H et al. The synchronization of chemotherapy to circadian rhythms and irradiation in pre-operative chemoradiation therapy with hyperthermia for local advanced rectal cancer. International Journal of Hyperthermia. 2006 Aug;22(5):399-406.

• Less recurrence than usual among people with bladder cancer undergoing chemotherapy who received doxorubicin in the morning and cisplatin in the evening compared to contemporary averages in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁵⁰Hrushesky WJ, Roemeling RV et al. High-dose intensity, circadian-timed doxorubicin and cisplatin adjuvant chemotherapy for bladder cancer. Cancer Treatment Reports. 1987 Oct;71(10):915-9.