Robert D. Levin

Circadian Clock Manipulation for Cancer Prevention and Control and the Relief of Cancer Symptoms

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can, in turn, be used to make cancer patients with advanced disease feel and function more normally.

Actigraphic assessment of daily sleep–activity pattern abnormalities reflects self‐assessed depression and anxiety in outpatients with advanced non‐small cell lung cancer

Objectives: We measured subjectively evaluated depression and anxiety, and objectively measured daily sleep–activity patterns in inpatients and outpatients with advanced non‐small cell lung cancer (NSCLC) and determined whether cancer‐associated depression and anxiety are accompanied by characteristic circadian rhythm abnormalities.

Validation of actigraphy to assess circadian organization and sleep quality in patients with advanced lung cancer

Background Many cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure many standard sleep parameters, as well as daily activity. Actigraphic and subjective sleep data are in agreement when determining activity-sleep patterns and sleep quality/quantity, each of which are severely affected in cancer patients. We investigated the relationship between actigraphic measurement of circadian organization and self-reported subjective sleep quality among patients with advanced lung cancer. Methods This cross-sectional and case control study was conducted in 84 patients with advanced non-small cell lung cancer in a hospital setting for the patients at Midwestern Regional Medical Center (MRMC), Zion, IL, USA and home setting for the patients at WJB Dorn Veterans Affairs Medical Center (VAMC), Columbia, SC, USA. Prior to chemotherapy treatment, each patients sleep-activity cycle was measured by actigraphy over a 4-7 day period and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Results The mean age of our patients was 62 years. 65 patients were males while 19 were females. 31 patients had failed prior treatment while 52 were newly diagnosed. Actigraphy and PSQI scores showed significantly disturbed daily sleep-activity cycles and poorer sleep quality in lung cancer patients compared to healthy controls. Nearly all actigraphic parameters strongly correlated with PSQI self-reported sleep quality of inpatients and outpatients. Conclusions The correlation of daily activity/sleep time with PSQI-documented sleep indicates that actigraphy can be used as an objective tool and/or to complement subjective assessments of sleep quality in patients with advanced lung cancer. These results suggest that improvements to circadian function may also improve sleep quality.

Dose escalation study of an anti- thrombocytopenic agent in patients with chemotherapy induced thrombocytopenia

BackgroundPreclinical studies demonstrated that small chain RNA fragments accelerate the recovery of platelets numbers in animals exposed to high doses of chemotherapeutic drugs. There is anecdotal data supporting the same application in humans. The Phase I clinical trial described here was designed to investigate the relationship between the administration of small chain RNA fragments and the recovery in platelets following Chemotherapy-Induced Thrombocytopenia (CIT).MethodsCancer patients with solid tumors that experienced post chemotherapy thrombocytopenia with a nadir of < = 80,000 platelets/ml were eligible for this clinical trial. There were no exclusions based on ECOG status, tumor type, tumor burden or chemotherapeutic agents. Patients received a unique preparation of RNA derived from either E. coli or yeast. Ten patients per group received 20, 40, or 60 mg as a starting dose. Subjects self-administered RNA fragments sublingually on an every other day schedule while undergoing chemotherapy. The dose was escalated in 20 mg increments to a maximum dose of 80 mg if the nadir was < 80,000 platelets/ml at the start of the next cycle. Subjects were treated for three cycles of chemotherapy with the maximum effective dose of RNA fragments. Subjects continued on planned chemotherapy as indicated by tumor burden without RNA fragment support after the third cycle. Subjects kept a diary indicating RNA fragment and magnesium administration, and any experienced side effects.ResultsPatients receiving E. coli RNA fragments demonstrated a more rapid recovery in platelet count and higher nadir platelet count. None of the patients receiving the E. coli RNA fragments required a chemotherapy dose reduction due to thrombocytopenia. The optimal dose for minimizing CIT was 80 mg. Conversely, subjects receiving yeast RNA fragments with dose escalation to 80 mg required a chemotherapy dose reduction per American Society of Clinical Oncology guidelines for grade 3 and 4 thrombocytopenia.ConclusionsPatients receiving myelosuppressive chemotherapy experienced an improvement in the platelet nadir and shorter recovery time when receiving concurrent E coli RNA fragments, when compared to patients who received yeast RNA fragments. These data indicate that 60 and 80 mg doses of E. coli RNA accelerated platelet recovery. Further clinical investigations are planned to quantify the clinical benefits of the E. coli RNA at the 80 mg dose in patients with chemotherapy induced thrombocytopenia.Trial RegistrationClinical Trials.gov Identifier: NCT01163110

Abstract 4673: A randomized, double-blind, multicenter trial evaluating the chronotherapeutic role of concomitant melatonin in the treatment of stage IIIB and IV non-small cell lung carcinoma.

Background: A recently published meta-analysis suggests that melatonin administered concurrently with chemotherapy leads to significant improvements in tumor response and survival in solid tumors, however, the role of melatonin in cancer treatment still remains disputable. We investigated the impact of chronotherapeutic administration of melatonin on tumor response and overall survival in stage IIIB and IV non-small cell lung cancer (NSCLC) patients undergoing conventional chemotherapy. Methods: Veteran Affairs Medical Center (VAMC) and Cancer Treatment Centers of America® at Midwestern Regional Medical Center (MRMC), a non-VA site, entered 42 patients each. The patients were randomized to receive placebo 8 am and placebo 8 pm (arm 1; n=29), or melatonin 20 mg 8 am and placebo 8 pm (arm 2; n=27), or placebo 8 am and melatonin 20 mg 8 pm (arm 3; n=28). All study participants received treatment with cisplatin (25 mg/m2/day) followed by etoposide (100 mg/m2/day) chemotherapy. Patient survival was defined as the time between the study start date and date of death from any cause/date of last contact. Kaplan-Meier analysis with log-rank test was used to evaluate the equality of survival distributions across the three treatment arms. Tumor response was evaluated using the RECIST guidelines. Results: 64 patients had stage IV while 20 had stage IIIB disease. 65 patients were males while 19 were females. All patients had expired at the time of this analysis. Mean age at study entry was 61.3 years (57 years for MRMC versus 65.7 for VAMC). There were no significant differences in the three treatment arms with respect to age, gender, tumor stage and performance status. Median survival time in the 3 treatment arms was 10.4 (arm 1), 6.8 (arm 2) and 8.0 (arm 3) months respectively (log rank p=0.81). Similarly, there was no significant difference in the treatment arms with regard to tumor response, such that 48.3%, 37.0% and 32.1% patients had stable disease in arm 1, arm 2 and arm 3 respectively (Chi-square p=0.49). Conclusions: Contrary to the recently reported meta-analysis, we found that neither the addition nor the timing of a high oral dose of melatonin added therapeutically to the combination of cisplatin and etoposide. The melatonin dose used in this study is at least 20x the usual replacement dose and this may have resulted in melatonin being inappropriately present in the circulation during both day and night, an un-physiologic state, which might be responsible for the apparent lack of efficacy of this particular regimen. Citation Format: Robert D. Levin, James F. Grutsch, Christopher G. Lis, Digant Gupta, Patricia A. Wood, William JM Hrushesky. A randomized, double-blind, multicenter trial evaluating the chronotherapeutic role of concomitant melatonin in the treatment of stage IIIB and IV non-small cell lung carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2013-4673