[Rich66]

Excerpt from:
Implications of circadian clocks for the rhythmic delivery of cancer therapeutics:

The peak concentration of 5-FU occurs in the early rest span in both species when the drug is infused continuously at a constant rate for up to a one week span (Le´vi & Schibler 2007).
The apparent coupling between the circadian rest–activity cycle and the specific mechanisms that give rise to 24 hour rhythms in the PK and PD of medications across species has been the basis for the chronotherapeutic schedules given to
cancer patients. As a working hypothesis, the expected times of least toxicity in cancer patients were extrapolated from those experimentally demonstrated in synchronized mice or rats (i.e. animals that were housed under a regulated, typically 12 hour light–12 hour dark environment), by referring them to the respective rest–activity cycle of each species, e.g. with approximately 12 hour time lag. For instance, in mice the least toxicity of 5-FU occurs approximately 5 hours after light onset in the animal quarters, and this was predicted to correspond
to 04.00 in human beings, adhering to sleep between 23.00 and 07.00 alternating with activity between 07.00 and 23.00.

Figure 3. Rationale of circadian-based delivery of 5-FU and oxaliplatin, chronomodulated drugdelivery
schedule and main results in cancer patients. (a) Circadian organization of cell cycle phase distribution in humans. In healthy human beings, the proportion of S-phase cells rises and reaches a maximum near 16.00 daily in oral mucosa as well as in bone marrow. Since 5-FU is most toxic for S-phase cells, exposure at this time should be avoided in order to reduce toxic effects for both of these proliferating healthy tissues, which represent the main toxicity targets of this drug. (b) ChronoFLO schedule. Chronomodulated sinusoidal delivery schedules have been designed based on experimental data in mice as well as the rhythms in cell cycle phase distribution and detoxification processes shown in humans. Here, the reference chronoFLO5 consists in the sinusoidal delivery of 5-FU and leucovorin, for 12 hours with a peak at 04.00 in alternation with oxaliplatin for 12 hours with a peak at 16.00 for five
consecutive days every three weeks. This schedule has been administered with programmable-in-time multichannel electronic pumps and validated in patients with metastatic colorectal cancer registered in phase I, II and III clinical trials. (Adapted from Bjarnason et al. (2001), Bjarnason & Jordan (2002), Smaaland et al. (2002), Le´vi (2001) and Le´vi et al. (2007b).)
Review. Circadian clocks and cancer therapeutics 3583
Phil. Trans. R. Soc. A (2008)
The availability of portable multichannel programmable-in-time pumps constituted a key technological step for the implementation of cancer chronotherapeutics.
Indeed, these electronic devices make possible the continuous
chronomodulated delivery of up to four different medications in the patients’ usual activities in- or outside the home. The clinical relevance of the chronotherapy principle was first tested in a large population of patients with metastatic colorectal cancer, using standard methods of clinical trials.
(d ) Chronotherapeutics of colorectal cancer
Metastatic colorectal cancer is the second most common cause of cancer deaths in both men and women. Until the early 1990s, conventional treatment methods offered few therapeutic options other than the reference combination chemotherapy of 5-FU–leucovorin (LV). The chronomodulated protocols involved the time qualified infusion of 5-FU and LV, eventually associated with oxaliplatin, an active drug that was first recognized as such through chronotherapeutic development (Levi et al. 1992). The maximum delivery rate of 5-FU–LV was scheduled during sleep at 04.00 and of oxaliplatin at 16.00, based upon the extrapolations from experimental laboratory rodent modelling data. Courses lasted 4 or 5 days and were repeated every second or third week (figure 3b). The tolerability, maximum dose intensities and anti-tumour activity of this chronotherapeutic schedule were evaluated in phase I, II and III clinical trials involving over 2000 patients with metastatic colorectal cancer. In a first phase II single institution trial, 93 patients, 46 of whom had received previous chemotherapy, were treated with the chronomodulated combination of 5-FU–LV and oxaliplatin for 5 days every
three weeks. This new treatment achieved a 58 per cent response rate, a figure that was approximately fourfold higher than that produced by the conventional daily bolus of 5-FU–LV for 5 days every three weeks (Le´vi et al. 1992).



Journal of Clinical Oncology, Vol 14, 2950-2958, Copyright © 1996 by American Society of Clinical Oncology

ARTICLES

Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer

F Bertheault-Cvitkovic, A Jami, M Ithzaki, PD Brummer, S Brienza, R Adam, F Kunstlinger, H Bismuth, JL Misset and F Levi
Centre de Chronotherapie, Service des Maladies Sanguines, Immunitaires et Tumorales, France.
PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)- modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.



Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil

C. Qvortrup^1,2,*, M. Yilmaz³, D. Ogreid⁴, A. Berglund⁵, L. Balteskard⁶, J. Ploen⁷, T. Fokstuen⁸, H. Starkhammar⁹, H. Sørbye¹⁰, K. Tveit¹¹ and P. Pfeiffer^{1 1} Department of Oncology, Odense University Hospital
² Institute of Clinical Research, University of Southern Denmark, Odense
³ Department of Oncology, Aalborg University Hospital, Aalborg, Denmark
⁴ Department of Oncology, Rogaland Central Hospital, Stavanger, Norway
⁵ Department of Oncology, Radiology and Clinical Immunology University Hospital, Uppsala University Hospital, Uppsala, Sweden
⁶ Department of Oncology, Tromso University Hospital, Tromso, Norway
⁷ Department of Oncology, Vejle Hospital, Vejle, Denmark
⁸ Department of Oncology and Pathology, Karolinska Hospital, Stockholm
⁹ Department of Oncology, Linkoping University Hospital, Linkoping, Sweden
¹⁰ Department of Oncology, Haukeland University Hospital, Bergen
¹¹ Department of Oncology, Ullevål University Hospital, Oslo, Norway
^* Correspondence to: Dr C. Qvortrup, Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C 5000, Denmark. Tel: +45 65413147; Fax: +45 66135477; E-mail: camilla.qvortrup@ouh.regionsyddanmark.dk
Background: Oxaliplatin in combination with capecitabine prolongs survival in patients with metastatic colorectal cancer (mCRC). Chronomodulation might reduce toxicity and improve efficacy.
Patients and methods: A phase II study examining chronomodulated XELOX₃₀ (XELOX_30chron): oxaliplatin: 130 mg/m² on day 1, as a 30-min infusion between 1 and 3 p.m. Capecitabine: total daily dose of 2000 mg/m², 20% of the dose between 7 and 9 a.m. and 80% of the dose between 6 and 8 p.m. in patients with mCRC resistant to irinotecan. Seventy-one patients were enrolled. Response rate was 18%; median progression-free survival 5.1 months and median overall survival (OS) 10.2 months. Platelet count and performance status were significantly correlated to OS in multivariate analyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2% of patients, respectively, other grade 3 toxic effects were as follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experienced grade 4) and palmoplantart erytem 9%.
Conclusion: XELOX_30chron is a convenient second-line regimen with efficacy and safety profile similar to other oxaliplatin schedules. To further investigate chronomodulated XELOX, we have started a Nordic randomised phase II study comparing XELOX₃₀ and XELOX_30chron as first-line therapy in patients with mCRC.
Key words: capecitabine, chronotherapy, metastatic colorectal cancer, oxaliplatin, short-time infusion, XELOX
Received for publication October 24, 2007. Revision received December 28, 2007. Accepted for publication December 31, 2007.