Chronobiolox), Inm-nsrional. Val. 7.
No. 5/6. pp. 4 7 1 4 7 4 . 1990
0742-0528/90 $3.00 + 0.00
Printed in Great Britain
Pergamon Press plc International Society of Chronobiology
MEETING REPORT CHRONOBIOLOGY AND CHRONOTHERAPY OF CANCER
Chronobiol Int Downloaded from informahealthcare.com by Chulalongkorn University on 12/26/14 For personal use only.
Summary of a Symposium of the 15th International Cancer Congress (UICC), 21 August 1990, Hamburg, Germany, organized by B.J. Kennedy (Minneapolis, USA) and A. Reinberg (Paris, France). Francis Lkvi and Alain Reinberg CNRS SDI 1-6212, Hbpital Paul Brousse, 14-16 ave P. Vaillant-Couturier, 94800 Villejuif, France
Despite the fact that the Symposium had been programmed almost at the end of a 6-day Congress, at odd hours even for chronobiologists and in a lecture room rather hard to find (especially on a rainy day), it was well attended and each of the presentations was followed by active discussions. B.J. Kennedy opened the session with a short address explaining why and how a chronobiologic approach is important, from the point of view of a clinical oncologist. The existence of periodic (circadian, among others) processes in the clinical expression of cancers (chronopathology) as well as in effects of anticancer agents (chronotherapy) can be neither ignored nor underestimated. A. Reinberg, again briefly, gave the point of view of a chronopharmacologist with regard to the optimal dosing times of anticancer agents. Special reference was made to interindividual differences: genetically based strain-related changes in the time at which a given agent is best tolerated by mice; correlation between performance status (WHO criteria) and persistence of circadian rhythms (a battery of tests regarding ten variables) suggesting that interindividual differences in cancer patients should be taken into consideration for the chronotherapy of cancer. Then, full length presentations were delivered. F. U v i (Villejuif, France) discussed automated circadian chronotherapy and reported that continuous infusion of chemotherapy at a constant rate is associated with circadian or
other changes in drug plasma levels, as was shown for doxorubicin, 5-fluorouracil or vindesine. This has warranted the development of programmable-in-time ambulatory pumps. Single or multiple reservoir pumps now exist and have been approved by the French Ministry of Health. Phase I clinical trials have compared constant vs circadian rhythms at modulated rates. Continuous venous infusions of FUDR, 5FUra, oxaliplatin or doxorubicin were less toxic and allowed treatment with higher dose intensities if infusion rate was circadian rhythmic rather than flat (1,2). Phase I1 clinical trials of circadian rhythm-modulated chemotherapy have been performed in kidney cancers (W. Hrushesky and R. von Roemeling, USA and B. Damascielli, Italy). A 15-30% response rate was observed with minimal toxicity. These results compare favorably with those obtained following interleukin-2 therapy. (3,4). In patients with metastatic colorectal cancer, the chronotherapeutic delivery of 5-fluorouracil, folinic acid and oxaliplatin yielded a 61% response rate in 66patients, half of whom had failed prior chemotherapy. Doses were about twice those usually given. These efficacy results are 2-3 times better than those usually achieved in this disease. The use of the multichannel lntelliject pump@ (Aguettant, Lyon) has allowed such therapeutic advance in ambulatory outpatients. A specific chronotherapy unit is being developed in Paul Brousse Hospital to extend the benefits of such chronotherapy to other kinds of malignant diseases, in
47 1
Chronobiol Int Downloaded from informahealthcare.com by Chulalongkorn University on 12/26/14 For personal use only.
472
close cooperation with home care organizations. New tools are also being developed for individualizing cancer chronotherapy. R. von Roemeling (Albany, USA) spoke on circadian time dependencies in toxicity of anticancer drugs. The research documented circadian changes in the toxicity of a new platinum (Pt) complex (B 850040) in mice. The time of least toxicity was associated with high antitumour efficacy against murine L1210 leukemia. No apparent correlation between tissue uptake of Pt and toxicity was found along the circadian time scale. D r Roemeling emphasized that four Pt complexes (cisplatin, carboplatin and oxaliplatin) have exhibited similar circadian rhythms in mice, as also shown by Boughattas er a/.,and hypothetized that common mechanisms may govern the chronopharmacology of these important drugs in oncology, These results stressed the relevance of undertaking Phase I chronopharmacologic studies with chemotherapeutic drugs, as was done for FUdr (1). These studies have demonstrated a marked improvement in treatment tolerance following circadian rhythm-modulated as compared to constant venous infusion of this drug. Such increase in patients’ tolerance allowed to significantly enhance dose intensities. As a result, the efficacy of continuous circadian delivery of FUdr was demonstrated in patients with advanced kidney cancer (3,4). D r Roemeling stressed that more than two circadian schedules should be compared in the future since extrapolation from murine studies performed with a single bolus dose to continuous circadian delivery in cancer patients may be hazardous. C. Focan (Likge, Belgium) discussed chronotherapy in lung and ovarian cancer. Circadian chronotolerance has been documented in animals for at least 20 anticancer agents; more recently circadian chronotolerance has also been established in man for adriamycine, THP-adriamycine, cisplatin and etoposide. Circadian chronoefficacy of chemotherapy was also shown in animal systems and suggested in human cancer (ALL, solid tumors). In this presentation, updated available results in ovarian and lung cancers have been reviewed, especially with reference to the trials held under
Chronobiology International the auspices of the “Association de Chronobiologie MCdicale (ACM) (Chairmen: F. LCvi and C. Focan). 1. Ovarian cancer. A set of researchers in the USA have established the circadian tolerance, in women treated for advanced ovarian carcinoma, of 2 main drugs: adriamycin (best time schedule: 0600 hr) and cisplatin (best time schedule: 1800 hr). Similarly, U v i et a/. ( 5 ) confirmed the circadian tolerance of THP-adriamycin in the same type of patients and was able to show a dose response and survival relationship. The ACM is actually conducting a multicentric randomized trial aiming to compare tolerance and efficacy in stage 111-IV ovarian cancer previously treated with optimal surgery of a first line chemotherapy with THP-adriamycin 50 mg/m2 (given a t 0600 (A) or at 1800 (B) and cisplatin-100 mg/m2 (infused 10 hours after THP-adria, from 16.0020.00 (A) or 4.00-8.00 hr (B). At present 125 patients have been enrolled in the trial. 2. Lung cancer. 124 cases with advanced nonsmall (NSC) and small (SC) cell lung carcinoma previously untreated with chemotherapy have been entered in a randomized evaluation comparing chemotherapy with cisplatin 100mg/mz given at 1800 hr on day 4 and etoposide 100 mg/m2 administered daily for 3 days either a t 0600(A)or a t 1800 (B). An interim analysis (ECCO V) on 76 patients (A: 41; B: 35) and 261 courses (A: 140; B: 121) confirmed lesser hematological toxicity in group A while cisplatin was better tolerated in group B (fewer dose reductions or delays: P < 0.01). However at present, no difference could be established either in the overall doseintensities of drugs (absolute doses o r relative doses given vs projected) or in the tumor outcome (response rate; survival). R. Smaaland (University of Bergen, Norway) presented research done by using the Colony Forming Unit of Granulo-Monocytes (CFUGM) cultured in vitro. (R. Smaaland, O.D. Laerum and co-workers). They investigated circadian rhythms in human myelopoiesis and their relation to flow cytometric measured DNA synthesis of total bone marrow cells and peripheral blood granulocytes. Circannual rhythms of CFU-GM were also investigated. Twenty-one healthy male volunteers
Chronobiol Int Downloaded from informahealthcare.com by Chulalongkorn University on 12/26/14 For personal use only.
Meeting Report
473
were punctured either in the sternum or at both allowed a large reduction of myelosuppression iliac crests every 4th hour during one 24-hour (4‘-0-tetrahydropyrabyladriamycin), renal necperiod, altogether 7 times. Their diurnal rhythm rosis (cisplatin) or heart failure (doxorubicin). was validated by determination of cortisol levels Plasma and tissue pharmacokinetics also at the same time points. A large circadian accounted for the dosing-time dependent hemavariation of CFU-GM was seen in all the tologic, renal or intestinal toxicities. The shortest individuals, with a difference between the lowest half-lives of both distribution (t 1/2a) and and highest colony number ranging from 47.1 to elimination (t I/21J) phases as well as least tissue 233.0% (mean difference = 136.8% as compared platinum uptake corresponded to dosing cisplatin to the mean colony number of each volunteer). or carboplatin at the least toxic time. However, no For the pooled data there was a significantly such correlation was found for oxaliplatin (6,7). lower colony number at 2400 hr as compared to Circadian rhythms in cellular metabolism also daytime (0800, 1200 and 1600hr; P < 0.05; contribute to those in drug toxicities. The ANOVA). The majority of the individuals activity of hepatic dihydropyrimidine dehydroshowed a circadian stage dependent covariation genase corresponded to the peak in plasma 5-FU between the CFU-GM and fraction of cells in catabolite formation (8). Enzymes such as DNA synthesis, and for the pooled data dihydrofolate reductase, which constitutes the demonstrating the same pattern of change along major biochemical target for methotrexate, also the circadian scale for the DNA synthesis as for exhibited a circadian variation which likely the CFU-GM, with a significantly lower DNA accounted for that in cellular resistance for this synthesis at midnight compared to 0800, 1200 drug. Dosing time-dependent tolerance has been and 1600 hr ( P < 0.05 and P< 0.005),respectively; documented for over 25 anticancer agents in ANOVA). There was significantly higher colony laboratory rodents and some of their mechanisms formation during summer as compared to winter isolated. Results have successfully guided the (68.2f7.9~~45.4f6.9)(MeanskS.E.;P
No. 5/6. pp. 4 7 1 4 7 4 . 1990
0742-0528/90 $3.00 + 0.00
Printed in Great Britain
Pergamon Press plc International Society of Chronobiology
MEETING REPORT CHRONOBIOLOGY AND CHRONOTHERAPY OF CANCER
Chronobiol Int Downloaded from informahealthcare.com by Chulalongkorn University on 12/26/14 For personal use only.
Summary of a Symposium of the 15th International Cancer Congress (UICC), 21 August 1990, Hamburg, Germany, organized by B.J. Kennedy (Minneapolis, USA) and A. Reinberg (Paris, France). Francis Lkvi and Alain Reinberg CNRS SDI 1-6212, Hbpital Paul Brousse, 14-16 ave P. Vaillant-Couturier, 94800 Villejuif, France
Despite the fact that the Symposium had been programmed almost at the end of a 6-day Congress, at odd hours even for chronobiologists and in a lecture room rather hard to find (especially on a rainy day), it was well attended and each of the presentations was followed by active discussions. B.J. Kennedy opened the session with a short address explaining why and how a chronobiologic approach is important, from the point of view of a clinical oncologist. The existence of periodic (circadian, among others) processes in the clinical expression of cancers (chronopathology) as well as in effects of anticancer agents (chronotherapy) can be neither ignored nor underestimated. A. Reinberg, again briefly, gave the point of view of a chronopharmacologist with regard to the optimal dosing times of anticancer agents. Special reference was made to interindividual differences: genetically based strain-related changes in the time at which a given agent is best tolerated by mice; correlation between performance status (WHO criteria) and persistence of circadian rhythms (a battery of tests regarding ten variables) suggesting that interindividual differences in cancer patients should be taken into consideration for the chronotherapy of cancer. Then, full length presentations were delivered. F. U v i (Villejuif, France) discussed automated circadian chronotherapy and reported that continuous infusion of chemotherapy at a constant rate is associated with circadian or
other changes in drug plasma levels, as was shown for doxorubicin, 5-fluorouracil or vindesine. This has warranted the development of programmable-in-time ambulatory pumps. Single or multiple reservoir pumps now exist and have been approved by the French Ministry of Health. Phase I clinical trials have compared constant vs circadian rhythms at modulated rates. Continuous venous infusions of FUDR, 5FUra, oxaliplatin or doxorubicin were less toxic and allowed treatment with higher dose intensities if infusion rate was circadian rhythmic rather than flat (1,2). Phase I1 clinical trials of circadian rhythm-modulated chemotherapy have been performed in kidney cancers (W. Hrushesky and R. von Roemeling, USA and B. Damascielli, Italy). A 15-30% response rate was observed with minimal toxicity. These results compare favorably with those obtained following interleukin-2 therapy. (3,4). In patients with metastatic colorectal cancer, the chronotherapeutic delivery of 5-fluorouracil, folinic acid and oxaliplatin yielded a 61% response rate in 66patients, half of whom had failed prior chemotherapy. Doses were about twice those usually given. These efficacy results are 2-3 times better than those usually achieved in this disease. The use of the multichannel lntelliject pump@ (Aguettant, Lyon) has allowed such therapeutic advance in ambulatory outpatients. A specific chronotherapy unit is being developed in Paul Brousse Hospital to extend the benefits of such chronotherapy to other kinds of malignant diseases, in
47 1
Chronobiol Int Downloaded from informahealthcare.com by Chulalongkorn University on 12/26/14 For personal use only.
472
close cooperation with home care organizations. New tools are also being developed for individualizing cancer chronotherapy. R. von Roemeling (Albany, USA) spoke on circadian time dependencies in toxicity of anticancer drugs. The research documented circadian changes in the toxicity of a new platinum (Pt) complex (B 850040) in mice. The time of least toxicity was associated with high antitumour efficacy against murine L1210 leukemia. No apparent correlation between tissue uptake of Pt and toxicity was found along the circadian time scale. D r Roemeling emphasized that four Pt complexes (cisplatin, carboplatin and oxaliplatin) have exhibited similar circadian rhythms in mice, as also shown by Boughattas er a/.,and hypothetized that common mechanisms may govern the chronopharmacology of these important drugs in oncology, These results stressed the relevance of undertaking Phase I chronopharmacologic studies with chemotherapeutic drugs, as was done for FUdr (1). These studies have demonstrated a marked improvement in treatment tolerance following circadian rhythm-modulated as compared to constant venous infusion of this drug. Such increase in patients’ tolerance allowed to significantly enhance dose intensities. As a result, the efficacy of continuous circadian delivery of FUdr was demonstrated in patients with advanced kidney cancer (3,4). D r Roemeling stressed that more than two circadian schedules should be compared in the future since extrapolation from murine studies performed with a single bolus dose to continuous circadian delivery in cancer patients may be hazardous. C. Focan (Likge, Belgium) discussed chronotherapy in lung and ovarian cancer. Circadian chronotolerance has been documented in animals for at least 20 anticancer agents; more recently circadian chronotolerance has also been established in man for adriamycine, THP-adriamycine, cisplatin and etoposide. Circadian chronoefficacy of chemotherapy was also shown in animal systems and suggested in human cancer (ALL, solid tumors). In this presentation, updated available results in ovarian and lung cancers have been reviewed, especially with reference to the trials held under
Chronobiology International the auspices of the “Association de Chronobiologie MCdicale (ACM) (Chairmen: F. LCvi and C. Focan). 1. Ovarian cancer. A set of researchers in the USA have established the circadian tolerance, in women treated for advanced ovarian carcinoma, of 2 main drugs: adriamycin (best time schedule: 0600 hr) and cisplatin (best time schedule: 1800 hr). Similarly, U v i et a/. ( 5 ) confirmed the circadian tolerance of THP-adriamycin in the same type of patients and was able to show a dose response and survival relationship. The ACM is actually conducting a multicentric randomized trial aiming to compare tolerance and efficacy in stage 111-IV ovarian cancer previously treated with optimal surgery of a first line chemotherapy with THP-adriamycin 50 mg/m2 (given a t 0600 (A) or at 1800 (B) and cisplatin-100 mg/m2 (infused 10 hours after THP-adria, from 16.0020.00 (A) or 4.00-8.00 hr (B). At present 125 patients have been enrolled in the trial. 2. Lung cancer. 124 cases with advanced nonsmall (NSC) and small (SC) cell lung carcinoma previously untreated with chemotherapy have been entered in a randomized evaluation comparing chemotherapy with cisplatin 100mg/mz given at 1800 hr on day 4 and etoposide 100 mg/m2 administered daily for 3 days either a t 0600(A)or a t 1800 (B). An interim analysis (ECCO V) on 76 patients (A: 41; B: 35) and 261 courses (A: 140; B: 121) confirmed lesser hematological toxicity in group A while cisplatin was better tolerated in group B (fewer dose reductions or delays: P < 0.01). However at present, no difference could be established either in the overall doseintensities of drugs (absolute doses o r relative doses given vs projected) or in the tumor outcome (response rate; survival). R. Smaaland (University of Bergen, Norway) presented research done by using the Colony Forming Unit of Granulo-Monocytes (CFUGM) cultured in vitro. (R. Smaaland, O.D. Laerum and co-workers). They investigated circadian rhythms in human myelopoiesis and their relation to flow cytometric measured DNA synthesis of total bone marrow cells and peripheral blood granulocytes. Circannual rhythms of CFU-GM were also investigated. Twenty-one healthy male volunteers
Chronobiol Int Downloaded from informahealthcare.com by Chulalongkorn University on 12/26/14 For personal use only.
Meeting Report
473
were punctured either in the sternum or at both allowed a large reduction of myelosuppression iliac crests every 4th hour during one 24-hour (4‘-0-tetrahydropyrabyladriamycin), renal necperiod, altogether 7 times. Their diurnal rhythm rosis (cisplatin) or heart failure (doxorubicin). was validated by determination of cortisol levels Plasma and tissue pharmacokinetics also at the same time points. A large circadian accounted for the dosing-time dependent hemavariation of CFU-GM was seen in all the tologic, renal or intestinal toxicities. The shortest individuals, with a difference between the lowest half-lives of both distribution (t 1/2a) and and highest colony number ranging from 47.1 to elimination (t I/21J) phases as well as least tissue 233.0% (mean difference = 136.8% as compared platinum uptake corresponded to dosing cisplatin to the mean colony number of each volunteer). or carboplatin at the least toxic time. However, no For the pooled data there was a significantly such correlation was found for oxaliplatin (6,7). lower colony number at 2400 hr as compared to Circadian rhythms in cellular metabolism also daytime (0800, 1200 and 1600hr; P < 0.05; contribute to those in drug toxicities. The ANOVA). The majority of the individuals activity of hepatic dihydropyrimidine dehydroshowed a circadian stage dependent covariation genase corresponded to the peak in plasma 5-FU between the CFU-GM and fraction of cells in catabolite formation (8). Enzymes such as DNA synthesis, and for the pooled data dihydrofolate reductase, which constitutes the demonstrating the same pattern of change along major biochemical target for methotrexate, also the circadian scale for the DNA synthesis as for exhibited a circadian variation which likely the CFU-GM, with a significantly lower DNA accounted for that in cellular resistance for this synthesis at midnight compared to 0800, 1200 drug. Dosing time-dependent tolerance has been and 1600 hr ( P < 0.05 and P< 0.005),respectively; documented for over 25 anticancer agents in ANOVA). There was significantly higher colony laboratory rodents and some of their mechanisms formation during summer as compared to winter isolated. Results have successfully guided the (68.2f7.9~~45.4f6.9)(MeanskS.E.;P
