Circadian chemotherapy for gynecological and genitourinary cancers

CIRCADIAN CHEMOTHERAPY FORGYNECOLOGICAL AND GENITOURINARY

CANCERS

Minoru Kobayashi,1 Patricia A. Wood,2 andWilliam J. M. Hrushesky3,*

1WJB Dorn VA Medical Center/Department of Developmental Biology

and Anatomy, The University of South Carolina School of Medicine,

6439 Garners Ferry Road, Columbia, SC 292092Department of Pathology and Oncology/Hematology, WJB Dorn VA

Medical Center/The University of South Carolina School of Medicine,

6439 Garners Ferry Road, Columbia, SC 292093WJB Dorn VA Medical Center, Norman J. Arnold School of Public

Health, The University of South Carolina School of Medicine,

6439 Garners Ferry Road, Columbia, SC 29209

ABSTRACT

The circadian timing of surgery, anticancer drugs, radiation therapy, and

biologic agents can result in improved toxicity profiles, tumor control, and

host survival. Optimally timed cancer chemotherapy with doxorubicin or

pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced

ovarian cancer while minimizing side effects, and increased the response rate

in metastatic endometrial cancer. Therapy of metastatic bladder cancer with

doxorubicin–cisplatin was made more tolerable by this same circadian

approach resulting in a 57% objective response rate. This optimally timed

therapy is also effective in the adjuvant setting, decreasing the expected

frequency of metastasis from locally advanced bladder cancer. Circadian

fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given

between 15:00h and 21:00h) has been shown effective for metastatic renal cell

carcinoma resulting in 29% objective response and stable disease of more than

237

Copyright q 2002 by Marcel Dekker, Inc. www.dekker.com

*Corresponding author. Fax: (803) 695-6829; E-mail: [email protected]

CHRONOBIOLOGY INTERNATIONAL, 19(1), 237–251 (2002)

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1 yr duration in the majority of patients. Toxicity is reduced markedly when

FUDR infusion is modulated to circadian rhythms. In a multicenter trial in

patients with metastatic renal cell cancer, patients were randomized to a flat or

a circadian-modified FUDR infusion. This study confirmed a significant

difference in toxicity and dose intensity, favoring the circadian-modified

group. Hormone refractory metastatic prostate cancer has been treated with

circadian-timed FUDR chemotherapy; however, without objective response.

Biological agents such as interferon-a and IL-2 have shown low but effective

disease control in metastatic renal cell cancer, however, with much toxicity.

Each of these cytokines shows circadian stage dependent toxicity and efficacy

in model systems. In summary, the timing of anthracycline, platinum, and

fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic–

therapeutic ratio of these agents in the treatment of gynecologic and

genitourinary cancers. (Chronobiology International, 19(1), 237–251, 2002)

Key Words: Chemotherapy; Chronotherapy; Circadian Rhythm; Gynecolo-

gical cancer; Genitourinary cancer

This brief review focuses upon the rationale and results of circadian-timed cancer

chemotherapy for gynecological (e.g., ovarian, endometrial) and genitourinary

(e.g., bladder, kidney, and prostate) cancers. The timing of chemotherapy within

the circadian cycle has been shown to affect the toxic–therapeutic index at least to

some extent of those medicines used to treat these cancers.

CIRCADIAN CYTOKINETIC RHYTHMS IN GYNECOLOGICALAND GENITOURINARY CANCERS

Circadian cytokinetic studies on human tumors are rather difficult to perform

because of the need for repeated biopsy. In one study of subcutaneous metastasis

in cervical cancer, the circadian profile of cell proliferation measured by mitotic

index and in vitro labeling index was similar to that in skin cancers. The peaks of

mitotic and labeling index each occur around midnight and noon, respectively (1).

Klevecz (2) examined tumor and normal mesothelial cell DNA synthesis in

peritoneal lavage fluid taken from more than 30 patients with ovarian cancer

(Fig. 1). These specimens were obtained every 1–3h for up to 72h. Circadian

rhythms of the cell cycle phase distribution by DNA content of these normal and

malignant cells were examined. Malignant and benign cells were identified by

flow cytometry with a combination of DNA content and concurrent cell-type

specific staining. The distribution of G2 and S phase (DNA synthesis) cells in each

population was evaluated with reference to the time of day of sampling in the

presumably diurnally active women. Average DNA synthesis was lowest in the

diploid mesothelial cell population, highest in the aneuploid malignant cell

KOBAYASHI, WOOD, AND HRUSHESKY238

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population, and intermediate in the diploid tumor cell population. A highly

significant circadian rhythm in tumor cell DNA synthesis was found in both

diploid and aneuploid tumor cells as well as in normal diploid mesothelial cells.

The peak of DNA synthesis in tumor cells (mid to late morning) was about 12h

apart from the peak in benign mesothelial cell DNA synthesis (evening). The time

of the circadian peak of DNA synthesis differed greatly between the malignant and

benign cell populations, while the degree of daily variation around the daily mean

level was similar for each cell population. These data suggest that ovarian cancer

cells are, to some extent, in communication with the circadian kinetic pacemaker

of patients with ovarian cancer and that cell-cycle specific therapy should be

thereby more effective if delivered at certain times of the day.

Considered together, these data, limited though they are, raise the possibility

that the circadian time structure of DNA synthesis and/or mitosis is determined not

by whether a cell is benign or malignant but rather by the tissue of origin of that

cell, i.e., its ontogeny. To test this hypothesis, however, benign and malignant

tissue samples of the same cell type must be obtained concurrently, around the

clock. This has been done in a single carefully studied patient with epidermoid

carcinoma (3). This patient remained normally circadian synchronized to her

Figure 1. Circadian rhythm characteristics of the cell-cycle phase distribution of three types of

cells in ovarian tumor cells: diploid mesothelial cells, diploid tumor cells, and aneuploid tumor cells.

The average percentage of each cell population in S þ G2 phase determined by flow cytometry is

depicted by three cosine functions best fitting the raw data; 24h mean S þ G2 phase percentages are

lowest in benign mesothelial cells, higher in diploid cells, and the highest in aneuploid cancer cells.

The daily peaks and troughs of the benign and malignant cells are almost 12h out of phase, while

aneuploid and diploid cancer cells share similar circadian patterns.

GYNECOLOGICAL AND GENITOURINARY CANCERS 239

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environment despite widespread metastatic cancer. The cell division (mitosis) of

her normal skin cells and skin-derived metastatic cancer also remained similarly

circadian coordinated, but cell division in cancer compared to noncancerous cells

was threefold greater during the times of day when the circadian control system

permitted cell division.

CIRCADIAN-TIMED DOXORUBICIN/CISPLATINCHEMOTHERAPY OF OVARIAN CANCER

Pre-clinical studies have defined the circadian time when host tolerance to

doxorubicin and cisplatin is best and worst (4–9). When doxorubicin is given to

tumor-bearing rats just before awakening and cisplatin is given late in the daily

activity span, the times during the 24h when the respective medications cause least

toxicity, tumor response frequency, complete remission rate, and cure rate are each

higher than if equal doses of the drugs are given at the wrong circadian times (10). In a

clinical study based upon these findings, 37 patients with advanced (bulky stage III or

IV) ovarian cancer were randomized to receive doxorubicin 60 mg/m2 at 06:00h

(schedule-A) or 18:00h (schedule-B), with cisplatin 60 mg/m2 given 12h later,

monthly for 9 mon (11,12). Cumulative bone marrow toxicity was greatest in patients

treated with schedule B. The majority of schedule B patients also experienced a

greater than 33% reduction of doxorubicin dose and/or treatment delays because of

bone marrow toxicity. Schedule A patients experienced fewer dose reductions and

Figure 2. The frequency of treatment complications or dose-schedule modifications according to

the different circadian schemes of chemotherapy for advanced ovarian cancer. Patients treated with

evening doxorubicin and morning cisplatin (schedule B) experienced twice as many toxic reactions

as those given therapy at an opposite circadian time (schedule A). Moreover, evening doxorubicin

and morning cisplatin (schedule B) resulted in fourfold as many dose reductions and treatment

delays.


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treatment delays as well as fewer episodes of infection and bleeding and required only

half as many blood transfusions (Fig. 2). Cisplatin-induced gastrointestinal (GI)

toxicity, neurotoxicity, and nephrotoxicity were also diminished markedly by

administration of cisplatin in the evening. Additionally, average achievable dose

intensity, in mg/kg/wk or percentage of planned dose intensity, was lower for

schedule B than schedule A. This prospectively randomized study also demonstrated

a fourfold survival advantage for those patients treated with schedule A. At 5 yr, the

probability of survival for patients treated with schedule A was 44% compared to only

11% for those treated with schedule B (Fig. 3).

CIRCADIAN-TIMED PIRARUBICIN AND CISPLATINCHEMOTHERAPY OF OVARIAN CANCER

The efficacy and toxicity of circadian-timed pirarubicin (50 mg/m2, 1h bolus) in

association with cisplatin (100 mg/m2, 4h infusion) was assessed in 31 patients with

advanced ovarian cancer (13). Twenty-eight patients with ovarian cancer were

assessable for toxicity and 25 for treatment response (4), IIIb (15), IV (6). Nine

patients had received prior treatment. Patients were randomized to receive schedule A

(pirarubicin at 06:00h then cisplatin from 16:00h to 20:00h) or schedule B

(pirarubicin at 18:00h then cisplatin from 04:00h to 08:00h). Schedule A was

hypothesized to be less toxic since pirarubicin was found to be best tolerated in the late

Figure 3. Complete remission rate of rat solid tumor (A) or 5 yr survival rate in patients with

ovarian cancer (B) according to the different circadian timing of chemotherapy treatment. In the rat

model, a 2.5-fold higher complete tumor remission was achieved when doxorubicin was given at the

usual time of daily awaking and cisplatin given later in the daily activity span compared to when

cisplatin was given at the usual time of awaking and doxorubicin given later in the daily activity

span. In women with ovarian cancer, the probability of 5 yr survival was higher if doxorubicin and

cisplatin were administered at the predicted optimal circadian times.


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rest span and cisplatin near the middle of the activity span in pre-clinical studies

(14,15). Clinical complete response (CR) occurred in 52%, and partial response (PR)

in 12%, with an overall objective response rate of 64% (schedule A, 73%; schedule B,

57%). Median disease progression-free interval and overall survival times were 10

and 19 mon, respectively. Of 12 patients in clinical CR evaluated at second-look

laparotomy, four had a pathological CR (33%), and 3 had microscopic residual

disease. The overall rate of pathological CR was 16%. Schedule A was associated

with significantly less myelosuppression and renal toxicity than schedule B. Of the

total of four patients withdrawn for toxicity, three were on schedule B (one death).

The median dose intensities (DIs) of pirarubicin and cisplatin had to be reduced by 30

and 47%, respectively, because of side effects over the five initial courses of

treatment. The decrease was significantly more pronounced for schedule B than

schedule A in previously untreated patients. Pirarubicin and cisplatin are active

against advanced ovarian cancer, and in diurnally active patients its toxicity can be

modulated significantly by scheduling this anthracyclin early in the morning and

cisplatin late in the afternoon, as compared with the more toxic schedule of

pirarubicin in the evening and cisplatin in the morning.

CIRCADIAN-TIMED DOXORUBICIN AND CISPLATINCHEMOTHERAPY FOR ENDOMETRIAL UTERINE CANCER

Patients with advanced or recurrent endometrial cancer were treated with

circadian-timed doxorubicin–cisplatin chemotherapy to determine its effectiveness

and toxicity (16). This phase II study prescribed doxorubicin 60 mg/m2 over 30 min at

06:00h followed by cisplatin 60 mg/m2 over 30 min at 18:00h every 28 d. This

monthly treatment was continued for eight cycles or to a maximum tolerable

doxorubicin dose of 480 mg/m2 for patients without progression. Thereafter,

responders continued on cisplatin alone. A review of 30 evaluable patients showed six

(20%) CR, 12 (40%) PR, and seven (23%) stable disease. The number of treatment

courses ranged from two to 14 with a median of 6.5. The median white blood cell nadir

for the 27 patients experiencing leukopenia was 1600 per mm3. For the 16 patients

experiencing thrombocytopenia, the median nadir was 48,500 per mm3. There were

no treatment-related deaths. Circadian-timed delivery of doxorubicin–cisplatin

chemotherapy was reasonably well tolerated and demonstrated a 60% notable

response rate in patients with advanced or recurrent endometrial carcinoma.

HIGH-DOSE INTENSITY, CIRCADIAN-TIMED DOXORUBICIN,AND CISPLATIN CHEMOTHERAPY FOR METASTATIC

BLADDER CANCER

Forty-three patients with widely metastatic transitional cell carcinoma of the

bladder were treated with a high-dose intensity, circadian-timed doxorubicin


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(morning) and cisplatin (evening), followed by cyclophosphamide, 5-FU, and

cisplatin maintenance for up to 2 yr (17). Fifty-seven percent of the 35 evaluable

patients with widespread metastatic cancer responded objectively. Twenty-three

percent had complete disappearance of all cancer. Median survival from first

treatment for complete responders was more than 2 yr and for partial responders

1 yr. Three of the complete responders were alive without evidence of cancer for

more than 2 yr after ceasing all therapy. High-dose intensity circadian-timed

combination chemotherapy can induce durable CR of widespread bladder cancer

in the majority of patients resulting in excellent quality of life and only moderate

toxicity.

HIGH-DOSE INTENSITY, CIRCADIAN-TIMED DOXORUBICIN,AND CISPLATIN ADJUVANT CHEMOTHERAPY FOR

LOCALLY ADVANCED BLADDER CANCER

Thirteen patients with bladder cancer received monthly circadian-timed

doxorubicin (morning)–cisplatin (evening) chemotherapy immediately after radical

cystectomy for nine planned monthly treatments. In five patients, cancer had spread

through the serosa of the bladder wall and/or into the perivesical fat (stage C) (18). In

eight patients, cancer had spread to other pelvic tissue and pelvic lymph nodes (stage

D1). Ten of the 13 patients showed no recurrence of disease after a median follow up

period of 3.5 yr; these patients had received no chemotherapy for a median duration of

3 yr following initial chemotherapy. Two of three patients who ultimately failed

treatment had local tumor recurrence that occurred much later than is the usual case

(40 and 52 months). This circadian-timed two-drug regimen, given in full doses for

nine courses as adjuvant treatment, delays and may prevent local and distant

recurrence of locally advanced bladder cancer. This circadian based adjuvant

chemotherapy consisting of morning doxorubicin and evening cisplatin is well

tolerated compared to other combination regimens.

CIRCADIAN-SHAPED FLUORODEOXYURIDINECHEMOTHERAPY ENHANCES ITS THERAPEUTIC INDEX

Seven equal doses of fluorodeoxyuridine (FUDR) were administered either

at a variable or constant rate to female F344 rats standardized for rhythm study to

test if circadian timing of FUDR is important for its toxicity and anti-tumor

activity (19). For the variable rate infusion, the daily dose of FUDR was

proportioned into four 6h portions, respectively of 68, 15, 2, and 15%, to achieve a

quasi-sinusoidal pattern. Peak drug delivery occurred during one of six different

times of day. At a dose level resulting in 50% overall mortality, lethal toxicity

differed significantly, depending upon the circadian stage of maximum drug flow.

Variable-rate infusions were more toxic than, or as toxic as, constant-rate infusion.


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The FUDR lethality was lowest when constant-rate infusion was used or when

variable-rate infusion peaked during the late activity to early rest span. The

circadian pattern of variable-rate infusion also determined antitumor activity in

tumor-bearing rats. At a therapeutic dose level and at identical dose intensity, the

variable rate infusion pattern, with peak drug flow coinciding with the late activity

to early rest span, resulted in significantly greater delay in tumor growth than

observed with either the constant-rate infusion or other variable-rate patterns. The

toxicity and antitumor activity of FUDR depended on the circadian timing of the

infusion peak when the drug is given by variable-rate infusion. Since some of the

circadian-shaped infusions studied are toxicologically and therapeutically inferior

to constant-rate infusion, this supports the conclusion that the circadian pattern,

and not the quasi-intermittency of circadian FUDR administration, is primarily

responsible for the observed pharmacodynamic differences.

CIRCADIAN-SHAPED INFUSIONS OF FLUORODEOXYURIDINEFOR PROGRESSIVE METASTATIC RENAL

CELL CARCINOMA

Sixty-eight patients with progressive metastatic renal cell carcinoma (RCC)

were treated with continuous infusion FUDR on an outpatient basis (20). Thirty-

seven percent of these patients had previously failed other systemic treatment.

Using implantable pumps for automatic drug delivery, FUDR was continuously

infused for 14 d at monthly intervals. The starting dose was 0.15 mg/kg/d (iv;

n ¼ 61) or 0.25 mg/kg/d (intra-arterial [ia]; n ¼ 7); iv doses were increased or

decreased in increments of 0.025 mg/kg/d as permitted by toxicity. Diarrhea (with

or without mild abdominal cramping) and nausea/vomiting limited FUDR iv

infusion, and hepatic function abnormalities limited FUDR ia infusion. The use of

a circadian-modified infusion schedule, in which 68% of the daily dose was

administered between 15:00h and 21:00h, permitted higher FUDR doses to be

safely given compared to a constant rate infusion schedule. Of 63 patients

accessible for response, 56 received systemic FUDR infusion. Four CR (7.1%);

and seven PR (12.5%) were observed (objective response rate 19.6%). The median

objective response duration was 10.8 mon. Four additional patients showed minor

tumor responses (7.1%) (Table 1). In a subgroup of seven accessible patients given

hepatic arterial FUDR for metastatic RCC limited to the liver, we observed one

CR and three PR (57.2%). Overall, objective response was seen in a quarter of

accessible patients treated, 15 of 63, while only 15 of the 63 as patients (25.4%)

had objective tumor progression. The median follow-up time for all 68 patients

was 28 mon and their median survival duration 15 mon. Continuous, circadian-

modulated infusion of FUDR is an effective outpatient treatment for progressive

metastatic RCC, producing durable tumor response and causing little toxicity.

In the phase III study, 116 patients with metastatic RCC were randomized

to a flat or a circadian-modified infusion of FUDR for 14 d every 28 d and 104


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patients were available for the data analysis (21). In the circadian-modified arm,

65% of the daily dose was given from 20:00h to 02:00h. The starting dose was

0.125 mg/kg/d. They received a median of three courses of chemotherapy (1–

22 courses) and median follow-up of surviving patients was 12 mon. Diarrhea,

the dose-limiting toxicity, was less frequent in the circadian-modified arm.

There were two deaths related to dehydration caused by diarrhea. The median

dose by the fifth course was 0.175 mg/kg/d. More dose escalation was achieved

and less dose reduction was required in the circadian-modified arm. One CR

and 10 PR were observed (objective response rate; 11.5%). Responses

continued in 8/11 patients at a median of 12 mon. An additional 12 patients

(11.5%) remained progression-free for over 1 yr. At 1 yr, failure-free survival

was 35% and overall survival 45%. The difference in toxicity between the flat

and circadian-modified infusion of FUDR was validated. The response rate was

similar to that seen with interferon and/or interleukin-2 treatment; however, it

was more durable.

CIRCADIAN-SHAPED INFUSIONS OF FLUORODEOXYURIDINEFOR HORMONE REFRACTORY METASTATIC

PROSTATE CANCER

A phase-II trial of FUDR circadian infusion in hormone-refractory

metastatic prostate cancer has been reported (22). Fluorodeoxyuridine

(0.15 mg/kg/d) was delivered such that approximately 70% of the drug was

administered between 15:00h and 21:00h and 30% was during the rest of the day

for 14 d every 4 wk. Two of 18 evaluable patients (11.1%) showed a decrease in

PSA lasting 5–8 mon. Neither objective responses nor improvement in bone scans

was noted. The major toxicity was moderate to severe diarrhea. Fluorodeoxyur-

idine chemotherapy was tolerable, but it was not effective for hormone refractory

metastatic prostate cancer.

Table 1. Responses to Circadian-Modulated Fluorodeoxyuridine Infusion in Metastatic Renal Cell

Carcinoma (from Ref. (20)

Assessable CR PR MR SD PD

No. of patients 56 4 7a 4 26 15

Proportion (%) 100 7.1 12.5 7.1 46.4 26.9

Durationb

(months; mean ^ SD)

9.3 ^ 1.4 9.4 ^ 2.1 6.0 ^ 2.8

Abbreviations: SD; stable disease, PD; progressive disease.a Two patient in PR undrewent surgical resection of residual tumor and revealed surgical CR.b Duration of treatment: all 61 patients; 8.1 ^ 0.8 mon.


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CIRCADIAN-MODULATED INTERFERON INFUSION FORGENITOURINARY TRACT CANCERS

Only two phase I studies (23,24) of the circadian infusion of genitourinary

tract cancers with interferon-a have been reported, and each involved only a small

number of patients. It is noteworthy that two objective responders were observed

in patients with previously treated metastatic renal cell cancer. Circadian infusion

enabled a large increment in total daily dose and dose intensity, although there was

large inter-patient variability in the maximally tolerated dose compared to

standard administration or continuous flat infusion (Table 2).

DISCUSSION

Clinical trials to date have confirmed preclinical findings that optimal timing

of chemotherapy to circadian rhythms can lead to decreased toxicity and allow

delivery of a more dose-intense therapy. Several prospective randomized studies

also have demonstrated a better objective response rate and/or survival in free-

living genetically distinct patients with advanced metastatic ovarian, bladder, and

kidney cancer given circadian-based chemotherapy (11,12,21).

In spite of this clinical evidence, many problems still must be resolved for

cancer chronotherapy to be considered a routine tool for improving the results of

human cancer treatment. On the basis of animal data, the initial drug

administration may or may not induce disturbances in the spontaneous circadian

rhythms of cell division in normal and tumor tissues. This could theoretically lead

to a change in drug sensitivity of target cells. Clinical trials with continuous

multiday infusion and intermittent therapies demonstrating reproducible circadian

day outcome differences mitigate, to some extent, against this theoretical

possibility. Moreover, when drugs are given in combination in the same cycle of

treatment, they may have complex effects upon one another’s optimal timing of

administration. It is common in advanced cases of ovarian, uterine, or bladder

cancer treatment to use several cycles of treatment consisting of combinations of

three or more drugs. So far, chronotoxicity and chronoefficacy have been

documented only when a couple of drugs have been administered. It has, for

example, become increasingly common to use FUDR in combination with

interferon and/or interleukin-2 to enhance the limited response of each single

agent in the treatment of advanced renal cell cancer. Only two phase I studies of

the circadian infusion of interferon-a have been conducted on a small number of

patients with urinary tract cancers (23,24). Circadian clinical studies of these

recombinant proteins are essential, not only as single agents but also in

combination therapy to confirm their clinical feasibility.

The advent of new agents and techniques, such as myeloid growth factors,

strong anti-emetic agents (serotonin S3 receptor antagonist), and autologous

peripheral blood stem-cell transplantation, attenuates the hematological or emetic


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toxicity of chemotherapeutic drugs. However, gastrointestinal toxicity is more

debilitating when using FUDR for metastatic renal cell cancer and chronotherapy

has remained a valuable tool for treatment with this chemotherapy. Recently, high-

dose chemotherapy with autologous peripheral blood stem-cell transplantation and

granulocyte-colony stimulating factor has been attempted to achieve high-dose

intensity and to overcome myelotoxicity especially in advanced or refractory

ovarian and testicular cancers. Chronobiologic administration of salvage agents as

well as chemotherapeutic drugs is likely to enhance the utility of colony-

stimulating factors, growth factors, cytokines, and other biological therapies. It

appears that the circadian time structure is sometimes altered in cancer patients.

Those with less advanced cancer and better performance status show better

circadian rhythmicity (25,26), making these individuals the best candidates for

chronotherapy trials. Nevertheless, the evidence provided in this review

demonstrates clearly that even patients with advanced gynecological and

urogenital cancer can benefit from optimal circadian-timed chemotherapy.

Attempts to organize circadian time structure in cancer patients by behavior, light,

melatonin, or other hormonal and pharmacologic means might result in a still

better outcome of circadian-timed therapy or a better quality of life. This remains

an open and interesting question ripe for clinical study.

ACKNOWLEDGMENT

This work was supported in part by VA Merit Award (WJMH), National Institute of

Health grant RO1 CA31635 and RO1CA50749 (WJMH), NYS Breast Cancer Research

Program grant (WJMH), ARMY IDEA grant (WJMH), and the Robison Family

Foundation (WJMH).

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Documents

Circadian chemotherapy for gynecological and genitourinary cancers