A Recent Illustration of Some Essentials of Circadian Chronotherapy Study Design
Bibliographic record
Abstract
TO THE EDITOR: In 1985, a comparison of the circadian timing of doxorubicin 60 mg/m 2 and cisplatin 60 mg/m 2 given every 28 days to patients with large-volume stage III and stage IV ovarian cancer was published. 1 This comparison of morning doxorubicin and evening cisplatin with evening doxorubicin and morning cisplatin was based on studies in a rat model that predicted that morning doxorubicin followed by evening cisplatin would be less toxic and more effective. 2 The two circadian schedules, compared with one another, kept the order of the drugs constant and the interval between them constant, because other studies had shown that the sequence of and intervals between cytotoxic drugs are also temporal sources of potential relevance to both cytotoxic drug toxicity and efficacy. Patients treated with the morning doxorubicin and evening cisplatin schedule had fewer infections and fewer bleeding episodes; required fewer RBC transfusions; had less nausea, fewer vomiting episodes, and less emesis; had less severe renal damage; and experienced less frequent and less severe peripheral neuropathy. The WBC and platelet counts in patients treated with this schedule recovered by day 21, while the opposite circadian schedule resulted in cumulative marrow toxicity. This resulted in diminished dose intensity. At the same time, the patients treated with the least toxic schedule had a four-fold greater 5-year rate of survival. 3 These findings were confirmed with related drugs in European ovarian cancer patients. 4 A presentation of these data to the members of the Gynecologic Oncology Group (GOG) followed. The ovarian cancer committee had other priorities, but the endometrial cancer committee expressed interest, even though no chronotherapeutic data were available for that cancer. A single-arm study of 6 AM doxorubicin, followed by cisplatin 12 hours later, resulted in an unexpectedly high objective response rate in advanced endometrial cancer. 5 GOG investigators subsequently wished to determine whether circadian doxorubicin and cisplatin timing was relevant to toxicity and outcome in patients with advanced endometrial cancer, and insisted that the control arm not specify drug timing. The ultimate study design specified the order of drugs for both regimens, doxorubicin first and cisplatin second, and required that in the control arm, both drugs be given together, while in the circadian arm, these agents were to be given 12 hours apart.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.204 | 0.279 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.002 | 0.004 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.005 | 0.002 |
| Research integrity | 0.008 | 0.012 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; the direct Gemma label and the distilled Codex classifier agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".