Timing Affects Chemotherapy’s Effectiveness and Tolerability in Metastatic Colon Cancer

VILLEJUIF, France—Infusions of oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (LV) timed to circadian rhythms are better tolerated and have better anticancer activity in patients with metastatic colorectal cancer than the same drugs infused traditionally at a constant rate, said Francis Lévi, MD, PhD, chairman of the International Organization for Cancer Chronotherapy in the Department of Medical Oncology, Hôpital Paul Brousse, Villejuif, France.

He presented the results at the 36th annual meeting of the American Society of Clinical Oncology (ASCO).

In an interview with ONI, Dr. Lévi explained why timing makes a difference. “Experiments in mice have shown that the tolerability of over 30 anticancer drugs varies by 50% or more as a function of circadian dosing time,” he said. “The anticancer activity of most of these drugs is also usually better—by severalfold for some agents—if they are given at a time when they are best tolerated.”

He said that chronotherapy is also being tested in patients with pancreatic, biliary, breast, and lung cancers.

In the study reported at ASCO, Dr. Lévi and his collaborators pooled data from two previous trials of chronomodulated infusion of oxaliplatin, 5-FU, and leucovorin vs constant-rate infusion to determine their relative efficacy. All 278 patients had metastatic colorectal cancer.

In both arms, patients received 600 to 700 mg/m² of fluorouracil, 300 mg/m² of leucovorin, and 20 to 25 mg/m² of oxaliplatin each day for 5 days, followed by 16 days’ intermission before the cycle was repeated.

A total of 140 patients received the drugs in a constant infusion, while the other 138, with the help of a four-channel pump, received infusions that varied throughout the day.

Oxaliplatin was given from 10 AM to 10 PM, with a peak at 4 PM, and 5-FU and leucovorin were given from 10 PM to 10 AM, with a peak at 4 AM (see Figure).

Dr. Lévi told ONI that these times were chosen to coordinate with the circadian rhythms of several proteins important in cellular drug metabolism and proliferation, such as the enzyme dehydropyrimidine dehydrogenase, which catabolizes 5-FU.

“The introduction of a drug at a time when the normal body cells can eliminate it best results in less toxicity than constant exposure along the 24-hour time scale or exposure at other circadian times,” he said.

In the study, patients underwent CT scans every 2 months until progression.

Patients on chronotherapy tolerated the three-drug treatment better than the constant-rate patients did. Chronotherapy subjects had only one fifth as much severe mucosal toxicity and half as much peripheral sensory neuropathy, with both differences being statistically significant.

Efficacy was also better in the chronotherapy group. The primary endpoint of the study was objective response as determined by CT scans and independent review. Fifty-one percent of the chronotherapy group achieved an objective response, significantly better than the 30% response rate of the flat-infusion group.

For a secondary endpoint, median progression-free survival, the chronotherapy group again did better, although not significantly so (9.3 months vs 7.2 months).

After chemotherapy, some previously inoperable metastases shrank enough that patients were able to have them resected. Thirteen percent of the flat-infusion group and 23% of the chronomodulated-infusion group were able to undergo complete resection of such tumors. Dr. Lévi told ONI that this result showed that the chronotherapy was more active, with nearly twice as many patients in the chronotherapy arm rendered disease free.

Dr. Lévi and his coauthors also looked at time to treatment failure (which included withdrawal due to toxicity, death, or progressive disease as well as relapse after complete response or complete resection of metastases). Here again, the chronotherapy group did significantly better than the flat-infusion group, with a median time to treatment failure of 6.5 months vs 5.0 months.

At 5 years, the chronotherapy group had a survival rate of 11%, with a median survival of 16.5 months. A phase III trial is now investigating whether chronotherapy improves survival as well as response rate.

Dr. Lévi concluded that, compared with constant-rate infusion, chronomodulated infusion of oxaliplatin plus 5-FU/LV was better tolerated in metastatic colorectal cancer patients and produced a better response rate, including a highly significant 34% reduction in the relative risk of treatment failure.

“Chronomodulated chemotherapy with 5-FU, LV, and l-OHP [oxaliplatin] can be offered as first-line treatment in patients with metastatic colorectal cancer, with a 17% chance of being alive at 3 years and an 11% chance of being alive at 5 years,” Dr. Lévi told ONI.

He added, “These figures are unprecedented for the treatment of metastatic colorectal cancer. In order to achieve a similar survival, the patients in the flat-infusion arm had to suffer up to fivefold more severe side effects and to receive chronotherapy upon failure of the constant-rate infusion arm.”