Stage IV Colorectal Cancer: Oxaliplatin-Free Interval Predicts Oxaliplatin Sensitivity in Retreated Patients

BARCELONA—Patients with metastatic colorectal cancer were just as sensitive to a second course of treatment with an oxaliplatin-containing regimen as to the first, depending on the length of the oxaliplatin-free interval between the two treatment periods, according to the results of a study reported by French researchers at the ESMO World Congress on Gastrointestinal Cancer here. Aimery de Gramont, MD, Professor of Oncology at Hôpital Saint-Antoine in Paris, presented his group's findings from a study of 330 patients whose Stage IV colorectal cancer was treated initially either by surgery—with or without preoperative or postoperative FOLFOX (oxaliplatin, fluorouracil [5-FU], and leucovorin)—or FOLFOX therapy alone for unresectable metastatic disease. All patients were retreated with FOLFOX after a chemotherapy-free “holiday” or after an interval with maintenance therapy in which oxaliplatin was excluded. The study confirmed—as expected—that sensitivity to oxaliplatin the second time around was proportional to the response and progression-free survival (PFS) time at first administration of FOLFOX: the PFS/overall survival rates ranged from 8.7 to 19.5 months among patients with a complete response (CR) to 3.2 to 9.7 months in patients who only achieved stable disease. But Dr. de Gramont and his colleagues also found that oxaliplatin sensitivity increased markedly in proportion to the length of the oxaliplatin-free interval, and that this effect was found whether FOLFOX was reintroduced to treat relapse or was part of a chemotherapy “stop and go” strategy. “If you have an oxaliplatin-free interval of one year you have a very sensitive population to oxaliplatin reintroduction,” Dr. de Gramont said. “And you can expect the same results as with oxaliplatin in first-line in the advanced setting.” Among these patients, progression-free survival was seven months, and overall survival was 22 months. When the interval was between six and 12 months, median progression-free survival was five months and overall survival was 17 months—“But the results are still better than any second-line therapy,” he said. And patients who had the shortest interval without oxaliplatin still had partial responses, indicating that oxaliplatin was still effective the second time—patients with less than a six-month interval from the end of initial oxaliplatin treatment to the start of retreatment still had a median progression-free survival of three months and overall survival of nine months.AIMERY DE GRAMONT, MD, said he and his colleagues now want to look at the efficacy of using oxaliplatin in patients who received it first as adjuvant therapy, or whose initial therapy included irinotecan or a targeted agent.“It's not a fully resistant population—you still have response even if the interval is less than three months, and results are in the range of those of second- and third-line therapies,” Dr. de Gramont noted. He said they still need to look at the efficacy of using oxaliplatin among patients who first received it as adjuvant therapy, or whose initial therapy included irinotecan or a targeted agent. The study concluded that a prolonged interval between two FOLFOX therapies, or a prolonged progression-free survival at first-line FOLFOX predict the efficacy of oxaliplatin reintroduction, and that a shorter oxaliplatin-free period still does not identify a completely refractory population. Question-and-Answer Period One of the questions Dr. de Gramont was asked was whether there was any difference between patients who had FOLFOX before rather than after surgery. He replied that the numbers of patients in each group was very small—only 22 and 23, respectively—so it wasn't possible to draw any conclusions. Regarding neurotoxicity, Dr. de Gramont explained that to enter the study and qualify for oxaliplatin reintroduction patients needed to have less than Grade 2 neurotoxicity, so that was not a problem. Another audience member wanted to know if there were plans to examine cell make-up to identify populations of platinum-sensitive cells, since the results of platinum reintroduction were very similar to what has been documented in ovarian cancer. “It's true that we observed almost the same finding, but we could not find a refractory population except for the patients who have progression on oxaliplatin,” Dr. de Gramont replied, noting that even if patients had a very short break, there are still those who can respond to oxaliplatin. Even so, though, data implicating differences between cell populations in ovarian cancer are not that clear, he said. Another audience member asked if reintroducing oxaliplatin was necessarily different from using another agent such as irinotecan, since the interval before progression is a prognostic factor and not necessarily a predictive factor for oxaliplatin rather than another agent. Dr. de Gramont said that he and his colleagues are now waiting for results among patients receiving irinotecan as first-line treatment, and that they did not yet have a population to study. Capecitabine Equivalent to 5-FU in Irinotecan-Bevacizumab Regimens In another study reported at the meeting, a Phase II trial showed that adding the oral drug capecitabine was as effective as adding infusions of 5-FU/folinic acid (FA) to a bevacizumab-irinotecan regimen in patients with metastatic colorectal cancer. Michel Ducreux, MD, PhD, Head of the Gastrointestinal Service at Institut Gustave Roussy in Villejuif, France, presented findings from the FNCLCC ACCORD 13/0503 study of 145 patients randomized to receive either bevacizumab plus FOLFIRI (5-FU, FA, irinotecan) every two weeks for 12 cycles (in the reference arm) or bevacizumab plus XELIRI (capecitabine, irinotecan) with capecitabine given twice a day for two weeks at a dose of 2000 mg/m2 every day, for 14 days, and irinotecan plus bevacizumab given every three weeks for eight cycles. Patients older than 65 received a lower daily dose of capecitabine (800 mg/m2 bid) to minimize the risk of side effects such as diarrhea, and bevacizumab was continued until disease progression. The objective response rate was 58% in both groups, and the “crude” six-month progression-free survival rate was 84% for the FOLFIRI patients and 79% for those receiving XELIRI—essentially the same. Overall survival was 23 months in both groups of patients. “Capecitabine is a very interesting drug because it can be given to patients as an oral drug,” Dr. Ducreux said in an interview. “Patients need to go to the hospital only once every three weeks, so it is quite convenient for them. “It is now clear that XELIRI plus bevacizumab could be considered one of the front-line standards of care for patients with metastatic colorectal cancer.”MICHEL DUCREUX, MD, PHD, said that due to capecitabine's convenience, he was now in favor of beginning therapy with XELIR-bevacizumab most of the time and switching to 5-FU only if problems with diarrhea emerge.Increased Diarrhea During the question-and-answer period, he was asked if the higher incidence of diarrhea noted with capecitabine was an issue for the patients in the study. “You have to consider that 5-FU was more toxic in terms of neutropenia, so there is some kind of balance,” he replied. Correct dosing was key, and he and his colleagues found that correct dosing of capecitabine, irinotecan, and bevacizumab “could achieve a highly effective regimen without major problem in terms of safety.” Dr. Ducreux said that due to capecitabine's convenience, he was now in favor of beginning therapy with XELIR-bevacizumab in most patients and switching to 5-FU only if problems with diarrhea emerge. Another question was about the 12% rate of Grades III and IV thrombosis among patients receiving XELIRI, a rate also seen in a European Organization for Research and Treatment of Cancer study and why that rate was higher than with FOLFIRI. Dr. Ducreux said he did not have a specific explanation, but in any case, the problem was not that severe. More Expensive? As for the additional cost of using capecitabine rather than 5-FU, he said that even though the drug itself costs more, administering 5-FU requires professionals in attendance—“If you consider the global cost of administering the FOLFIRI regimen, you have to consider the fact that you have to give 48-hour infusions, and this is costly.” Individualization, though, is key, he emphasized. “Capecitabine is not so easy for older patients, because there is a risk they could forget they have taken the pills. And for active patients who want to continue to work, it could be very important to go to the hospital and receive chemotherapy only every three weeks rather than every two weeks and to take pills between the two IV administrations. “Capecitabine could be very interesting for younger patients who want to continue to work and who are clearly able to manage their own treatments.”