BARCELONA—The optimal duration of chemotherapy for metastatic colorectal cancer remains controversial. In a session here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, one expert argued that continuous maintenance is mandatory, while another recommended an intermittent schedule with “drug holidays.”
Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, said that maintenance therapy in first-line is a crucial component of treatment in prolonging a patient's life, and maintaining quality of life using the least amount of therapy necessary to control the disease.
The other speaker, Roberto LaBianca, MD, Chief of the Department of Oncology Hematology at Ospedale Papa Giovanni XXIII in Italy, said that treatment interruptions, or chemotherapy-free intervals, appear to be safe and desirable, especially considering the toxicities of treatment.
Axel Grothey: Maintenance Is Mandatory
Axel Grothey, MD, began: “The goal of palliative therapy, as I tell my patients, is to extend a patient's life and maintain quality of life as long as possible, using the least amount of treatment necessary to control the disease.
“And we have been quite successful at doing this—median survival in clinical trials is three years, and all of us have patients in our clinical practice who survive metastatic disease for five and six years.”
He said that early on, the cumulative neurotoxicity of oxaliplatin-based first-line therapy led to trials investigating stop-and-go strategies, because patients often had to discontinue therapy before they even had disease progression. “In the last decade, first-line progression-free survival in the chemo-biologic era has not changed, although overall survival continues to improve, mainly due to post-progression therapy. We just have more tools available, and maintenance therapy is one of these tools.
“We overemphasize what first-line therapy can do. We really need to talk about a treatment strategy that extends a patient's life, and maintenance therapy is a part of it.”
Grothey noted that the first major trial of intermittent-versus-continuous therapy was the MRC CR06 trial, published in 2003 (Maughan et al: Lancet 2003;361:457-464). And although that trial didn't show clear evidence of a benefit in continuing therapy indefinitely until disease progression, “it was conducted at a time when we were using oxaliplatin and 5FU-mitomycin.”
The OPTIMOX studies subsequently put this idea in question, he said, particularly OPTIMOX-2, which tested maintenance therapy versus a chemotherapy-free interval (Chibaudel et al: JCO 2009;27:5727-33). “This actually showed a potential detriment to stopping treatment and not continuing some maintenance therapy,” Grothey said. “It was not a statistically significant difference for overall survival—which the study was not powered to show—but there clearly was a statistically significant difference for progression-free survival with continuous therapy.”
Grothey said he expected LaBianca to cite a recent meta-analysis of continuous versus intermittent therapy by Scott Berry et al (Ann Oncol 2015;26:477-485), which showed no significant overall survival benefit for continuous therapy.
“The problem, though, is that the trials in the meta-analysis included very heterogeneous treatment approaches, including trials that had maintenance in both study arms such as OPTIMOX-1,” Grothey said.
“Also, maintenance therapy was not necessarily rationally designed in these trials, and key trials such as AIO 0207 [Arnold et al: ASCO 2014, Abstract 3503] and DREAM [Chibaudel et al: ESMO 2014, Abstract 4970] were not included in the meta-analysis.”
“If we really want to use a maintenance therapy, fluoropyrimidine-bevacizumab is probably the best way,” Grothey said. He cited the Phase III trial comparing IFL (irinotecan-fluorouracil [5FU]/leucovorin [LV]) plus placebo, IFL plus bevacizumab, and 5FU/LV plus bevacizumab (Hurwitz et al: NEJM 2004;350:2335-2342).
“The 5FU/LV-bevacizumab arm was on par with the IFL-bevacizumab arm. Fluoropyrimidine-bevacizumab is a very active treatment approach.”
Grothey also cited the prospective U.K. AVEX trial (Cunningham et al: Lancet Oncology 2013;11:1077-1085) of capecitabine with or without bevacizumab in previously untreated patients with metastatic colorectal cancer, which showed a highly statistically significant progression-free survival benefit for the combination.
He said the effect of maintenance therapy versus no treatment is best illustrated in the CAIRO-3 trial (Simkens et al: Lancet 2015; 385:1843-1852): “We all would agree that CAIRO-3 clearly showed maintenance therapy delaying tumor progression with a rationally designed regimen of a fluoropyrimidine—capecitabine in this case—plus bevacizumab. And there was no clinically relevant difference in quality of life between maintenance and observation.”
Grothey summarized his argument as follows:
- There is clear evidence that tumor control is prolonged in first-line therapy when maintenance strategies are used;
- Maintenance therapy with fluoropyrimidine plus a VEGF inhibitor has good clinical rationale and very limited side effects;
- Maintenance strategies are mandatory to mitigate toxicities from first-line therapy—in particular, when oxaliplatin is used as a component of upfront therapy; and
- The maintenance setting can be a very attractive platform for drug development, and is actually being used as such in the randomized FOCUS 4 and MODUL trials.
“Maintenance therapy is a part of our treatment strategy that can prolong survival for patients. It's not one breakthrough event that changed the landscape in colorectal cancer; it's the addition of a lot of rational uses of sequential approaches.”
Roberto LaBianca: Chemotherapy-Free Intervals
The main message from Roberto LaBianca, MD was that in the absence of compellingly negative data, treatment interruptions, or chemotherapy-free intervals, appear to be safe and desirable.
“Continuation of therapy until progression is always needed in metastatic colorectal cancer, as the disease can now be considered a chronic disease, with median survival beyond two years and even more,” he said. “But it can have heavy side effects—chiefly cumulative, but also acute, and chiefly related to oxaliplatin and neurotoxicity.
“These toxicities influence the potential duration of therapy, even in responding patients, and they also influence the patient's quality of life.”
Continuous therapy also has a heavy impact on the budgets of health systems both local and national, he said, and gave these definitions of types of schedules:
- Stop-and-go: Stop all agents and restart on progression;
- On-off: Intermittent administration of chemotherapy;
- Maintenance: Stop an intensive schedule, but keep the patient on a less potent chemotherapy schedule with or without biologics, or stop all cytologic drugs and continue with biologics.
3 Important Trials
LaBianca cited three important trials, starting with the MRC CR06 trial. Patients received 12 weeks of 5FU- or raltitrexed-based chemotherapy, and then were randomly selected to receive either intermittent treatment (stopping chemotherapy and restarting on progression) or continuous treatment (continuous chemotherapy until progression).
“There was no difference between treatment arms in progression-free survival and overall survival, but there were lower toxicities and a better quality of life with an intermittent schedule.”
That trial opened the way to the French OPTIMOX trials described earlier by Grothey. The maintenance arm in OPTIMOX-2 had a longer median duration of disease control and median progression-free survival from the time of randomization, LaBianca pointed out, as well as a trend toward improved median overall survival (24 versus 20 months), although mainly for patients with negative prognostic factors in whom stopping chemotherapy had a detrimental effect.
Those authors reported that the planned complete discontinuation of chemotherapy had a negative impact on the duration of disease control and median progression-free survival compared with the maintenance therapy strategy, suggesting that chemotherapy discontinuation cannot be decided before therapy is started in patients with advanced colorectal cancer.
The third trial LaBianca cited was the Phase III MRC COIN trial of intermittent versus continuous first-line oxaliplatin-fluoropyrimide (Adams et al: Lancet Oncol 2011;12:642-653). Those authors reported that although the trial did not show non-inferiority of intermittent compared with continuous chemotherapy in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, fewer cumulative toxic effects, and improved quality of life.
LaBianca also discussed the Italian Group for the Study of Gastrointestinal Cancer—GISCAD trial of intermittent versus continuous treatment, which he led (Annals Oncol 2011;22:1236-1242), which showed that overall and progression-free survival were essentially the same in both arms of the study. He and his colleagues concluded that reducing therapy in this population did not diminish the efficacy of treatment.
As Grothey predicted, LaBianca also cited the Berry et al meta-analysis and systematic review of continuous versus intermittent chemotherapy strategies, which found that intermittent strategies of delivering systemic treatment in metastatic colorectal cancer did not result in a clinically significant reduction in overall survival compared with a continuous strategy of delivery, and should be part of an informed discussion of treatment options with patients.
ESMO Clinical Practice Guidelines
LaBianca cited recent clinical practice guidelines from the European Society for Medical Oncology (Van Cutsem et al: Ann Oncol 2014;25 supp3:iii1-iii9). Those authors acknowledged that the optimal duration of chemotherapy for metastatic colorectal cancer remains controversial, but that treatment interruptions of combination chemotherapy or less intensive cytotoxic treatment should be considered if cumulative toxicity occurs, if the metastases are not resectable, or if disease control is reached after induction chemotherapy.
Quote from Leonard Saltz
LaBianca also quoted remarks from Leonard Saltz, MD, who spoke as a discussant at the 2014 ASCO Annual Meeting: “In the absence of compelling negative data, treatment interruptions, or chemotherapy-free intervals, appear to be safe and desirable. And as with so many things in cancer care, it is unlikely that one size will fit all: use and timing will need to be individualized.”
LaBianca cautioned that when considering treatment breaks, physicians must consider the patient's clinical characteristics, response to previous treatment, biological and molecular considerations, and quality of life.
“For most patients it is important to have a ‘chemo holiday’ because in two or three years of disease it is important to have real holidays. A chemo holiday means patients can go to the seaside or the mountains and not go every day to our hospitals.”