Advanced colon ca: Is sequential treatment preferred?

STOCKHOLM-Clinical trials have not clearly determined if advanced colorectal cancer patients should receive their first line of chemotherapy in combination or in sequence. In a debate at ESMO 2008, Cornelis J.A. Punt, MD, PhD, from Radboud University Nijmegen Medical Centre in Nijmegen, the Netherlands, and Aimery de Gramont, MD, of Hospital Saint-Antoine in Paris, discussed the pearls and pitfalls of each approach.

Dr. Punt argued that combinations may be preferred if tumor shrinkage is the goal or salvage therapy is not feasible, but in most patients sequential treatment is valid and may be very useful in conjunction with newer agents. Dr. de Gramont argued that sequential monotherapy should be limited to those relatively few patients who have comorbidities or are too frail to receive a combination therapy, or those who have a good performance status and no chances of salvage surgery, benefit of maintenance therapy or chemotherapy breaks.

Upfront sequential treatment

Sequential treatment is a valid option for the majority of patients with advanced colorectal cancer. The pivotal trials of combination therapy do not convincingly demonstrate that sequential delivery is inferior in most patients, argued Dr. Punt, a professor in the department of medical oncology.

Large trials by Jean-Yves Douillard, MD, and Leonard Saltz, MD, evaluated 5-FU/leucovorin with and without irinotecan (Lancet 355:1041-1047, 2000; NEJM 343:905-914, 2000). Median overall survival (OS) was increased with irinotecan by 3.3 months in Dr. Douillard’s study but only 2.2 months in Dr. Saltz’s trial. Based on these findings, combination 5-FU/LV plus irinotecan (IFL) became standard treatment.

A look at the second-line therapies in these trials, however, reveals an imbalance between the control and experimental arms that may have had an impact on survival, according to Dr. Punt. In the NEJM study, for instance, 70% of the control arm received second-line treatment, but only half received the most effective regimen.

The same occurred in the Richard M. Goldberg, MD, study of IFL vs FOLFOX4 (JCO 22:23-30, 2004), which established the FOLFOX4 combination as standard treatment. FOLFOX was associated with a signifi cant benefit in time to progression (TTP) and OS. Again, while 60% of patients in the FOLFOX4 arm received the most effective second-line treatment (irinotecan), only 24% in the IFL arm received their best option (oxaliplatin), Dr. Punt pointed out.

Also, Dr. Punt noted that while OS was increased by 4.5 months with FOLFOX4, median TTP was improved by just 1.8 months, suggesting the greatest treatment effect occurred after the first progression and was not dependent on the first-line treatment.

Therefore, if the control groups in these trials had received their best second-line options, differences in overall survival would probably have been smaller, he said. Without a more significant survival benefit, combination chemotherapy- 5-FU/LV with irinotecan or oxaliplatin- would not have been accepted as the new standard, Dr. Punt stressed.

Exposure to best drugs

Axel Grothey, MD, and colleagues (JCO 22:1209-1214, 2004) found a correlation between median OS and exposure, regardless of timing, to all three effective agents-5-FU, irinotecan, and oxaliplatin. Only one study-CAIRO-1-used all three agents to test sequential vs combination treatment, fi nding no difference in median OS between the arms (Lancet 370:135- 142, 2007). Similarly, the large five-arm randomized FOCUS trial tested the same principle and found no diff erence in OS except in the arm receiving single-agent irinotecan second-line (Lancet 70:143-52, 2007), Dr. Punt said.

CAIRO-1 and FOCUS are the only studies in which salvage treatments were a prospective part of the study design. Both demonstrated that upfront combination treatment is not superior to sequential treatment. The studies concluded that fluoropyrimidine monotherapy is a valid treatment option, according to Dr. Punt. Surprisingly, an editorial accompanying publication of the FOCUS trial stated that the evidence continues to support initial combination chemotherapy as the backbone of treatment for metastatic colorectal cancer, at least for most patients, Dr. Punt said.

His group’s rebuttal to the editorial stated that findings from CAIRO-1 and FOCUS, based on nearly 3,000 patients, do not run contrary to previous evidence but come from the first studies of their kind. “We also pointed out that, based on seven phase III trials and a meta-analysis, fewer than 10% of patients fall into the category the commentators assigned to ‘most patients,’ ie, eligible for secondary resections,” Dr. Punt said.

In other words, “most patients” are not the majority of patients at all, he added. Combination chemotherapy does produce higher response rates, so if the primary objective is to downsize tumors for palliation or resection this approach may be preferred. Higher response rates, however, do not translate into OS advantages.

Furthermore, the benefit of secondary resection of initially nonresectable liver metastases aft er downsizing has not been tested in a prospective randomized trial. “Our information comes from a single center’s consecutive series of 1104 patients (led by Ren Adam, MD) where 138 patients (12.5%) underwent secondary resection, resulting in a 5-year survival of 33%. Analyzing these data according to intention-to-treat, the 5-year survival of 33% is equal to 4% of the intention-to-treat population, and this 4% can also be achieved with chemotherapy” (Ann Surg 240:644-657, 2004).

Lastly, what is the optimal combination? Two phase III studies of FOLFOXIRI vs FOLFIRI followed essentially the same design and demonstrated comparable outcomes with FOLFOXIRI (ASCO GI Cancers Symposium 2006 abstract 3513; Br J Cancer 94:798-805, 2006). However, OS was significantly better only in the one study, probably because FOLFIRI performed well in the other study, Dr. Punt pointed out.

Th is does not convincingly support the use of FOLFOXIRI, he said. Furthermore, FOLFOXIRI is toxic, may be difficult to combine with targeted agents, leaves no option for salvage chemotherapy, and has not been prospectively tested against the sequential use of the drugs. “In the future, better predictive models should help us select the optimal strategy in individual patients,” Dr. Punt said.

Combination treatment is superior

“The majority of patients with advanced colorectal cancer should be treated with combination chemotherapy, especially now that we can take advantage of chemotherapy- free intervals and maintenance chemotherapy, lessening the toxicity that was once a concern,” said Dr. de Gramont, a professor of oncology at Hospital Saint-Antoine.

Admittedly, it has sometimes been difficult to show survival advantages in clinical trials, he said. In CAIRO-1, median OS was about 17 months per arm, perhaps because 36% of controls received third-line treatment and thus got all three effective drugs, which Grothey et al correlated with survival.

With the combination, however, progression- free survival (PFS) was improved by two months and first-line response rates were doubled, though toxicity was greater in the first-line setting, Dr. de Gramont explained.

In the five-arm FOCUS study, first-line monotherapy was found to be less active than combination treatment, though PFS was similar after second-line therapy. For OS, sequential monotherapy (mLV5FU followed by irinotecan) was significantly inferior to upfront FOLFIRI, although the other arms that initiated monotherapy but used combinations second-line fared no worse than the upfront combination arms.

Finally, a third study, FFCD 2000-05, compared LV5FU2 followed by FOLFOX6 with FOLFOX6, and median OS was approximately 16 months for each (ASCO 2007 abstract 4069).

In these three trials, OS was the same between sequential and combination therapy-about 16 months. However, in other combination trials during the same time period, OS was higher, approximately 20 to 21 months [JCO 22:229-237, 2004); OPTIMOX1 (JCO 24:394-400, 2006); Dr. Goldberg, et al., JCO 22:23-30, 2004)].

The surgical connection Furthermore, salvage surgery was not considered in the first three trials but was allowed in the others, and we know that surgery is important, he said. Dr. Adam and colleagues showed that combination chemotherapy renders 14% of initially unresectable patients resectable. “With regimens that produce a 50% response rate (and there are many), you can expect a 10% R0 resection rate and perhaps a cure,” Dr. de Gramont said.

Combination chemotherapy is also less toxic now, thanks to new concepts in chemotherapy delivery, such as maintenance therapy (which has the benefit of monotherapy) and chemotherapy-free intervals. OPTIMOX1 established that the “oxaliplatin stop-and-go” approach using maintenance therapy (sLV5FU2 × 12) reduced toxicity without compromising survival. OPTIMOX2 evaluated a chemotherapy-free interval but was associated with disappointingly lower OS [19 vs 26 months with maintenance; ASCO 2007 abstract 4013)].

“From this, we learned that we cannot decide to stop chemotherapy before we begin treatment and that at least 6 months of chemotherapy should be given before offering a chemotherapy-free interval, as this signifi cantly prolongs survival. Patients who can be considered eligible for this chemotherapy break are those whose carcinoembryonic antigen (CEA) normalizes within 3 months of therapy; this predicts for excellent OS, even when chemotherapy is stopped, and is difficult to achieve with 5-FU alone,” according to Dr. de Gramont.

“Among advanced colorectal cancer patients, I maintain that only a limited number of patients could be treated with front-line monotherapy. Those who are frail or have comorbidities, or have all the following conditions: a good performance status, no DPD defi ciency, MSS tumor, low TS level, no chances of salvage surgery or benefit of maintenance therapy or chemotherapy breaks.

For all others, combination therapy that incorporates maintenance treatment, which lessens toxicity, is the preferred approach,” Dr. de Gramont concluded.

Emerging data suggest that future maintenance therapy incorporating targeted agents (sLV5FU/capecitabine plus bevacizumab) will produce long PFS and minimal toxicity, he said.