But side effects are more difficult.

After a randomized clinical trial comparing Avastin with XELIRI (Xeloda, irinotecan) to Avastin with FOLFIRI (5-FU, leucovorin, irinotecan), researchers concluded that excessive side effects made using the XELIRI combination unwise.

Efficacy-wise there were no sigificant differences between the two regimens for:

• median progression-free survival(10.0 for FOLFIRI and 8.9 months for XELIRI)
• overall survival (25.7 and 27.5 months)
• response rates (45.5 and 39.8 percent)

However diarrhea, fever due to low white cell blood counts, and hand-foot syndrome were significantly more common in patients treated with XELIRI. They also had more treatment delays and dose reductions, and discontinued treatment because of side effects more often.

J Souglakos and his colleagues concluded,

The progression-free survival of FOLFIRI-Bevacizumab is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with metastatic colorectal cancer.

SOURCE: Souglakos et al., British Journal of Cancer, January 12, 2012.

During a recent clinical trial, colorectal cancer patients with hand-foot syndrome lived longer, and it took longer for their cancer to get worse.

Researchers comparing two Xeloda-based chemotherapies for people with advanced colorectal cancer, studied skin side effects from both Xeloda and Erbitux® (cetuximab).  They found that about a third of patients experienced at least some hand-foot syndrome, and these patients lived almost 10 months longer than patients without skin changes.

What was studied?

As part of a Phase II clinical trial, the German AIO Colorectal Study Group randomized 185 patients in 35 cancer centers across Germany to receive either CAPOX-C (capecitabine, oxaliplatin, and cetuximab) or CAPIRI-C (capecitabine, irinotecan, and cetuximab).  Their primary goal was to see if there was a difference in objective response rate — the percentage of complete and partial tumor shrinkage.  They also looked at time to cancer progression, overall survival time, safety, and side effects.

In studying at side effects, they analyzed skin toxicity known to be associated with capecitabine:  hand-foot syndrome and nail changes.

Hand-foot syndrome or palmar-plantar erythrodysesthesia (PPE) ranges from mild redness and swelling on the palms of the hands and soles of the feet to severe and painful cracking and sores that can interfere with walking or using hands and fingers.  It appears to get worse with heat and friction.  Patients are told to avoid hot water and aerobic exercise like running and jumping.  Using hand tools can also create friction and make hand-foot syndrome worse.

What was found?

Comparing patients with no capecitabine-related skin toxicity (grade 0) with those with mild to severe symptoms (grades 1 to 3):

• 32.2 percent of all patients had some skin toxicity: 31 percent had hand-foot syndrome, 8 percent had nail changes.  Only 2 patients had nail changes without hand-foot syndrome as well.
• Patients with skin toxicity had longer time before cancer got worse (progression-free survival): median 9.9 months vs. 5.6 months.
• Skin toxicity also meant longer median survival time (overall survival):  32.8 months vs. 22.4 months.
• Disease control (complete or partial tumor shrinkage or stable disease) was greater in those with skin changes:  97.9 percent vs 86.1 percent.
• Dose reductions were necessary more often in patients with skin toxicity:  45.1 percent required them compared to 29.3 percent without skin changes.

There were more skin problems in the CAPOX regimen (39.4%) than the CAPIRI plan (25.6%), although the research team attributes this to a higher dose of capecitabine used with CAPOX.

Hand-foot syndrome began to be diagnosed after a median of three treatment cycles and reached its maximum at five cycles.

The research team concluded:

In the setting of first-line chemotherapy with CAPIRI with cetuximab or CAPOX with cetuximab, capecitabine skin toxicity appears to be an early indicator of treatment efficacy. Capecitabine-induced skin toxicity is predictive for a longer progression-free survival and overall survival. The percentage of hand-foot syndrome is associated with higher dosing, so that patients not showing any HFS might be treated with higher doses.

SOURCE

Stintzing et al., British Journal of Cancer, Volume 105, Number 4, August 2011.  doi:10.1038/bjc.2011.227

Colon cancer patients over 70 actually had a greater reduction in disease-free survival than did younger ones with a new regimen of Xeloda® and oxaliplatin compared to older IV 5-FU treatments according to a new analysis reported at the GI Cancers Symposium in Orlando.

With the bolus IV 5-FU and leucovorin regimens, stage III colon cancer patients over 70 had about a 60 percent chance of being alive and free from cancer three years after surgery. With a combination of Xeloda (capecitabine) and oxaliplatin in a treatment called XELOX, their three-year disease-free survival was 66 percent.

Younger patients had about a 3 percent absolute improvement between the two treatments from 69 percent to 72 percent.

The Xeloxa clinical trial compared the oral drug Xeloda plus intravenous oxaliplatin to then standard IV 5-FU and leucovorin regimens after surgery for stage III colon cancer. The trial (NO16968) enrolled nearly 1,900 patients, including more than 400 who were age 70 and over.

After three years, there was a six percentage point increase in disease-free survival in the older patients. The spread remained true when the cut-off age was dropped to 65. Patients 65 and older had a 62 percent chance of disease-free survival at three years on the older 5-FU treatments compared to 68 percent on the XELOX regimen.

Speaking during a GI Symposium press briefing, Daniel G Haller, MD, of the University of Pennsylvania, said,

XELOX is a new standard of care for patients with early colon cancer, regardless of age. Patients receiving XELOX immediately after surgery live disease-free for longer, and there is a trend towards superior overall survival with XELOX.

SOURCE: Haller et al., Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): No impact of age on disease-free survival (DFS), Abstract #284, 2010 GI Cancers Symposium.

Disclosure: C3 has accepted funding for projects and educational programs from Roche and sanofi-aventis in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Roche announced results of a Phase III clinical trial that compared XELOX chemotherapy to bolus 5-FU and leucovorin.  The trial, nicknamed XELOXA (NO16968), enrolled almost 1,900 patients in 29 countries.

Its primary goal was to see if combining the oral drug Xeloda® (capecitabine) with Eloxatin® (oxaliplatin) could improve disease-free survival for stage III colon cancer patients.

In a press release, Roche said that full results of the trial will be presented at upcoming scientific meetings.

Patients were randomly assigned to one of two trial arms for a total of 24 weeks after their surgery:

• XELOX:  8 treatment cycles consisting of IV oxaliplatin on day 1, oral capecitabine on days 1-14, 7 days of rest.
• 5-FU/LV:  Bolus IV injections of 5-FU modified by IV leucovorin in either the Mayo Clinic plan or Roswell Park plan depending on center.

Further analyses of the XELOXA trial are planned to determine:

• Whether XELOX improves overall survival.
• Whether patients find the XELOX treatment more convenient and are more satisfied with it.
• How much medical care is used with both treatments.

An analysis of XELOX safety and side effects was published in 2007 in the Journal of Clinical Oncology. That study found that overall treatment side effects were similar in both the XELOX and 5-FU/LV groups, but the type of side effects differed.

• Overall, patients on XELOX experienced less diarrhea and hair loss, but they had more neuropathy, vomiting, and hand-foot syndrome than those who got FU/LV.
• Compared to the Mayo Clinic 5-FU treatment, patients on XELOX had more serious (grade 3-4) GI side effects and fewer changes in blood counts.
• Compared to the Roswell Park regimen, XELOX patients had fewer serious GI problems and more changes in blood counts.
• Treatment-related deaths (6 per 1000) were the same in both groups.

William M. Burns, CEO of Roche’s Pharmaceuticals Division, said,

While Xeloda is already approved for the treatment of early-stage colon cancer as monotherapy, the results of this study mean that physicians will now be able to offer their patients Xeloda as a combination chemotherapy. This is an important development for patients as colon cancer, if caught early enough, can be cured, so physicians need a wide range of treatment options.

Roche is planning to ask health authorities to extend the current Xeloda labeling to include use with oxaliplatin for stage III colon cancer.

Disclosure: C3 has accepted funding for projects and educational programs from Roche in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Researchers analyzed a pool of all six trials to find out if one approach is better than the other. While they found that there are different side effects, the time until cancer gets worse (progression-free survival) and overall survival time are the same.

The percentage of patients who got infusional 5-FU  and had their tumors shrink (response rate) was greater than those who had shrinkage with capecitabine .  However, this did not translate into better progression-free interval or longer survival time.

Six randomized phase II or III studies compared CAPOX to some infusion 5-FU regimen combined with oxaliplatin.  Nearly 3,500 people took part in the clinical trials.  Two trials also included Avastin® (bevacizumab).

While there was a 15 percent better response rate with infusion 5-FU, there was no difference in either progression-free interval or overall survival time.

Patients who received Xeloda had more blood clots, serious diarrhea, and changes in the skin on their hands and feet (hand-foot syndrome). 5-FU treatment caused more low white cells counts (neutropenia).

In discussing side effects, the researchers noted that lower doses of Xeloda might have reduced its side effects and that lower doses are being used in some new studies of the drug.

Writing in the Journal of Clinical Oncology, Hendrik-Tobias Arkenau and a collaborating team of international researchers said,

The combination of capecitabine and oxaliplatin resulted in lower response rate, but this did not affect progression-free survival and overall survival, which were similar in both treatment arms. The toxicity analysis showed the characteristic toxicity of each of the different FU schedules, with thrombocytopenia and hand-foor syndrome consistently more prominent in the capecitabine regimens.

Further, they wrote,

Thus, the use of capecitabine and oxaliplatin is a valid alternative for patients with metastatic colorectal cancer and can be regarded as appropriate backbone for the addition of novel targeted agents in clinical practice and future clinical trials.

SOURCE: Arkenau et al., Journal of Clinical Oncology, published ahead of print, November 17, 2008.