When Avastin is added to the combination of Xeloda and irinotecan as an initial treatment for advanced colorectal cancer, the treatment is equally effective as Avastin with FOLFIRI.

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.

Developing tender swelling or rash on their hands and feet may actually be good news for patients being treated with Xeloda® (capecitabine).

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

It doesn’t hurt to stop XELOX chemotherapy combined with Avastin after six treatments and continue with Avastin alone until colorectal cancer gets worse, according to a study reported at the 2010 Annual Meeting of the American Society of Clinical Oncology in Chicago.

Many patients have to stop oxaliplatin chemotherapy with before getting its maximum effectiveness because of peripheral neuropathy — tingling, numbness, or pain in their hands and feet.  Xeloda® (capecitabine) can cause painful skin redness and cracking on the hands and feet or hand-foot syndrome, which can also affect time on chemotherapy.

Giving only six treatments of Avastin® (bevacizumab) plus XELOX chemotherapy and then stopping XELOX and using only Avastin until cancer progressed was as effective for the initial or first-line treatment of colorectal cancer as continuing XELOX.  XELOX combines Xeloda® (capecitabine) with oxaliplatin.

In addition, the strategy reduced both severe peripheral neuropathy and hand-foot syndrome.

In the MACRO study, 480 patients who had not received previous chemotherapy for metastatic colorectal cancer were randomly assigned to get either get

• XELOX and Avastin until their cancer progressed or side effects made it impossible for them to continue treatment or
• Six treatments (18 weeks) of XELOX and Avastin followed by Avastin alone until progression.

After a median follow-up of 16 months, there were no significant differences in response rate, progression-free survival, or overall survival time.

• Median progression-free survival was 11.0 months when XELOX continued and 10.3 months when XELOX was dropped and Avastin continued as a single agent.
• Median overall survival was 25.3 months with continuous XELOX and 20.7 months continuing Avastin alone.
• Overall response rate was 60 percent for the continuing strategy and 57 percent for Avastin as a single agent after XELOX was stopped.

Severe grade three or worse side effects were

• Diarrhea:  11 percent in continuing strategy and 13 percent when Avastin was used alone.
• Hand-foot syndrome:  12 percent versus 6 percent.
• Neuropathy: 24 percent versus 7 percent

The researchers also pointed out that about 1 in 10 patients in both arms of the trial were able to have successful surgery to remove metastatic tumors.

Josef Tabernero, MD, and his colleagues concluded,

Bevacizumab (BEV) as a maintenance therapy following induction XELOX-BEV was not inferior to continuation XELOX-BEV. This study suggests that maintenance therapy with single agent bevacizumab is an appropriate option following induction XELOX-BEV in patients with metastatic colorectal cancer. Further studies evaluating single agent bevacizumab after standard chemotherapy in metastatic colorectal cancer are warranted.

SOURCE: Tabernero et al., 2010 ASCO Annual Meeting Abstracts, Abstract #3501

C3 has accepted donations from Roche and Genentech in  the form of unrestricted educational grants. C3 has ultimate authority over web site content.

Update from 2010 GI Cancers Symposium

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.

I wanted to share with you another novel clinical trial using a compound targeting two receptors on tumor cells. Both receptors we know very well: one is HER2, the target for Herceptin, and the other one is EGFR, the target for Erbitux.

One compound targeting both receptors is on the market known as Tykerb® (lapatinib) which is approved for breast cancer patients in combination with Xeloda® (capecitabine).

We are utilizing our pharmacogenomic understanding of these pathways to explore genetic signatures to predict who benefits from these therapies and have initiated a global trial for patients with gastric cancer using Xeloda and Tykerb.

We have also learned that HER2 is not only found in breast cancer but also in gastric cancer, bile duct cancer and potentially ovarian and bladder cancers. We have initiated  a study with Boehringer Ingelheim Germany, together with the Massachusetts General Hospital  using these compounds for patients with different cancers who have overexpression of either EGFR or HER2.

This is another example to select patients for specific therapies more wisely to make sure we increase benefits for our patients. Almost all of our clinical trials are now designed to test tumors first to identify patients whoare  more likely to benefit from targeted therapies by testing to be sure that the target of the drug is present in the tumor.

We have seen very promising data on the HER2-overexpressing gastric and bile duct cancers which seem to have significant benefit from HER2 inhibitors such as Herceptin.

This novel compound is highly effective in inhibiting both important growth factor receptors. This trial is now open for accrual at USC and Mass General.

A combination of Xeloda and Eloxatin (XELOX) was better than standard 5-FU and leucovorin chemotherapy in reducing recurrences of stage III colon cancer after surgery.  Significantly more patients receiving XELOX were alive without cancer three years after treatment began.

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.

Infusional 5-FU or oral Xeloda® (capecitabine) are two different drugs that can be combined with Eloxatin® (oxaliplatin) to treat colorectal cancer that has spread.  Six different randomized clinical trials have compared the two approaches.

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.

An immediate switch from 5-FU treatment to Xeloda® (capecitabine) for stage III colon cancer caused so much toxicity that a trial designed to test patient preferences for treatment had to be stopped.

Patients in the Patient Preference in Adjuvant Therapy (PACT) trial who switched after 6 weeks from weekly 5-FU with leucovorin to oral capecitabine experienced excessive side effects. The trial was designed to determine which approach to treatment patients liked best.

Patients were randomized to two groups:  the first group began treatment with weekly intravenous 5-FU and leucovorin for 6 weeks (start period) and then switched to oral Xeloda for six weeks (switch period).  The second group began with Xeloda during the start period and got 5-FU during the switch period. Finally, patients would choose the treatment they preferred to complete the final 12 weeks of treatment (preference period.)

However, the trial was halted after 40 of a planned 74 patients were enrolled because of the high toxicity in the first group who made the 5-FU to Xeloda switch.  Serious grade 3 or higher side effects in those now getting Xeloda included diarrhea, hand-foot syndrome, and lethargy.  One patient had low white counts with blood infection, and one experienced angina.

During the start period:

• The Xeloda group had moderately higher percentages of severe (grade 3 or higher) side effects than the 5-FU group (28 percent versus 0 percent)
• 44 percent of the Xeloda group required a lower dose or postponed treatments compared to 6 percent of the 5FU group.

Durng the switch period:

• 79 percent of the 5-FU patients who switched to Xeloda had severe grade 3 side effects compared to none of the patients who switched from Xeloda to 5FU.
• Only 2 of 14 5-FU patients who switched to Xeloda were able to tolerate the full dose.

During the preference period:

20 patients reached the end of the twelfth week of treatment before the study was closed and were able to make a choice of which treatment they preferred.

• 3 patients, who had taken Xeloda in the switch period, had already dropped out of treatment entirely because of severe side effects.
• 5 patients chose to return to Xeloda.  All 5 had taken Xeloda in the start period, switched to 5-FU, and now wanted to return to Xeloda.
• 4 of those 5 patients who returned to Xeloda after the switch period on 5-FU developed severe side effects during the preference period.
• 2 of 12 patients (17 percent) choosing 5-FU developed severe side effects.
• 1 patient, who had been in the original Xeloda arm during the start period and had switched to 5FU, asked to return to Xeloda.  Despite not having side effects from Xeloda during the start period, she developed serious side effects, had a heart attack, and died.

The researchers don’t know the reason that the sequence of 5-FU with leucovorin and Xeloda made such a startling difference in side effects, but they think that leucovorin (folic acid) may be at the bottom of the mystery.  It is possible that leucovorin allows folate to build up in cells and contributes to more serious side effects when Xeloda is begun.

They point out the recent studies that found more side effects from 5-FU and Xeloda in the United States where food is fortified with folic acid.

Although this study looked specifically at treatments that used 5-FU and leucovorin or Xeloda alone, the researchers believe that doctors should also take care with switching combination therapies.

This caution should also be extended to switching patients from combination regimens containing FU/LV to capecitabine-containing equivalents (eg, from infusional FU/LV with oxaliplatin to capecitabine with oxaliplatin).

The team, headed by Dr. Ivo M. Hennig, concluded,

In chemotherapy-naive patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.

SOURCE: Hennig et al., Journal of Clinical Oncology, Volume 26, Number 20, July 10, 2008.

What this means for patients

Patients need to be aware that an immediate switch from intravenous 5-FU given with leucovorin and Xeloda (capecitabine) may be dangerous.  They should discuss such switches carefully with their oncologists.

Because folate in cells may be the reason for increased serious side effects, patients should discuss all sources of supplementary folic acid with their doctors, including that in enriched foods and multivitamins.

The National Institutes of Health Office of Dietary Supplements has more information about folate in food and folic acid supplements.