Two manufacturers have some doses of the drug on intermittent back order and are shipping it as it becomes available.  A third has all dose vials on back order and estimates shipping sometime in the fourth quarter of 2011.

According to the FDA and ASHP:

• APP Pharmaceuticals is shipping fluorouracil intermittently as it becomes available.  They say this is due to increased demand.
• Teva has all fluorouracil injection presentations on back order due to manufacturing delays.  They estimate releasing it in the fourth quarter of 2011.
• Mylan Institutional has 50 ml vials on intermittent back order and is shipping them as they become available.  It is only available for drop shipment orders through wholesalers at this time.  They attribute the shortage to increased demand.

ASHP management suggestions include:

• Consider evaluating the health-care system’s total supply of fluorouracil before beginning patients on combination chemotherapy regimens containing fluorouracil. If adequate supplies are not available, select an alternative regimen.
• Consult a Hematology/Oncology specialist for patient- and neoplasm-specific recommendations.
• Refer to the ASHP Guidelines on Managing Drug Product Shortages for more guidance on developing a multidisciplinary plan when the supply must be allocated.

The ASHP Guidelines for Managing Drug Product Shortages in Hospitals and Health Systems has information about managing drug shortages but also includes a good overview about how shortages arise.

It is possible to use Xeloda® (capecitabine) in place of some 5-FU and leucovorin regimens, but there are important safety concerns to think about.  Some research has found that an immediate switch from 5-FU to Xeloda may mean severe side effects. A waiting period to allow folate build-up in cells may be necessary.  Be sure your doctor is aware of this possibility.

More Information

American Society of Healthcare Pharmacists Drug Shortages: Fluorouracil

ASHP Guidelines for Managing Drug Shortages in Hospitals and Health Systems

Of every 100 people with colon cancer, about 15 will have cancers that arise when mistakes in DNA during cell division are not caught and fixed.  Scientists call this defective mismatch repair or dMMR.

More often, colon cancer occurs when mutations in chromosomes accumulate but DNA repair pathways remain intact and mismatch repair is proficient (pMMR). This is true for about 85 percent of colon cancer.

Both prognosis and the potential benefit from FU-based chemotherapy appear to be very different for these two types of colon cancer. Knowing mismatch repair status of colon tumors can help patients and their doctors make better treatment decisions.

Patients with defective mismatch repair have better disease-free and overall survival and don’t seem to benefit from 5-FU at either stage II or stage III.  Stage II patients with dMMR have significantly poorer overall survival if they get chemo after surgery.

Caution:  These results come from studies of 5-FU plus levamisole or 5-FU plus leucovorin.  They don’t include any information from the current standard treatments of FOLFOX or FLOX which contain oxaliplatin in addition to 5-FU and leucovorin.

Defective mismatch repair is uncovered when either tumors have microsatellite instability (MSI) or immunohistochemical tests can’t find the proteins that are expressed by genes that control mismatch repair — MLH1, MSH2, MSH6, and PMS2.  Measuring either MSI or lack of MLH1 or MSH2 expression gives similar results in deciding whether a tumor is mismatch defective or proficient.

Almost all defective mismatch repair tumors are located in the right side of the colon.  They are poorly differentiated, often have lots of mucus, and tend to be infiltrated with immune-system cells (lymphocytes). Some scientists speculate that it is this improved immune-response that gives them their survival advantage.

Daniel Sargent, Ph.D., and his team analyzed mismatch repair status in the tumors of 457 patients in five different clinical trials with stage II or III colon cancer who had received either FU-based chemotherapy after surgery to remove their cancer or surgery alone.  They then pooled their information with a group of 570 patients who had been analyzed earlier.  The entire set included 1,027 patients, including 165 (16 percent) with defective mismatch repair.

They analyzed the impact of either proficient or defective mismatch repair as both a prognosis marker (its effect on survival despite treatment) and predictive marker (if chemotherapy treatment changes outcomes).

Pooled Results

Mismatch Repair Status as a Prognostic Marker

• Patients with defective mismatch repair (dMMR) who didn’t get 5-FU had significantly better disease-free and overall survival than patients with proficient mismatch repair (pMMR).
• When patients got chemotherapy, mismatch repair status had no impact on survival.

Mismatch Repair Status as a Predictive Marker for FU- based chemotherapy

• There was no benefit of FU-based chemotherapy for either stage II or stage III colon cancer patients with defective mismatch repair.
• There was no benefit of FU chemo for stage II patients with proficient mismatch repair.
• Stage III patients with pMMR did benefit from chemotherapy with 5-FU.
• Stage II patients with dMMR had worse overall survival when they got 5-FU than when they had surgery alone.

Graph of Predictive Value of dMMR in Adjuvant Colon Cancer

A — Stage II, dMMR
B–  StageIII dMMR
C — Stage II pMMR
D — Stage III pMMR

Click on graph to enlarge it.

Dr. Sargent’s analysis confirmed an earlier study reported in 2003 in the New England Journal of Medicine by Christine Ribic that found no benefit to treatment with 5-FU for patients with stage II or III colon cancer with high microsatellite stability, who may possibly be harmed by  5-FU-based chemotherapy and have a better overall prognosis after diagnosis.

His team concluded,

In conclusion, this prospectively specified analysis of data from randomized, clinical trials provides independent, supportive evidence of the following: dMMR colon cancers have a favorable stage adjusted prognosis compared with the majority of colon cancers; and patients with dMMR colon cancers do not benefit from FU based adjuvant therapy.

Further, they point out,

These findings support the conclusion that average-risk patients with colon cancer who are considered for FU based adjuvant therapy should have the tumor MMR status assessed to inform the likelihood of patient benefit of chemotherapy. Our conclusions are restricted to patients being considered for single agent, fluoropyrimidine-based therapy (ie, patients with stage II disease), and the conclusions provide guidance as to who should not be treated (ie, the dMMR subset). We believe that dMMR status in the setting of stage II disease should be considered a clinically useful marker of tumor biology and represents an additional step in individualized cancer therapy.

SOURCE: Sargent et al.,  Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer. Journal of Clinical Oncology, Volume 28, Number 20, pages 3219-3226,July 10, 2010.

Image:  Figure #2, Sargent et al., JCO

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.

5-FU (fluorouracil) is the backbone of most colorectal cancer treatment, given alone or in combination with other drugs.  What does KRAS status mean when 5-FU is the only treatment?

To see whether or not, KRAS mutation status affected outcome of 5-FU treatment, researchers analyzed tumor tissue from patients who had 5-FU treatment only.  Patients in the study had cancer that had spread to their liver (liver metastases), and the liver mets could not be surgically removed.

They found:

• 38.7 percent of the patients had a KRAS mutation in their tumors.
• KRAS mutations in liver tumors matched exactly with those in primary tumors in the colon.
• There was no significant difference in the percentage of liver tumors that got smaller with 5-FU treatment (objective response rate).
• There was no difference in survival between the group of patients with mutated KRAS and those with normal or wild-type KRAS.

Marie-Christine Etienne-Grimaldi and her French colleagues concluded,

The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.

Other research has found that Avastin®(bevacizumab) treatment outcomes are not affected by KRAS status.

SOURCE:Etienne-Grimaldi et al.,Clinical Cancer Research, Volume 14, Number 15, August 1, 2008.

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.