• Fluorouracil (5-FU) as of 8/31/11: On back order from Teva, APP Pharmaceuticals, and Mylan Institutional.  Manufacturing delays at Teva appear to have caused increased demand from other companies.
• Leucovorin as of 8/31/11:   Bedford has some powderized sizes available and limited allocations of others.  Teva is importing folinic acid solution and it is available for drop shipment, but powdered leucovorin is on back order. APP is releasing powderized leucovorin as it becomes available.
• Irinotecan as of 8/26/11:  Teva and Sandoz have back orders of some doses because of manufacturing problems.  Hospira shortages are due to increased demand.  Some dosage vials are available from APP and as Camptosar from Pfizer.  Three generic manufacturers stopped making irinotecan in 2010 and another one did so in May 2011.
• Fusilev as of 6/21/11:  Although it was in shortage previously, Spectrum has announced that they have ample supplies currently and for the future.  ASHP reminds physicians and pharmacists that dosing errors can occur when substituting Fusilev (levoleucovorin) for leucovorin.

Check the links to ASHP updated sites for more detailed information about which sizes are available, reasons given for shortages, and when shortages are expected to be resolved.

Take action!

Email your Members of Congress in support of legislation that would combat future drug shortages. We make it easy in our online action center.

Some customers discovered small particles of foreign material in one lot of the irinotecan vials.  Further inspection found fungal microbes in the vials they sent back.

It is unlikely that you as a patient would see the recalled vials or particles directly since irinotecan is diluted before your IV infusion.  However, you might develop an infection or other adverse event.  If that happens, call your doctor immediately!

The FDA and APP Pharmaceuticals tell patients

RECOMMENDATION: Consumers should contact their physician or healthcare provider if they have experienced any problems that may be related to taking or using this product.

The recalled lots are 870DE00301, 870CZ00301, 870DE00101, 870DE00201 and 870DE00401.

Irinotecan is used to treat metastatic colorectal cancer as alone or in combination with other chemotherapy in the FOLFIRI regimen.  It also is sometimes given with Erbitux® or Vectibix®.

APP has initiated this voluntary recall of Irinotecan Hydrochloride Injection to the retail level due to the discovery of foreign material and non-sterility in one lot of Irinotecan Hydrochloride Injection. Non-sterility of a chemotherapeutic product administered via the intravenous route has the potential to result in infections, which could be fatal, especially in patients who are immunocompromised. APP is not aware of any adverse patient events resulting from this product and is continuing its diligent investigation of the situation. Consumers should contact their physician or healthcare provider if they have experienced any problems that may be related to taking or using this product. This recall is being conducted with the knowledge of the U.S. Food and Drug Administration.

FDA Safety Announcement.

Irinotecan (also called CPT-11 and/or Camptosar) is often used to treat advanced colorectal cancer. But it causes diarrhea in most patients–severe in 30 percent—that often limits the dose a patient can tolerate.

Now researchers at the University of North Carolina at Chapel Hill have found a way to block one specific troublemaking enzyme thought to play a big role in causing the diarrhea.

Irinotecan is complicated: After it has killed tumor cells, the drug is filtered out of the bloodstream by the liver, where it’s changed to an inactive compound and discharged into the intestine to be excreted. But in the intestine, the drug can be reactivated by an enzyme that is made by bacteria that normally live in the gut. The reactivated toxic drug then damages the intestinal lining—leading to severe diarrhea.

Matthew Redinbo, PhD, and his team wanted to block the enzyme that reactivates irinotecan, yet not kill the intestinal bacteria, because it’s vital for digestion, vitamin manufacturing and fighting infections. Sorting through a database of 10,000 chemical compounds, the research team found four chemicals that, at least in a test tube, blocked the enzyme without harming the bacteria. They tested one compound in mice: Those given irinotecan plus the compound had far less severe diarrhea than mice given just irinotecan.

An accompanying Science editorial noted that this experiment is only the first step in a long process of test tube and then animal testing, before human testing could even begin. But the editors also noted that, while much research is aimed at finding new treatments, this kind of research can vastly improve current anticancer drugs.

Addendum: The lead researcher, Redinbo, initially began the research after seeing a friend suffer through therapy and ultimately die from colorectal cancer. Only late in the process did he discover that another team member shared a similar experience. “As scientists, our [personal] experiences can have a profound effect on our work,” Redinbo said.

Source: Science (5 November 2010) and Medical News Today (Nov. 6)

Disclosure:  The Colorectal Cancer Coalition has received funding from Pfizer, the company that manufactures Camptosar, in the form of unrestricted educational grants.  The Coalition has ultimate authority over website content.

About 15 percent of colon cancers develop when damaged DNA is not repaired and mutated cells grow into malignant tumors.  So-called deficient mismatch repair (dMMR) tumors have features different from most colorectal cancer, including a better prognosis.  They also have a very poor response to 5-FU-based chemotherapy.

However, researchers studying tumor tissue from patients enrolled in a clinical trial comparing 5-FU and leucovorin alone to 5-FU, leucovorin, and irinotecan found that those with deficient mismatch repair tumors who received irinotecan had better disease-free survival and overall survival at five years than patients whose mismatch repair genes were working.  Those with dMMR on the 5-FU-only arm of the trial had no similar benefit.

Deficient mismatch repair can be identified by measuring  mutated microsatellites — short lengths of DNA that are abnormally shorter or longer because they were not caught and corrected during cell division.  This is known as microsatellite instability or MSI. dMMR can also be diagnosed by looking for missing mismatch repair gene expression in tumor tissue.

To find out if there was any benefit for irinotecan in deficient mismatch repair tumors, researchers tested tissue saved after surgery for both MSI and loss of MLH1 and MSH2 gene expression from patients enrolled in the CALGB-89803 clinical trial.

CALGB-89803 randomly assigned stage III colon cancer patients after surgery to chemotherapy to an IV shot of 5-FU plus intravenous leucovorin (FU/LV) or the same 5-FU and leucovorin treatment plus irinotecan (IFL).   Chemotherapy was given every week.

For all of the nearly 1,300 people enrolled in the trial, there was no significant difference in overall survival after 5 years (70 percent for IFL and 72 percent for FU/LV).  There was a significant increase in toxic side effects in the IFL arm and some unexpected deaths.

However, when tumors were analyzed by deficient mismatch repair status (dMMR), as evidenced by high microsatellite instability (MSI-H) compared to intact mismatch repair (iMMR) or low or stable microsatellite stability (MSI-L/S), adding irinotecan did make a difference in disease free survival and overall survival five years after surgery:

Five year disease free survival

• All patients:  61 percent
• FU/LV and MMR-D (MSI-high): 57 percent
• FU/LV and MMR-I (MSI low or stable): 51 percent   (no significant difference)
• IFL and MMR-I: 59 percent
• IFL and MMR-D: 76 percent  (significant difference in this group)

Overall survival at five years

• All patients:  67 percent
• FU/LV MMR-D:  67 percent
• FU/LV MMR-I:   72 percent
• IFL  MMR-I:   70 percent
• IFL MMR-D: 78 percent  (significant difference in this group of patients)

Some, but not all, dMMR tumors are caused by inherited genetic mutations in mismatch repair genes.  Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC) leads to colorectal, uterine, and other cancers through such inherited mutations.

Since colon cancer caused by deficient mismatch repair does not benefit from 5-FU chemotherapy, it is common to test for MSI or missing MLH1 or MSH2 gene expression in tissue removed during surgery before prescribing chemotherapy.  Testing tissue also screens for Lynch syndrome.

Monica M. Bertagnolli, M.D. and her colleague in the Cancer and Leukemia Group B (CALGB) concluded,

Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

SOURCE:  Bertagnolli et al., Journal of Clinical Oncology, Volume 17, Number 11, April 10, 2009.

The PETACC-3  (Pan European Trial Adjuvant Colon Cancer)  trial was designed to see if adding irinotecan to 5-FU and leucovorin could increase the percentage of stage III patients who were alive and cancer-free (disease-free survival).  It also studied overall survival and relapse-free survival.

In a randomized Phase III trial over 2,000 patients with stage  III colon cancer received either:

• Twelve standard treatments every two weeks of LV5FU2 (a two-hour infusion of leucovorin followed by a 400 mg/m² bolus injection of 5-FU and a 22 hour continuous infusion of 5-FU each day for two days — the deGramont regimen)
• Twelve treatments every two weeks  LV5FU2 (standard deGramont regimen)with an additional infusion of 180 mg/m² of irinotecan on the first day.

Patient characteristics were well-balanced between the two groups, with more men than women (55 percent vs 45 percent), a median age of 60, and about a third of patients in both groups over 65.  About two thirds had cancer found in fewer than 4 nearby lymph nodes.  None had any sign of cancer elsewhere in their bodies.

Results found no significant differences in survival for stage III patients between the two treatments:

• Five-year disease-free survival was 56.7 percent with the added irinotecan, 54.3 percent without.
• Five-year overall survival was 73.6 percent with irinotecan, 71.3 percent without.

Serious (grade 3 and 4) side effects were more common in the irinotecan group:

• Any  severe adverse event:  24.3 percent in LV5FU2 only group versus 37.7 percent with added irinotecan
• Diarrhea: 5.6 percent with standard treatmnet, 11.9 percent with irinotecan
• Neutropenia (lowered white cells counts): 6.0 percent versus 28.2 percent with irinotecan
• Nausea:  1.2 percent versus 5.5 percent with added irinotecan

About half of patients in the irinotecan arm had some hair loss compared to about one in five patients receiving infusional 5FU.

The results of the trial are similar to those found by Dr. Leonard Saltz and colleagues in the CALGB 89803 clinical trial that compared bolus 5FU with leucovorin to the same bolus regimen with irinotecan (CPT-11).  In that study adding irinotecan did not increase either disease-free or overall survival and did result in more serious side effects and some unexpected deaths.

The addition of CPT-11 to weekly bolus FU plus leucovorin did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.

The ACCORD-2 trial compared infusional 5FU (LV5FU2) with and without irinotecan and found no difference in disease-free survival, even after adjusting for higher-risk colon cancers in the group of patients who received irinotecan.  ACCORD-2 also found substantially higher levels of grade 3 and 4 neutropenia in the irinotecan group — 4 percent versus 28 percent.  Marc Ychou wrote,

Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

Irinotecan, also known by its original scientific designation CPT-11 and its brand name Camptosar®, was approved by the FDA in 1998 to treat colorectal cancer that had progressed on standard treatment with 5-FU and leucovorin.  It is now available in generic form.

Writing in the Journal of Clinical Oncology on May 18, 2009 Eric Van Cutsem and the PETACC team concluded,

In summary, PETACC-3 has failed to demonstrate a statistically significant DFS, RFS, or OS advantage for the addition of irinotecan to infusional FU/LV in the adjuvant treatment of stage III colon cancer.

SOURCES: Van Cutsem et al.,Journal of Clinical Oncology, JCO Early Release, May 18, 2009.

Saltz et al., Journal of Clinical Oncology, Volume 25, Number 23, August 10, 2007.

Ychou et al., Annals of Oncology, Volume 2, Number 4, April 2009.

Verna Cox with Sen. Bob Casey in Washington

C3 Advocate Verna Cox was featured in the Philadelphia Daily News yesterday, and there’s a link to her story as well as links to the winning entries in the Get Screened Video Contest.

This week, we also report research showing that the elderly benefit from irinotecan chemotherapy treatments, a potential vaccine for travelers diarrhea, and no link between coffee drinking and colorectal cancer.

Research Reports

• In a large randomized trial comparing various combinations of irinotecan, 5-FU, or Xeloda (capecitabine), elderly colorectal cancer patients treated with irinotecan-based chemotherapy had no more serious side effects than younger patients.  Patients over 70 also benefitted equally from treatment with  similar rates of tumor shrinkage, time until cancer got worse, and overall survival time. Nadine A. Jackson, MD, MPH, from Dana-Farber Cancer Institute in Boston published the results of her team’s analysis in Cancer online April 20, 2009.
• A vaccine against traveler’s diarrhea (Campylobacter jejuni) may be possible based on research in mice and monkeys.  Vaccinated against C. jejuni, mice developed strong immune responses and had significantly fewer symptoms when exposed to the bacteria.  Monkeys who were also exposed were completely protected from developing diarrhea.  Besides traveler’s diarrhea, C. jejuni can cause irritable bowel syndrome. Dr. Patricia Guerry, from the Naval Medical Research Center in Maryland, says that a vaccine for humans is “very feasible.”  Her colleagues’ research was published in the March, 2009 issue of Infection and Immunity.
• Reviewing 12 studies prospective studies that followed almost 647,000 people, researchers found no connection between drinking coffee and colorectal cancer.  There was a small decrease in risk for women and colon cancer, particularly for Japanese women.  Youjin Je and colleagues at the Harvard School of Public Health report their analysis in the April 1, 2009 International Journal of Cancer.

Other Headlines

• Winning videos from the Get Screened Video Contest sponsored by EndColonCancerNow.Org at the Fred Hutchinson Cancer Research Center are now online.  Zach Smith of Spokane, WA was the grand-prize winner, awarded $2,500 for Your Choice.  Watch Zack’s video and  those from the four runner-ups. You can also see entries from the 15 finalists.
• C3 advocate Verna Cox’s story was featured in the Philadelphia Daily News and on Philly.com on  April 23, 2009.  Verna discusses her diagnosis and treatment very frankly and what pushed her to become an advocate to prevent others from getting colorectal cancer.  She says, “My strategy is — and it’s spiritual — if I can help somebody as I travel on, then my living will not be in vain.”  Her story is part of the ongoing Beating Cancer section in the Philadelphia newspapers.