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Modulation of Adjuvant 5-Fluorouracil Treatment by Folinic Acid and Interferon-Alpha in Colon and Rectal Cancer: Presentation ESSO

By Chris Berrie

VENICE, ITALY -- December 4, 2006 -- While the addition of folinic acid (FA) to 5-fluorouracil and levamisol (5-FU/LEV) is effective and well tolerated as adjuvant therapy in patients with colon cancer, differential chemosensitivity is revealed as a lack of efficacy of this adjuvant therapy in patients with rectal cancer.

Furthermore, say researchers from the Oncology and Gastrointestinal Tumours Study Group (FOGT), in both cases, modulation of 5-FU/LEV treatment using interferon-alpha (INF-alpha) is ineffective and toxic.

This comparison of 2 multicentre, randomised, phase 3 trials was presented by co-principal investigator Karl-Heinz Link, MD, professor of surgery, department of surgery, Asklepios Paulinen Hospital, Wiesbaden, Germany, here at the 13^th Congress of the European Society of Surgical Oncology (ESSO).

There remains the need to optimise adjuvant treatment of colorectal cancer and to determine the efficacy of standard therapy modulation, Dr. Link said during his presentation on November 30th. He noted that in patients with lymph-node-positive colon cancer, the benefits of combined chemotherapy with 5-FU and LEV have been reported in previous studies, and combined postoperative chemoradiotherapy has been recommended for patients with locally advanced rectal cancer, he said.

Dr. Link and colleagues compared across patients with colon (FOGT1; n = 855) and rectal (FOGT2; n = 797) cancers the efficacy of modulation of adjuvant 5-FU/LEV treatment with FA and INF-alpha.

The researchers enrolled patient with curatively resected colon or rectal cancer (R0), including at least 12 lymph nodes. Postoperative staging of colon cancer were done according to the International Union Against Cancer (UICC) TNM classification that was stage 2b (clinical; T4, pN0, M0) or stage 3 (pTx, pN+, M0); for rectal cancer, stages allowed were stage 2 (pT3/T4, pN0, M0) or stage 3 (pTx, pN+, M0).

The design provided for stratification (centre, T1/2 vs T3/4, N0 vs N1/2) and randomisation (10-15 days postsurgery) to 1 of 3 arms within each trial: 5-FU/LEV, 5-FU/LEV plus FA, and 5-FU/LEV plus INF-alpha.

Treatments included oral LEV 50 mg 3 times daily for 3 days every 2 weeks, IV 5-FU 450 mg/m² for 60 to 120 minutes (loading, days 1-5; weekly, day 28 for 48 weeks), IV FA 200 mg/m² for 10 minutes prior to 5-FU, and subcutaneous INF-alpha starting on day 28 and 106 IU dosed 6 times 3 times weekly. Patients with rectal cancer received adjuvant radiation treatment 6 to 8 weeks postsurgery for a total dose of 50.4 Gy, with chemotherapy reduced to 80% dosing.

With the hypothesis that modulation of 5-FU/LEV treatment increases patient survival, the primary endpoint of the study was overall survival, with secondary endpoints of recurrence-free survival, toxicity and compliance.

At a median follow-up of 5.2 years, patients with colon cancer showed significant 5-year overall survival improvement in favour of FA addition (n = 278; 71%) over 5-FU/LEV alone (n = 282; 59%; P = .004). No benefit was seen with inclusion of INF-alpha (n = 295).

With median follow-up of 4.8 years, patients with rectal cancer showed a similar beneficial trend for FA addition (n = 223; 79%) over 5-FU/LEV (n = 282; 71%) for 3-year overall survival. However, as Prof Link said, "We were very much disappointed to see that after 5 years, this initial, tentative, difference disappeared and there was no benefit found for this full adjuvant therapy in the rectal cancer patients." Again, inclusion of INF-alpha demonstrated no benefits.1

When the recurrence rates and localisations were examined according to treatments, for patients with colon cancer, recurrence was in all cases mainly distant only (24%-34%), which appeared as the target for FA benefit. Local recurrence alone was low (3.5%-4.3%), with higher local plus distant recurrence (7.0%-9.2%).

For rectal cancer, recurrence was again mainly distant only (25.8%-27.5%), with equivalent local only (4.8%-6.1%) and local plus distant (4.1%-5.7%) recurrence. Dr. Link noted a 4.6% decrease in recurrence rate for these patients, despite no effects seen for 5-year overall survival.

World Health Organisation (WHO) grade 3/4 toxicities for patients with colon cancer were mainly neutropenia, nausea, vomiting and diarrhoea, with 1 toxicity-related death (5-FU/LEV group; neutropenia, pneumonia). While toxicity showed only a small increase with addition of FA to 5-FU/LEV (13% vs 9%, respectively), INF-alpha was associated with a more than doubling rate (31%).

For rectal cancer, WHO grade 3/4 toxicities were mainly diarrhoea, leucopenia, skin and nausea. Again, these were largely unchanged with addition of FA to 5-FU/LEV (27% vs 31%, respectively). However, Dr. Link said, "We stopped [INF-alpha] treatment in the rectal cancer [group] because the toxicity [of 55%] was too high." There were 2 toxic deaths recorded in this group (cardiac, diarrhoea).

Overall, Dr. Link stressed that while both trials demonstrated INF-alpha to be toxic and ineffective, comparison between the 2 trials reveals differential chemosensitivities that indicate differences in tumour biology between these cancer types. Similarly, this highlights not only the need for more intense treatment regimens to improve prognosis of locally advanced rectal cancer, but also that the main problem with recurrence of both colon and rectal cancers lies in that of distant metastases, which thus need to be specifically targeted with more effective treatments.

This study was supported by Roche (interferon-alpha) and Medac (folinic acid).

REFERENCE:
1. Link et al. Increase of Survival Benefit in Advanced Resectable Colon Cancer by Extent of Adjuvant Treatment: Results of a Randomized Trial Comparing Modulation of 5-FU + Levamisole With Folinic Acid or With Interferon-[alpha]. Ann. Surgery. 2005; 242:178-187.


[Presentation title: Modulation of Adjuvant 5-FU Treatment by Folinic Acid and Interferon-Alpha in Colon and Rectal Cancer: Comparison of Two Phase 3 Trials Including 1652 Patients. Abstract 024]

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