Yu Jo Chua醫師接受羅氏藥廠與賽諾菲安萬特藥廠的演講費。其他作者也表示與這兩家藥廠有資金上的往來。
Intensive Chemotherapy May Help in Poor-Risk, Localized Rectal Cancer
By Nick Mulcahy
Medscape Medical News
January 28, 2010 — Neoadjuvant chemotherapy with 2 agents — instead of just 1 — before standard treatment is feasible in poor-risk, potentially operable, localized rectal cancer, concludes a new phase?2 study of 105 patients published online January?26 in The Lancet Oncology.
The 5-year overall survival of 75% seen with this approach in poor-risk patients "compares favorably" with rates in randomized trials of other treatment approaches in better-risk, earlier-stage, rectal primary tumors (5-year overall survival, 63% to 68%), note the authors.
However, because this study is a nonrandomized, single-group study, the results are mainly for the generation of hypotheses and to help the design other clinical trials — not for changing clinical practice, they suggest. The study's lead author was Yu Jo Chua, MBBS, from the Royal Marsden Hospital in Surrey, United Kingdom.
In the study, a combined chemotherapy regimen of capecitabine and oxaliplatin, given before chemoradiotherapy and surgery, was "well tolerated," report the authors. They note that there have been safety concerns about the use of combination therapy, as opposed to a single agent, with radiation in these patients.
Indeed, the study protocol was amended after 2 years to exclude patients with a recent history of clinically significant cardiac problems because 8 of 77 patients experienced cardiac events.
Other Studies: Past, Present, and Future
This is not the first study to show that neoadjuvant combination chemotherapy is feasible in this setting.
Previously, these same investigators showed that fluorouracil and mitomycin?C provided a "high rate of tumor downstaging." However, since that earlier study was completed, the preferred standard has become oxaliplatin–fluoropyrimidine combinations. Therefore, capecitabine, a fluoropyrimidine, was used in the current study.
The next step for this group of researchers is the multicenter randomized EXPERT-C trial, which will assess the addition of cetuximab (Erbitux, Bristol-Myers Squibb) to this newly studied chemotherapy combination in poor-risk patients. "Giving chemotherapy and radiation therapy with or without cetuximab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed," according to the clinical trial description.
The team notes that combination chemotherapy with radiotherapy is being used in 2 other trials: Prodige 2-ACCORD and STAR. Both trials have shown that combination chemotherapy increases "pathological complete response rates."
This is important to the investigators because they are in search of a surrogate efficacy end point. However, neither of these trials has enough follow-up data yet to ascertain whether the improvement in complete response rate translates into improvement in long-term outcomes, they say.
Surrogate Efficacy End Point Found?
In this phase?2 study, poor-risk patients were defined as having at least 1 of the following features:
tumor extending to within 1?mm of, or beyond, the mesorectal fascia (i.e., circumferential resection margin threatened or involved)
T3 low-lying tumor at or below the levators
tumor extending 5?mm or more into perirectal fat
T4 tumor (i.e., invading surrounding structures or peritoneum)
T1-4N2 tumors.
Status was assessed with the help of a high-resolution, thin-slice magnetic resonance image of the pelvis.
Neoadjuvant chemotherapy consisted of 12 weeks of oxaliplatin (130?mg/m2 given on day?1 of every cycle) and capecitabine (1000?mg/m2 twice daily for 14 days) in cycles lasting 3 weeks. Next, 54?Gy of pelvic radiation was administered over 6 weeks with continuous concomitant capecitabine (825?mg/m2 twice daily).
Surgery comes next, with a total mesorectal excision (anterior or abdominoperineal resection at the surgeon's discretion) 6 weeks after completion of chemoradiotherapy.
After recovery from surgery, patients receive another 12 weeks of capecitabine monotherapy (1250?mg/m2 twice daily for 14 days, every 3 weeks).
Another pelvic agnetic resonance image was taken after completion of neoadjuvant chemotherapy and after chemoradiotherapy.
All 95 patients in the study who underwent total mesorectal excision were assessable for complete pathological response, the study's primary end point, which was defined as the absence of any detectable residual tumor cells in the resected specimen.
Of the 95 patients, 21 had a pathological complete response that exceeded the prespecified objectives of the trial. None of these 21 patients had disease recurrence, which encouraged the investigators. The median follow-up time for survivors was 55 months.
These findings "support the value of pathological complete response as a surrogate efficacy end point," write the investigators.
Intensive Follow-Up
The investigators highlighted another aspect of the study — the intensive posttreatment follow-up for recurrent disease. The follow-up allowed 80% of 26 recurrences to be detected while patients were asymptomatic, report the authors.
In the surveillance plan, patients were seen every 3 months for the first year, every 6 months during the second year, and annually during years?3, 4, and 5. A computed tomography scan of the chest, abdomen, and pelvis was performed at the end of the year for the initial 2 years of follow-up.
Posttreatment follow-up included the measurement of carcinoembryonic antigen at every clinic visit.
In terms of adverse events, the grade?3 to 5 toxic events from treatment included skin toxicities (42% of patients during chemoradiotherapy) and diarrhea (10% of patients during neoadjuvant chemotherapy).
Dr. Yu Jo Chua reports receiving honoraria from Roche and Sanofi-Aventis. Other authors also report relationships with these 2 companies.
