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作者：Nick Mulcahy  
出處：WebMD醫學新聞

　　January 28, 2010 — 根據一項於1月26日發表於Lancet Oncology期刊、收納105位病患的第二期研究顯示，以兩種藥物進行術前化療，而不是只使用一種藥物，對低風險、潛在適合開刀、局部直腸癌病患是可行的。
　　
　　作者們表示，以這個方式治療低風險病患的5年整體存活率為75%，比其他研究中之較佳風險、癌症初期、直腸原發性腫瘤好（5年整體存活率為63%-68%）。
　　
　　然而，他們表示，這是一項非隨機分派、單組研究，結果主要是為了產生新的假設，以及協助其他臨床研究的設計，並非為了改變臨床執業。試驗主要作者是英國薩里郡皇家馬斯登醫院的Yu Jo Chua內外全科醫學士。
　　
　　作者們表示，在這項研究中，結合capecitabine與oxaliplatin的化學治療療程，在化放療與手術前投予，其耐受性是良好的。他們表示，相較於單一治療，對這些病患進行合併治療曾有安全性隱憂。
　　
　　事實上，這項研究計劃書在兩年後排除了最近有臨床顯著心臟問題的病患，因為77位病患中有8位發生心臟事件。
　　
　　【其他研究：過去、現在與未來】
　　這並不是第一項顯示術前合併化學治療在這個情況是可行的研究。
　　
　　過去，同一群研究者已經證實fluorouracil與mitomycin C造成腫瘤降級的機率較高。然而，自從較早期研究完成後，偏好的標準治療已經變成oxaliplatin-fluoropyrimidine合併治療。因此，capecitabine，一種fluoropyrimidine被目前這項研究採用。
　　
　　該團隊研究者的下一步是多中心隨機分派EXPERT-C試驗，這項研究將探討加上cetuximab（Erbitux，必治妥藥廠）於新研究之化學治療合併療程對高風險病患的效果。根據臨床研究的描述，投予術前化學治療與放射線治療加上或未加上cetuximab可能使得腫瘤變小以及降低需要被移除的正常組織數目。
　　
　　該團隊表示，合併化學治療與放射線治療是根據另外兩項研究：Prodige 2-ACCORD與STAR試驗。這兩項研究已經證實合併化學治療可以增加「病理完全反應率」。
　　
　　這對研究者來說是很重要的，因為他們在尋找替代療效終點。然而，這兩項研究都沒有足夠的後續追蹤數據，來查明完全反應率的增加是否可以轉換為長期預後的改善。
　　
　　【發現替代療效試驗終點？】
　　在這項第二期臨床研究中，低風險病患被定義至少符合下列其中一項特徵：
　　* 腫瘤在腸繫肌膜擴大大於等於1公厘（例如威脅到或是牽涉到環狀切除區間）
　　* 位於或低於提肌的T3腫瘤
　　* 超過5公厘且侵入直腸周圍脂肪的腫瘤
　　* T4腫瘤（例如侵入周圍組織或腹膜）
　　* T1-4N2腫瘤
　　
　　研究在高解析度、高密度骨盆核磁共振造影的協助下進行評估。
　　
　　術前化學治療包括12週的oxaliplatin（130 mg/m2在每個週期的第一天投予）以及capecitabine（1000 mg/m2每天兩次，每個週期投予14天），共持續3週。接下來，進行54葛雷的骨盆腔放射性治療6週，同時使用capecitabine（825 mg/m2每天兩次）。
　　
　　接下來登場的是外科治療，在化學放射治療後6週進行全肌膜切除（前端或腹會陰部位切除，依照外科醫師的決定）。
　　
　　術後恢復後，病患接受另一次為期12週的capecitabine單一治療（1250 mg/m2每天兩次，持續14天，每3個星期一次）。
　　
　　完成術前化學治療與化學放射線治療後，進行另一次的骨盆核磁共振造影。
　　
　　研究中接受切除的95位病患接受完全病理反應評估，這項研究的主要試驗終點，定義為在切除的組織中沒有任何可偵測腫瘤細胞。
　　
　　在這95位病患中，21位有完全病理反應的病患超過了這項研究的預先目標。這21位病患沒有任何疾病再發現象，這鼓舞了研究者們。存活者後續追蹤時間中位數為55個月。
　　
　　研究者們寫到，這些發現支持了病理反應作為代理療效終點的價值。
　　
　　【密集地後續追蹤】
　　研究者們強調這項研究的另一面，密集治療後續追蹤疾病再發。研究者們報告，這樣的後續追蹤使得26件疾病再發中，80%在病患仍無症狀時偵測。
　　
　　在後續追蹤計畫中，病患在第1年每3個月回診一次，第2年時每6個月回診一次，之後於第3、4、5年時每年一次。在頭兩年的後續追蹤中，每年年底進行胸部、腹部與骨盆腔進行電腦斷層掃描。
　　
　　治療後追蹤包括每次回診時檢驗癌胚抗原（CEA）。
　　
　　在不良反應方面，因為治療造成的第三級到第五級毒性反應包括皮膚毒性（接受化學放射線治療時為42%）以及腹瀉（接受術前化學治療時為10%）。
　　
　　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.

Lancet Oncol. Published online January?26, 2010.