転移性大腸癌 腫瘍径変化は余命を反映しない

転移性大腸癌　奏功（腫瘍径の変化）と生命延長効果は関連しない
N9741試験とAVF2107試験の比較解析

転移性大腸癌に対する1st line化学療法を検討した2試験では・・
AVF2107試験：　IFL+bevacizumab vs. FU/LV+bevacizumab vs. IFL+プラセボ
N9741試験：　IFL vs. FOLFOX vs. IROX

IFL+bevacizumab vs. IFL　　 　奏功例　　　　　　　　非奏功例
増悪のHazard ratio　　　　　0.53(p=0.0002)　　　0.63(p=0.0188)
死亡のHazard ratio　　　　　0.60(p=0.0136)　　　0.76(p=0.0188)

FOLFOX vs. IFL 　　　　　　　　奏功例　　　　　　　　非奏功例　　　　　　SD例
PFS改善のHazard ratio　　0.89(p=0.3166)　　　0.75(p=0.0029)　　　0.78(p=0.0795)
死亡のHazard ratio　　 　　0.71(p=0.0047)　　　0.74(p=0.0030)

IFLよりも有効性が示されているレジメンにより、
奏功例か否かの評価は生命予後の指標になっていないことが示された。



PURPOSE:
In the phase III study AVF2107g, bevacizumab (BV) demonstrated a
survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study,Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also　demonstrated a survival benefit compared with IFL. As these two superior　therapies have differing mechanisms of action, we explored whether the improved　survival associated with the superior therapy was dependent on tumor response.

PATIENTS AND METHODS:
For these retrospective, exploratory analyses, patients　were defined as responders or nonresponders by whether complete or partialresponse was achieved with first-line therapy.

RESULTS:
Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements　in progression-free survival (PFS) and overall survival (OS) regardless of　objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of　0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated　nonresponders. FOLFOX-treated　nonresponders had an HR of 0.75 (P = .0029) for PFS　and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders.

CONCLUSION:
In both AVF2107g and N9741, objective response did not predict the magnitude of　PFS or OS benefit from the superior therapy; nonresponders, despite a poorer　prognosis than responders, achieved extended PFS and OS from BV plus IFL or　FOLFOX compared with IFL. On the basis of these data, tumor response in　metastatic colorectal cancer is not a necessary factor for a therapy to provide　benefit to an individual patient.



Grothey A et al.
Response-independent survival benefit in metastatic colorectal cancer: a
comparative analysis of N9741 and AVF2107.
J Clin Oncol. 2008 Jan 10;26(2):183-9. PMID: 18182660

S1+CDDP vs S1 alone for Gastric cancer (SPIRITS試験)

SPIRITS trial

進行胃癌に対しS1内服にCDDPを加えると余命が2ヶ月延長する。
全余命：13→11ヶ月



BACKGROUND: S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer(SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone.

METHODS: Chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle.
The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670.

FINDINGS: 305 patients were enrolled; S-1 plus cisplatin 148/ S-1 alone150.

Median overall survival 13.0 months [IQR 7.6-21.9] vs. 11.0 months [5.6-19.8];
Hazard ratio for death 0.77; 95% CI 0.61-0.98; p=0.04.
Progression-free survival median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p<0.0001). S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41).
We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no
treatment-related deaths in either group.

INTERPRETATION: S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.


S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer : a phase III trial.
Koizumi W,et al.Kitasato University, Japan.
Lancet Oncol. 2008 Mar;9(3):215-21. PMID: 18282805

喫煙と糖尿病リスク、Meta-analysis

喫煙者の糖尿病発症
25件の前向きコホート研究による　補正相対リスク1.44(1.31-1.58)

Active smoking and the risk of type2 diabetes: a systematic review and meta-analysis.
Willi C et al. JAMA 2007; 298:2654-2664.PMID: 18073361

因果関係か交絡か？

〔因果関係を支持〕
①時間的前後関係
②ヘビースモーカーの方がリスクが高い量反応関係
③生物学的妥当性：喫煙はインスリン抵抗性をおこしインスリン分泌を抑制

〔交絡の可能性〕
①喫煙者は運動不足でアルコール摂取が多く不健康だから
②ヘビースモーカーには肥満者が多く、禁煙の成功率は低い。
③禁煙の失敗は体重増加の原因
④喫煙者は中心性肥満が多い（喫煙の抗エストロゲン作用）