Adjuvant cytotoxic and endocrine therapy in pre- and postmenopausal patients with breast cancer and one to nine infiltrated nodes: five-year results of the Hellenic Cooperative Oncology Group randomized HE 10/92 study

SUMMARY: The present randomized phase III trial was designed to detect a 15% benefit in relapse-free survival (RFS) or overall survival (OS) from the incorporation of adjuvant tamoxifen to the combination of CNF [cyclophosphamide, 500 mg/m2; mitoxantrone (Novantrone), 10 mg/m2; fluorouracil, 500 mg/m2 chemotherapy and ovarian ablation in premenopausal patients with node-positive breast cancer and conversely from the incorporation of CNF chemotherapy to adjuvant tamoxifen in node-positive postmenopausal patients. From April 1992 until March 1998, 456 patients with operable breast cancer and one to nine infiltrated axillary nodes entered the study. Premenopausal patients were treated with six cycles of CNF chemotherapy followed by ovarian ablation with monthly injections of triptoreline 3.75 mg for 1 year (Group A, 84 patients) or the same treatment followed by 5 years of tamoxifen (Group B, 92 patients). Postmenopausal patients received 5 years of tamoxifen (Group C, 145 patients) or 6 cycles of CNF followed by 5 years of tamoxifen (Group D, 135 patients). Adjuvant radiation was administered to all patients with partial mastectomy. After a median follow-up period of 5 years, 125 patients (27%) relapsed and 79 (17%) died. The 5-year actuarial RFS for premenopausal patients was 65% in Group A and 68% in Group B (p = 0.86) and for postmenopausal patients 70% in Group C and 67% in Group D (p = 0.36). Also, the respective OS rates were 77% and 80% (p = 0.68) for premenopausal and 84% and 78% (p = 0.10) for postmenopausal patients. Severe toxicities were infrequently seen, with the exception of leukopenia (18%), among the 311 patients treated with CNF. In conclusion, the present study failed to demonstrate a 15% difference in RFS in favor of node-positive premenopausal patients treated with an additional 5 years of tamoxifen after CNF adjuvant chemotherapy and ovarian ablation. Similarly, six cycles of CNF preceding 5 years of tamoxifen did not translate to a 15% RFS benefit in node-positive postmenopausal patients.     

Adjuvant chemotherapy with 5-fluorouracil, doxorubicin and mitomycin-C (FAM) for 6 months after curative resection of gastric carcinoma.

AIM: This study aimed to evaluate the efficacy and safety of 5-fluorouracil (5-FU), doxorubicin and mitomycin-C (FAM) adjuvant chemotherapy in patients who had undergone curative resection of gastric carcinoma. METHODS: From Nov 1999 to Jan 2002, 291 consecutive patients with stage IB-IIIB gastric adenocarcinoma were given FAM adjuvant chemotherapy. Chemotherapy comprised intravenous 5-FU 600 mg/m(2) (days 1, 8, 29 and 36), doxorubicin 30 mg/m(2) (days 1 and 29) and mitomycin-C 10 mg/m(2) (day 1), every 8 weeks for 6 months. RESULTS: The median follow-up time was 60.6 months, 92 patients died, and 93 patients had recurrent disease. The 5-year overall survival (OS) rates were 85.9% for stage IB, 72.1% for stage II, 58.0% for stage IIIA, and 48.2% for stage IIIB (p=0.002). The 5-year relapse-free survival (RFS) rates were 85.2% for stage IB, 71.2% for stage II, 53.3% for stage IIIA, and 39.2% for stage IIIB (p<0.001). A total of 769 cycles of chemotherapy were delivered, and 15 patients experienced grade 3 or higher leukopenia. The most common grade 3 or higher non-hematologic toxicity was nausea/vomiting (11 patients), followed by stomatitis (3 patients). CONCLUSIONS: Adjuvant chemotherapy with FAM for 6 months for gastric carcinoma indicated comparable RFS and OS with an acceptable toxicity profile.     

Five-year oncologic outcomes and prognostic factors for locally advanced low rectal cancer after low anterior resection

Objective： The aim of the study is to investigate the longterm oncologic outcomes including local recurrence, distant metastases and overall survival （OS） for patients with low rectal cancer underwent low anterior resection （LAR） with total mesorectal excision （TME）, and to analyze the prognostic factors for them. Methods： Between January 2001 and December 2009, 147 patients with clinical stage II and III rectal cancers located 3-6 cm from the anal verge underwent LAR with TME without temporary diverting stoma. The median distal resection margin （DRM） was 1.0 （range, 0.3-5） cm. Anastomostic leakage occurred in 29 （19.7%） patients. Thirty patients received surgery alone, 20 patients received preoperative chemoradiotherapy （CRT）, 43 patients received postoperative CRT, and adjuvant chemotherapy was administered for 108 patients. The median cycle of adjuvant chemotherapy was 6 （range, 2-20） cycles. The median followup was 74.8 （range, 30.1-146.3） months. Results： In all patients, 5-year recurrence-free survival （RFS）, disease-free survival （DFS） and OS were 70.4%, 54.2% and 60.5%, respectively. Forty-three （29.3%） patients suffered local recurrence. Patients received preoperative CRT with a downstaging yp0/1 who had a better 5-year RFS, DFS and OS, which were 100%, 90.9%, and 90.9%, respectively. For patients with pathologic stage Ⅱ and stage Ⅲ, the 5-year RFS, DFS, and OS were 79.2% and 60.1%, 67.9% and 39.1%, 72.1% and 48.2%, respectively. On multivariable analysis, RFS was associated with anostomostic leakage, DFS was associated with anastomostic leakage and pathologic N stage, and OS was associated with anastomostic leakage, pathologic N and T stage. For patients with anastomostic leakage, the 5-year RFS, DFS, and OS were 51.7%, 32.4%, and 38.3%, respectively, which were worse than that for patients without anastomostic leakage, the latter were 75.2%, 59.7%, 65.7%, respectively （P 〈 0.05）. DRM and radiotherapy were associated with RFS on univariable     

Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: a randomized clinical study

Between 1977 and 1980, 118 breast cancer patients with locally advanced disease, T3B-4, any N, M0 or T1-3, tumor positive axillary apex biopsy, were randomized to one of three arms: I: radiotherapy (RT) to the breast and adjacent lymph node areas; II: RT followed by 12 cycles of cyclophosphamide, methotrexate, 5 fluorouracil (CMF) and tamoxifen during the chemotherapy period; III: 2 cycles of adriamycin and vincristine (AV), alternated with 2 cycles of CMF, then RT, followed by another 4 cycles of AV, alternated with 4 CMF; tamoxifen during the entire treatment period. The median follow-up period was 5 1/2 years. The adjuvant chemo- and hormonal therapy did not improve the overall survival; the 5-year survival was 37% for all three treatment arms. There was no statistically significant difference in RFS between the three modalities, nor when arm I was compared to arm II and III together, p = 0.11. Local recurrence (LR) was observed in 24 of the 86 patients (28%) who had reached complete remission (CR). LR was not statistically different over the three treatment arms. In 18 of the 24 patients with LR, distant metastases appeared within a few months from the local recurrence. In arm III, the CR rate after 4 cycles AV plus CMF and RT hardly changed after another 8 cycles of chemotherapy. The menopausal status did not influence the treatment results. Dose reduction in more than 4 cycles of chemotherapy was accompanied by better results, p = 0.04. In conclusion: adjuvant chemo- and hormonal therapy did not improve RFS and overall survival. These findings do not support the routine use of adjuvant chemo- and endocrine therapy for inoperable breast cancer.     

HER2 as a potential biomarker guiding adjuvant chemotherapy in stage II colorectal cancer

BackgroundHER2 is a well-established therapeutic target in breast and gastric cancers, while the role of HER2 in colorectal cancer is unclear, and no studies have explored the impact of HER2 on the outcome of stage II colorectal cancer patients treated with 5-fluorouracial based adjuvant chemotherapy.MethodsWe analyzed HER2 mRNA expression of 206 patients in GSE39582 dataset and explored the impact of HER2 expression on benefit from adjuvant chemotherapy for stage II colon cancer patients. We further validated the finding by retrospectively analyzing HER2 detection of immunohistochemistry in a cohort of 282 patients in Fudan University Shanghai Cancer Center (FUSCC).ResultsIn GSE39582 dataset, chemo-treated HER2-high patients had a better overall survival (OS) and relapse-free survival (RFS) versus chemo-naïve HER2-high patients (5-year OS: 100% vs 69.5%, 5-year RFS: 100% and vs 64%, P = 0.027 and 0.025, respectively). On the contrary, chemo-treated HER2-low patients had a worse RFS compared with chemo-naïve HER2-low patients (5-year RFS: 65.6% vs 82.1%, P = 0.022). In FUSCC cohort, chemo-treated HER2-positive patients exhibited better OS vs chemo-naïve HER2-positive patients (5-year OS: 100% vs 73.8%, P < 0.001), and showed marginal evidence of a lower probability of recurrence (5-year RFS: 74.4% vs 58.7%, P = 0.072). After stratifying by mismatch repair (MMR) status, the results only kept consistency in patients with pMMR status.ConclusionsHER2-positve patients with stage II colorectal cancer can benefit from 5-fluorouracial based adjuvant chemotherapy, especially for patients with pMMR status.     

The efficacy of fluoropyrimidine-based adjuvant chemotherapy on biliary tract cancer after R0 resection

Background: The optimal treatment strategy for biliary tract cancer (BTC) after curative-intent resection remains con-troversial. The purpose of this study was to evaluate the efficacy of fluoropyrimidine-based adjuvant chemotherapy for BTC patients undergoing microscopically margin-negative (R0) resection. Methods: We retrospectively analyzed the clinical data of BTC patients who underwent curative-intent R0 resection. Patients were eligible if they received either fluoropyrimidine-based adjuvant chemotherapy or observation after R0 resection. Results: A total of 153 patients were included. In the entire patient cohort, no significant differences were observed in 5-year overall survival (OS) rates (48.4% vs. 39.6%,P= 0.439) or 3-year recurrence-free survival (RFS) rates (49.1% vs. 39.5%,P= 0.299) between patients who received fluoropyrimidine-based adjuvant chemotherapy or observation. However, for patients with stages Ⅱ and Ⅲ BTC, chemotherapy significantly improved 5-year OS rate (52.4% vs. 35.6%, P= 0.002) and 3-year RFS rate (55.5% vs. 39.1%,P= 0.021) compared with observation. Conclusion: Fluoropyrimidine-based adjuvant chemotherapy may prolong the survival of patients with stages Ⅱ and Ⅲ BTC after R0 resection.     

Multivariate survival and outcome analysis of 154 patients with gastric cancer at a single Chinese institution

This study was conducted to analyze and elucidate key prognostic factors for gastric cancer (GC), and to understand the current status of GC diagnosis and treatment in Hubei Province, China. Major clinical and pathological information on 154 GC patients was retrospectively collected, including gender, age, tumor site, surgical approach, histological type, TNM stage and chemotherapy cycles. Overall survival (OS) was analyzed in relation to these factors. The median OS was 12.0 months (0.5-69.0 months), and 1-, 2-, 3- and 5-year survival rates were 53.0%, 23.0%, 8.0% and 1.0%, respectively. The median OS by TNM stage was 21.0 months for stages I+II and 11.5 months in stages III+IV (P=0.043), and 1-, 2-, 3- and 5-year survival rates were 72.0% vs 50.0%, 40.0% vs 19.0%, 16.0% vs 6.0% and 0% vs 1.0 %, respectively. The median OS by chemotherapy cycles was 18.0 months in chemotherapy ≥6 cycles group and 11.0 months in chemotherapy <6 cycles group (P=0.009), and 1-, 2-, 3- and 5-year survival rates were 68.0% vs 49.0%, 41.0% vs 18.0%, 12.0% vs 7.0% and 0% vs 1.0%, respectively. Multivariate analysis identified tumor site, surgical approach and chemotherapy cycles as independent predictors for improved survival. Implementation of standardized radical surgery and reasonable adjuvant therapy could improve survival and prognosis of GC patients.     

Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5.

PURPOSE: Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy. PATIENTS AND METHODS: Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death. RESULTS: With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed in OS (P =.195). CONCLUSION: Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer.     

Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group.

PURPOSE: The multidrug resistance protein 1 (MRP1) is expressed in human breast cancer cells and may contribute to the clinical drug resistance of breast cancer patients. Therefore, we determined the impact of MRP1 expression on the clinical outcome of adjuvant therapy in patients with early-stage breast cancer. PATIENTS AND METHODS: Immunostaining for MRP1 was performed on tissue sections from 516 premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease. Statistical analyses were performed to assess the effect of MRP1 expression on survival and to test for interaction between MRP1 expression and treatment. RESULTS: MRP1 expression independently predicted shorter relapse-free survival (RFS) and overall survival (OS) in patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF; RFS: hazard ratio [HR] = 1.48; 95% CI, 1.16 to 1.88; P = .002; OS: HR = 1.82; 95% CI, 1.10 to 3.01; P = .02), but it did not predict shorter RFS and OS in patients who received tamoxifen plus goserelin (RFS: HR = 0.99; 95% CI, 0.74 to 1.31; P = .9; OS: HR = 0.68; 95% CI, 0.40 to 1.15; P = .1). Tests for interaction between MRP1 expression and treatment were statistically significant for both RFS (P = .04) and OS (P = .006). CONCLUSION: Our data suggest that MRP1 expression plays an important role in the clinical resistance to adjuvant CMF chemotherapy but does not seem to affect response to adjuvant endocrine treatment with tamoxifen plus goserelin. Thus, MRP1 may be a useful marker for the selection of patients with early-stage breast cancer for the appropriate adjuvant therapy after prospective confirmatory evaluation.     

Tamoxifen in high-risk premenopausal women with primary breast cancer receiving adjuvant chemotherapy. Report from the Danish Breast Cancer co-operative Group DBCG 82B Trial

Following modified radical mastectomy, pre- and perimenopausal (amenorrhoea for < 5 years) patients with stage II or III breast cancer received CMF (cyclophosphamide 600, methotrexate 40, 5-fluorouracil 600 mg/m2 intravenously (i.v.) every 4 weeks, 9 cycles). The effect on recurrence-free survival (RFS) and overall survival (OS) of the addition of adjuvant tamoxifen (TAM) to adjuvant chemotherapy was examined by randomisation either to no additional treatment (n = 314), or concurrently TAM 30 mg daily for 1 year (n = 320). 40% had positive, 12% negative and 48% unknown receptor status. One year after surgery 21% versus 35% (CMF + TAM versus CMF) were still menstruating (P < 0.01). With a median follow-up of 12.2 years there was no difference in RFS (10-year RFS 34% versus 35%, P = 0.81) or OS (45% versus 46%, P = 0.73). In a Cox proportional hazards model, tumour size, number of metastatic lymph nodes, frequency of metastatic nodes in relation to total number of nodes removed, degree of anaplasia, age, and menostasia within the first year after operation were significant independent prognostic factors for RFS, and the same factors except age for OS. No significant interactions with TAM were seen. Thus, in this group of pre- and perimenopausal high-risk early breast cancer patients with heterogeneous receptor status given CMF i.v., concurrent TAM for 1 year did not improve the outcome. These results do not exclude that receptor positive patients may benefit from adjuvant TAM for longer periods given sequentially to chemotherapy.     

可手术的乳腺癌术前化疗的远期效果

目的探讨术前化疗对可手术的乳腺癌的远期疗效。方法可手术的乳腺癌患者５３７例,分为两组：术前化疗组（Ａ组）２５３例;术后辅助化疗组（Ｂ组）２８４例。Ａ组术前联合化疗,每周一次共４次,休２周行根治性手术。两组患者术后两周内开始化疗、化疗方案和完成化疗周期相同。结果（１）Ⅲ期患者,Ａ组５年总生存率（ＯＳ）５９％,无病存活率（ＤＦＳ）５４．９％,均明显高于Ｂ组２８．３％和２０．８％（Ｐ＜０．０５）。（２）Ⅱ期患者,Ａ组８年ＯＳ８１．４％,ＤＦＳ７６．３％,均高于Ｂ组６７．４％和６２．９％（Ｐ＜０．０５）。Ⅲ期患者,Ａ组８年ＯＳ４６．９％,ＤＦＳ４０．６％,也高于Ｂ组２０．７％和１３．３％（Ｐ＜０．０５）。（３）Ａ组Ｔ３、Ｔ４和转移淋巴结数≥４个的患者,５年、８年生存率均高于Ｂ组（Ｐ＜０．０５）。结论可手术的Ⅲ期乳腺癌,术前化疗可提高患者５年、８年生存率,明显改善Ⅱ期患者的远期疗效。     

An evaluation of perioperative and continuous infusion of tegafur as surgical adjuvant chemotherapy of resected gastric cancer]

Perioperative continuous intravenous infusion of Tegafur (FT) seems theoretically an effective adjuvant chemotherapy for patients with gastric carcinoma. Then we estimated the clinical effect of this therapy on the survival of patients who had undergone curative (Stage I, II, III) and non-curative (Stage IV) resection of a primary gastric carcinoma. One hundred fifty patients received chemotherapy and two hundred thirty-seven were observed. Results showed a significant difference in survival curves of Stage I (p less than 0.01) and Stage III (p less than 0.01). The 5-year survival rate was 100% for the adjuvant therapy arm and 82% for the observation arm in Stage I. In stage III, the survival curve of both arms was similar from the beginning to the 5th year, but the 7-year survival rate was 53% and 39%, respectively. There was no serious side effect of chemotherapy. These results demonstrate that this chemotherapy regimen is beneficial and recommendable as a perioperative adjuvant chemotherapy for resected gastric cancer in which the cancer cells were almost removed.     

Long-term outcome of preoperative chemotherapy with 5'-deoxy-5-fluorouridine (5'-DFUR) for gastric cancer

We performed a multicenter clinical trial of preoperative chemotherapy for gastric cancer. Patients aged 75 years or less with advanced gastric cancer were enrolled and randomized into the following groups: Group I, which received oral 5'-DFUR (610 mg/m2/day x 10 days or over) preoperatively, and Group II, which received no treatment preoperatively. Patients in both groups also received intravenous MMC 1 and 2 days after surgery and were orally administered 5'-DFUR for two years postoperatively. There were 171 patients (Group I: 91, Group II: 80) enrolled and analyzed, and the 5-year survival rate was 63.4% in Group I and 64.9% in Group II (p = 0.698). Among patients classified as having curability B, the 5-year survival rate of each group was 51.8% and 36.8%, respectively (p = 0.426). However, the 5-year survival rate of patients showing good compliance with oral 5'-DFUR therapy was significantly higher than that of patients with poor compliance (53.3% vs 22.0%, p = 0.010). The pyrimidine nucleoside phosphorylase (PyNPase) activity in gastric carcinoma tissue from Group I was lower than that from Group II, and Group II patients tended to die of hematogeneous metastases. In conclusion, although this clinical trial failed to demonstrate a significant benefit of preoperative chemotherapy because of the low dose of 5'-DFUR, we believe that good compliance with oral anticancer treatment contributes to long-term survival and that 5'-DFUR reduces hematogeneous metastasis of gastric carcinoma.     

Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study).

BACKGROUND: This randomized, multicenter, phase III trial evaluated the efficacy and safety of the combination of epirubicin, leucovorin, 5-fluorouracil and etoposide (ELFE regimen) as adjuvant therapy for radically resected gastric cancer patients. PATIENTS AND METHODS: From June 1996 to June 2001, 228 stage IB-IIIB gastric cancer patients were enrolled. All patients received a total or subtotal gastrectomy with at least a D1 lymphoadenectomy and were randomly assigned to receive surgery alone or surgery followed by chemotherapy. RESULTS: A total number of 630 cycles was delivered with a median number of 5. With a median follow-up of 60 months, the 5-year overall survival (OS) was 48% in the treatment arm and 43.5% in the control arm [hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.69-1.21; P = 0.610); the 5-year disease-free survival (DFS) was 44% in the treatment arm and 39% in the control arm (HR 0.88; 95% CI 0.78-0.91; P = 0.305). In node-positive patients, the 5-year OS was 41% in the treatment arm and 34% in the control arm (HR 0.84; 95% CI 0.69-1.01; P = 0.068), while the 5-year DFS was 39% in the treatment arm and 31% in the control arm (HR 0.88; 95% CI 0.78-0.91; P = 0.051). The most common grade 3-4 toxic effects according to World Health Organization criteria were hematological and gastrointestinal. CONCLUSIONS: In radically resected gastric cancer patients, adjuvant chemotherapy with ELFE regimen does not improve OS over surgery alone.     

An association between preoperative anemia and decreased survival in early-stage non-small-cell lung cancer patients treated with surgery alone

PURPOSE: Surgical resection is the mainstay of therapy for patients presenting with Stage I and II non-small-cell lung cancer (NSCLC). Despite optimal staging and surgery, these patients are still at significant risk for failure. The purpose of this study is to report a retrospective analysis of the outcome of patients treated with surgery alone, as well as to analyze prognostic factors associated with survival. MATERIALS AND METHODS: From May 2000 to November 2002, there was a total of 125 patients who were treated with surgery for NSCLC at University of Maryland Medical Center. Of these, 82 Stage I and II patients who received surgery alone as the definitive therapy were identified. The median age of the entire cohort was 68 years (range, 43-88 years). There were 48 males and 34 females. Sixty-three patients (76.8%) underwent lobectomies whereas 19 patients (23.2%) underwent nonlobectomy (wedge resection or segmentectomy) procedures. Patients who received neoadjuvant or adjuvant radiation therapy or chemotherapy were excluded from the study. Factors included in univariate and multivariate analyses were age, sex, tumor histology, pathologic stage, p53 status, preoperative hemoglobin (Hgb), and type of surgery performed. Endpoints of the study were relapse-free survival (RFS) and overall survival (OS). RESULTS: Median follow-up was 20.8 months (range, 0.4-43.2 months). For the entire cohort, the 2-year RFS was 66.0% and 2-year OS was 76.3%. Median survival for the entire cohort has not been achieved. In univariate analysis, the only factor that achieved statistical significance was preoperative Hgb level. Patients who had preoperative Hgb <12 mg/dL experienced significantly worse RFS (mean RFS: 26.6 months vs. 34.9 months, p = 0.043) and OS (median OS: 27 months vs. 42.5 months, p = 0.011). For Stage I patients (n = 72), the 2-year RFS and OS were 66.4% and 77.1%, respectively. In the subgroup of stage IA patients (n = 37), there was a trend toward decreased overall survival in the anemic patients (2-year OS of 65.6% vs. 90.9%, p = 0.07). For Stage II patients (n = 10), the 2-year RFS and OS were 60.0% and 66.7%. In the Cox multivariate regression analysis, the only factor that achieved statistical significance was preoperative Hgb, with patients with Hgb <12 mg/dL having decreased RFS (RR 4.1, p = 0.020) and OS (RR 2.9, p = 0.026). There was a trend toward worse RFS (p = 0.056) and OS (p = 0.068) in p53-negative patients (n = 39). Stage, histologic type, type of surgery performed, age, and sex did not affect outcome. CONCLUSIONS: In our cohort of mostly Stage I NSCLC patients treated with surgery only, preoperative Hgb <12 mg/dL predicted for worse outcome. This effect was observed even in the traditionally low-risk subgroup of completely resected stage IA patients. Much has been written in the literature about anemia causing possible worsening of tumor hypoxia within solid tumors, thereby increasing radio-resistance. This has been a popular argument to explain poorer outcomes of anemic patients with solid tumors who undergo radiotherapy. However, our data suggest that anemia may be a sign of a more aggressive tumor that is at an increased risk of failure independent of the treatment modality.     

Genetic polymorphism of IGF-I predicts recurrence in patients with gastric cancer who have undergone curative gastrectomy

BackgroundTo our knowledge, no reports have evaluated the effects of genetic polymorphisms of insulin-like growth factor-I (IGF-I) on clinical outcomes of gastric cancer patients.MethodsWe retrospectively analyzed the impact of IGF-I polymorphisms on recurrence-free survival (RFS) in 430 patients with gastric cancer who underwent curative gastrectomy between 2001 and 2005 in our institution.ResultsAmong the 430 gastric cancer patients, 345 were pathological stage I or II, while 85 were stage III or IV. The median 5-year RFS rate was 85.3% (95% confidence interval [CI] 81.4–88.5). In a multivariate Cox model (adjusted for age, gender, histology, pathological stage, adjuvant chemotherapy, and history of diabetes), two IGF-I polymorphisms, rs1520220 and rs2195239, were significantly associated with RFS (hazard ratio [HR] 0.60, 95% CI 0.40–0.91; and HR 0.60, 95% CI 0.41–0.89, respectively, in a per-allele model). When stratified by stage (I–II versus III–IV), rs1520220 in particular was associated with RFS in patients with stage III–IV disease, with a P-value for interaction of 0.01.ConclusionsOur findings indicate that genetic polymorphisms of IGF-I may have a substantial effect on recurrence for gastric cancer patients who have undergone curative gastrectomy. This information may help identify population subgroups that could benefit from IGF-I-targeting agents.     

High p27Kip1 expression predicts superior relapse-free and overall survival for premenopausal women with early-stage breast cancer receiving adjuvant treatment with tamoxifen plus goserelin.

PURPOSE: To determine the predictive value of p27Kip1 in premenopausal women with early-stage hormone receptor-positive breast cancer. PATIENTS AND METHODS: We retrospectively examined tumor specimens from 512 patients with breast cancer who were enrolled onto Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5. In this trial, premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease were randomly assigned to receive either 5 years of tamoxifen plus 3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil. p27Kip1 expression was assessed by immunohistochemistry, and its association with clinical outcome was determined. Statistical analyses were performed to test for interaction between p27Kip1 status and treatment. RESULTS: High p27Kip1 expression (nuclear p27Kip1 staining in >/= 50% of tumor cells) independently predicted superior relapse-free survival (RFS) and overall survival (OS) in both the total study population (RFS: relative risk [RR], 0.53; 95% CI, 0.34 to 0.82; P =.004; OS: RR, 0.29; 95% CI, 0.15 to 0.58; P <.001) and patients treated with combination endocrine therapy (RFS: RR, 0.32; 95% CI, 0.16 to 0.63; P =.001; OS: RR, 0.16; 95% CI, 0.05 to 0.53; P =.003). The interaction between p27Kip1 expression and treatment was statistically significant for RFS (P =.04) but not for OS (P =.27). CONCLUSION: High p27Kip1 expression was an independent predictor of responsiveness to hormonal therapy and thus may be useful for the selection of premenopausal women with early-stage hormone receptor-positive breast cancer for adjuvant combination endocrine therapy.     

Class III beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer: analysis of NCIC JBR.10.

PURPOSE: High class III beta-tubulin (bTubIII) expression in advanced non-small cell lung cancer is known to correlate with reduced response rates and inferior survival with anti-microtubule agents. JBR.10 showed a 12% and 15% improvement in 5-year recurrence-free survival (RFS) and overall survival (OS), respectively, with the addition of cisplatin and vinorelbine following resection of stage IB-II non-small cell lung cancer. We sought to determine the effect of bTubIII on patient outcome and benefit from adjuvant chemotherapy in the JBR.10 trial. EXPERIMENTAL DESIGN: We did a semiquantitative immunohistochemical assay for bTubIII on primary tumor tissue available from 265 of the 482 patients in JBR.10. Tumors were classified as bTubIII "low" or "high" using a validated method. We examined the prognostic effect of bTubIII in patients treated with or without chemotherapy and the survival benefit from chemotherapy in low versus high bTubIII subgroups. RESULTS: High bTubIII expression was associated with poorer RFS and OS in patients treated with surgery alone but not in patients treated with adjuvant chemotherapy. The RFS and OS benefits of adjuvant chemotherapy were greater in high versus low tubulin expressors. However, with Cox regression, the interaction between bTubIII status and chemotherapy treatment in predicting RFS or OS did not reach statistical significance. CONCLUSIONS: Chemotherapy seemed to overcome the negative prognostic effect of high bTubIII expression. Greater benefit from adjuvant chemotherapy was seen in patients with high bTubIII expression. This is contrary to what has been seen in the setting of advanced disease; possible reasons for this difference are being explored.     

Anemia is a significant prognostic factor in local relapse-free survival of premenopausal primary breast cancer patients receiving adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy.

PURPOSE: To determine the effects of anemia on local relapse-free, relapse-free, and overall survival (LRFS, RFS, and OS, respectively) in premenopausal, primary breast cancer patients receiving adjuvant polychemotherapy, and to determine which conventional prognostic factors affected these outcomes. EXPERIMENTAL DESIGN: Four hundred twenty-four premenopausal patients with early-stage primary breast cancer and hormone receptor-expressing tumors were treated with i.v. cyclophosphamide/methotrexate/5-fluorouracil (CMF) polychemotherapy as part of an adjuvant phase III trial (Austrian Breast and Colorectal Cancer Study Group Trial 5). The influence of anemia (hemoglobin <12 g/dL) on LRFS, RFS, and OS was evaluated in a retrospective analysis. RESULTS: Of 424 patients, 77 (18.2%) developed anemia on CMF chemotherapy. After a median follow-up time of 5 years, 8.9% of nonanemic patients had local relapse compared with 19.6% of anemic patients (P=0.0006). Although mastectomy was associated with anemia (26% versus 13.7% in breast conserving surgery; P=0.002), multivariate analysis did not show mastectomy per se to be a significant risk factor for LRFS. Age, lymph node status, and hemoglobin had an independent significant influence on LRFS (P<0.005). Anemic patients had a relative risk of 2.96 (95% confidence interval, 1.41-6.23) for developing local relapse in comparison with nonanemic patients. CONCLUSION: Premenopausal breast cancer patients who developed anemia during the CMF regimen had significantly worse LRFS. In Austrian Breast and Colorectal Cancer Study Group Trial 5, anemia may have contributed to an almost doubled incidence of local recurrence in the chemotherapy arm. Molecular targets associated with tumor hypoxia and distinct from erythropoiesis should receive further attention in experimental and clinical settings.     

MDR1 gene C3435T polymorphism is associated with clinical outcomes in gastric cancer patients treated with postoperative adjuvant chemotherapy

Objective: To evaluate the impact of the multi-drug resistance 1(MDR1) C3435T polymorphism on clinical outcomes in gastric cancer patients treated with postoperative adjuvant chemotherapy. Methods: From January 2005 to December 2008, 102 patients with surgically resected gastric cancers were enrolled into this study in the Affiliated Jiangsu Cancer Hospital of Nanjing Medical University. The polymorphism was tested using real time polymerase chain reaction (RT-PCR) cycling probes and the relationship with clinical outcomes after postoperative adjuvant chemotherapy was analyzed by SPSS 17.0. Results: The CT/TT genotype of C3435T was significantly associated with a shorter progression-free survival (PFS) and overall survival (OS) compared with the CC genotype [PFS: adjusted hazard ratio(HR)= 2.01, 95% confidence intervals(CI): 1.17-3.45, P = 0.012; OS: adjusted HR = 2.37, 95% CI: 1.31-4.28, P=0.004]. TNM stage was also associated with PFS (adjusted HR = 2.33, 95% CI: 1.34-4.05, P = 0.003) and OS (adjusted HR = 2.62, 95% CI: 1.44-4.76, P = 0.002) in gastric cancer patients treated with postoperative adjuvant chemotherapy. Conclusion: Our results suggest that the MDR1 gene C3435T polymorphism is associated with clinical outcomes in gastric cancer patients treated with postoperative adjuvant chemotherapy. This now needs to be confirmed by a randomized prospectively controlled study.