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.     

Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement.

BACKGROUND: Overt ipsilateral axillary lymph node metastases of breast cancer are the most significant prognostic indicators for women who have undergone surgery, yet the clinical relevance of minimal involvement (isolated tumor cells and micrometastases) of these nodes is uncertain. PATIENTS AND METHODS: We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000. RESULTS: Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases). CONCLUSION: Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.     

Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.

PURPOSE: Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. The value of adding surgery to chemotherapy and radiotherapy is unknown. PATIENTS AND METHODS: Patients with locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B). Primary outcome was overall survival time. RESULTS: The median observation time was 6 years. The analysis of 172 eligible, randomized patients (86 patients per arm) showed overall survival to be equivalent between the two treatment groups (log-rank test for equivalence, P < .05). Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%; 95% CI, 52.1% to 76.5%) than in the chemoradiotherapy group (2-year progression-free survival, 40.7%; 95% CI, 28.9% to 52.5%; hazard ratio [HR] for arm B v arm A, 2.1; 95% CI, 1.3 to 3.5; P = .003). Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%, respectively; P = .03). Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival (HR, 0.30; 95% CI, 0.19 to 0.47; P < .0001). CONCLUSION: Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.     

Evaluation and external validation of minor lymphatic pelvic pathway for distant metastases in cervical cancer patients treated with concurrent chemoradiotherapy

To evaluate and validate the minor lymphatic pathway for distant metastases in cervical cancer. This is a retrospective cohort of cervical cancer patients underwent curative concurrent chemoradiotherapy. We used original dataset from 1 university hospital and validation dataset from 3 university hospitals. Lymphadenopathy status in CT imaging was reviewed by radiologist in either the obturator and external iliac nodes (major pathway) or the internal iliac and presacral nodes (minor pathway). We then used Cox regression to adjust for all potential confounders, including paraaortic nodes, T stage, histology, age, total treatment time, total number of nodes, total short axis of nodes. 397 and 384 patients were in the original and validation datasets (median follow-up period, 59.5 month’s). The minor pathway was independent prognostic factor in multivariable analysis [HR=2.64; 95%CI=1.07–6.55; P = 0.036] and [HR=14.84; 95%CI=3.15–70.01; P= 0.001] in original and validation datasets, respectively. Whereas, the major pathway was statistically non-significant. Further validation showed that the minor pathway had the highest HR for distant metastases with both the EMBRACE (HR=6.05; 95% CI=1.30–28.08; P = 0.022) and the FIGO 2018 (HR=7.43; 95% CI=2.94–18.78; P<0.001) in the original dataset. A similar result was found with the validation dataset: EMBRACE, HR=30.91; 95% CI=2.78–343.62; P = 0.005; and FIGO 2018, HR=42.41; 95% CI=8.83–203.60; P<0.001.This is the first clinical study to validate that the minor lymphatic pathway was predominantly associated with distant metastases in cervical cancer. This finding should be validated in larger cohort to further integrate in standard staging for prediction of distant metastases.     

Outcome analysis of patients with well-differentiated oral cavity squamous cell carcinoma

The prognosis of well-differentiated oral cavity squamous cell carcinoma (OSCC) is better than less-well-differentiated neoplasms. The aim of this retrospective study was to identify prognostic factors in patients with well-differentiated OSCC. The 5-year outcomes of 467 patients with well-differentiated OSCC who underwent radical surgery and neck dissection were analyzed. In the entire cohort, the presence of pathological node metastases (pN+ vs. pN0) was an independent predictor of 5-year outcomes. In pN0 patients, tumor depth (?8 mm) was the only independently prognostic factor for 5-year survival rates on multivariable analysis (disease-free survival [DFS], P = 0.001, hazard ratio [HR] = 2.634, 95% confidence interval [95% CI] = 1.496–4.636; disease-specific survival [DSS], P < 0.001, HR = 6.794, 95% CI = 2.364–19.525). In pN+ patients, level IV/V neck nodal metastases (DFS, P < 0.001, HR = 47.483, 95% CI = 8.942–252.122; DSS, P < 0.001, HR = 14.301, 95% CI = 5.337–38.323), and ?3 positive nodes (DFS, P = 0.037, HR = 2.107, 95% CI = 1.047–4.242; DSS, P = 0.044, HR = 2.093, 95% CI = 1.020–4.295) were independently associated with 5-year outcomes. Our results suggest that a tailored treatment approach in well-differentiated OSCC patients should take into account the presence of either pN0 or pN+ disease.     

Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial

BACKGROUND: Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer. METHODS: 128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m(2) cisplatin on day 1, 800 mg/m(2) fluorouracil on days 1-4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat. FINDINGS: Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0.82 [95% CI 0.61-1.10] and 0.89 [0.67-1.19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0.0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0.003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0.47 [0.25-0.86] vs 1.02 [0.72-1.44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup. INTERPRETATION: Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamous-cell tumours.     

Prediction of mesorectal nodal metastases after chemoradiation for rectal cancer: results of a randomised trial: implication for subsequent local excision.

BACKGROUND AND PURPOSE: For patients with rectal cancer treated with full thickness local excision the risk of mesorectal nodal metastases has to be very low. The aim was to assess this risk after preoperative radiotherapy in relation to pathological T-category. PATIENTS AND METHODS: Three hundred sixteen patients with resectable cT3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent surgery performed within 7 days or chemoradiation (50.4, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by surgery after 4-6 weeks. The pathological reports of patients who fulfilled entry criteria and had preoperative irradiation followed by transabdominal surgery were analysed. RESULTS: Significant downstaging of primary tumour (P<0.001) and of nodal disease (P=0.007) was observed after chemoradiation in comparison with short-course irradiation. In chemoradiation group, for patients with complete pathological response and for ypT1 category, the rate of nodal metastases was low - 5% (95% confidence interval [CI] 0-14%) and 8% (95% CI 0-24%), respectively. The rate of ypN-positive disease in chemoradiation group was similar to that recorded in short-course irradiation group for ypT2 category 26% (95% CI 14-38%) vs. 28% (95% CI 16-40%), P=0.83 and for ypT3-4 category 55% (95% CI 41-69%) vs. 64% (95% CI 54-74%), respectively, P=0.37. For ypT2 category after chemoradiation, the rate of nodal disease remained high even in subgroup with low residual cancer cells density (20%, 95% CI 4-36%). CONCLUSIONS: For patients with tumours downstaged by chemoradiation to ypT0 and ypT1 full thickness local excision may be considered as an acceptable approach, because the risk of mesorectal lymph nodes metastases is low. The selection criteria for preoperative radio(chemo)therapy and local excision are discussed.     

A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node-positive breast cancer

The sequential doxorubicin --> CMF (CMF=cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF x 6 cycles (CMF); (b) doxorubicin x 4 cycles followed by CMF x 6 cycles (A --> CMF); (c) CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (CMF --> GT); and (d) doxorubicin x 4 cycles followed by CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (A --> CMF --> GT). The study used a 2 x 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A --> CMF or arms a+c vs b+d) and (2) the effect of adding GT after chemotherapy (arms a+b vs c+d). At a median follow-up of 72 months, A --> CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR)=0.740 (95% confidence interval (CI): 0.556-0.986; P=0.040) and produced a nonsignificant improvement of overall survival (OS) (HR=0.764; 95% CI: 0.489-1.193). The addition of GT after chemotherapy significantly improved DFS (HR=0.74; 95% CI: 0.555-0.987; P=0.040), with a nonsignificant improvement of OS (HR=0.84; 95% CI: 0.54-1.32). A --> CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients.     

Comparison of treatment outcomes of surgery and radiotherapy,including concurrent chemoradiotherapy for stage Ib2-IIb cervical adenocarcinoma patients: a retrospective study

ObjectiveThe study compared the treatment outcomes of surgery versus radiotherapy, including concurrent chemoradiotherapy, in stage Ib2–IIb cervical adenocarcinoma patients in Japan.MethodsOf 57,470 patients diagnosed with stage I–IV cervical cancer from January 2001–December 2011, 1,932 patients with stage Ib2–IIb cervical adenocarcinoma were initially treated by surgery or radiotherapy. The primary endpoint was 5-year overall survival (OS) in all and 614 propensity score-matched (PSM) patients (307 per group). We compared OS and prognosis factors based on age, primary stage, and treatment arm.ResultsIn Japan, >80% (n=1,573) of stage Ib2–IIb cervical adenocarcinoma patients underwent surgery. The 5-year OS of surgery vs. radiotherapy groups were 82.1% (n=704) vs. 79.7% (n=59) (hazard ratio [HR]=1.494; 95% confidence interval [CI]=0.826–2.702; p=0.181) for stage Ib2, 76.6% (n=239) vs. 66.7% (n=54) (HR=1.679; 95% CI=0.986–2.858; p=0.053) for stage IIa, and 71.1% (n=630) vs. 58.9% (n=246) (HR=1.711; 95% CI=1.341–2.184; p<0.001) for stage IIb. In 614 PSM patients balanced for age and carcinoma stage Ib2–IIb, the 5-year OS of surgery vs. radiation groups was 73.0% (n=307) vs. 65.5% (n=307) (HR=1.394; 95% CI=1.044–1.860; p=0.023).In multivariable analysis, age (HR=1.293; 95% CI=1.045–1.601; p=0.018), treatment arm, radiotherapy (HR=1.556; 95% CI=1.253–1.933; p<0.001), and stage IIb (HR=1.783; 95% CI=1.443–2.203; p=0.018) were independent prognosis factors for 5-year OS in stage Ib2–IIb adenocarcinoma patients.ConclusionAge (>65 years), treatment arm (radiotherapy), and stage IIb significantly affect OS in cervical adenocarcinoma patients. Surgery may be considered for <65-year-old patients with stage IIb adenocarcinoma.     

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.     

A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study.

PURPOSE: The aims of this randomized controlled trial were to determine whether there were differences in the disease-free survival (DFS) and toxicity between conventional radiotherapy (CRT) and a continuous 3 week accelerated radiotherapy regimen (ART) in stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. PATIENTS AND METHODS: Patients from 14 centres throughout Australia and New Zealand were randomly assigned to either CRT, using a single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. The accrual began in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. RESULTS: The median potential follow-up time was 53 months (range, 14-101). The DFS at 5 years was 41% (95% CI, 33-50%) for ART and 35% (95% CI, 27-43%) for CRT (P=0.323) and the hazard ratio was 0.87 in favour of ART (95% CI, 0.66-1.15). The 5-year disease-specific survival rates were 40% for CRT and 46% for ART (P=0.398) and the loco-regional control was 47% for CRT vs. 52% for ART (P=0.300). The respective hazard ratios were 0.88 (95% CI, 0.65-1.2) and 0.85 (0.62-1.16), favouring the accelerated arm. In the ART arm, confluent mucositis was more severe (94 vs. 71%; P<0.001) and peaked about 3 weeks earlier than in the CRT arm, but healing appeared complete in all cases. There were statistically significant reductions in the probability of grade 2 or greater late soft tissue effects over time in the ART arm (P<0.05), except for the mucous membrane where late effects were similar in both arms. CONCLUSIONS: Differences in DFS, disease-specific survival and loco-regional control have not been demonstrated. ART resulted in more acute mucosal toxicity, but this did not result in greater prolongation of the treatment time compared with the CRT arm. There were less late effects in the ART arm, with the exception of late mucosal effects. This trial has confirmed that tumour cell repopulation occurs during conventionally fractionated radiotherapy for head and neck cancer. However, it has also provided additional evidence that overall improvements in the therapeutic ratio using accelerated fractionation strategies are seriously constrained by the need to limit total doses to levels that do not exceed acute mucosal tolerance. The accelerated schedule tested has been shown in this trial to be an acceptable alternative to conventionally fractionated irradiation to 70 Gy.     

局部晚期鼻咽癌化疗和放射综合治疗--随机临床研究

目的：研究局部晚期鼻咽癌化疗和放射综合治疗的疗效及毒副反应。方法：1995年9月—1997年7月，86例病理确诊为鼻咽癌、根据福州九二新分期为N2-3的初治患者随机分组，综合治疗组41例，其中2例拒绝接受放疗后的辅助化疗，即综合治疗组可评估39例，单纯放疗组45例。综合治疗组接受2程诱导化疗[每天顺铂(DDP)20mg／m^2，第1～3天，每天氟尿嘧啶(5-FU)500mg／m^2，第1—3天，第二程化疗在第14天进行，放疗在第27天开始)及放疗后3程的辅助化疗。放疗为常规分割放疗。原发灶用^60Co治疗，每次1．85—1．9Gy，一周5次，7—7．5周总剂量65．1—70．3Gy／35—37次。颈部行双侧全颈根治性照射7—7．5周共56．6—65．5Gy／35—38次。如有残留，则局部缩野加量。两组鼻咽加量及颈淋巴结加量无显著差异。结果：中位随访期5．04年，综合治疗组和单纯放疗组五年生存率为72．3％，58．4％，(P=0．154)；无瘤生存率为59．9％，47．7％，(P=0．207)；鼻咽局控率为89．5％，81．4％，(P=0．151)；颈部局控率为88．3％，75．2％，(P=0．134)；无远处转移生存率为76．3％，60．3％，(P=0．181)，发生转移的中位时间分别为1．08年和0．88年。虽未达统计学意义，但综合治疗组有较单纯放疗组提高疗效的趋势。综合治疗组的主要毒性反应为白细胞降低、血小板降低及胃肠道反应。两组急性粘膜反应的严重程度差异无显著性。无与治疗有关的死亡发生。两组后期反应差异无显著性。结论：经5年观察，综合治疗有提高局控、降低远处转移、延迟远处转移的发生、提高无瘤生存率的可能，但均未达统计学意义，综合治疗未明显增加放疗反应。     

Systematic lymphadenectomy in ovarian cancer at second-look surgery: a randomised clinical trial

Background:The role of systematic aortic and pelvic lymphadenectomy (SAPL) at second-look surgery in early stage or optimally debulked advanced ovarian cancer is unclear and never addressed by randomised studies.Methods:From January 1991 through May 2001, 308 patients with the International Federation of Gynaecology and Obstetrics stage IA-IV epithelial ovarian carcinoma were randomly assigned to undergo SAPL (n=158) or resection of bulky nodes only (n=150). Primary end point was overall survival (OS).Results:The median operating time, blood loss, percentage of patients requiring blood transfusions and hospital stay were higher in the SAPL than in the control arm (P<0.001). The median number of resected nodes and the percentage of women with nodal metastases were higher in the SAPL arm as well (44% vs 8%, P<0.001 and 24.2% vs 13.3%, P:0.02). After a median follow-up of 111 months, 171 events (i.e., recurrences or deaths) were observed, and 124 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for progression and death were not statistically different (hazard ratio (HR) for progression=1.18, 95% confidence interval (CI)=0.87-1.59; P=0.29; 5-year progression-free survival (PFS)=40.9% and 53.8%; HR for death=1.04, 95% CI=0.733-1.49; P=0.81; 5-year OS=63.5% and 67.4%, in the SAPL and in the control arm, respectively).Conclusion:SAPL in second-look surgery for advanced ovarian cancer did not improve PFS and OS.     

Cyclooxygenase 2 expression in rectal cancer is of prognostic significance in patients receiving preoperative radiotherapy.

PURPOSE: To determine the effect of cyclooxygenase (COX)-2 expression on clinical behavior in irradiated and nonirradiated rectal carcinomas. EXPERIMENTAL DESIGN: Tumor samples were collected from 1,231 patients of the Dutch TME trial, in which rectal cancer patients were treated with standardized surgery and randomized for preoperative short-term (5 x 5 Gy) radiotherapy or no preoperative radiotherapy. Tissue microarrays were constructed from primary tumor material, and COX-2 expression was assessed by immunohistochemistry. Tumor cell apoptosis was determined by M30 immunostaining. RESULTS: A high level of COX-2 expression after radiotherapy was associated with low levels of tumor cell apoptosis (P=0.001). COX-2 expression had no significant effect on patient survival or tumor recurrence in nonirradiated tumors. However, in patients receiving preoperative radiotherapy, high level of COX-2 expression was associated with higher incidence of distant recurrences [P=0.003; hazard ratio (HR), 1.7; 95% confidence interval (95% CI), 1.2-2.5] and shorter disease-free survival (P=0.002; HR, 1.8; 95% CI, 1.2-2.5) and overall survival (P=0.009; HR, 1.5; 95% CI, 1.1-2.0), independent of patient age, tumor stage, tumor location, or the presence of tumor cells in the circumferential resection margin. CONCLUSIONS: A high level of COX-2 expression after preoperative radiotherapy in resection specimens is associated with apoptosis resistance, high distant recurrence rates, and a poor prognosis in rectal cancer.     

Role of endocrine responsiveness and adjuvant therapy in very young women (below 35 years) with operable breast cancer and node negative disease.

BACKGROUND: There is limited knowledge about prognosis, and treatment effects in young women with node-negative disease. PATIENTS AND METHODS: We evaluated biological features, treatment recommendations and prognosis for 841 premenopausal patients with pT1-3, pN0 and M0, operated from 1997 to 2001. RESULTS: Patients below 35 years (101, 12%) were more likely to have tumors > 2 cm (35.6% versus 24.2%, P = 0.002), grade 3 (48.5% versus 31.9%, P = 0.009) and with elevated Ki-67 expression (62.4% versus 50.7%, P = 0.002). At the multivariate analysis a statistically significant difference in disease-free survival (DFS, HR 4.44; 95% CI 2.53 to 7.78, P < 0.0001), risk of distant metastases (DDFS) (HR 3.23; 95% CI 1.32 to 7.94, P = 0.011) and overall survival (OS) (HR 2.89; 95% CI 1.06 to 7.87, P = 0.038) was observed for younger versus older patients and in the subgroup with endocrine responsive tumors (DFS, HR 5.17, 95% CI 2.72-9.83, P = < 0.0001; DDFS, 3.76, 95% CI 1.33-10.6, P = 0.013; OS, 4.71, 95% CI 1.09-20.4, P = 0.039 ). CONCLUSIONS: Compared with less young, very young patients with endocrine responsive and node-negative breast cancer have a worse prognosis. Tailored treatments should be explored in this cohort of patients.     

Functional polymorphisms of the microsomal epoxide hydrolase gene: a reappraisal on a early-onset lung cancer patients series

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.     

Randomized trial of 2 versus 5 years of adjuvant tamoxifen for women aged 50 years or older with early breast cancer: Italian Interdisciplinary Group Cancer Evaluation Study of Adjuvant Treatment in Breast Cancer 01.

PURPOSE: To compare 2 with 5 years of adjuvant tamoxifen therapy in the treatment of early breast cancer. PATIENTS AND METHODS: Women with breast carcinoma T1-3, N0-3, M0, who were between 50 and 70 years of age, were eligible irrespective of menopausal status, tumor grade, or estrogen receptor (ER) status. Patients who were event-free after 2 years of tamoxifen therapy were randomly assigned to stop or continue tamoxifen therapy for an additional 3 years. The primary end point was length of disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity. RESULTS: From 1989 through 1996, 1,901 patients were randomly assigned either to stop treatment (n = 958) or to receive tamoxifen for 3 additional years (n = 943). The median duration of postrandomization follow-up was 52 months. We found no statistically significant differences between the 5-year arm and the 2-year arm in terms of DFS (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.76 to 1.08) and OS (HR, 1.16; 95% CI, 0.92 to 1.46). In ER-positive patients, a statistically significant prolongation of DFS related to longer treatment duration was observed (HR, 0.74; 95% CI, 0.59 to 0.93), whereas no difference in OS could be detected (HR, 0.98; 95% CI, 0.72 to 1.32). No differences in terms of endometrial cancers, cardiac or cerebrovascular events, or fractures were detected, whereas a doubling in the risk of thromboembolic events was found in the 5-year arm. CONCLUSION: Our results confirm previous research that shows that 5 years of tamoxifen decreases recurrence compared to 2 years in patients with ER-positive tumors.     

Pathological complete response after preoperative systemic therapy and outcome: relevance of clinical and biologic baseline features

In order to evaluate the outcome of patients with breast cancer according to response after primary therapy and according to clinical and biologic baseline features, we identified patients who were treated with preoperative therapy and who underwent surgery at the European Institute of Oncology (IEO), Milan, Italy, between 1995 and 2006. The outcome of patients who achieved pathological complete remission (pCR) and patients with residual disease (RD) at final surgery was analyzed. Of the 687 patients treated with preoperative therapy, we identified 82 patients who achieved pCR (12%) and 605 patients with RD (88%). A statistically significant difference in disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) was observed for patients with pCR compared with those who had RD (5 year DFS 73% vs. 59% P = 0.029; 5 year DDFS 81% vs. 72% P = 0.085; 5 year OS 88% vs. 77% P = 0.033). At the multivariate analysis, for patients achieving pCR, large tumor size (>5 cm) correlated with worse DFS (HR 3.18; 95% CI 1.34–7.51); clinical nodal involvement was associated with poorer DFS and DDFS (HR 6.94; 95% CI 1.62–29.73 and HR 9.87 95% CI 1.29–75.53, respectively). pCR after preoperative systemic therapy correlated with significant improved outcome. A substantial rate of relapse was observed for patients with large tumors and with clinical nodal involvement at baseline. Further improvement in adjuvant treatment might be warranted.     

Hypofractionated Whole-Breast Irradiation With or Without Boost in Elderly Patients: Clinical Evaluation of an Italian Experience

Purpose

To examine local control, disease-free survival (DFS), and toxicity in elderly (≥ 65 years) breast cancer patients treated with hypofractionated radiotherapy (hypo-RT) with or without a boost to the tumor bed.

High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients

To estimate the risk of venous thrombosis associated with pancreatic malignancies we followed a cohort of patients with pancreatic cancer (n = 202). We calculated incidence rates of venous thrombosis and compared this with population rates using a Standardised Morbidity Ratio (SMR). The effects of location, histology and treatment were assessed by Cox-modelling. The incidence of venous thrombosis was 108.3/1000 patient-years (95% confidence interval (CI) 64.4-163.8), 58.6-fold increased (SMR 58.6, 95% CI 36.9-92.9). Patients with a tumour of the corpus/cauda had a 2-fold increased risk compared with those with a tumour of the caput. Patients treated with chemotherapy had a 4.8-fold increased risk (HR(adj) 4.8, 95% CI 1.1-20.8), whereas radiotherapy did not increase the risk. In a postoperative period of 30 d, patients had a 4.5-fold increased risk of venous thrombosis (HR(adj) 4.5, 95% CI 0.5-40.9). The risk was 1.9-fold increased in the presence of distant metastases (HR(adj) 1.9, 95% CI 0.7-5.1). Anti-thrombotic prophylaxis seems warranted in the first month after surgery, during and after treatment with chemotherapy, and when distant metastases have been diagnosed.