Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. Importance of delivered cycles and nomogram for intraperitoneal chemotherapy in ovarian cancer. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.
To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies.
                Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response.
                There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model.
                Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy. To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC).
                A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy.
                Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033).
                Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease. The optimal integration of chemotherapy with radiation (RT) for patients with early-stage breast cancer remains uncertain. We present the long-term results of a prospective randomized trial to address this question.
                Two hundred forty-four patients were randomly assigned after conservative breast surgery to receive 12 weeks of cyclophosphamide, doxorubicin, methotrexate, fluorouracil, and prednisone (CAMFP) before RT (CT-first) or after RT (RT-first). Median follow-up for surviving patients was 135 months.
                There were no significant differences between the CT-first and RT-first arms in time to any event, distant metastasis, or death. Sites of first failure were also not significantly different.
                Among breast cancer patients treated with conservative surgery, there is no advantage to giving RT before adjuvant chemotherapy. However, this study does not have enough statistical power to rule out a clinically important survival benefit for either sequence. This study investigated the role of preoperative chemotherapy in squamous cell cancer of the esophagus.
                A prospective randomized trial was undertaken in 147 patients: 74 received preoperative chemotherapy comprising cisplatin and 5-fluorouracil and 73 had surgical therapy alone. End points were cancer and therapy-related deaths.
                Sixty-six patients (89%) in the chemotherapy group underwent resection compared with 69 (95%) in the control group (p = not significant). Of the 60 patients who had resection after completing the chemotherapy program, 35 (58%) had a significant response, of whom four (6.7%) had a complete pathologic response. Postoperative mortality rates were 8.3% and 8.7% in the chemotherapy and control groups, respectively (p = not significant). Significant downstaging was evident with chemotherapy; curative resections were possible in 67% of these patients compared with 35% in the control group (p = 0.0003). T3 and T4 tumors were found in 67% and 91% of the chemotherapy and control groups, respectively (p = 0.0002). The respective figures for N1 disease were 70% and 88% (p = 0.009). An intent-to-treat analysis of survival showed no significant difference between the two groups. Median survivals were 16.8 and 13 months, respectively (p = 0.17). Of those who completed the chemotherapy and resection, responders fared better than control patients. Median survivals were 42.2 months and 13.8 months, respectively (p = 0.003). Median survival (8.3 months) was worse for nonresponders than for control patients (p = 0.03). The recurrence pattern suggested a significant reduction in locoregional disease with chemotherapy.
                Preoperative chemotherapy was safe and resulted in significant downstaging and an increased likelihood of curative resection. Survival was not better than that in the surgery-alone group, but responders did fare better than nonresponders. Intraperitoneal (IP) chemotherapy has gained enthusiasm in the treatment of ovarian cancer. Despite having a better survival advantage than intravenous (IV) chemotherapy, IP chemotherapy still poses significant morbidity and complications. Identifying the subset of patients who could best benefit from IP chemotherapy, and those who would least benefit from this treatment, thus avoiding potential complications, is critical.
                Between January 2001 and December 2007, 367 patients with stage III epithelial ovarian cancer underwent randomized trial for IP/IV chemotherapy were recruited to construct a nomogram, which is a graphical representation of Cox proportional hazards model adopting six weighted risk factors including age, CA125, IP/IV delivery, stage, histology, and upper abdominal metastases. The nomogram was internally validated for discrimination and calibration. The concordance index was used for quantifying the predictive ability of overall survival with bootstrapping to correct for bias.
                The cycles of completed IP chemotherapy had an impact on overall survival (> or =5 vs. < or =4 cycles, P=0.02). A nomogram for predicting median survival and 5-year survival probability was constructed with a concordance index of 0.72. Upper abdominal tumor metastases (P<0.001) and colon resection (P=0.02) predicted increased chances for early discontinuation of IP chemotherapy.
                At least five IP cycles are needed to achieve better survival. Nomogram can help to identify the subset of patients who can least benefit from IP chemotherapy, thus avoiding potential IP complications and help to facilitate discussion between patient and physician, risk stratification, and help to guide clinical care. Surgery is the standard treatment for patients with resectable esophageal carcinoma, but the long term prognosis of these patients is unsatisfactory. Some randomized trials of preoperative chemotherapy suggest that the prognosis of patients who respond may be improved.
                This randomized, controlled trial compared patients with clinically resectable esophageal epidermoid carcinoma who underwent surgery alone (Arm A) with those who received preoperative chemotherapy (Arm B). Overall survival and the prognostic impact of major response to chemotherapy were analyzed. Forty-eight patients were enrolled in each arm. Chemotherapy consisted of two or three cycles of cisplatin (100 mg/m2 on Day 1) and 5- fluorouracil (1000 mg/m2 per day continuous infusion on Days 1-5). In both study arms, transthoracic esophagectomy plus two-field lymphadenectomy was performed. The two groups were comparable in terms of patient characteristics.
                Forty-seven patients were evaluable in each arm. The curative resection rate was 74.4% (35 of 47 patients) in Arm A and 78.7% (37 of 47 patients) in Arm B. Treatment-related mortality was 4.2% in both arms. The response rate to preoperative chemotherapy was 40% (19 of 47 patients), including 6 patients (12.8%) who achieved a pathologic complete responses. Overall survival was not improved significantly. The 19 patients in Arm B who responded to chemotherapy and underwent curative resection had significantly better 3-year and 5-year survival rates (74% and 60%, respectively) compared with both nonresponders (24% and 12%, respectively; P = 0.0002) and patients in Arm A who underwent complete resection (46% and 26%, respectively; P = 0.01): Patients who achieved a pathologic complete response (P = 0.01), but not those who achieved a partial response (P = 0.2), had significantly improved survival.
                Patients with resectable esophageal carcinoma who underwent preoperative chemotherapy and obtained a pathologic complete response had a significantly improved long term survival. Major efforts should be undertaken to identify patients before neoadjuvant treatments who are likely to respond.
                Copyright 2001 American Cancer Society. Despite technical improvements that have minimized the morbidity and mortality of hepatic surgery, the long-term outcome of resection of hepatic metastases of colorectal cancer remains poor, with the majority of patients experiencing treatment failure in the liver. Because arterial chemotherapy regimens targeted to the liver have demonstrated high response rates, an intergroup trial of adjuvant therapy for patients undergoing hepatic resection of liver metastases from colorectal cancer was initiated.
                Patients with one to three potentially resectable metastases were randomized preoperatively to receive no further therapy (control arm, 56 patients) or postoperative hepatic arterial floxuridine combined with intravenous continuous-infusion fluorouracil (chemotherapy arm, 53 patients). After exclusion of patients identified as ineligible for the planned treatment at the time of surgery, there were 45 control patients and 30 on the chemotherapy arm. The study was powered to evaluate improvement in time to recurrence and hepatic disease-free survival, not overall survival.
                The 4-year recurrence-free rate was 25% for the control arm and 46% for the chemotherapy group (P =.04). The 4-year liver recurrence-free rate was 43% in the control group and 67% in the chemotherapy group (P =.03). The median survival of the 75 assessable patients was 49 months for the control arm and 63.7 months for the chemotherapy arm (P =.60). The median survival of all 109 patients was 47 months for the control arm compared with 34 months for the chemotherapy arm (P =.19)
                These data demonstrate that adjuvant intra-arterial and intravenous chemotherapy was beneficial in prolonging time to recurrence and pre-venting hepatic recurrence after hepatic resection of colorectal cancer. To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy.
                Six hundred ninety-eight breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0) were enrolled onto a randomized phase III trial that compared four cycles of fluorouracil, epirubicin, and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively (the first cycle administered within 36 hours after surgery). Patients were followed up for OS, progression-free survival (PFS), and locoregional recurrence (LRR).
                At a median follow-up of 56 months, there was no significant difference in terms of OS (hazards ratio, 1.16; P =.38), PFS (hazards ratio, 1.15; P =.27), and time to LRR (hazards ratio, 1.13; P =.61). Fifty-seven patients (23%) were downstaged by the preoperative chemotherapy, whereas 14 patients (18%) underwent mastectomy and not the planned breast-conserving therapy.
                The use of preoperative chemotherapy yields similar results in terms of PFS, OS, and locoregional control compared with conventional postoperative chemotherapy. In addition, preoperative chemotherapy enables more patients to be treated with breast-conserving surgery. Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy, future trials should involve quality-of-life studies to investigate whether patients will benefit from this treatment modality. Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.
                Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.
                In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).
                Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.
                Copyright 2010 Elsevier Ltd. All rights reserved.
This analysis shows a significant increase in survival attributable to pre-operative chemotherapy. This is currently the best estimate of the effectiveness of this therapy, but is based on a small number of trials and patients. This analysis was unable to address important questions such as whether particular types of patients may benefit more or less from pre-operative chemotherapy or whether the early stopping of a number of included RCTs impacted on the results. These issues may be addressed by an ongoing individual patient data (IPD) meta-analysis.