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PubMed2002

Preoperative concurrent chemotherapy and radiation therapy followed by surgery for esophageal cancer.

Currently, the most promising strategy to improve the prognosis of advanced esophageal cancer is preoperative chemoradiation (CRT) followed by surgery. The superiority of CRT over radiation therapy alone has been demonstrated by several randomized studies. Many phase II studies of CRT followed by surgery have shown that the pathologic complete response (CR) rate ranges from 17 to 40%, and the median survival time (MST) is 12 to 31.3 months. Five randomized trials have compared preoperative CRT followed by surgery with surgery alone for resectable esophageal cancer, and four of them did not find any significant survival benefit for the combined treatment group. There are several issues in interpreting these findings, such as the quality of the surgery, the accuracy of the preoperative staging, the statistical power and design of the trials. Until comprehensive evaluation can be done, the standard therapy for resectable esophageal cancer should be considered to be surgery alone. The histological response in the resected specimen correlates well with the prognosis. Patients with pathologic CR display significantly better survival than those with microscopic residual cancer cells in the resected specimens. These findings suggest that more potent regimens leading to higher pathologic CR rates should improve the prognosis. Chemotherapy or radiation therapy sensitivity testing needs to be established. If accurate prediction of the response is possible prior to therapy, non-responders can be excluded. Cell cycle-related genes, apoptosis-related genes, and drug metabolizing genes have been investigated in many pilot studies and need to be evaluated by large-scale clinical studies. At present, pathologic CR can not be accurately diagnosed before surgery. Endoscopic biopsy is also unreliable for the diagnosis. In the future, new diagnostic tools such as positron emission tomography scanning, a sensitivity test or molecular markers may enable accurate diagnosis of pathologic CR to guide the choice of treatment strategies for individual patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Cisplatin plus gemcitabine with or without vinorelbine as induction chemotherapy prior to radical locoregional treatment for patients with stage III non-small-cell lung cancer (NSCLC): results of a prospective randomized study.

To evaluate possible improvement in objective response of adding vinorelbine (V) to the combination of cisplatin/gemcitabine (CG) in induction chemotherapy for stage III NSCLC, patients (n=154) aged < or =75 years, Karnofsky index > or =70%, were stratified by stage (IIIA versus IIIB) and randomly assigned to receive: C (50mg/m(2) i.v.) plus G (1250mg/m(2) i.v.) or CG plus V (25mg/m(2) i.v.). All drugs were administered on days 1 and 8 of an every 3-week cycle. At conclusion, local treatment (LT) with surgery and/or radiotherapy was scheduled. The results indicated that, following a median of 3 cycles, the overall efficacy was 65% in the CG and 61% in the CGV group. Most patients in both groups received radiotherapy as part of their LT. Pathological complete response was confirmed by surgery in 18% in the CG and 25% in the CGV group. Median progression-free survival was 368 days in the CG and 322 days in the CGV group. There were no statistically significant differences in toxicities between groups. We conclude that the CG and CGV combinations had similar efficacy and moderate toxicity, without accruing to the triplet combination.

Adult↗
PubMed2000

Neoadjuvant intraarterial infusion chemotherapy in patients with stage IB2-IIIB cervical cancer.

OBJECTIVES: The purpose of this study was determine the effect of neoadjuvant intraarterial chemotherapy (NAIC) on the prognosis of patients with locally advanced cervical cancer. METHODS: From January 1992 to December 1997, 26 previously untreated patients with stage IB2-IIIB cervical cancer were enrolled in the study. NAIC was administered for more than two courses every 3 weeks using a combination of 17.5 mg/m(2) bleomycin, 7 mg/m(2) mitomycin-C, and 75 mg/m(2) cisplatin via the bilateral internal iliac artery. Pathologic findings were evaluated with histologic examinations of surgical specimens. A nonrandomized control group of 120 patients who underwent conventional treatment between 1980 and 1991 was used for comparison. RESULTS: Nineteen (73.1%) of the 26 patients responded to initial chemotherapy, permitting a radical hysterectomy with pelvic lymphadenectomy in 14 patients. The remaining 5 patients received radiotherapy. One of 7 nonresponders was able to undergo radical surgery. Pathologic complete responses were found in 4 of the 15 patients who underwent radical surgery. The incidence of lymph node metastasis, parametrial infiltration, and vascular space involvement in the 15 patients who received NAIC followed by radical surgery was significantly lower than that in the control group (13.3, 6.7, and 13.3% vs 54.2, 43.8, and 60.4%). The overall 5-year estimated survival rate was significantly higher for all 26 patients who received NAIC (80.0%) than for the control group (59.6%). In stage II and III, the 5-year survival rate for patients who received NAIC was significantly higher than that in the control group (83.3 and 77.8% vs 68.1 and 49.8%). CONCLUSIONS: These preliminary results suggest that NAIC is able to eliminate effectively the pathologic risk factors in the pelvic cavity, to improve the operability in patients with stage IIIB cervical cancer, considered inoperable, and to improve the prognosis of patients with locally advanced cervical cancer.

Adenocarcinoma↗
PubMed1995

Preoperative chemoradiotherapy for locoregional esophageal cancer: preliminary report.

Conventional treatment of esophageal cancer with surgery or radiation alone has afforded few long-term survivors. In order to improve outcome and determine the efficacy of a combined modality approach, this prospective study was performed. Between May 1993 and August 1994, 27 patients with loco-regional squamous cell carcinoma of the esophagus were treated with 2 courses of combined fluorouracil(1000mg per square meter of body-surface area daily for 5 days) and cisplatin(60mg per square meter on the first day)(D1 and D29) plus 48Gy of radiation therapy(RT) over 4 weeks. A transhiatal esophagectomy was planned 3-4 weeks after chemoradiotherapy. Twenty-seven patients completed a full course of therapy. Clinical response was evaluable in 26 patients: 22 patients showed improvement and relief from dysphagia, 2 patients stable disease, and 2 patients progression. One patient died of sepsis 1 week after completion of chemoradiotherapy and was excluded from the analysis. Ten patients underwent operation after chemoradiation. Of them, 5 showed complete histologic response. One of the complete responders died of recurred disease 8.5months after operation, the other 2 patients died of sudden death, and sepsis from wound deheiscence 7 days after operation, respectively. Nine patients refused operation because of excellent relief of their dysphagia and 6 patients were denied because of disease progression(2), fear of operations(2), old age and family member's disapprovement(1), and underlying liver cirrhosis(1). The last one patient was awaiting for operation. Of 13 patients who refused or denied operation, 6 patients finished further chemotherapy and radiatherapy(external radiation 1200 cGy+intracavitary radiation 900 cGy, 2 cycles of 5FU+cisplatin). This intensive preoperative chemoradiotherapy is feasible, and allows for a high rate of resectability and a high rate of complete pathologic response in a locoregional esophageal cancer. Toxicity is considerable but manageable. This study warrants further investigation.

Adult↗
PubMed2001

Docetaxel in squamous cell cancer of the head and neck.

Single-agent docetaxel induces a response in 21-42% of patients with recurrent squamous cell cancer of the head and neck (SCCHN). When used in combination with 5-fluorouracil (5-FU), response rates (RRs) of between 24 and 27% have been reported. In contrast, in combination with cisplatin, docetaxel has achieved a RR of 33% in previously treated patients and 86% in a subgroup of chemotherapy-naive advanced stage patients. The docetaxel/cisplatin combination appears to be highly active. High-dose induction chemotherapy for patients with locally advanced but potentially curable SCCHN is producing promising results: following combination therapy involving docetaxel, cisplatin, 5-FU and leucovorin (TPFL), RR are high and 75% of patients are alive at 2 years. Intermediate-dose induction chemotherapy involving docetaxel is also promising: the TAX 708 trial found an excellent 93% RR in 41 evaluable patients treated with docetaxel plus cisplatin and 5-FU (TPF). The rate of pathological complete response was also high. The toxicities with TPF therapy were similar to those seen with cisplatin/5-FU regimens without docetaxel. A phase III trial of this approach is currently being conducted.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Response to neoadjuvant chemotherapy in lobular and ductal breast carcinomas: a retrospective study on 860 patients from one institution.

BACKGROUND: We compared the impact of neoadjuvant chemotherapy on pathologic response and outcome in operable invasive lobular breast carcinoma (ILC) and invasive ductal breast carcinoma (IDC). PATIENTS AND METHODS: We extracted from our database all patients with pure invasive lobular (n=118, 14%) or pure invasive ductal carcinomas (n=742, 86%). Their treatment included neoadjuvant chemotherapy, adapted surgery, radiotherapy and adjuvant hormonal treatment. RESULTS: Compared with IDC, ILC presented with larger tumors (T3: 38.1% versus 21.4%, P=0.0007), more N0 nodes status (55.9% versus 43.3%, P=0.01), less inflammatory tumors (5.9% versus 11.8%, P=0.01), more hormone receptor positivity (65.5% versus 38.8%), lower histological grade (P<0.0001). Final surgery was a mastectomy in 70% of patients with ILC (34% were reoperated after initial partial mastectomy) and in 52% of IDC after 8% of reoperation (P=0.006). A pathological complete response (pCR) was achieved in 1% of ILC and 9% of IDC (P=0.002). The outcome at 60 months was significantly better for ILC, but histologic type was not an independent factor for survival in multivariate analysis. CONCLUSIONS: ILC appeared less responsive to chemotherapy but presented a better outcome than IDC. While new information on biological features of ILC is needed, we consider that neoadjuvant endocrine therapy in hormone receptor-positive ILC may be a more adapted approach than neoadjuvant chemotherapy.

Breast Neoplasms↗
PubMed2006

Concurrent chemoradiotherapy with cyclophosphamide, pirarubicin, and cisplatin for patients with locally advanced salivary gland carcinoma.

CONCLUSION: This concurrent chemoradiotherapy with CPA, THP, and CDDP showed major antitumor activity with manageable toxicity as treatment of advanced salivary gland carcinoma patients. The high response rate (RR) justifies further evaluation of this chemoradiotherapy combination. OBJECTIVES: The aim of this study was to evaluate the efficacy and toxicity of a concurrent chemoradiotherapy using cyclophosphamide (CPA), pirarubicin (THP), and cisplatin (CDDP) in patients with locally advanced salivary gland carcinoma. PATIENTS AND METHODS: Seventeen patients with previously untreated stage III-IV salivary gland carcinoma were entered in this trial between January 2000 and September 2005. Chemotherapy consisted of CPA 400 mg/m2 on day 1, THP 40 mg/m2 by 6-h infusion on day 1, and CDDP 60 mg/m2 by 2-h infusion on day 1. Radiotherapy (2.0 Gy/fraction/day, mean total dose: 67.2 Gy (64.0-72.0 Gy)) administered 5 days per week, was targeted to begin on day 1. RESULTS: The RR was 76% (13/17) and the pathological complete response (CR) was 24% (4/17). The primary site CR was 29% (5/17) and metastatic lymph node CR was 33% (4/12). The 5-year survival rate was 70%. Neutropenia, leukocytopenia and mucositis were common adverse effects, but all 17 patients were assessable for toxicity.

Aged↗
PubMed2001

Radiotherapy, concomitant protracted-venous-infusion 5-fluorouracil, and surgery for ultrasound-staged T3 or T4 rectal cancer.

BACKGROUND: A prospective study was undertaken to evaluate the response and toxicity of neoadjuvant chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. PATIENTS AND METHODS: Since 1995, 30 patients (18 males; median age, 56 (range, 25-83) years) have received preoperative chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. All patients underwent an endorectal ultrasound, CT scan, and review in our multidisciplinary Gastrointestinal Tumor Board before treatment. All patients had pathology-demonstrated invasive adenocarcinoma of the rectum. Eleven patients were Stage T3N0, 14 were T3N1, and five were T4N1. Patients received radiotherapy to the primary tumor and draining lymph nodes (45 Gy) followed by a tumor boost (50.4-54 Gy). Protracted-venous-infusion 5-fluorouracil (225 mg/m2 per day, seven days per week) was administered throughout treatment. Surgical resection was performed six to ten weeks after completing chemoradiotherapy. Using endorectal ultrasound measurements, the primary tumor was a median of 4 (range, 0-12) cm from the anal verge, encompassed 50 (range, 20-90) percent of the rectal circumference, and was 6 (range, 3-12) cm in diameter. RESULTS: No Grade 4 toxicity was observed during chemoradiotherapy. Three patients experienced Grade 3 toxicity (diarrhea), and four patients required a treatment interruption of greater than three days. All patients completed at least 90 percent of the prescribed radiotherapy dose. All patients underwent surgical resection. Ninety-four percent had clear surgical margins. All pathologic specimens had significant evidence of necrosis, hyalinization, and fibrosis. Thirty-three percent of the specimens had a complete pathologic response (defined as no evidence of viable tumor cells). Of the 19 patients with ultrasound-staged N1 disease, only five had pathologic evidence of nodal involvement after chemoradiotherapy. Of the 25 patients with ultrasound-staged T3 disease, pathologic staging revealed eight with T0, two with T1, five with T2, and ten with T3 disease. Of the five patients with ultrasound-staged T4 disease, pathologic staging revealed two with T0, one with T2, and two with T3 disease. No patient developed progressive disease while on treatment. Two patients have experienced local failure at 6 and 20 months, and one patient failed in the liver at seven months. Twenty-seven patients remain free of disease with a median follow-up of 20 (range, 3-53) months. CONCLUSION: Our experience suggests that preoperative chemoradiotherapy is well tolerated, down-stages tumors, and sterilizes regional lymph nodes.

Adenocarcinoma↗
PubMed2004

Gene expression profiling for molecular characterization of inflammatory breast cancer and prediction of response to chemotherapy.

Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer with a 5-year survival limited to approximately 40%. Diagnosis, based on clinical and/or pathological criteria, may be difficult. Optimal systemic neoadjuvant therapy and accurate predictors of pathological response have yet to be defined for increasing response rate and survival. Using DNA microarrrays containing approximately 8,000 genes, we profiled breast cancer samples from 81 patients, including 37 with IBC and 44 with noninflammatory breast cancer (NIBC). Global unsupervised hierarchical clustering was able to some extent to distinguish IBC and NIBC cases and revealed subclasses of IBC. Supervised analysis identified a 109-gene set the expression of which discriminated IBC from NIBC samples. This molecular signature was validated in an independent series of 26 samples, with an overall performance accuracy of 85%. Discriminator genes were associated with various cellular processes possibly related to the aggressiveness of IBC, including signal transduction, cell motility, adhesion, and angiogenesis. A similar approach, with leave-one-out cross-validation, identified an 85-gene set that divided IBC patients with significantly different pathological complete response rate (70% in one group and 0% in the other group). These results show the potential of gene expression profiling to contribute to a better understanding of IBC, and to provide new diagnostic and predictive factors for IBC, as well as for potential therapeutic targets.

Adult↗
PubMed2003

[Remission rate of mediastinal lymph nodes after multimodal therapy of lung cancer--is it a prognostic factor?].

OBJECTIVE: General acceptance in the oncologic community has been gained for combined modality treatment of non-small cell lung (NSCLC) cancer in locally advanced stage IIIA and IIIB disease. However, no optimal regimen has been established. This study (chemotherapy and radiochemotherapy followed by operation) assesses feasibility, response, resectability, and survival in patients with stage IIIA and IIIB lung cancer. Currently, only little data is available about the prognostic significance of tumor clearance of mediastinal nodes. Thus, an important aim of our study was to evaluate the prognostic significance of the extent of tumor reduction in mediastinal nodes by a neoadjuvant multimodality protocol. PATIENTS: In a phase II protocol, 26 patients underwent neoadjuvant radiochemotherapy. Subsequently, a radical lymphadenectomy was performed during surgery. The extent of tumor regression was determined according to the methodology initially described by Salzer-Kuntschik for osteosarcoma: Grade I: no vital tumor cells, grade II: some tumor cells, grade III: less than 10 % vital tumor cells, grade IV: 10-50 % vital tumor cells, grade V: more than 50 % vital tumor cells, grade VI: no effect of chemotherapy. RESULTS: Complete pathologic response was seen in 30.7 % of primary tumors, in 38.5 % of mediastinal lymph nodes, and in 23 % of corresponding specimens simultaneously. Median survival was 34.7 months for those patients with grade I, 12.6 months with grade II, and 8.9 months for patients showing a grade III/IV regression in mediastinal nodes. Response rate to neoadjuvant chemotherapy in mediastinal nodes proved to be the only statistically significant parameter for long-term survival: In cases with no vital tumor cells in the operation specimen, median survival was 34.7 months in comparison to those with vital cells showing a median survival of only 11.4 months (P = 0.01). CONCLUSION: Patients with locally advanced NSCLCs can enjoy long-term survival after multimodal therapy. However, the complications related to therapy are considerably. Especially, clearance of tumor cells from mediastinal lymph nodes is an important independent prognostic factor.

Adult↗
PubMed2004

Proliferation markers predictive of the pathological response and disease outcome of patients with breast carcinomas treated by anthracycline-based preoperative chemotherapy.

The cell proliferation rate has been correlated to the response of breast carcinomas to preoperative chemotherapy (CT) and to disease outcome. However, this parameter is not yet used to select which tumours should be treated with preoperative CT. Furthermore, there is no consensus in the method used to evaluate cell proliferation. In poor prognosis breast carcinomas (PPBCs) treated by intensive preoperative CT, we compared the predictive value of S phase fraction (SPF), mitotic index (MI) and Ki67. We also evaluated the prognostic significance of the variation of the MI after CT. A series of 55 T2-T4N0N1M0 breast carcinomas were treated with 4 cycles of cyclophosphamide, 5-fluorouracil (5-FU) and doxorubicin. SPF was determined by flow cytometry on pre-therapeutic needle aspiration products. MI and Ki67 were evaluated on pre-therapeutic biopsy samples and on the tumours after CT. Fifteen patients (27%) had a pathological complete response (pCR), whereas 40 (73%) had residual disease. All three proliferative markers were found to have predictive value, but this value was higher for MI than for SPF (P = 0.04) and Ki67 (P = 0.03): the rate of pCR was 50% in cases with MI > 17/3.3 mm2, but was only 7% in cases with MI under this threshold (P = 0.0003). A significant decrease of MI (mean 10.97) was observed after CT (P = 0.001). Furthermore, we observed that even for patients with residual tumour, the variation of MI after CT was a prognostic parameter and overall survival. The sequential analysis of MI in breast cancers treated by preoperative CT thus provides a surrogate for predicting long-term outcome.

Adult↗
PubMed2000

Identification of long-term survivors in primary breast cancer by dynamic modelling of tumour response.

Although clinical response to primary chemotherapy in stage II and III breast cancer is associated with a survival advantage, it is the degree of pathological response in the breast and ipsilateral axilla that best identifies patients with a good long-term outcome. A mathematical model of the initial response of 39 locally advanced tumours to anthracycline-based primary chemotherapy has been previously shown to predict subsequent clinical tumour size. This model allows for the possibility of primary resistant disease, the presence of which should therefore be associated with a worse outcome. This study reports the application of this model to an additional five patients with locally advanced breast cancer, as well as to 63 patients with operable breast cancer, and confirms the biological reality of the model parameters for these 100 breast cancers treated with primary anthracycline-based chemotherapy. The tumours that responded to chemotherapy had higher cell-kill (P < 0.0005), lower resistance (P < 0.0001) and slower tumour regrowth (P < 0.002). Furthermore, ER-negative tumours had higher cell-kill (P < 0.05), as compared with ER-positive tumours. All patients with a pathological complete response had zero resistance according to the model. Furthermore, the long-term implication of chemo-resistant disease was demonstrated by survival analysis of these two groups of patients. At a median follow-up of 3.7 years, there was a statistically significantly worse survival for the 37 patients with locally advanced breast cancer identified by the model to have more than 8% primary resistant tumour (P < 0.003). The specificity of this putative prognostic indicator was confirmed in the 63 patients presenting with operable disease where, at a median follow-up of 7.7 years, those women with a resistant fraction of greater than 8% had a significantly worse survival (P < 0.05). Application of this model to patients treated with neoadjuvant chemotherapy may allow earlier identification of clinically significant resistance and permit intervention with alternative non-cross-resistant therapies such as taxoids.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

[Predictive factors in esophageal cancer after neoadjuvant therapy].

BACKGROUND: Preoperative chemoradiation therapy (PCX) was introduced to improve the outcome of patients with oesophageal cancer (EC), but conflicting results have been released. Some 20-30% of patients show a complete pathological response, however, the perioperative morbidity and mortality is increased. To search for factors indicating response prior to the onset of PCX we investigated the proliferative activity (MIB-1), the expression of vascular endothelial growth factor (VEGF), and the capillary density (CD34) tissue specimens of ECs were available by endoscopy prior to the start of the treatment. METHODS: Forty-six (MIB-1) and 21 (VEGF, CD34) tissue specimens of ECs were available from 56 patients undergoing pretherapeutic endoscopy, PCX and surgery. Perioperative morbidity was divided into surgery and non-surgery related morbidity. MIB-1, VEGF and CD34 expression were investigated immunohistochemically. Multivariate analysis was carried out to prove independence of investigated variables. RESULTS: Postoperative morbidity was noticed in 54 of 56 operated patents. Eight of 56 patients who received PCX died in hospital. Survival was significantly different between the group of complete responders (n=14) and non-responders (n=23; P = 0.0026). None of investigated tumour samples from patients with a complete response (CR) had a proliferation index of less than 45. Tumour samples from patients with a CR showed a VEGF expression of 10.7 compared with 36.58 of tumours with no response (P = 0.035). CD34 expression showed a correlation with VEGF expression. The relation of mean indices of VEGF expression and proliferative activity in tumours from patients with complete, partial or no response was 10. 7:58.8, 18.3:53.8 and 36.6:43.5, respectively. CONCLUSIONS: According to these results, it may be expected that tumours with a VEGF/MIB-1 ratio of 1:5 or less prior to PCX will respond to this therapy.

Adult↗
PubMed1996

Surgically documented responses to paclitaxel and cisplatin in patients with primary peritoneal carcinoma.

Intra-abdominal carcinomatosis indistinguishable from ovarian cancer may occur after removal of the ovaries or in association with surface ovarian involvement. Because its histologic pattern and behavior approximate those of ovarian cancer, this entity, known as primary peritoneal carcinoma, has been treated in a similar fashion--cytoreductive surgery followed by systemic chemotherapy. This review was undertaken to assess the efficacy of combination chemotherapy with paclitaxel and cisplatin, the current front-line chemotherapeutic regimen for ovarian cancer, in patients with primary peritoneal carcinoma. Sixteen patients diagnosed between January 1989 and July 1994 with primary peritoneal carcinoma were treated at the Hospital of the University of Pennsylvania. The records of the three patients whose initial chemotherapeutic regimen included paclitaxel and cisplatin were reviewed. An additional case from the Robert Wood Johnson Medical Center, Camden, New Jersey, was included. Pathologic review of all cases was conducted at the time of clinical management and again as part of this study. Reassessment laparotomy was performed in all patients after the completion of chemotherapy. Complete clinical information was available on all patients. All four patients presented with intra-abdominal carcinomatosis, and large volume (> 1 cm) residual disease was present following initial cytoreduction. Following chemotherapy, second-look laparotomy documented one complete pathologic response and three partial (>50% tumor volume reduction), but marked, responses. Combination chemotherapy with paclitaxel and cisplatin produces surgically documented responses in patients with primary peritoneal carcinoma.

Antineoplastic Agents↗
PubMed1997

The role of second-look laparotomy in the long-term survival in ovarian cancer.

BACKGROUND: To elucidate the role of second-look laparotomy in the management of ovarian cancer patients, were retrospectively reviewed our experience with this procedure in epithelial ovarian cancer patients. PATIENTS AND METHODS: The hospital records of 617 patients with advanced ovarian cancer were reviewed. The 308 patients who underwent second-look laparotomy were followed from four to 18 years with a median follow-up of 12 years after start of primary chemotherapy. RESULTS: Patients who achieved pathological complete response (PCR), microscopic partial response (PPR mic.), macroscopic partial response (PPR mac.), stable disease (PSD), and progressive disease (PPD) at second-look laparotomy had a median survival time of 149, 39.5, 24, 14, and eight months, respectively. Secondary surgical cytoreduction could be performed only in 101 patients with macroscopic persistent disease. The group of all patients with secondary tumor debulking had no survival advantage compared with the group of patients with PPR mac., PSD, and PPD, unable to have secondary cytoreduction. Patients left with no tumor after second-look laparotomy did not survive as long as patients who achieved PCR and PPR mic. at second-look laparotomy. Factors prolonging survival after second-look laparotomy included younger age, good pre-treatment performance status, smaller primary residual tumor size, longer interval between start of chemotherapy and second-look laparotomy, and the pathologically proven CR or PR mic. CONCLUSION: Second-look laparotomy appears to have a minor role in the routine management of ovarian cancer patients, especially in the context of the limited effectiveness of second-line therapy. This procedure should be limited to clinical treatment protocols to determine effectiveness of new agents.

Adult↗
PubMed2004

Future options with trastuzumab for primary systemic and adjuvant therapy.

HER2 positivity can be detected early in breast cancer development and is associated with a poor outcome. Primary systemic therapy with trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) in combination with taxanes and other cytotoxic agents has been studied in phase II clinical trials in women with HER2-positive breast cancer. These combinations have achieved pathologic complete response rates of 12% to 42% and clinical complete response rates of 30% to 67%. These results compare favorably with those of primary systemic therapy using standard combinations in patients with unselected (HER2-positive or -negative) breast cancer. Consequently, larger studies are in progress in which trastuzumab is administered before surgery in combination with chemotherapy. Trastuzumab is continued as monotherapy afterward to complete 1 year of treatment or until disease progression. These studies aim to provide further proof of the clinical benefits associated with trastuzumab as primary systemic therapy. They will also investigate the molecular determinants of sensitivity and resistance. In addition, four major randomized trials, in more than 13,500 patients, are investigating the impact of adding trastuzumab to standard adjuvant therapy. Planned interim cardiac safety analyses have been passed without concerns. Recruitment to these studies has either recently been completed or continues as planned. Together, this extensive program, which includes analysis of predictive molecular and pathologic makers, will establish the efficacy, safety, and role of trastuzumab in early breast cancer.

Antibodies, Monoclonal↗
PubMed1997

A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03.

PURPOSE: National Surgical Adjuvant Breast and Bowel Project Protocol R-03 was designed to determine the worth of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. METHODS: Thus far, 116 patients of an eventual 900 with primary operable rectal cancer have been randomized to receive multimodality therapy to begin preoperatively (59 patients) or identical therapy beginning after curative surgery (57). All patients received seven cycles of 5-fluorouracil (FU)/leucovorin (LV) chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In Cycles 2 and 3, FU and low-dose LV chemotherapy was given during the first and fifth week of radiation therapy (5,040 cGy). The preoperative arm (Group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (Group 2) received all radiation and chemotherapy after surgery. Primary study end points included disease-free survival and survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. RESULTS: Overall treatment-related toxicity was similar in both groups. Although seven preoperative patients had events after randomization that precluded surgery, eight events occurred during an equivalent follow-up period in the postoperative group. No patient was deemed inoperable because of progressive local disease. Sphincter-saving surgery was intended in 31 percent of Group 1 patients and 33 percent of Group 2 patients at the time of randomization. Such surgery was actually performed in 50 percent of the preoperatively treated patients and 33 percent of the postoperatively treated patients. The use of protective colostomy in patients undergoing sphincter-sparing surgery and the development of perioperative complications in all surgical patients were similar in both groups. There was evidence of tumor downstaging in evaluable patients undergoing preoperative therapy, with 8 percent of Group 1 patients having had a pathologic complete response. CONCLUSION: These data do suggest that the preoperative chemotherapy and radiation therapy regimen used are, at least, as safe and tolerable as standard postoperative treatment. There is presently a trend to tumor downstaging and sphincter preservation in the preoperative arm. Whether this arm will have greater or lesser survival and long-term toxicity awaits the completion of this relevant study.

Adenocarcinoma↗
PubMed2004

NF-kappaB activation in esophageal adenocarcinoma: relationship to Barrett's metaplasia, survival, and response to neoadjuvant chemoradiotherapy.

OBJECTIVE: To examine the expression of the transcription factor nuclear factor kappa B (NF-kappaB) in Barrett's epithelium and adenocarcinoma and the impact of NF-kappaB expression on tumor stage and response to neoadjuvant chemotherapy and radiation therapy. SUMMARY BACKGROUND DATA: Progression of Barrett's esophagus to adenocarcinoma is associated with a wide range of cellular and molecular abnormalities. Nuclear factor-kappa B (NF-kappaB) regulates several genes involved in inflammatory, immune and apoptotic responses, but its role in esophageal inflammation and tumorigenesis has not been reported. METHODS: Mobility shift assay was used to measure NF-kappaB activity in nuclear extracts of fresh-frozen biopsies from tumor and uninvolved tissues (n = 30) and esophageal cell lines OE33, SKGT-4, and OE21. RelA expression was assessed by immunohistochemical staining (n = 97). The NF-kappaB/RelA and IkappaB protein expressions were also examined by Western blotting. RESULTS: NF-kappaB was not expressed in normal esophageal squamous epithelium, in contrast to increased expression in 40% of patients with Barrett's epithelium. Sixty-one percent of resected tumors (n = 97) displayed NF-kappaB immunoreactivity, and 87.5% of the NF-kappaB-positive tumors were Stage IIb and III compared with only 12.5% of patients with Stage I and IIa disease (P < 0.05). The expression of NF-kappaB inversely correlated with major or complete pathologic responses to neoadjuvant chemotherapy and radiation therapy, with 15/20 (75%) responders in the NF-kappaB-negative group compared with 7/38 (18%) in the NF-kappaB-positive group (P < 0.00001). Moreover, incubation of esophageal cell lines OE33, SKGT-4, and OE21 with deoxycholic acid or low pH induced NF-kappaB expression. CONCLUSIONS: Bile acids and low pH induce NF-kappaB expression in esophageal cell lines. NF-kappaB activation is common in esophageal adenocarcinoma. In patients with Barrett's epithelium and an associated esophageal adenocarcinoma, there is a progressive expression of NF-kappaB through Barrett's tumorigenesis. The absence of NF-kappaB expression in esophageal adenocarcinoma correlates with response to neoadjuvant chemoradiotherapy and may be of value in predicting response to neoadjuvant therapy.

Adenocarcinoma↗