Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer.

BACKGROUND: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC. RESULTS: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48). CONCLUSIONS: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice. Cancer 2015;121:2586-2593. © 2015 American Cancer Society.

Breast conserving surgery after neoadjuvant therapy for large primary breast cancer

Aim: The aim of this study was to evaluate the safety of breast conserving surgery ill patients with breast tumours satisfactorily downstaged after neoadjuvant therapy. Methods: A retrospective cohort study was undertaken to analyze the loco-regional recurrence (LRR) after breast conserving surgery. We enrolled 88 patients with breast cancer subjected to neoadjuvant therapy (NAT group) who achieved an objective response due to neoadjuvant treatment and compared them with 191 patients with early breast cancer (EBC group) who were submitted to primary conserving surgery. Lumpectomy or quadrantectomy with axillary lymph node dissection was performed in all patients who received adjuvant radiotherapy. Systemic adjuvant therapy was offered to all patients. The mean periods of observation were 61.3 months in the NAT group and 67.5 months in the EBC group. Results: The mean age was 53 years in the NAT group and 56 years in the EBC group (p = 0.04). There was no histological type and histological grade difference between groups. In the NAT group, the mean diameter of residual tumour was lower and the mean volume of breast tissue resection was higher than in the EBC group (p = 0.01 and p = 0.002, respectively). The ipsilateral recurrence rate was 7.9% in the NAT group and 7.8% in the EBC group (p = 0.9). The most important predictive factor of recurrence in the NAT group was the age of patient. Conclusion: Breast conserving therapy is a safe procedure in satisfactorily downstaged breast cancer after neoadjuvant therapy. (c) 2008 Elsevier Ltd. All rights reserved.

LAPATAX: A randomized phase II trial of FEC-docetaxel combined with lapatinib and/or trastuzumab as neoadjuvant therapy of HER2- positive breast cancer-EORTC 10054 trial.

Background: Patients with HER2 +ve breast cancer suitable for neoadjuvant chemotherapy (NAC) have been shown in a series of clinical trials to have the best outcome when treated with anthracyclines (A), taxanes (T), and trastuzumab (Tz). Recent evidence confirms that adjuvant Tz is more effective when given concomitantly rather than sequentially with T (Perez SABCS 2009). Whilst there remains uncertainty as to the most efficacious A-T regimen and duration of Tz, there is widespread use in Europe of FEC-D [3 cycles of 5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100) followed by 3 cycles of docetaxel 100 mg/m2 (D) q3w] following the results of PACS-01. The advent of TKI anti-HER2 agents such as L could offer superior outcomes if combined with NAC. However, a phase I study in heavily pre-treated advanced breast cancer reported difficulties in combining lapatinib (L) with D 100 mg/m2 (LoRusso JCO 2008). Methods: EORTC 10054 is designed as a two-part study to compare FEC-D with either Tz, L or their combination as NAC for patients with HER2 +ve large operable or locally advanced breast cancer. Before and on-treatment frozen tumor and blood samples will be taken to better define which tumours are particularly sensitive to either Tz and/or L. Stage 1: (complete) a dose- finding study has confirmed that with primary prophylactic G-CSF, D 100 mg/m2 can be safely and effectively given with L 1,250 mg daily continuously. The dose-limiting toxicity was myelosuppression, and there was no significant diarrhoea or cardiac toxicity (ESMO 2009 abstr P- 5073). Stage 2: (opening Q1 2010) will enroll 150 patients from European centres into a 3-arm randomized trial whose primary endpoint is pathological complete response. All patients will receive FEC-D before primary surgery: 3 cycles of FEC (without anti-HER2 therapy) followed by 3 cycles of D plus either Tz (conventional weekly schedule), monotherapy L, or the combination of Tz and L, using doses based on the EGF100161 dose-finding study in 1st line metastatic therapy of D+L+Tz. After surgery all patients will receive standard 3-weekly Tz, radiotherapy and endocrine therapy as per local guidelines.

Neoadjuvant therapy with denosumab in a giant cell tumour. A case report

Introduction: Giant cell tumour (GCT) is a benign but locally aggressive primary osteolytic bone tumour, prone to local recurrence after surgery. Denosumab is a human antibody against RANKL, an over-expressed ligand present on normal multinucleated cells, responsible for bone destruction in GCT. We report the case of a patient with an advanced GCT of the distal radius. The lesion was treated with adjuvant denosumab , followed by curettage. Clinical case: A 28 years old patient presented with a classical honeycomb osteolytic lesion in the left distal radius. Core-needle biopsy confirmed the diagnosis of GCT. Due to the proximity to the radio-carpal joint and advanced scalloping of the metaphyseal cortical bone, joint-salvage surgery was not possible. We initiated a neo-adjuvant treatment with denosumab (XGEVA), 120mg/ week for 1 month, followed by monthly injections for 6 months. During this time, a substantial bone recorticalization, without progression of the size of the tumour was noted. No local or systemic side effects were observed. We performed intra-lesional (curettage) excision and bone grafting after 6 months. Histological analysis revealed islets (10%) of viable tumour cells within fibrous tissue. Post-op evolution was eventless. Discussion: While surgery remains the treatment of choice for GCT, joint-salvage may not always be possible in case of extensive epiphyseal involvement. The presence of osteoclast-like giant cells seems to make those lesions prone to the specific anti-RANKL treatment with denosumab. Denosumab appears to slow down tumour growth and promote recorticalization of eroded bone. It might allow less aggressive surgery in selected cases.

Interim endoscopy results during neoadjuvant therapy for gastric cancer correlate with histopathological response and prognosis

BACKGROUND Neoadjuvant chemotherapy for locally advanced gastric cancer leads to major histopathological response in less than 30 % of patients. Data on interim endoscopic response assessment do not exist. This exploratory prospective study evaluates early endoscopy after 50 % of the chemotherapy as predictor for later response and prognosis. METHODS Forty-seven consecutive patients were included (45 resected; 33 R0 resections). All patients received baseline endoscopy and CT scans, after 50 % of their chemotherapy (EGD-1, CT-1) and after completion of chemotherapy (EGD-2, CT-2). Interim endoscopic response (EGD-1) was assessed after having received 50 % (6 weeks) of the planned 12 weeks of neoadjuvant chemotherapy. Post-chemotherapy response was clinically assessed by a combination of CT scan (CT-2) and endoscopy (EGD-2). Histopathological response was determined by a standardized scoring system (Becker criteria). Endoscopic response was defined as a reduction of >75 % of the tumor mass. RESULTS Twelve patients were responders at EGD-1 and 13 at EGD-2. Nine patients (19.1 %) were clinical responders and 7 patients (15.6 %) were histopathological responders after chemotherapy. Specificity, accuracy, and negative predictive value of the interim EGD-1 for subsequent histopathological response were 31/38 (82 %), 36/47 (76 %), and 31/33 (93 %); and for recurrence or death, 28/30 (93.3 %), 38/47 (80.9 %), and 28/35 (80.0 %). Response at EGD-1 was significantly associated with histopathological response (p = 0.010), survival (p < 0.001), and recurrence-free survival (p = 0.009). CONCLUSIONS Interim endoscopy after 6 weeks predicts response and prognosis. Therefore, tailoring treatment according to interim endoscopic assessment could be feasible, but the findings of this study should be validated in a larger patient cohort.

Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy

Background: Approximately 25 per cent of patients with oesophageal cancer who undergo neoadjuvant chemoradiotherapy have no evidence of tumour in the resected specimen (complete pathological response). Those who do not respond have a poor 5-year survival compared with complete responders, regardless of whether or not they undergo surgery. Selecting for surgery only those who have a response to neoadjuvant therapy has the potential to improve overall survival as well as to rationalize the management of non-responders. This study assessed the accuracy of oesophagogastroscopy in this setting. Methods: A prospective database of 804 patients undergoing oesophageal resection for carcinoma was reviewed. Endoscopic assessment of the response to neoadjuvant therapy in 100 consecutive patients was compared with the pathological assessment of response. The survival for each level of response was compared. Results: At endoscopy 30 patients were considered to have had a complete response. This was confirmed pathologically in 15 patients. Survival was improved in those with a pathologically confirmed complete response (3-year survival rate 62.4 (s.e. 12.9) per cent) compared with non-responders (16.3 (s.e. 6.6) per cent). Those with microscopic residual disease also had an improved 3-year survival rate (46.3 (s.e. 12.2) per cent); however, oesophagogastroscopy failed to identify this subset. Conclusion: Oesophagogastroscopy may be useful in the assessment of tumour response to neoadjuvant therapy. However, owing to its poor accuracy patients should not be excluded from further therapeutic intervention on the basis of this assessment alone.

The expression and prognostic significance of bcl-2-associated transcription factor 1 in rectal cancer following neoadjuvant therapy

Date of Acceptance: 12/07/2015 © 2015 John Wiley & Sons Ltd. Acknowledgements This study was supported by funding from the Encompass kick start and SMART:Scotland award schemes of Scottish Enterprise and Friends of Anchor. The Grampian Biorepository assisted with the immunohistochemical investigations.

The expression and prognostic significance of bcl-2-associated transcription factor 1 in rectal cancer following neoadjuvant therapy

Date of Acceptance: 12/07/2015 © 2015 John Wiley & Sons Ltd. Acknowledgements This study was supported by funding from the Encompass kick start and SMART:Scotland award schemes of Scottish Enterprise and Friends of Anchor. The Grampian Biorepository assisted with the immunohistochemical investigations.

Can Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography Be Used As a Useful Method to Evaluate the Treatment Response to Neoadjuvant Therapy Combined With Sorafenib and Anti-VEGF in Children Diagnosed With Metastatical Bone Sarcoma?

Background: The prognosis is still poor for patients with a metastatic bone tumor and new treatment approaches (anti-VEGF and tyrosine kinase inhibitors vs) are therefore needed. Objectives: The aim of our study was to evaluate how the primary and metastatic lesions of our patients with a bone tumor were affected by these treatments and to determine the importance of the 18F-FDG PET method. Patients and Methods: Twenty metastatic bone tumor cases were included. Sorafenib and anti-VEGF were added to the standard treatment in cases with widespread metastatic disease at diagnosis or after neoadjuvant chemotherapy showing less than 90% tumor necrosis in the surgical sample. Positron emission tomography (PET) imaging was performed at diagnosis, the preoperative period following neoadjuvant chemotherapy, during postoperative follow-up, and when treatment was discontinued. Results: The primary treatment region median SUVmax level decreased from 7.35 to 2.5 in the living patients (n = 16) while there was no significant decrease in the patients who succumbed to the disease (P < 0.001). Comparison of the pre- and post-treatment metastasis region median SUVmax levels in patients with metastatic involvement showed a decrease from 2.1 to 0 in the surviving patients but only from 4.8 to 3.2 in the deceased patients (P < 0.01). Survival results indicated that 28.6% of the patients receiving classical treatment only died while all the patients receiving additional sorafenib and anti-VEGF survived. Conclusions: 18F-PET may be a useful technique before and during the follow-up of neoadjuvant treatment in pediatric metastatic bone tumor patients. The addition of sorafenib and anti-VEGF to classical treatment has a favorable contribution to the response and therefore the survival duration.

Quimioterapia neoadjuvante torna ressecável carcinoma de cabeça de pâncreas

We present a case of non-resectable head pancreatic cancer by mesenteric venous invasion in which treatment with Gemcitabine (Gemzar) 1.000 mg/m 2 weekly for 3 weeks, followed by a 1-week rest, normalized CA 19.9 and promoted tumor resecability in a second operation (ultrasound, helicoidal tomography and magnetic ressonance exams). The value of the adjuvant treatment (radiochemotherapy) and the association with immunotherapy (Interferon) is discussed.

Complete Clinical Response After Neoadjuvant Chemoradiation Therapy for Distal Rectal Cancer: Characterization of Clinical and Endoscopic Findings for Standardization

BACKGROUND: Complete tumor regression may develop after neoadjuvant chemoradiation therapy for distal rectal cancer. Studies have suggested that selected patients with complete clinical response may avoid radical surgery and close surveillance may provide good outcomes with no oncologic compromise. However, definition of complete clinical response is often imprecise and may vary between different studies. The aim of this study is to provide a clear definition for a complete clinical response after neoadjuvant chemoradiation therapy in patients with distal rectal cancer in addition to actual endoscopic videos from patients managed nonoperatively. METHODS: Patients with nonmetastatic distal rectal cancer treated by neoadjuvant chemoradiation therapy, including 50.4 Gy and concomitant 5-fluorouracil and leucovorin, were assessed for tumor response at least 8 weeks after chemoradiation therapy completion. Complete and incomplete clinical responses were defined based on clinical and endoscopic findings. Patients with complete clinical response were not immediately operated on and were closely followed. Early and late endoscopic findings were recorded. RESULTS: Definition of a complete clinical response should be based on very strict clinical and endoscopic criteria. The finding of any residual superficial ulceration, irregularity, or nodule should prompt surgical attention, including transanal full-thickness excision or even a radical resection with total mesorectal excision. Standard or incisional biopsies should be avoided in this setting. Complete clinical responders should harbor no more than whitening of the mucosa, teleangiectasia with mucosal integrity to be considered for a nonoperative approach. In the presence of these findings, regularly scheduled reassessments may provide a safe alternative to these patients with early detection of recurrent disease. CONCLUSION: Strict definition of the clinical and endoscopic findings of patients experiencing complete clinical response after neoadjuvant chemoradiation therapy may provide a useful tool for the understanding of outcomes of patients managed with no immediate surgery allowing standardization of classifications and comparison between the experiences of different institutions.

Interval between surgery and neoadjuvant chemoradiation therapy for distal rectal cancer: Does delayed surgery have an impact on outcome?

Background: The optimal interval between neoadjuvant chemoradiation therapy (CRT) and surgery in the treatment of patients with distal rectal cancer is controversial. The purpose of this study is to evaluate whether this interval has an impact on survival. Methods and Materials: Patients who underwent surgery after CRT were retrospectively reviewed. Patients with a sustained complete clinical response (cCR) 1 year after CRT were excluded from this study. Clinical and pathologic characteristics and overall and disease-free survival were compared between patients undergoing surgery 12 weeks or less from CRT and patients undergoing surgery longer than 12 weeks from CRT completion and between patients with a surgery delay caused by a suspected cCR and those with a delay for other reasons. Results: Two hundred fifty patients underwent surgery, and 48.4% had CRT-to-surgery intervals of 12 weeks or less. There were no statistical differences in overall survival (86% vs. 81.6%) or disease-free survival rates (56.5% and 58.9%) between patients according to interval (<= 12 vs. >1 2 weeks). Patients with intervals of 12 weeks or less had significantly higher rates of Stage III disease (34% vs. 20%; p = 0.009). The delay in surgery was caused by a suspected cCR in 23 patients (interval, 48 +/- 10.3 weeks). Five-year overall and disease-free survival rates for this subset were 84.9% and 51.6%, not significantly different compared with the remaining group (84%; p = 0.96 and 57.8 %; p = 0.76, respectively). Conclusions: Delay in surgery for the evaluation of tumor response after neoadjuvant CRT is safe and does not negatively affect survival. These results support the hypothesis that shorter intervals may interrupt ongoing tumor necrosis. (C) 2008 Elsevier Inc.

Absence of lymph nodes in the resected specimen after radical surgery for distal rectal cancer and neoadjuvant chemoradiation therapy: What does it mean?

Purpose: The number of retrieved lymph nodes during radical surgery has been considered of great importance to ensure adequate staging and radical resection. However, this finding may not be applicable after neoadjuvant therapy in which, not only is there a decrease in lymph nodes recovered, but also a subgroup of patients with absence of lymph nodes in the resected specimen. Methods: Patients with absence of lymph nodes were compared with patients with ypN0 disease and patients with ypN+ disease. Results: Thirty-two patients (11 percent) had absence of lymph nodes, 171 patients (61 percent) had ypN0 disease, and 78 patients (28 percent) had ypN+ disease. Patients with absence of lymph nodes had significantly lower ypT status (ypT0-1, 40 vs. 13 percent; P < 0.001) and decreased risk of perineural invasion (6 vs. 21 percent; P = 0.04) compared with ypN0 patients. Five-year disease-free survival (74 percent) was similar to patients with ypN0 (59 percent; P = 0.2), and both were significantly better than patients with ypN+ disease (30 percent; P < 0.001). Conclusions: Absence of lymph nodes retrieved from the resected specimen is associated with favorable pathologic features (ypT and perineural invasion status) and good disease-free survival rates. In this setting, absence of retrieved lymph nodes may reflect improved response to neoadjuvant chemoradiation therapy rather than inappropriate or suboptimal oncologic radicality.

Transanal Endoscopic Microsurgery for Residual Rectal Cancer After Neoadjuvant Chemoradiation Therapy Is Associated With Significant Immediate Pain and Hospital Readmission Rates

BACKGROUND: Transanal endoscopic microsurgery may represent appropriate diagnostic and therapeutic procedure in selected patients with distal rectal cancer following neoadjuvant chemoradiation. Even though this procedure has been associated with low rates of postoperative complications, patients undergoing neoadjuvant chemoradiation seem to be at increased risk for suture line dehiscence. In this setting, we compared the clinical outcomes of patients undergoing transanal endoscopic microsurgery with and without neoadjuvant chemoradiation. METHODS: Thirty-six consecutive patients were treated by transanal endoscopic microsurgery at a single institution. Twenty-three patients underwent local excision after neoadjuvant chemoradiation therapy for rectal adenocarcinoma, and 13 patients underwent local excision without any neoadjuvant treatment for benign and malignant rectal tumors. Chemoradiation therapy included 50.4 to 54Gy and 5-fluorouracil-based chemotherapy. All patients underwent transanal endoscopic microsurgery with primary closure of the rectal defect. Complications (immediate and late) and readmission rates were compared between groups. RESULTS: Overall, median hospital stay was 2 days. Immediate (30-d) complication rate was 44% for grade II/III complications. Patients undergoing neoadjuvant chemoradiation therapy were more likely to develop grade II/III immediate complications (56% vs 23%; P = .05). Overall, the 30-day readmission rate was 30%. Wound dehiscence was significantly more frequent among patients undergoing neoadjuvant chemoradiation therapy (70% vs 23%; P = .03). Patients undergoing neoadjuvant chemoradiation therapy were at significantly higher risk of requiring readmission (43% vs 7%; P = .02). CONCLUSION: Transanal local excision with the use of endoscopic microsurgical approach may result in significant postoperative morbidity, wound dehiscence, and readmission rates, in particular, because of rectal pain secondary to wound dehiscence. In this setting, the benefits of this minimally invasive approach either for diagnostic or therapeutic purposes become significantly restricted to highly selected patients that can potentially avoid a major operation but will still face a significantly morbid and painful procedure.