Higher Pathological Response Research Articles

Efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin and S-1 for resectable locally advanced gastric cancer.

The prognosis for locally advanced gastric cancer (AGC) remains unsatisfactory, even with S-1 adjuvant chemotherapy. We investigated the efficacy of neoadjuvant chemotherapy consisting of docetaxel, cisplatin and S-1 (DCS). We retrospectively reviewed 59 patients who underwent neoadjuvant DCS therapy for clinical stage III tumors or serosa-positive tumors between January 2009 and December 2013 at Niigata Cancer Center Hospital. The patients received S-1 (40 mg/m(2) bid) on days 1-14, and docetaxel (35 mg/m(2)) and cisplatin (35 mg/m(2)) on days 1 and 15 every 4 weeks. Forty-three patients (72.9 %) received two courses of DCS therapy, while 16 patients (27.1 %) received one course of treatment. The clinical response rate of the primary tumor was 74.6 %, and the disease control rate was 100 %. A pathological response, defined as one-third or more of the affected tumor, was observed in 71.2 % of patients. The common grade 3/4 adverse events from chemotherapy were leucopenia (16.9 %), neutropenia (44.1 %), febrile neutropenia (8.5 %), anemia (10.2 %), anorexia (8.5 %) and nausea (6.8 %). Postoperative complications occurred in 11 patients (18.6 %). There was no treatment-related mortality or reoperation. The 3- and 5-year overall survival rates were 88 and 68.6 %, respectively. Clinical responders had a significantly higher survival rate than non-responders. Multivariate analysis identified clinical response as the only independent prognostic factor. Neoadjuvant DCS therapy demonstrated a very high clinical and pathological response rate with acceptable toxicities. Therefore, this therapy may improve the prognosis of locally AGC.

Abstract P5-18-06: Trastuzumab can be safely administered concurrently with anthracycline for adjuvant treatment of HER2-positive breast cancer

Abstract Background Anthracycline and trastuzumab are the preferential choices in the treatment of HER2-positive breast cancer. Due to the unacceptably high rates of cardiotoxicity observed in the metastatic breast cancer, concurrent administration of anthracycline and trastuzumab (A+H) is contraindicated. However, in the neoadjuvant setting, A+H has shown high rates of pathological complete response and very low cardiotoxicity. So far, all the large adjuvant trials have only evaluated the sequential strategy of administration anthracycline and trastuzumab (A-H), whereas the safety and efficacy of A+H has never been evaluated prospectively. Thus, we conducted a prospective study to evaluate the cardiac safety and efficacy of A+H regimen in the adjuvant treatment of HER2-positive breast cancer. Methods This is a prospective, randomized and controlled trial. Participants, with HER2-positive, operable breast cancer, but without previous neoadjuvant treatment, were randomized to receive adjuvant A+H or A-H. If anthracycline was administered alone or sequentially to taxane, the dose of doxorubicin and epirubicin was 60mg/m2 and 90-100mg/m2, respectively. If anthracycline was given concurrently with taxane, the dose of doxorubicin and epirubicin was 50mg/m2 and 75mg/m2, respectively. Trastuzumab was given every 3 weeks (loading dose of 8mg/kg, followed by 6mg/kg) for one year. Left ventricular ejection fraction (LVEF) was monitored by echocardiogram (ECHO) at baseline (before chemotherapy) and 3, 6, 9, 12 and 24 months after the initial dose of trastuzumab. The primary endpoint was cardiac safety. The second endpoints were disease-free survival (DFS) and overall survival. ClinicalTrials.gov ID: NCT01413828. Results Between August 2011 and March 2014, 196 HER2-postive breast cancer patients (98 in the A+H group and 98 in the A-H group) were enrolled and randomized. Women in the two groups had similar baseline characteristics including age, tumor stage, hormonal receptor status, chemotherapy regimen, radiation therapy and endocrine therapy. Trastuzumab was well-tolerated in both groups and the primary cardiac event was asymptomatic decrease in LVEF. In the A+H group, there were 11 (11.2%) patients showed more than 10% but less than 20% reduction in LVEF (NCI-CTC Grade I). In the A-H group, there were 14 (14.3%) patients showed NCI-CTC Grade I LVEF reduction and 1 (1.0%) patient showed more than 20% reduction in LVEF (NCI-CTC Grade II). There was no case of congestive heart failure. The difference of the rates of cardiac events between the two groups was not significant (P=0.400). The mean LVEF of the baseline and 3, 6, 9, 12 and 24 months after initial dose of trastuzumab also showed no difference between the two groups. Patients in both groups had excellent disease control at a median follow up of 16 months. There were numerically more DFS events in the A-H group (6/98, 6.1%) than the A+H group (10/98, 10.2%), but the difference of DFS did not reach the statistical significance (P=0.485). There was no death in both groups. Conclusions Trastuzumab administered concurrently with anthracycline is a safe adjuvant regimen and might improve the survival of patients with HER2-positvie breast cancer. Citation Format: Songjie Shen, Qiang Sun, Ying Xu, Yidong Zhou, Jinghong Guan, Feng Mao, Yan Lin, Xuejing Wang. Trastuzumab can be safely administered concurrently with anthracycline for adjuvant treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-18-06.

Surgical outcomes of patients undergoing extrafascial hysterectomy following neoadjuvant high-dose rate brachytherapy for locally advanced endometrial cancer clinically extending to the cervix or parametria

Objectives: Recent data have shown high rates of clinical and pathologic response to neoadjuvant radiation therapy for locally advanced endometrial cancer. There are limited data on the surgical outcomes of these patients in the era of modern radiation and surgical techniques. We sought to characterize surgical outcomes following extrafascial hysterectomy in this population.

Application of regional arterial infusion chemotherapy in short-term neoadjuvant chemotherapy for advanced gastric cancer

To explore the feasibility of short-term neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (AGC), and to compare clinical efficacy of short-term neoadjuvant chemotherapy with different ways. Clinical data of 310 AGC patients treated with one course of NACT using EOF regimen(epirubicin, oxaliplatin and fluorouracil plus calcium folinate) in our hospital from January 2008 to December 2011 were retrospectively analyzes. Efficacy was compared between regional arterial infusion chemotherapy and intravenously chemotherapy. All the 310 AGC patients completed one course of NACT and none was interrupted by adverse events. Postoperative pathological remission rate was 33.9% (105/310) and 5 patients (1.6%) had complete pathological remission. The pathologic response rate in the regional arterial infusion chemotherapy group was higher than that in the intravenously chemotherapy group(42.4% vs. 23.6%, P = 0.001). Multivariate analysis revealed that chemotherapy method(HR=1.827, 95% CI:1.006-3.316, P = 0.048) was associated with significantly higher pathologic response. Pathological response rate is quite low following short-term NACT. Regional arterial infusion chemotherapy with short-term NACT can improve the pathological response rate of advanced gastric cancer.

Neoadjuvant radiotherapy with or without chemotherapy followed by extrafascial hysterectomy for locally advanced endometrial cancer clinically extending to the cervix or parametria

PurposeFor locally-advanced uterine cancer clinically extending to the cervix, two treatment paradigms exist: surgical staging radical hysterectomy with tailored adjuvant therapy or neoadjuvant therapy followed by a less extensive simple hysterectomy. Currently, insufficient data exists to guide consensus guidelines and practical application of preoperative radiotherapy. Materials and methodsRetrospective IRB approved cohort study from 1999 to 2014 of 36 endometrial cancer patients with clinical involvement of cervix±parametria treated with neoadjuvant external beam radiotherapy (45–50.4Gy in 25–28 fractions) and image-based HDR brachytherapy (5–5.5Gy times 3–4 fractions)±chemotherapy followed by extrafascial hysterectomy performed at a median of 6weeks after radiotherapy. ResultsAll patients had clinical cervical extension, 50% also had parametria extension, and 31% had nodal involvement. At the time of surgery 91% had no clinical cervical involvement, 58% had no pathologic cervical involvement, and all had margin negative resection. The pathologic complete response rate was 24%. Median follow-up from the time of surgery was 20months (range: 0–153). The 3-year local control, regional control, distant control, disease free survival and overall survival rates were 96%, 89%, 84%, 73%, and 100%. The 3-year rate of grade 3 complications was 11%, with no grade 4+ toxicity. ConclusionsNeoadjuvant radiation therapy±chemotherapy followed by extrafascial hysterectomy appears to be a viable option for patients with endometrial cancer clinically extending to the cervix and parametria. The HDR brachytherapy schema of 5–5.5Gy times 3–4 fractions, for a cumulative EQD2 of 60–70Gy, is well tolerated with high rates of clinical and pathological response.

A Prospective Pilot Study of Target-guided Personalized Chemotherapy with Intensity-modulated Radiotherapy in Patients With Early Rectal Cancer

To investigate the feasibility of personalizing chemotherapy in patients with rectal cancer. Patients with cT3 or cN1 and cM0 rectal cancer were eligible. A set of 6 molecular markers including KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), ERCC-1, and thymidylate synthase (TS) using immunohistochemistry were performed in a tumor biopsy. All patients were treated with capecitabine 625 to 825 mg/m/12 h M-F in combination with either irinotecan or oxaliplatin based on Topo-1 and ERCC-1 expression plus either bevacizumab or cetuximab based on the mutation status. All patients received intensity-modulated radiation therapy. A surgery was performed 6 to 8 weeks after the treatment. Fifteen patients (94%) had T3 tumor and 10 (62%) N+ disease of 16 patients enrolled. In all patients, the full set of markers was analyzed within 10 days. Seven patients had K-ras mutation, and 4, 5, and 10 expressed Topo-1, ERRC-1 and TS, respectively. All patients had wild-type BRAF and PI3K tumors. The median time from obtaining informed consent to the treatment period was 18 days and all patients completed the chemoradiation treatment. Fifty percent achieved a complete pathologic response to treatment. Four patients (25%) developed grade 3 proctitis or diarrhea. There were no relevant surgical complications. Sixty-nine percent of the patients received adjuvant XELOX. The individualization of neoadjuvant chemotherapy in patients with rectal cancer is feasible and leads to a high rate of pathologic response.

A phase II study of weekly nab-paclitaxel in combination with cisplatin as neoadjuvant chemotherapy in patients (pts) with locally advanced esophageal squamous cell carcinoma (SCC).

122 Background: This phase II study was aimed to define the pathological response rate and safety of combining weekly nab-paclitaxel and cisplatin as neoadjuvant chemotherapy in pts with locally advanced esophageal SCC. Methods: Pts with resectable locally advanced thoracic esophageal SCC staged by EUS, CT and/or PET-CTscan. All pts received nab-paclitaxel (100 mg/m2, d1, d8, d22 and d29) and cisplatin (75 mg/m2, d1 and d22) as neoadjuvant chemotherapy, followed by esophagectomy.Postoperation: 2 cycles of adjuvant chemotherapy with same regimen was given in 4-6 weeks after the resection.The primary endpoint was pathological response rate. The second endpoints included R0 resection rate,down-staging rate, 3 years overall survival (OS) and disease-free survival (DFS). Results: From 01/2011 to 10/2012, 35 pts were enrolled. 31 male:4 females; IIA/IIB/IIIA/IIIB/IIIC in 3 (8.6%), 5 (14.3%),10 (28.6%), 8 (22.9%) and 9 (25.7%) pts. 30/35 pts went to surgery (85.7%). 30 had R0 resection (100%). Pathological complete response (pCR) was achieved in 4 pts (13.3%). Near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) in 2 pt (6.7%). Down-staging was observed in 19 of 30 patiens (63.3%). 5 pts did not going to surgery: 2 for progressive disease, 3 for refused. 24/30 pts (80.0%) received adjuvant chemotherapy, 7 pts (23.3%) received adjuvant chemoradiotherapy. Grade 3/4 toxicities in 35 evaluable pts during chemotherapy were as follow: neutropenia (11.4%), anemia (8.6%), thrombocytopenia (5.7%), nausea/vomiting (14.3%), neutropenia fever (8.6%), asthenia (20.0%). Surgical complications: 1 anastomotic leaks (3.3%). No treatment-related death. At a median follow up of 12 months (8~20mos), 29 pts were all disease-free survival. Conclusions: In pts with locally advanced esophageal SCC, weekly nab-paclitaxel and cisplatin as neoadjuvant chemotherapy achieved a high pathological response rate and R0 resection rate. The toxicity was well tolerated. Evaluation of nab-paclitaxel and cisplatin in randomized trials was warranted. Clinical trial information: NCT01258192.

Prognostic Factors for Locally Advanced Cervical Cancer Treated With Neoadjuvant Intravenous and Transuterine Arterial Chemotherapy Followed by Radical Hysterectomy

The aim of this study was to identify prognostic factors associated with neoadjuvant transuterine arterial chemotherapy (TUAC) followed by type III radical hysterectomy. The medical histories of patients with stage IB2 to IIB cervical cancer who received neoadjuvant TUAC between 1996 and 2009 at our institution were retrospectively reviewed. Seventy-three patients received TUAC using cisplatin combined with intravenous nedaplatin, irinotecan, paclitaxel, or etoposide administration. Forty-seven patients (64%) had squamous cell carcinoma. The radiological response rate was 96% (95% confidence interval, 91%-100%). Radical hysterectomy was completed for 95% of enrolled patients. Examination of the resected cervical specimens showed that tumor cells were absent in 19 cases and stromal invasion was less than 3 mm in 7 cases. Among these 26 patients, 23 (32%) had pathologically negative pelvic lymph nodes and no recurrence during the follow-up period. The 5-year relapse-free survival and overall survival rates were 69% and 74%, respectively. Among 23 patients with recurrence or progressive disease, the median survival time after recurrence or progression was 12 months. In multivariate analysis, a tumor size of more than 60 mm and pathological positive lymph nodes were negative prognostic factors for overall survival. Tumor size, pathological response, and lymph node metastases were prognostic factors for cervical cancer. The high pathological response rate associated with TUAC makes it a promising treatment for bulky cervical cancer.

Phase II study of liposome-encapsulated doxorubicin plus cyclophosphamide, followed by sequential trastuzumab plus docetaxel as primary systemic therapy for breast cancer patients with HER2 overexpression or amplification

Purpose of the studyTrastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response (pCR). Non-pegylated liposome-encapsulated doxorubicin (NPLD) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC. MethodsPreoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Clinical staging was exploratory evaluated by CT-PET. Results43 pts were treated from december 2005 to September 2011, 39 of them were evaluable for the purpose of study. Median age was 53 years (range: 31–78), the majority of pts had tumour stage cT2 (63%), tumour grade 3 (86%), clinical nodes involvement N+ (77%), ER positive (56%) and Ki-67 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. There was an association between Ki-67 ≥20% at baseline and pCR (p = 0.018). No cardiac toxicity or discontinuation of trastuzumab was reported. CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes. ConclusionsThis study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active. NPLD is a safe option to minimize cardiotoxicity.

Circulating HMGB1 Levels Increase in Locally-Advanced Breast Cancer Patients Treated on a Protocol of Neoadjuvant Paclitaxel and Radiation

Overall survival (OS) has been correlated to the interaction between circulating HMGB1 (cHMGB1, released from dying tumor cells) and toll-like receptor 4 (TLR4, expressed by dendritic cells [DCs] and required for tumor antigen cross-presentation) in breast and esophageal cancer patients treated with radiation therapy (RT) and chemotherapy (CT). We previously demonstrated that locally advanced breast cancer (LABC) patients treated with neoadjuvant concurrent paclitaxel (PTX) and RT achieved high pathologic response rates (34% pCR and pPR) with an associated OS benefit. Importantly, hormone receptor (HR) -ve tumors (thought to be more immunogenic) achieved an even higher pathologic response (54%) versus HR +ve tumors (18%). We hypothesized that neoadjuvant concurrent PTX and RT can increase cHMGB1, thereby, contributing to host anti-tumor immune responses and OS in LABC patients. Thus, we measured the amount of cHMGB1 pre and post-neoadjuvant concurrent PTX and RT in LABC patients. Women ≥ 18 years of age with biopsy-proven LABC (stages IIB-IIIC) were eligible and treated with PTX (30 mg/m2 intravenously twice a week) for 10-12 weeks. Daily RT was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of PTX treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy per fraction. Statistical analysis was achieved with a paired T-test. Pre and post-treatment blood samples were identified from 21 LABC (12 HR +ve and 9 HR -ve) patients treated with neoadjuvant concurrent PTX and RT. There was a significant increase in cHMGB1 in all patients, from 1.82 ± 0.26 ng/mL to 2.75 ± 0.45 ng/mL (p = 0.037). Interestingly, when analyzed separately, HR -ve patients demonstrated a significant increase of cHMGB1 (from 2.24 ± 0.34 ng/mL to 3.86 ± 0.75 ng/mL, p = 0.043), whereas, HR +ve patients did not (from 1.51 ± 0.36 ng/mL to 1.91 ± 0.45 ng/mL, p = 0.43). These results demonstrate an increase of cHMGB1 in LABC patients, specifically those that are HR -ve, treated with neoadjuvant PTX and RT. However, further research is warranted to link cHMGB1 with improved outcomes in these patients.

Clinical tools do not predict pathological complete response in patients with esophageal squamous cell cancer treated with definitive chemoradiotherapy

Chemoradiotherapy for locally advanced esophageal squamous cell carcinoma is associated with high rates of pathological complete response. A pathological complete response is recognized to be an important predictor of improved survival, to the extent that observation rather than surgery is advocated by some in patients with presumed pathological complete response based on their clinical response. The goal of this study was to look at the ability of clinical variables to predict pathological complete response after chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. We reviewed retrospectively patients with locally advanced esophageal squamous cell carcinoma who underwent chemoradiotherapy followed by surgery and compared those with pathological complete response to patients with residual disease. Between January 1996 and December 2010, 116 patients met inclusion criteria. Fifty-six percent of patients had a pathological complete response and a median survival of 128.1 months versus 28.4 months in patients with residual disease. When compared with patients with residual disease, patients with a pathological complete response had a lower post-neoadjuvant positron emission tomography (PET) maximum standardized uptake value (SUVmax), a larger decrease in PET SUVmax, a less thick tumor on post-chemoradiotherapy computed tomography and a higher rate of normal appearing post-chemoradiotherapy endoscopy with benign biopsy of the tumor bed. However, none of these characteristics alone was able to correctly identify patients with a pathological complete response, and none has significant specificity. Although the rate of pathological complete response after chemoradiotherapy is high in patients with esophageal squamous cell carcinoma, the ability of identifying patients with pathological complete response is limited. A reduction of the PET SUVmax by >70%, a normal appearing endoscopic examination, and no residual disease on biopsy all were seen in >65% of the patients with a pathological complete response. Even if these findings were unable to confirm the absence of residual disease in the primary tumor, they can help guide expectant management in high-risk patients.

P53 in breast cancer subtypes and new insights into response to chemotherapy

Despite an obvious central role of p53 in the hallmarks of cancer, TP53 status is not yet used for the management of breast cancer. Recent findings may lead to reconsider the role of p53 in breast cancer.TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas. Their distribution is highly linked to molecular tumor subtypes found in 26% of luminal tumors (17% of luminal A, 41% of luminal B), in 50% of HER2 amplified tumors, in 69% of molecular apocrine breast carcinomas and in 88% of basal-like carcinomas. The type of mutation is linked to the tumor subtype with higher frequency of base-pair substitutions in luminal tumors, whereas molecular apocrine and basal-like tumors present much higher frequency of complex mutations (deletions/insertions). The timing of TP53 mutation also depends on the tumor subtype, being the first important event in luminal tumors but occurring after PTEN loss in basal-like tumors.Regarding response to cytotoxic chemotherapy, the situation is far from the p53-dependent apoptosis paradigm with subsequent clinical response. We reported that TP53 mutated non inflammatory locally advanced breast carcinomas had a high rate of complete pathological response to dose-dense doxorubicin–cyclophosphamide chemotherapy, while TP53 wild-type (WT) tumors never achieved complete response. Using human breast cancer xenograft models, we suggested that this could be due to the induction of senescence in TP53 WT tumor cells. A recent work confirmed these findings in MMTV-Wnt1 mammary tumors, showing that growth arrest and senescent phenotype, not apoptosis, were induced in TP53 WT tumors following doxorubicin treatment, while lack of arrest in mutant tumors resulted in aberrant mitoses, cell death and a superior clinical response. Furthermore, in ER positive (ER(+)) breast tumors, it has been recently reported that ER represses the p53-mediated apoptotic response induced by DNA damage. Taken together, these data can help to better understand p53-mediated response to doxorubicin-based chemotherapy in breast cancer: in ER(+) TP53 WT breast cancers, ER-induced inhibition of p53 apoptotic response would lead preferentially to tumor cell senescence and subsequent resistance to treatment. Conversely, in ER negative (ER(−)) TP53 mutated breast cancers, accumulation of genetic abnormalities would lead to mitotic catastrophe and subsequent better response.In view of these recent results, p53 impact in breast cancer should be reconsidered.

Weekly nab-paclitaxel in combination with cisplatin as neoadjuvant chemotherapy in patients (pts) with locally advanced esophageal squamous cell carcinoma (SCC): Preliminary results of a phase study.

e15062 Background: This phase II study was aimed to define the pathological response rate and safety of combining weekly nab-paclitaxel and cisplatin as neoadjuvant chemotherapy in pts with locally advanced esophageal SCC. Methods: Pts with resectable locally advanced thoracic esophageal SCC staged by EUS, CT and/or PET-CTscan. All pts received nab-paclitaxel (100 mg/m2, d1, d8, d22 and d29) and cisplatin (75 mg/m2, d1 and d22) as neoadjuvant chemotherapy, followed by esophagectomy.Postoperation: 2 cycles of adjuvant chemotherapy with same regimen was given in 4-6 weeks after the resection.The primary endpoint was pathological response rate. The second endpoints included R0 resection rate,down-staging rate, 3 years overall survival (OS) and progression-free survival (PFS). Results: From 01/2011 to 10/2012, 31 pts were enrolled . 28 male:3 females; II A/II B/III A/III B/III C in 2 (6.5%), 4 (12.9%), 9 ,(29.0%), 8 (25.8), and 8 (25.8%) pts. 26/31 pts went to surgery (83.9%). 26 had R0 resection (100%).Pathological complete response (pCR) was achieved in 3 pts (11.5%). Near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) in 1 pt (3.8 %). Down-staging was observed in 15 of 26 patiens (57.7%). 5 pts did not going to surgery: 2 for progressive disease (6.5%), 3 for refused. 20/26 pts (76.9%) received adjuvant chemotherapy,3 pts (11.5%) received adjuvant chemoradiotherapy. Grade 3/4 toxicities in 31 evaluable pts during chemotherapy were as follow: neutropenia (12.9%), anemia (6.5%), thrombocytopenia (3.2%), nausea/vomiting (12.9%), neutropenia fever (6.5%), asthenia (12.9%). Surgical complications: 1anastomotic leaks (3.8%). No treatment-related death. At a median follow up of 9 months, 26 pts were all disease-free survival. Conclusions: In pts with locally advanced esophageal SCC, weekly nab-paclitaxel and cisplatin as neoadjuvant chemotherapy achieved a high pathological response rate and R0 resection rate .The toxicity was well tolerated. Evaluation of nab-paclitaxel and cisplatin in randomized trials was warranted. Clinical trial information: NCT01258192.

Liposome-encapsulated doxorubicin plus cyclophosphamide followed by trastuzumab plus docetaxel as neoadjuvant therapy for HER2-positive breast cancer (BC): A multicenter single-arm phase II study.

641 Background: Trastuzumab combined to sequential chemotherapy with taxanes and anthracyclines as primary treatment achieved high rates of pathologic complete response (pCR) in HER2 positive BC. Liposome-encapsulated doxorubicin (DLNP) shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab associated with chemotherapy for early or locally advanced HER2 positive BC. Methods: Primary objective of the study was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Preoperative treatment included DLNP (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Patients (pts) were scheduled to receive adjuvant trastuzumab (8 mg/mq loading dose, then 6 mg/mq iv) every 3 weeks for 12 cycles and radiation and hormonal therapy according to guidelines. Results: From December 2005 to September 2011, 43 pts were treated at 3 centers in Italy. 39 out of 43 pts were evaluable for the purpose of the study. Median age was 53 years (range: 31-78). The majority of pts had cT2 (63%), grade 3 (93%), N+ (77%) ER positive (56%) and MIB-1 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. The histological regression score (Von Minckwitz G, J Clin Oncol 2012) is shown in the Table. A significant correlation between MIB-1 ≥20% at baseline and pCR was observed (p=0.018). Pts with pCR had a time to response (29.4 weeks, 95% CI 28-31) lower than pts without pCR (32.9 weeks, 95% CI 27-39). No cardiac toxicity or discontinuation of trastuzumab was reported. After a median follow-up of 30 months only 2 pts relapsed, both with pCR. Conclusions: This study confirms the high activity of trastuzumab combined with chemotherapy based on anthracyclines and taxanes as primary treatment for HER2 positive BC. DLNP is an active and safe option to minimize cardiotoxicity. [Table: see text]

Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5 FU) and cisplatin for locally advanced resectable esophageal cancer: A retrospective study.

119 Background: Neoadjuvant CCRT has become the standard treatment for esophageal cancer. Most clinicians use a conventional cisplatin/5 FU combination which is associated with moderate to severe toxicity. For the last 15 years we have used contiuous low-dose 5-FU combined with two doses of cisplatin. Methods: Between July 1997 and June 2012, 155 patients with locally advanced esophageal cancer (T3 or N1 and higher), received CCRT consistent of cisplatin 75 mg/m2 on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m2/day) on the days of radiation. Results: Median age of patients was 63 year (30-76).Seventeen percent of pts were female and 85% had adenocarcinoma. (3, 34, 86 and 31 pts had stage I, II, III and IVa disease respectively. One hundred and twenty seven pts had N1 disease. Radiation dose (RT) ranged from 45-60 Gy (median 56Gy). Median weight loss was 6.5%. All patients completed treatment. 20% of patients had >=grade 3 toxicity, with 29 patients requiring hospital admission. 53% of patients had surgical resection between 37-149 days following CCRT (median 62 days). R0 resection was achieved in 96% of patients. A pathological complete response was achieved in 38 of 83 pts (45%) who underwent surgical resection. With a median follow up of 26 months (1.2 -144 months), 36% of pts recurred and total of 50% died. Conclusions: Compared to conventional chemotherapy regimen, our CCRT regimen for locally advanced esophageal cancer is well tolerated and associated with a high pathological response rate.

High pathologic response rate of hepatic colorectal cancer metastases (HCRM) following neoadjuvant bevacizumab (Bev)-based treatment (tx).

529 Background: Pathologic response of HCRM to neoadjuvant tx is associated to better outcome. In retrospective analyses Bev-based tx improved tumor regression grade (TRG), while cetuximab (Cmab) increased RECIST response and R0 resections in prospective studies. The aim of this analysis was to assess the effect of Bev vs Cmab-based tx in terms of HCRM pathological response and outcome. Methods: Fifty-eight pts with HCRM were resected at National cancer Institute of Milan from 2007 to 2012 following Bev (n=30) or Cmab (n=28) based neoadjuvant tx. Pathological response was classified from TRG 1 for pathological complete response (pCR), to TRG5 for no response; TRG 1-3, for histological response; TRG 4-5 for scarce/no response (Rubbia-Brandt L, Ann Oncol 2007). Results: KRAS missing in 9 pts (3 Bev/6 Cmab), mutated in 18 pts (60%) in Bev vs 4 (14%) in Cmab group.Median number of resected metastases: 4.6 vs 3.9; mean TRG: 2.9 (2.2-4) in Bev vs 3.8 (3-5) in Cmab group (p=0.04 at Kruskal-Wallis test). Pathological response rate was higher for Bev vs Cmab (70% vs 39%; p=0.037 at Chi-square test). Bev also increased pCRs (20% vs 0%, p=0.024 at Fisher’s test). With generalized estimating equation for all resected nodules, mean TRG was lower in Bev vs Cmab group: 2.6 (2-4) vs 3.7 (3-4), p<0.001. At univariate analysis, no PFS and OS difference was observed according to tx. Multivariable Cox models shown below: Conclusions: Bev-based tx obtained an excellent pathological response rate, despite the high proportion of KRAS mutated tumors, and further prospective confirmation of these data is planned. [Table: see text]

Phase II trial on neoadjuvant intravenous and trans-uterine arterial chemotherapy for locally advanced bulky cervical adenocarcinoma

ObjectiveA phase II trial on neoadjuvant trans-uterine arterial chemotherapy (TUAC) followed by type III radical hysterectomy (RH) was conducted for patients with bulky cervical adenocarcinoma (AC). MethodsTumors of >4cm were eligible. The neoadjuvant regimen comprised paclitaxel (60mg/m2 intravenously on days 1, 8, and 15) and cisplatin (70mg/m2 TUAC followed by transcatheter embolization with gelatin sponge particles on day 2) repeated every 3weeks for 3cycles. The primary endpoints were clinical and pathological responses. ResultsTwenty-two patients (median age, 51years; range, 33–75years) were enrolled. The International Federation of Gynecology and Obstetrics stages were IB2 (9 patients), IIA–IIB (8), IIIB (3), and IVA (2). The adeno/adenosquamous ratio was 16/6. The overall clinical response rate was 95.4% (95% confidence interval [CI], 86.7–100%). RH was completed in 19 patients (86%), including 2 stage IVA patients who underwent anterior or posterior pelvic exenteration. Of the 19 patients, no residual malignant cells were found pathologically in 4; thus, the pathological complete response rate was 18% (4/22). No patients experienced grade 4 thrombocytopenia or febrile neutropenia or required platelet transfusions. The 5-year progression-free survival and overall survival rates in stages IB2–IIB were 70.0% (95%CI, 48.1–92.1%) and 69.5% (95%CI, 47.0–92.0%), respectively. The 2 patients with stage IVA tumors were alive without recurrence for 72 and 84months after enrollment. ConclusionsTUAC showed high clinical and pathological response rates. TUAC is promising for stage IB2–IIB and IVA bulky AC.

Concurrent chemo-radiotherapy in the treatment of early breast cancer: Current status

Concurrent chemo-radiotherapy (CCRT) in early cancer was investigated by few authors and remains controversial. This treatment is more commonly used for locally advanced cancer and showed high rate of complete pathological response. A search of articles published in English literature, between 1980 and November 2012, was conducted on Medline using the following terms: breast cancer, chemotherapy, radiotherapy, and Trastuzumab. We identified five phase I/II trials and three randomized phase three trials evaluating concurrent chemoradiotherapy in the adjuvant of cancer. In patients with early cancer having positive lymph nodes, phases III clinical trials showed that CCRT improved local control after conservative surgery. However, these randomized trials used non-standard regimen: Cyclophosphamide, methotrexate and fluorouracil (CMF) or fluorouracil, mitoxantrone and cyclophosphamide (FNC). In addition, in phases II clinical trials, concurrent use of taxanes and anthracycline with standard whole-breast irradiation showed high rate of toxicity: Pulmonary toxicity with taxane; and cardiac and skin toxicity with anthracycline. Consequentely, CCRT is not be used in practice because of concerns of toxicity with the standard drugs (anthracyclines and taxanes) and radiation. Anthracyclines with partial irradiation (PBI) was feasible according to one phase I clinical trial, and should be investigated in randomized clinical trials. Concurrent Trastuzumab plus radiotherapy is safe and can be used in HER2-positive cancer; in this case, cardiac volume sparing and patient selections for internal mammary chain irradiation are highly recommended. The present paper aimed to review the current data evaluating the efficacy and safety of CCRT in early cancer.

Neoadjuvant therapy with weekly docetaxel and cisplatin, 5‐fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long‐lasting pathological complete response

This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5-fluorouracil (5-FU) and concomitant radiotherapy (RT) in untreated stage II-III adenocarcinoma and squamous cell carcinoma of mid-distal thoracic esophagus. The schedule consisted of a first phase of chemotherapy alone and of a second phase of concurrent chemoradiation. Doses were as follows: docetaxel 35 mg/m(2) and cisplatin 25 mg/m(2) on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5-FU c.i. (180 mg/m(2) on days 1-21 and 150 mg/m(2) on days 29-63); RT (50 Gy) started at day 29. Surgery was planned 6 to 8 weeks after the completion of chemoradiation. A total of 74 patients were enrolled; pathological complete remission (pCR) was found in 47% (35 of 74) and near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) (pnCR) in 15% of the patients (11 of 74). Grade 3-4 neutropenia, nonhematological toxicity, and toxic deaths occurred in 13.5%, 32.4%, and 4% of the patients, respectively. Median follow-up was 55 months (range, 3-108 months). Median survival of all 74 patients was 55 months, whereas it was not reached in the pCR subset. The 3- and 5-year survival rates were, respectively, 83% and 77% for pCR, 73% and 44% for pnCR, and 21% and 14% for Residual Tumor subsets (P < .001). This study shows that 1) this intensive weekly schedule produced a high pathological response rate, 2) responders had high and long-term durable survival rates.

A DNA Repair BRCA1 Estrogen Receptor and Targeted Therapy in Breast Cancer

BRCA1 is a key mediator of DNA repair pathways and participates in the maintenance of the genomic integrity of cells. The control of DNA damage repair mechanisms by BRCA1 is of great interest since molecular defects in this pathway may reflect a predictive value in terms of a cell’s sensitivity to DNA damaging agents or anticancer drugs. BRCA1 has been found to exhibit a hormone-dependent pattern of expression in breast cells. Wild-type BRCA1 is required for the inhibition of the growth of breast tumor cells in response to the pure steroidal ERα antagonist fulvestrant. Also a loss of BRCA1-mediated transcriptional activation of ERα expression results in increased resistance to ERα antagonists. Platinum-based drugs, poly(ADP-ribose) polymerase (PARP) inhibitors, and their combination are currently included in chemotherapy regimens for breast cancer. Preclinical and clinical studies in a BRCA1-defective setting have recently indicated a rationale for the use of these compounds against hereditary breast cancers. Initial findings indicate that neoadjuvant use of cisplatin results in high rates of complete pathological response in patients with breast cancer who have BRCA1 mutations. Cisplatin produces a better response in triple-negative breast cancer (TNBC) than in non-TNBC diseases in both the neoadjuvant and adjuvant settings. This implies that TNBC cells may harbor a dysfunctional BRCA1 repair pathway.