Long-term outcomes of neoadjuvant immunotherapy plus chemotherapy in patients with early-stage triple-negative breast cancer: an extracted individual patient data and trial-level meta-analysis.

BACKGROUND: Neoadjuvant immunotherapy (nIO) has emerged as a treatment option for stage II-III triple-negative breast cancer (TNBC). While randomised clinical trials (RCTs) demonstrated pathological complete response rate benefit to nIO added to chemotherapy, additional data on long-term outcomes is warranted. We performed this analysis to evaluate long-term efficacy outcomes of nIO in TNBC. METHODS: We searched databases for RCTs evaluating nIO in early-stage TNBC. A meta-analysis of extracted individual patient data (EIPD) was performed to evaluate EFS and OS, with data from reported Kaplan-Meier plots. Additionally, we conducted a trial-level meta-analysis using fixed and random effects models. RESULTS: The literature search resulted in four included RCTs with available EFS or OS (KEYNOTE-522, IMpassion031, I-SPY2 and GeparNuevo). EIPD showed that the addition of nIO to chemotherapy provides statistically significant benefits in EFS (HR 0.62, 0.50-0.76; p < 0.001) and OS (HR 0.62, 0.46-0.82, p < 0.001). Number needed to treat to avoid one EFS or OS event in 4 years was 9 and 14, respectively. Trial-level meta-analysis yielded similar results (EFS: HR 0.64, 0.51-0.79; OS: 0.57, 0.37-0.89). CONCLUSIONS: Results show that nIO combined with chemotherapy can provide significant EFS and OS benefits, supporting its use as standard treatment for early-stage TNBC.

Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial.

BACKGROUND: Dual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB's end-of study analyses aimed to evaluate the long-term efficacy and safety of pertuzumab plus trastuzumab and chemotherapy for previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer. METHODS: Eligible patients were randomized 1:1 to pertuzumab/placebo plus trastuzumab and chemotherapy every 3 weeks. PRIMARY ENDPOINT: overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. RESULTS: The intention-to-treat population comprised 388 patients in the pertuzumab arm and 392 in the placebo arm. The safety population comprised 385 and 388 patients, respectively. Median follow-up was ≥ 44.4 months. Median OS was increased by 3.9 months (hazard ratio 0.85 [95% confidence intervals, 0.72-0.99]) and median PFS by 1.3 months (hazard ratio 0.73 [95% confidence intervals, 0.62-0.85]) in the pertuzumab vs. the placebo arm. ORR was numerically higher (57.0% vs. 48.6%) and median DoR 1.8 months longer with pertuzumab treatment. There was a trend for more favorable hazard ratios in certain subgroups related to HER2 amplification/overexpression. Safety was comparable between arms, except for serious and grade 3-5 adverse events, and any-grade diarrhea, which were more frequent with pertuzumab. CONCLUSIONS: JACOB did not meet its primary endpoint. Nonetheless, the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up. Trial registration NCT01774786; https://clinicaltrials.gov/ct2/show/NCT01774786 .

Outcomes of Patients With Local Regrowth After Nonoperative Management of Rectal Cancer After Neoadjuvant Chemoradiotherapy.

BACKGROUND: Clinical complete responders after chemoradiation for rectal cancer are increasingly being managed by a watch-and-wait strategy. Nonetheless, a significant proportion will experience a local regrowth, and the long-term oncological outcomes of these patients is not totally known. OBJECTIVE: The purpose of this study was to analyze the outcomes of patients who submitted to a watch-and-wait strategy and developed a local regrowth, and to compare these results with sustained complete clinical responders. DESIGN: This was a retrospective study. SETTING: Single institution, tertiary cancer center involved in alternatives to organ preservation. PATIENTS: Patients with a biopsy-proven rectal adenocarcinoma (stage II/III or low lying cT2N0M0 at risk for an abdominoperineal resection) treated with chemoradiation who were found at restage to have a clinical complete response. INTERVENTIONS: Rectal cancer patients treated with chemoradiation who underwent a watch-and-wait strategy (without a full thickness local excision) and developed a local regrowth were compared to the remaining patients of the watch-and-wait strategy. MAIN OUTCOME MEASURES: Overall survival between groups, incidence of regrowth' and results of salvage surgery. RESULTS: There were 67 patients. Local regrowth occurred in 20 (29.9%) patients treated with a watch-and-wait strategy. Mean follow-up was 62.7 months. Regrowth occurred at mean 14.2 months after chemoradiation, half of them within the first 12 months. Patients presented with comparable initial staging, lateral pelvic lymph-node metastasis, and extramural venous invasion. The regrowth group had a statistically nonsignificant higher incidence of mesorectal fascia involvement (35.0% vs 13.3%, p = 0.089). All regrowths underwent salvage surgery, mostly (75%) a sphincter-sparing procedure. 5-year overall survival was 71.1% in patients with regrowth and 91.1% in patients with a sustained complete clinical response (p = 0.027). LIMITATIONS: This study was limited by its retrospective evaluation of patient selection for a watch-and-wait strategy and outcomes, as well as its small sample size. CONCLUSIONS: Local regrowth is a frequent event when following a watch-and-wait policy (29.9%); however, patients could undergo salvage surgical treatment with adequate pelvic control. In this series, overall survival showed a statistically significant difference from patients managed with a watch-and-wait strategy who experienced a local regrowth compared to those who did not. See Video Abstract at http://links.lww.com/DCR/B773.RESULTADOS DE LOS PACIENTES CON REBROTE LOCAL, DESPUÉS DEL MANEJO NO QUIRÚRGICO DEL CÁNCER DE RECTO, DESPUÉS DE LA QUIMIORRADIOTERAPIA NEOADYUVANTEANTECEDENTES:Los respondedores clínicos completos, después de la quimiorradiación para el cáncer de recto, se tratan cada vez más mediante una estrategia de observación y espera. No obstante, una proporción significativa experimentará un rebrote local y los resultados oncológicos a largo plazo de estos pacientes, no se conocen por completo.OBJETIVO:El propósito de este estudio, fue analizar los resultados de los pacientes sometidos a una estrategia de observación y espera, que desarrollaron un rebrote local, y comparar estos resultados con respondedores clínicos completos sostenidos.DISEÑO:Este fue un estudio retrospectivo.ENTORNO CLINICO.Institución única, centro oncológico terciario involucrado en alternativas a la preservación de órganos.PACIENTES:Pacientes con un adenocarcinoma de recto comprobado por biopsia (estadio II / III o posición baja cT2N0M0, en riesgo de resección abdominoperineal), tratados con quimiorradiación, y que durante un reestadiaje, presentaron una respuesta clínica completa.INTERVENCIONES:Los pacientes con cáncer de recto tratados con quimiorradiación, sometidos a una estrategia de observación y espera (sin una escisión local de espesor total) y que desarrollaron un rebrote local, se compararon con los pacientes restantes de la estrategia de observación y espera.PRINCIPALES MEDIDAS DE VALORACION:Supervivencia global entre los grupos, incidencia de rebrote y resultados de la cirugía de rescate.RESULTADOS:Fueron 67 pacientes. El rebrote local ocurrió en 20 (29,9%) pacientes tratados con una estrategia de observación y espera. El seguimiento medio fue de 62,7 meses. El rebrote se produjo a la media de 14,2 meses después de la quimiorradiación, la mitad de ellos dentro de los primeros 12 meses. Los pacientes se presentaron con una estadificación inicial comparable, metástasis en los ganglios linfáticos pélvicos laterales e invasión venosa extramural. El grupo de rebrote tuvo una mayor incidencia estadísticamente no significativa de afectación de la fascia mesorrectal (35,0 vs 13,3%, p = 0,089). Todos los rebrotes se sometieron a cirugía de rescate, en su mayoría (75%) con procedimiento de preservación del esfínter. La supervivencia global a 5 años fue del 71,1% en pacientes con rebrote y del 91,1% en pacientes con una respuesta clínica completa sostenida (p = 0,027).LIMITACIONES:Evaluación retrospectiva de la selección de pacientes para una estrategia y resultados de observar y esperar, tamaño de muestra pequeño.CONCLUSIONES:El rebrote local es un evento frecuente después de la política de observación y espera (29,9%), sin embargo los pacientes podrían someterse a un tratamiento quirúrgico de rescate con un adecuado control pélvico. En esta serie, la supervivencia global mostró una diferencia estadísticamente significativa de los pacientes manejados con una estrategia de observación y espera que experimentaron un rebrote local, en comparación con los que no lo hicieron. Consulte Video Resumen en http://links.lww.com/DCR/B773. (Traducción-Dr. Fidel Ruiz Healy).

Feasibility of SBRT for hepatocellular carcinoma in Brazil - a prospective pilot study.

BACKGROUND: The aim of the study was to evaluate the feasibility and safety of stereotactic body radiotherapy (SBRT) for the treatment of hepatocellular carcinoma in Brazil. SBRT is an evolving treatment in HCC patients not candidates to other local therapies. Its adoption in clinical practice has been heterogeneous, with lack of data on its generalizability in the Brazilian population. MATERIALS AND METHODS: We conducted a prospective pilot study involving HCC patients after failure or ineligibility for transarterial chemoembolization. Patients received SBRT 30 to 50 Gy in 5 fractions using an isotoxic prescription approach. This study is registered at clinicaltrials.gov NCT02221778. RESULTS: From Nov 2014 through Aug 2019, 26 patients received SBRT with 40 Gy median dose. Underlying liver disease was hepatitis C, hepatitis B and alcohol-related in, respectively, 50%, 23% and 19% of patients. Median lesion size was 3.8 cm (range, 1.5-10 cm), and 46% had multiple lesions. Thirty-two percent had tumor vascular thrombosis; median pretreatment alpha-fetoprotein (AFP) was 171.7 ng/mL (range, 4.2-5,494 ng/mL). 1y-local progression-free survival (PFS) was 86% (95% CI: 61% to 95%), with higher local control in doses ≥ 45Gy (p = 0.037; HR = 0.12). 1y-liver PFS, distant PFS and OS were, respectively, 52%, 77% and 79%. Objective response was seen in 89% of patients, with 3 months post-SBRT median AFP of 12 ng/mL (2.4-637 ng/mL). There were no grade 3 or 4 clinical toxicities. Grade 3 or 4 laboratory toxicities occurred in 27% of patients. CONCLUSION: SBRT is feasible and safe in patients unresponsive or ineligible for TACE in Brazil. Our study suggests doses ≥ 45 Gy yields better local control.

Adjuvant Treatment with 5-Fluorouracil and Oxaliplatin Does Not Influence Cardiac Function, Neurovascular Control, and Physical Capacity in Patients with Colon Cancer.

BACKGROUND: Adjuvant chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin increases recurrence-free and overall survival in patients with colon adenocarcinoma. It is known that these drugs have been associated with cardio- and neurotoxicity. We investigated the effects of 5-FU ± oxaliplatin on cardiac function, vascular responses, neurovascular control, and physical capacity in patients with colon cancer. METHODS: Twenty-nine patients with prior colectomy for stage II-III adenocarcinoma and clinical indication for adjuvant chemotherapy were allocated to receive 5-FU (n = 12) or 5-FU + oxaliplatin (n = 17), according to the oncologist's decision. All the analyses were performed just before and after the end of chemotherapy. Cardiac function was assessed by echocardiography and speckle tracking, and cardiac autonomic control was assessed by heart rate variability (HRV). Vascular endothelial function was assessed by flow-mediated dilation (FMD). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique, and muscle blood flow by venous occlusion plethysmography. Physical capacity was evaluated by cardiopulmonary exercise test. RESULTS: Chemotherapy (pooled data) did not significantly change left ventricular ejection fraction (58 ± 1 vs. 55 ± 2%, p = .14), longitudinal strain (-18 ± 1 vs. -18 ± 1%, p = .66), and HRV. Likewise, chemotherapy did not significantly change FMD, muscle blood flow, and MSNA (33 ± 2 vs. 32 ± 1 bursts/min, p = .31). Physical capacity was not significantly changed in both groups. Similar findings were observed when the patients were subdivided in 5-FU and 5-FU + oxaliplatin treatment groups. 5-FU and 5-FU + oxaliplatin did not significantly change cardiac function, HRV, vascular responses, MSNA, and physical capacity. CONCLUSION: This study provides evidence that adjuvant treatment with 5-FU ± oxaliplatin is well tolerated and does not promote changes compatible with long-term cardiotoxicity. IMPLICATIONS FOR PRACTICE: Adjuvant chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin increases recurrence-free and overall survival in patients with colon adenocarcinoma; however, these drugs have been associated with cardio- and neurotoxicity. This study investigated the effects of these drugs on cardiac function, vascular responses, neurovascular control, and physical capacity in patients with colon cancer. It was found that 5-FU and oxaliplatin did not significantly change cardiac function, cardiac autonomic control, vascular endothelial function, muscle sympathetic nerve activity, and physical capacity. This study provides evidence that adjuvant treatment with 5-FU ± oxaliplatin is well tolerated and does not promote changes compatible with long-term cardiotoxicity.

Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype?

BACKGROUND: Gastric cancer (GC) has been defined in distinct molecular subtypes with different therapeutic implications. However, its clinical significance and prognosis regarding standard chemotherapy (CMT) remains unclear. This study aimed to analyze the impact of perioperative or adjuvant treatment among subtypes of GC. METHODS: We retrospectively evaluated all stage II/III patients with GC who underwent a curative gastrectomy. Based on immunohistochemistry and in situ hybridization techniques, GC was classified into five subtypes: Epstein-Barr virus (EBV) positive, microsatellite instability (MSI), e-cadherin aberrant, p53-aberrant, and p53-normal. RESULTS: Among the 178 CG included, 111 patients received CMT and 67 were treated with surgery alone. Survival analysis showed that p53-aberrant GC treated with CMT had better disease-free survival (DFS) compared with surgery alone (P = .001).There was no significant difference in DFS between patients who received CMT and those with surgery alone for EBV, MSI, E-cadherin, and p53-normal GC. An improvement in overall survival was observed only for E-cadherin (P = .001) and p53-aberrant (P < .001) patients who received CMT. CONCLUSIONS: CMT showed different impact on the survival of CG according to the molecular subtype. No survival benefit was observed for EBV and MSI groups who received CMT. GC with p53-aberrant had a significant benefit in survival with standard therapy.

Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial.

BACKGROUND: Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy-naïve chemotherapy-refractory advanced colorectal cancer. PATIENTS AND METHODS: This single-center, single-arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy-naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4-week cycle. The primary endpoint was progression-free survival (PFS) rate at week 8. RESULTS: Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1-64.3); median PFS was 3.5 months (95% CI, 1.8-3.6). Median OS was 7.4 months (95% CI, 5.3-8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib-related grade ≥3 adverse events were hypertension (36%), hand-foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib-related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0-1 (5.4 months). CONCLUSION: These findings support the antitumor activity of regorafenib in antiangiogenic-naïve patients with chemotherapy-refractory mCRC. IMPLICATIONS FOR PRACTICE: The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment-refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single-center, single-arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic-naïve patients with chemotherapy-refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand-foot skin reaction.

Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer.

The purpose of the present study was to test the hypothesis that doxorubicin (DX) and cyclophosphamide (CY) adjuvant chemotherapy (CHT) acutely impairs neurovascular and hemodynamic responses in women with breast cancer. Sixteen women (age: 47.0 ± 2.0 yr; body mass index: 24.2 ± 1.5 kg/m) with stage II-III breast cancer and indication for adjuvant CHT underwent two experimental sessions, saline (SL) and CHT. In the CHT session, DX (60 mg/m2) and CY (600 mg/m2) were administered over 45 min. In the SL session, a matching SL volume was infused in 45 min. Muscle sympathetic nerve activity (MSNA) from peroneal nerve (microneurography), calf blood flow (CBF; plethysmography) and calf vascular conductance (CVC), heart rate (HR; electrocardiography), and beat-to-beat blood pressure (BP; finger plethysmography) were measured at rest before, during, and after each session. Venous blood samples (5 ml) were collected before and after both sessions for assessment of circulating endothelial microparticles (EMPs; flow cytometry), a surrogate marker for endothelial damage. MSNA and BP responses were increased (P < 0.001), whereas CBF and CVC responses were decreased (P < 0.001), during and after CHT session when compared with SL session. Interestingly, the vascular alterations were also observed at the molecular level through an increased EMP response to CHT (P = 0.03, CHT vs. SL session). No difference in HR response was observed (P > 0.05). Adjuvant CHT with DX and CY in patients treated for breast cancer increases sympathetic nerve activity and circulating EMP levels and, in addition, reduces muscle vascular conductance and elevates systemic BP. These responses may be early signs of CHT-induced cardiovascular alterations and may represent potential targets for preventive interventions. NEW & NOTEWORTHY It is known that chemotherapy regimens increase the risk of cardiovascular events in patients treated for cancer. Here, we identified that a single cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide in women treated for breast cancer dramatically increases sympathetic nerve activity and circulating endothelial microparticle levels, reduces the muscle vascular conductance, and elevates systemic blood pressure.

Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study.

BACKGROUND: Adding pertuzumab to trastuzumab and chemotherapy improves survival in HER2-positive early breast cancer and metastatic breast cancer. We assessed the efficacy and safety of pertuzumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic gastric or gastro-oesophageal junction cancer. METHODS: JACOB was a double-blind, placebo-controlled, randomised, multicentre, phase 3 trial in patients aged 18 years or older with HER2-positive metastatic gastric or gastro-oesophageal junction cancer. Eligible patients had measurable or evaluable non-measurable disease at baseline, Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of 55% or more. Patients at 197 oncology clinics (in 30 countries) were randomly assigned (1:1) to receive either pertuzumab (840 mg intravenously) or placebo every 3 weeks, with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks intravenously), plus chemotherapy (cisplatin 80 mg/m2 every 3 weeks intravenously, oral capecitabine 1000 mg/m2 twice a day [2000 mg/m2 every 24 h] for 28 doses every 3 weeks, or 5-fluorouracil 800 mg/m2 every 24 h intravenously [120 h continuous infusion] every 3 weeks). Randomisation was by a central permuted block randomisation scheme (block size of 4) with an interactive voice or web response system, stratified by geographical region, previous gastrectomy, and HER2 positivity. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with Clinicaltrials.gov, number NCT01774786 (ongoing, but closed to enrolment). FINDINGS: Between June 10, 2013, and Jan 12, 2016, of 3287 patients assessed, 780 eligible patients were randomly assigned to receive either pertuzumab plus trastuzumab and chemotherapy (pertuzumab group, n=388) or placebo plus trastuzumab and chemotherapy (control group, n=392). Median duration of follow-up was 24·4 months (95% CI 22·3-26·1) in the pertuzumab group and 25·0 months (22·3-28·9) in the control group. After 242 deaths in the pertuzumab group and 262 deaths in the control group (the study was not stopped at this point), overall survival was not significantly different between treatment groups (median overall survival 17·5 months [95% CI 16·2-19·3] in the pertuzumab group and 14·2 months [12·9-15·5] in the control group; hazard ratio 0·84 [95% CI 0·71-1·00]; p=0·057). Serious adverse events occurred in 175 (45%) of 385 patients in the pertuzumab group and 152 (39%) of 388 patients in the control group. Diarrhoea was the most common serious adverse event in both groups (17 [4%] patients in the pertuzumab group vs 20 [5%] patients in the control group). The most common grade 3-5 adverse events were neutropenia (116 [30%] patients in the pertuzumab group vs 108 [28%] patients in the control group), anaemia (56 [15%] vs 65 [17%]), and diarrhoea (51 [13%] vs 25 [6%]). Treatment-related deaths occurred in seven (2%) patients in the control group; no treatment-related deaths occurred in the pertuzumab group. INTERPRETATION: Adding pertuzumab to trastuzumab and chemotherapy did not significantly improve overall survival in patients with HER2-positive metastatic gastric or gastro-oesophageal junction cancer compared with placebo. Further studies are needed to identify improved first-line treatment options in these types of cancer and to identify patients with HER2-driven tumours who might benefit from dual HER2-targeted therapy. FUNDING: F. Hoffmann-La Roche Ltd.

Return to work after breast cancer diagnosis: An observational prospective study in Brazil.

BACKGROUND: In North America and Europe, return-to-work (RTW) rates vary among breast cancer (BC) survivors, from 24% to 66% and from 53% to 82% at 6 and 36 months after diagnosis, respectively. To date, there is a lack of data on RTW rates after BC diagnosis in Latin America. Therefore, the primary objectives of this study were to define RTW rates at 12 and 24 months after BC diagnosis and to identify the factors associated with RTW in this population. METHODS: In total, 125 employed women from a single institution with newly diagnosed BC were interviewed by telephone at 6, 12, and 24 months after diagnosis. Those who had inoperable or metastatic disease were excluded. RESULTS: Overall, RTW rates were 30.3% and 60.4% at 12 and 24 months after BC diagnosis, respectively. Most women reported that they received support from their employer, but only 29.1% reported having been offered work adjustments. In multivariate analysis, the factors associated with positive RTW outcomes included higher household income (odds ratio [OR], 17.76; 95% confidence interval [CI], 3.33-94.75; P = .001), breast-conserving surgery (OR, 9.77; 95% CI, 2.03-47.05; P = .004), and work adjustments (OR, 37.62; 95% CI, 2.03-47.05; P = .004). The factors associated with negative RTW outcomes included adjuvant endocrine therapy (OR, 0.11; 95% CI, 0.02-0.74; P = .023), and depression diagnosed after BC (OR, 0.07; 95% CI, 0.01-0.63; P = .017). CONCLUSIONS: RTW rates in the current study were lower than those observed in developed countries but similar to the rates among low-income Americans. Workplace adjustments, higher income, breast-conserving surgery, endocrine therapy, and depression after BC played an important role in the RTW decision.

Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib.

BACKGROUND: Before the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib. METHODS: A database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model. RESULTS: Forty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 - 9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3-4 in 44.4% of the patients. CONCLUSION: In accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression.

Chemoradiotherapy versus chemotherapy as adjuvant treatment for localized gastric cancer: a propensity score-matched analysis.

BACKGROUND: Treatment of localized gastric cancer (LGC) consists of surgical resection followed by adjuvant treatment. Both chemoradiation (CRT) and chemotherapy (CT) regimens have shown benefit in survival outcomes versus observation. However, there are few data comparing these approaches. METHODS: This study included consecutive patients with LGC treated at Instituto do Cancer do Estado de Sao Paulo (ICESP) from 2012 to 2015. CRT was based on the INT-0116 regimen and CT consisted of a platinum and fluoropyrimidine doublet. Treatment choice was based on physician preference. Toxicity was evaluated for every cycle. Overall survival (OS) analysis was performed by Kaplan-Meier. A propensity score-matched analysis was performed to minimize selection bias. RESULTS: A total of 309 patients were evaluated, 227 in CRT group and 82 in CT group. The most prevalent grade 3/4 toxicities in CRT and CT groups were: nausea/vomiting (9.25 vs 4.9%), fatigue (9.3% vs 2.4%), mucositis (4.4% vs 1.2%), neutropenia (37.8% vs 20.9%), febrile neutropenia (3.9% vs 0%), anemia (4.3% vs 6.1%), thrombocytopenia (2.6% vs 4.9%), neuropathy (0 vs 2.4%) and hand-foot syndrome (0.4% vs 2.4%). Two grade 5 toxicities (febrile neutropenia and anemia) occurred in CRT group. There was no difference in the pattern of recurrence. After a median follow-up of 23.5 months (CRT) and 20.6 months (CT), there was no difference in OS between groups. CONCLUSIONS: CT and CRT present similar efficacy and tolerability as adjuvant treatment for LGC.

Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial.

LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. METHODS: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. RESULTS: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.

The Rising Incidence of Younger Patients With Colorectal Cancer: Questions About Screening, Biology, and Treatment.

OPINION STATEMENT: Colorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.

The Impact of Early Dermatologic Events in the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib.

BACKGROUND AND AIMS: The presence of dermatologic reaction as an adverse event to sorafenib treatment in patients with unresectable hepatocellular carcinoma has been indicated as a prognostic factor for survival in a recent prospective analysis. To date, this is the only clinical predictor of treatment response, which can be evaluated earlier in the treatment and, therefore, contribute to a better and more individualized patient management. MATERIAL AND METHODS: This retrospective study included 127 patients treated with sorafenib under real-life practice conditions in two hepatology reference centers in Brazil. Demographic data, disease/medical history and time of sorafenib administration as well as adverse events related to the medication were recorded in a database. RESULTS: Cirrhosis was present in 94% of patients, 85.6% were Child-Pugh A, 80.3%BCLC-C, 81% had vascular invasion and/or extrahepatic spread and 95% had a performance status 0 to 1.The median duration of treatment was 10.1 months (range: 0.1-47 months).The most common adverse event within the first 60 days of treatment were diarrhea (62.2%) and dermatological reaction (42%).The median overall survival for the cohort was 20 months, and it was higher for patients who developed dermatological reactions within the first 60 days compared to those who did not present this adverse event. CONCLUSION: This retrospective analysis showed the use of sorafenib in patients selected according to BCLC staging, and it is the first external validation of early dermatologic adverse events as a predictor of overall survival in patients with advanced hepatocellular carcinoma.

Pathologic Complete Response in Rectal Cancer: Can We Detect It? Lessons Learned From a Proposed Randomized Trial of Watch-and-Wait Treatment of Rectal Cancer.

BACKGROUND: Chemoradiotherapy has the potential to downsize and downstage tumors before surgery, decrease locoregional recurrence, and induce a complete sterilization of tumor cells for middle and low locally advanced rectal cancer. A watch-and-wait tactic has been proposed for patients with clinical complete response. OBJECTIVE: The purpose of this study was to verify our ability to identify complete clinical response in patients with rectal cancer based on clinical and radiologic criteria. DESIGN: This was a prospective study. SETTINGS: The study was conducted at a single institution, in the setting of a watch-and-wait randomized trial. PATIENTS: Consecutive patients with stage T3 to T4N0M0 or T(any)N+M0 cancer located within 10 cm from anal verge or T2N0 within 7 cm from anal verge were included in the study. Patients were staged and restaged 8 weeks after completion of chemoradiation (5-fluorouracil, 5040 cGy) by digital examination, colonoscopy, pelvic MRI, and thorax and abdominal CT scans. MAIN OUTCOME MEASURES: Clinical and radiologic judgments of tumor response were compared with pathologic response of patients treated by total mesorectal excision or clinical follow-up of patients selected for nonoperative treatment. RESULTS: A total of 118 patients were treated. Six patients were considered clinic complete responders (2 randomly assigned for surgery (1 ypT0N0 and 1 ypT2N0) and 4 patients randomly assigned for observation (3 sustained clinic complete response and 1 had tumor regrowth)). The 112 clinic incomplete responders underwent total mesorectal excision, and 18 revealed pathologic complete response. These 18 patients were not considered complete responders at restaging because they presented at least 1 of the following conditions: mucosal ulceration and/or deformity and/or substenosis of rectal lumen at digital rectal examination and colonoscopy (n = 16), ymrT1 to T4 (n = 16), ymrN+ (n = 2), involvement of circumferential resection margin on MRI (n = 3), extramural vascular invasion on MRI (n = 4), MRI tumor response grade 2 to 4 (n = 15), and pelvic side wall lymph node involvement on MRI (n = 1). Sensitivity for identification of ypT0N0 or sustained clinic complete response was 18.2%. LIMITATIONS: This study has a short follow-up and small sample size. Radiologists who reviewed the restaging examination were not blinded to the pretreatment stage. Only 1 radiologist read the images of each patient. CONCLUSIONS: Evaluation of clinic complete response according to current adopted criteria has low sensitivity because pathologic complete response more frequently presented as clinic incomplete response (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A221).

The impact of complete chemotherapy stop on the overall survival of patients with advanced colorectal cancer in first-line setting: A meta-analysis of randomized trials.

BACKGROUND: The impact of the duration of chemotherapy on the overall survival of patients with metastatic colorectal cancer (mCRC) is controversial and studies have failed to define a clear standard. METHODS: We searched medical literature databases and oncology conferences proceedings for randomized controlled trials (RCT) that compared the overall survival of mCRC patients who received continuous first-line chemotherapy until disease progression versus those who were offered complete treatment stop after a fixed number of cycles. Studies including targeted agents were also included. A meta-analysis of reported hazard ratios (HRs) for survival was performed. RESULTS: We retrieved 240 trials, of which six were eligible and five were included in the pooled analysis of overall survival (N = 3061). The overall survival between continuously delivered chemotherapy and complete stop was not statistically different (HR = 0.93, 95% CI 0.85-1.02; p = 0.12; I² = 5%). The results are similar when we analyzed separately the trials performing randomization before versus after induction therapy. The median chemotherapy free interval in the complete stop group was 3.9 months (3.6-4.3 months). Chemotherapy administered until progression was associated with more adverse effects and impaired quality of life. CONCLUSION: Compared with first-line continuous chemotherapy administered until disease progression, complete treatment stop did not have a detrimental impact on the overall survival of patients with mCRC. Identification of predictive biomarkers could help clinicians to select the patients who would benefit from continuous cancer-directed therapies.