Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: Comprehensive biomarker testing is essential in selecting optimal treatment for patients with metastatic colorectal cancer (mCRC); however, incomplete genotyping is widespread, with most patients not receiving testing for all guideline-recommended biomarkers, in part due to reliance on burdensome sequential tissue-based single-biomarker tests with long waiting times or availability of only archival tissue samples. We aimed to demonstrate that liquid biopsy, associated with rapid turnaround time (TAT) and lower patient burden, effectively identifies guideline-recommended biomarkers in mCRC relative to standard of care (SOC) tissue testing. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mCRC undergoing physician discretion SOC tissue genotyping submitted pretreatment blood samples for comprehensive circulating tumor DNA (ctDNA) analysis with Guardant360 and targeted RAS and BRAF analysis with OncoBEAM. RESULTS: Among 155 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 82 patients, versus 88 identified with comprehensive ctDNA (52.9% versus 56.8%, noninferiority demonstrated down to α = 0.005) and 69 identified with targeted PCR ctDNA analysis (52.9% versus 44.5%, noninferiority rejected at α = 0.05). Utilizing ctDNA in addition to tissue increased patient identification for a guideline-recommended biomarker by 19.5% by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives. ctDNA median TAT was significantly faster than tissue testing when the complete process from sample acquisition to results was considered (median 10 versus 27 days, P < 0.0001), resulting in accelerated biomarker discovery, with 52.0% biomarker-positive patients identified by ctDNA versus 10.2% by SOC tissue 10 days after sample collection (P < 0.0001). CONCLUSIONS: Comprehensive ctDNA genotyping accurately identifies guideline-recommended biomarkers in patients with mCRC at a rate at least as high as SOC tissue genotyping, in a much shorter time. Based on these findings, the addition of ctDNA genotyping to clinical practice has significant potential to improve the care of patients with mCRC.

Management of hyperbilirubinaemia in pancreatic cancer patients.

Development of hyperbilirubinaemia is common in patients with advanced pancreatic adenocarcinoma, both at diagnosis as well throughout disease evolution. For this reason, hyperbilirubinaemia determines chemotherapy treatment selection, and therefore it should be considered one of the most relevant conditions. There is very little evidence for the use of chemotherapy in this setting. This article summarises the main causes of hyperbilirubinaemia, how to treat them as well as their differential diagnosis. The current clinical evidence of the available drugs as well as the recommendations of use different combinations in the context of hyperbilirubinaemia are also reviewed.

Neoadjuvant treatment for borderline and resectable pancreatic ductal adenocarcinoma

Nowadays and given the improvement in response rate with the new schemes of treatment with chemotherapy, the interest in neoadjuvant treatment for pancreatic ductal adenocarcinoma, allowing the early application of systemic therapies, has also increased. However, treatment selection fundamentally depends on decisions taken by multidisciplinary committees due to the absence of randomized trials on this indication and because the available evidence is based primarily on small studies. The present manuscript tries to establish recommendations based on the available evidence and expert opinion to correctly select the indication, the type of treatment, as well as its duration and how to correctly follow-up patients during treatment with chemotherapy (AU)

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Neoadjuvant treatment for borderline and resectable pancreatic ductal adenocarcinoma.

Nowadays and given the improvement in response rate with the new schemes of treatment with chemotherapy, the interest in neoadjuvant treatment for pancreatic ductal adenocarcinoma, allowing the early application of systemic therapies, has also increased. However, treatment selection fundamentally depends on decisions taken by multidisciplinary committees due to the absence of randomized trials on this indication and because the available evidence is based primarily on small studies. The present manuscript tries to establish recommendations based on the available evidence and expert opinion to correctly select the indication, the type of treatment, as well as its duration and how to correctly follow-up patients during treatment with chemotherapy.

Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic cancer in Spain.

The management of patients with pancreatic cancer has advanced over the last few years. We convey a multidisciplinary group of experts in an attempt to stablish practical guidelines for the diagnoses, staging and management of these patients. This paper summarizes the main conclusions of the working group. Patients with suspected pancreatic ductal adenocarcinoma should be rapidly evaluated and referred to high-volume centers. Multidisciplinary supervision is critical for proper diagnoses, staging and to frame a treatment plan. Surgical resection together with chemotherapy offers the highest chance for cure in early stage disease. Patients with advanced disease should be classified in treatment groups to guide systemic treatment. New chemotherapeutic regimens have resulted in improved survival. Symptomatic management is critical in this disease. Enrollment in a clinical trial is, in general, recommended.

TTD consensus document on the diagnosis and management of exocrine pancreatic cancer

Exocrine pancreatic cancer (PC) is a very aggressive and heterogeneous tumor with several cellular signaling pathways implicated in its pathogenesis and maintenance. Several risk factors increase the risk of developing PC. Therapeutic strategies used are dictated by the extent of disease. Supportive treatment is critical because of the high frequency of symptoms. For localized disease, surgery followed by adjuvant gemcitabine is the standard. Neoadjuvant and new adjuvant chemotherapy regimens are being evaluated. Locally advanced disease should respond best guided by a multidisciplinary team. Various treatment options are appropriate such as chemotherapy alone or chemoradiotherapy with integration of rescue surgery if the tumor becomes resectable. In metastatic disease, chemotherapy should be reserved for patients with ECOG 0-1 using Folfirinox or gemcitabine plus nab-paclitaxel as the most recommended options. Several therapeutic strategies targeting unregulated pathways are under evaluation with an unmet need for biomarkers to guide management (AU)

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TTD consensus document on the diagnosis and management of exocrine pancreatic cancer.

Exocrine pancreatic cancer (PC) is a very aggressive and heterogeneous tumor with several cellular signaling pathways implicated in its pathogenesis and maintenance. Several risk factors increase the risk of developing PC. Therapeutic strategies used are dictated by the extent of disease. Supportive treatment is critical because of the high frequency of symptoms. For localized disease, surgery followed by adjuvant gemcitabine is the standard. Neoadjuvant and new adjuvant chemotherapy regimens are being evaluated. Locally advanced disease should respond best guided by a multidisciplinary team. Various treatment options are appropriate such as chemotherapy alone or chemoradiotherapy with integration of rescue surgery if the tumor becomes resectable. In metastatic disease, chemotherapy should be reserved for patients with ECOG 0-1 using Folfirinox or gemcitabine plus nab-paclitaxel as the most recommended options. Several therapeutic strategies targeting unregulated pathways are under evaluation with an unmet need for biomarkers to guide management.

Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer

INTRODUCTION: HER2 over-expression and/or amplification are present in 9-38% of gastric or gastroesophageal junction (GEJ) cancers and are correlated to poor outcome. We conducted a multicentre phase II trial to evaluate trastuzumab in combination with cisplatin in patients with untreated HER2-positive advanced gastric or GEJ cancer. MATERIALS AND METHODS: Chemo-naïve patients with measurable, non-resectable, advanced or metastatic gastric or GEJ adenocarcinoma, with HER2 over-expression and/or amplification (IHC 3+, or IHC 2+ and FISH+), age ≥18 years, ECOG ≤2, left ventricle ejection fraction ≥50% and adequate organ function were eligible. Treatment consisted of trastuzumab (8 mg/kg on cycle 1 day 1 as loading; 6 mg/kg in subsequent cycles) and cisplatin (75 mg/m(2)), both intravenously on day 1, every 21 days. RESULTS: Twenty-two out of 228 patients (10%) were HER2- positive and were included in this phase II trial. The median age was 66 years and ECOG 0/1 was 41%/59%. The median number of cycles was 4 (range 1-41). The confirmed ORR was 32% and disease control was achieved in 64% of patients. Median time to progression was 5.1 months. Grade 3 adverse events included asthenia (27%), neutropenia (18%), anorexia (14%), diarrhoea (9%) and abdominal pain (9%). There were no grade 4 toxicities or treatment-related deaths. Higher baseline HER extracellular domain (ECD) levels were associated with better outcome in terms of response and survival. CONCLUSIONS: Trastuzumab in combination with cisplatin is an active regimen and has a favourable toxicity profile in advanced HER2-positive gastric or gastroesophageal cancers (AU)

Conservative treatment with transurethral resection, neoadjuvant chemotherapy followed by radiochemotherapy in stage T2-3 transitional bladder cancer.

PURPOSE: Organ preservation has been investigated in patients (p) with infiltrating transitional cell carcinoma (TCC) of the bladder over the past decade as an alternative to radical cystectomy. This is a trimodal schedule study, including transurethral resection of bladder tumor (TURB), neoadjuvant chemotherapy and concomitant radiochemotherapy (RTC). PATIENTS AND METHODS: From April 1996 until August 2005, 29 evaluable patients (p) with T2-T3NXM0 bladder cancer were enrolled. After a transurethral resection of bladder tumor (TURB), we administered 2 cycles of induction chemotherapy with CMV (15 p) or Gemcitabine-Cisplatin (14 p) followed by radiotherapy 45 Gy 1.8 Gy/fraction and two cycles of concomitant cisplatin 70 mg/m(2). 2-3 weeks later, a cystoscopy with tumor-site biopsy was performed. If complete histological response, p were treated with consolidation radiotherapy until 64.8 Gy. For p with residual or recurrent tumor, cystectomy was performed. RESULTS: We included 28 men and 1 women (median age 63, range 39-72 years) with PS (ECOG) 0-1. The stage was: 21 p T2; 6 p T3a; and 2 p T3b. Toxicity was higher in CMV compared with Gem- Cis: grade (3/4) neutropenia 4/15 (26%) vs 1/14 (7%); febrile neutropenia 3/15 (20%) vs 1/14 (7%); grade (3/4) trombocytopenia 2/15 (13%) vs 1/14 (7%). Toxicities with concomitant RCT were low-moderate: urocystitis (26%) and enteritis (18%). RESPONSE: microscopically complete TURB was obtained in 20 p (69%), but not in 9 p (31%) (7 microscopic, and 2 macroscopic residual tumor). We found a complete histologic response after induction RCT in 25 p (86%). After a median follow-up of 69.4 months (m) (range: 8-97.7), there were 8 deaths, with a overall survival of 72%. Furthermore 14 of 29 p (48%) were alive with intact bladder, and median survival time with intact bladder was 63.6 m (50.1-77.2); were predictive of best outcome T2 stage vs T3 (p < 0.0001), and complete histologic resection in initial TURB vs residual tumor (p = 0.0004). CONCLUSIONS: Combined treatment provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients with TCC. Patients with T2 stage and complete histologic resection in initial TURB had the best outcome.

Conservative treatment with transurethral resection, neoadjuvant chemotherapy followed by radiochemotherapy in stage T2-3 transitional bladder cancer

PURPOSE: Organ preservation has been investigated in patients (p) with infiltrating transitional cell carcinoma (TCC) of the bladder over the past decade as an alternative to radical cystectomy. This is a trimodal schedule study, including transurethral resection of bladder tumor (TURB), neoadjuvant chemotherapy and concomitant radiochemotherapy (RTC). PATIENTS AND METHODS: From April 1996 until August 2005, 29 evaluable patients (p) with T2-T3NXM0 bladder cancer were enrolled. After a transurethral resection of bladder tumor (TURB), we administered 2 cycles of induction chemotherapy with CMV (15 p) or Gemcitabine-Cisplatin (14 p) followed by radiotherapy 45 Gy 1.8 Gy/fraction and two cycles of concomitant cisplatin 70 mg/m(2). 2-3 weeks later, a cystoscopy with tumor-site biopsy was performed. If complete histological response, p were treated with consolidation radiotherapy until 64.8 Gy. For p with residual or recurrent tumor, cystectomy was performed. RESULTS: We included 28 men and 1 women (median age 63, range 39-72 years) with PS (ECOG) 0-1. The stage was: 21 p T2; 6 p T3a; and 2 p T3b. Toxicity was higher in CMV compared with Gem- Cis: grade (3/4) neutropenia 4/15 (26%) vs 1/14 (7%); febrile neutropenia 3/15 (20%) vs 1/14 (7%); grade (3/4) trombocytopenia 2/15 (13%) vs 1/14 (7%). Toxicities with concomitant RCT were low-moderate: urocystitis (26%) and enteritis (18%). RESPONSE: microscopically complete TURB was obtained in 20 p (69%), but not in 9 p (31%) (7 microscopic, and 2 macroscopic residual tumor). We found a complete histologic response after induction RCT in 25 p (86%). After a median follow-up of 69.4 months (m) (range: 8-97.7), there were 8 deaths, with a overall survival of 72%. Furthermore 14 of 29 p (48%) were alive with intact bladder, and median survival time with intact bladder was 63.6 m (50.1-77.2); were predictive of best outcome T2 stage vs T3 (p < 0.0001), and complete histologic resection in initial TURB vs residual tumor (p = 0.0004). CONCLUSIONS: Combined treatment provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients with TCC. Patients with T2 stage and complete histologic resection in initial TURB had the best outcome (AU)

Primary signet-ring cell adenocarcinoma of the urinary bladder: A case report

El adenocarcinoma de células en anillo de selloprimario de vejiga es un tumor raro. Describimos uncaso de un varón de 53 años que consultó por hematuriamacroscópica. La imagen de la tomografíaaxial computerizada mostró un hidronefrosis derechay un tumor invasivo de la vejiga urinaria. Labiopsia mostró un carcinoma de células en anillo desello. No se detectó localización primaria digestivaen la exploración del tracto grastrointestinal. El pacientese trató con cistoprostatectomía total y quimioterapiaadyuvante con cisplatino y gemcitabina.El objetivo de este caso es presentar las característicasanatomoclínicas, tratamiento y evolución de esteinfrecuente tumor

Primary signet-ring cell adenocarcinoma of theurinary bladder is a rare tumor. We report in thisstudy the case of a 53 year old man consulting forgross hematuria. Computed tomography imagingdemonstrated right hydronephrosis and an invasivebladder tumor. The bladder biopsy showed a signetringcell carcinoma; the exploration of the gastrointestinaltract did nor reveal any other tumor localization.A total cystoprostatectomy was performedfollowed by adjuvant chemotherapy with cisplatinand gemcitabine. The aim of this study is to determinethe anatomoclinical, therapeutic and evolutionarycharacteristics of this rare tumor