Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study.

BACKGROUND: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. MATERIALS AND METHODS: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. RESULTS: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. CONCLUSIONS: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

A signature of circulating microRNAs predicts the response to treatment with FOLFIRI plus aflibercept in metastatic colorectal cancer patients.

The benefit of adding the antiangiogenic drug aflibercept to FOLFIRI regime in metastatic colorectal cancer (CRC) patients resistant to or progressive on an oxaliplatin-based therapy has been previously demonstrated. However, the absence of validated biomarkers to predict greater outcomes is a major challenge encountered when using antiangiogenic therapies. In this study we investigated profiles of circulating microRNAs (miRNAs) to build predictive models of response to treatment and survival. Plasma was obtained from 98 metastatic CRC patients enrolled in a clinical phase II trial before receiving FOLFIRI plus aflibercept treatment, and the circulating levels of 754 individual miRNAs were quantified using real-time PCR. A distinct signature of circulating miRNAs differentiated responder from non-responder patients. Remarkably, most of these miRNAs were found to target genes that are involved in angiogenic processes. Accordingly, some of these miRNAs had predictive value and entered in predictive models of response to therapy, progression of disease, and survival of patients treated with FOLFIRI plus aflibercept. Among these miRNAs, circulating levels of hsa-miR-33b-5p efficiently discriminated between responder and non-responder patients and predicted the risk of disease progression. Moreover, the combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept.

Short-course radiotherapy in stage IV rectal cancer with resectable disease.

INTRODUCTION: Stage IV rectal cancer with resectable disease presents challenging issues, as the radical treatment of the whole disease is difficult. Surgery and chemotherapy (CT) play an unquestionable role, but the contribution of pelvic radiotherapy (RT) is not very clear. METHODS: In 2009, we established a prospective treatment protocol that included CT, short-course preoperative radiotherapy (SCRT) with surgery of the primary tumour and all metastatic locations. RESULTS: Forty patients were included. Eight (20%) patients did not receive CT due to significant comorbidities. Radical surgery treatment was possible in 22 (55%) patients. The mean follow-up was 42.81 months (3.63-105.97). Overall survival at 24 and 36 months was 71.4% and 58.2%, respectively. There was good local control of the disease, as 97.2% of pelvic surgeries were R0 and there were no local recurrences. CONCLUSION: In stage IV with resectable metastatic disease, the proposed therapeutic regimen seems very appropriate in well selected patients able to tolerate the treatment. We bet on the role of pelvic RT, due to the good local control of the disease in our series.

Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy.

BACKGROUND: Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor. PATIENTS AND METHODS: Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes. RESULTS: After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2-7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFRS492Rmutation was not detected in untreated samples. CONCLUSIONS: No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.

2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary.

Cancer of unknown primary (CUP) is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP. The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.

SEOM clinical guideline on unknown primary cancer (2017).

Cancer of unknown primary site is a histologically confirmed cancer that manifests in advanced stage, with no identifiable primary site following standard diagnostic procedures. Patients are initially categorized based on the findings of the initial biopsy: adenocarcinoma, squamous-cell carcinoma, neuroendocrine carcinoma, and poorly differentiated carcinoma. Appropriate patient management requires understanding several clinical and pathological features that aid in identifying several subsets of patients with more responsive tumors.

SEOM Clinical Guideline of localized rectal cancer (2016).

Localized rectal adenocarcinoma is a heterogeneous disease and current treatment recommendations are based on a preoperative multidisciplinary evaluation. High-resolution magnetic resonance imaging and endoscopic ultrasound are complementary to do a locoregional accurate staging. Surgery remains the mainstay of treatment and preoperative therapies with chemoradiation (CRT) or short-course radiation (SCRT) must be considered in more locally advanced cases. Novel strategies with induction chemotherapy alone or preceding or after CRT (SCRT) and surgery are in development.

Recommendations in the management of epithelial appendiceal neoplasms and peritoneal dissemination from mucinous tumours (pseudomyxoma peritonei).

The epithelial appendiceal neoplasms are uncommon and are usually detected as an unexpected surgical finding. The general surgeon should be aware of the diversity of its clinical manifestations and biological behaviors along with the significance of the surgical treatment on the progression of the illness and the prognosis of the patients. The operative findings and, especially, tumor histology, determine the type of surgery. Intestinal histologic subtype behaves and should be treated similarly to the right colon neoplasms; while mucinous tumors, often discordant between histology and its aggressiveness, can be treated with a simple appendectomy or require complex oncological surgeries. Mucinous tumors are often associated with the presence of mucin or tumor implants in the abdominal cavity, being the clinical syndrome known as pseudomyxoma peritonei (PMP). PMP tends to present an indolent but deadly evolution and requires a multimodal approach as a single treatment with curative potential: complete cytoreductive surgery plus hyperthermic Intra-peritoneal chemotherapy (CCRS + HIPEC) now considered the standard of care in this pathology. The general surgeon should be aware of the governing principles of the treatment of appendiceal neoplasms with or without peritoneal dissemination, know the therapeutic frontiers in every situation (avoiding unnecessary or counterproductive surgeries) and sending early these patients to specialised centres in the radical management of malignant diseases of the peritoneum in the conditions and with the necessary information to facilitate a possible radical treatment.

Cytoreductive surgery and intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis from colorectal origin.

Peritoneal carcinomatosis (PC) is a common form of tumour metastasis stemming from gastrointestinal and colorectal cancers. For a long time, PC has been considered a terminal clinical condition treated only with palliative systemic chemotherapy and associated with very limited results. During the last decade, the treatment of advanced colorectal disease has greatly improved with the emergence of new chemotherapy drugs and biological agents. However, the median survival rates still do not surpass 24 months, even though most of these studies correspond to groups of patients with metastatic disease to the liver and/or lung. The approach and development of cytoreductive radical surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) are based on performing radical surgery of the entire visible tumour within the abdomen/peritoneum, followed immediately by HIPEC, which acts upon microscopic tumour that remains present after surgery and which is responsible for the persistence or relapse of peritoneal disease. Peritonectomy procedures are demanding surgical techniques that permit elimination of the tumour present in the peritoneal lining and any other organs and/or structures that are infiltrated. The synergistic effect of hyperthermia and chemotherapy has been well documented. Hyperthermia increases the cytotoxicity of some cytostatic agents and increases the penetration of certain drugs into the neoplastic cells. The prognosis for patients with PC who undergo combined treatment correlates with the volume of PC (tumour burden) measured as the Peritoneal Cancer Index (PCI) and the ability to perform a CRS, to completely eliminate the gross tumour. At least one phase III study and an important number of phase II studies have shown that CRS + HIPEC provides important survival benefits for patients with PC of colorectal origin. The combination of CRS + HIPEC is indicated for patients with good general health, a low PCI, absence of extra-abdominal metastasis and who can, technically, undergo CRS. The early identification of this group of patients, rapid referral to centres specialised in CRS + HIPEC, together with the correct application of this treatment, are key in achieving the best results.

Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer.

PURPOSE: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC). METHODS: Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m(2) of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and 8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032). CONCLUSION: This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC.

Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer.

BACKGROUND: The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. METHODS: Treatment consisted of capecitabine 1250 mg m(-2) (or 950 mg m(-2) for patients with a creatinine clearance of 30-50 ml min(-1)) twice daily on days 1-14 and bevacizumab (7.5 mg kg(-1)) on day 1 every 3 weeks. RESULTS: A total of 59 patients aged >or=70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand-foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance

Prognostic time dependence of deletions affecting codons 557 and/or 558 of KIT gene for relapse-free survival (RFS) in localized GIST: a Spanish Group for Sarcoma Research (GEIS) Study.

BACKGROUND: To assess whether deletions involving codons 557 and/or 558 (critical deletions) of exon 11 of KIT are relevant in the prognosis of relapse-free survival (RFS) in gastrointestinal stromal tumor (GIST) patients with a long follow-up. PATIENTS AND METHODS: A univariate and multivariate analysis for RFS were carried out on 162 localized GIST patients over the entire follow-up period and over the intervals 0-4 years and >4 years. Factors assessed among others were Fletcher/National Institutes of Health and Miettinen-Lasota/Armed Forces Institute of Pathology (M-L/AFIP) risk categories, critical deletions and non-deletion-type mutation (NDTM) within exon 11 of KIT. RESULTS: Multivariate analyses revealed that M-L/AFIP [relative risk (RR) 11.45, confidence interval (CI) 4.40-29.76, for the high-risk subgroup and RR 5.97, CI 2.09-17.06, for the intermediate subgroup] and critical deletions (RR 3.05, CI 1.59-5.85) were independent prognostic factors for RFS for the first 4 years and for the entire follow-up period. Beyond 4 years, the high-risk M-L/AFIP subgroup (RR 8.12, CI 1.48-44.4) and NDTM (RR 6.42, CI 1.17-35.12) were independent prognostic factors for RFS. The median follow-up was 84 months. CONCLUSION: Critical deletions represent a time-dependent prognostic factor limited to the first 4 years after surgery, which could help identify a subset with higher and earlier risk for relapse in GIST patients.

XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer.

The purpose of this phase II trial was to determine the efficacy and safety of the XELOX (capecitabine/oxaliplatin) regimen as first-line therapy in the elderly patients with metastatic colorectal cancer (MCRC). A total of 50 patients with MCRC aged > or = 70 years received oxaliplatin 130 mg m(-2) on day 1 followed by oral capecitabine 1000 mg m(-2) twice daily on days 1-14 every 3 weeks. Patients with creatinine clearance 30-50 ml min(-1) received a reduced dose of capecitabine (750 mg m(-2) twice daily). By intent-to-treat analysis, the overall response rate was 36% (95% CI, 28-49%), with three (6%) complete and 15 (30%) partial responses. In total, 18 patients (36%) had stable disease and 14 (28%) progressed. The median times to disease progression and overall survival were 5.8 months (95% CI, 3.9-7.8 months) and 13.2 months (95% CI, 7.6-16.9 months), respectively. Capecitabine was well tolerated: grade 3/4 adverse events were observed in 14 (28%) patients: 11 (22%) diarrhoea, eight (16%) asthenia, seven (14%) nausea/vomiting, three (6%) neutropenia, three (6%) thrombocytopenia, and two (4%) hand-foot syndrome. There was one treatment-related death from diarrhoea and sepsis. In conclusion, XELOX is well tolerated in elderly patients, with respectable efficacy and a meaningful clinical benefit response. Given its ease of administration compared with combinations of oxaliplatin with 5-FU/LV, it represents a good therapeutic option in the elderly.

Zoledronate-induced remission of acute panmyelosis with myelofibrosis.

Acute panmyelosis with myelofibrosis is a rare and aggressive form of acute myeloid leukemia. We describe a new case with a huge proliferation of megakaryocytes, blast cells and reticulin fibers. The patient was treated with zoledronate, a third-generation bisphosphonate, and a gradual recovery from pancytopenia was observed. A new bone marrow biopsy performed 4 months later showed a surprising disappearance of the leukemic infiltration. Ten months after the diagnosis, the patient is still in healthy condition. This may support the recently described anti-tumor activity of zoledronate.

Second-line chemotherapy for non-small cell lung cancer.

BACKGROUND: The role of second-line chemotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) who have relapsed or failed to respond to first-line treatment was unclear. OBJECTIVES: To determine the effectiveness of any second-line chemotherapy in patients with NSCLC. SEARCH STRATEGY: Medline (1966-July 2001), Embase (1974-July 2001), Cancerlit (1993-July) and the Cochrane Controlled Trials Register (CENTRAL, issue 2 2001) were searched. In addition a handsearch was performed and experts in the field contacted to identify any further studies that had not been found by the electronic searches. SELECTION CRITERIA: Randomised controlled clinical trials in which any second-line chemotherapy was compared with placebo or best supportive care in patients with NSCLC who had previously failed to any previous chemotherapy regimen. DATA COLLECTION AND ANALYSIS: Data were extracted by 2 independent reviewers and revised by a third author. MAIN RESULTS: Only one study was included. This study included a total of 204 patients who were randomised to receive either doxetaxel or best supportive care. Following an unacceptably high toxic death rate the dose of doxetaxel was reduced from 100 mg/m(2) to 75 mg/m(2). Docetaxel gave an extra 2.4 months survival - an average of 7.0 months vs 4.6 months on best supportive care. At 1 year after diagnosis 29% of doxetaxel treated patients were alive compared with 19% of the best supportive care group. REVIEWER'S CONCLUSIONS: Definitive recommendations cannot be made since evidence is only available from one randomised controlled trial which, though of reasonable quality had a number of limitations. There is currently no evidence to support second-line treatment of patients with poor performance status. Larger, well-designed controlled trials are needed to further evaluate whether the benefits of second-line chemotherapy to patients with non-small cell lung cancer outweigh its risks and costs.

Second-line chemotherapy for non-small cell lung cancer.

BACKGROUND: The role of second-line chemotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) who have relapsed or failed to respond to first-line treatment was unclear. OBJECTIVES: To determine the effectiveness of any second-line chemotherapy in patients with NSCLC. SEARCH STRATEGY: Bibliographic databases were searched. Handsearching and contact with experts was also performed. SELECTION CRITERIA: Randomised controlled clinical trials in which any second-line chemotherapy was compared with BSC in patients with NSCLC who had previously failed to any previous chemotherapy regimen. DATA COLLECTION AND ANALYSIS: Data was extracted by 2 independent reviewers and revised by all authors. MAIN RESULTS: Only one study was included. It randomised 204 patients to receive either doxetaxel or BSC. Following an unacceptably high toxic death rate the dose of doxetaxel was reduced from 100 mg/m(2) to 75 mg/m(2). Doxetaxel gave an extra 2.4 months of survival - an average of 7.0 months vs 4.6 months on BSC. At 1 year after diagnosis 29% of doxetaxel treated patients were alive compared with 19% of the BSC group. REVIEWER'S CONCLUSIONS: Definitive recommendations cannot be made since evidence is only available from one randomised controlled trial which, though of reasonable quality, had a number of limitations. There is currently no evidence to support second-line treatment of patients with poor performance status. Larger, well-designed controlled trials are needed to further evaluate whether the benefits of second-line chemotherapy to patients with NSCLC outweigh its risks and costs.

Peripheral primitive neuroectodermal tumor (PPNET) of pelvic origin: report of a case arising from an unusual location.

A peripheral primitive neuroectodermal tumor arising from the abdominopelvic cavity is reported in a 24-year-old young male without any previous remarkable pathology. He was admitted to our hospital with complaints of urinary symptoms (acute urinary retention) and mild intestinal occlusion that had been present for three months. Physical examination and CT scan revealed a pelvic mass occupying the entire pelvic cavity. The diagnostic workup included a CT-guided biopsy which defined the tumor as a sarcomatous type. Radical surgery was performed including tumor resection, pelvic exenteration (bladder and prostate gland) and urinary and fecal diversion. Adjuvant chemotherapy (VAIA) was delivered once the histology was confirmed. We reviewed the available literature focusing on the varied nomenclature of this tumor (peripheral neuroepithelioma, Askin's tumor, Ewing's extraosseous tumor, peripheral adult neuroblastoma, peripheral primitive extracranial neuroectodermal tumor (PPNET), the clinical features, the role of diagnostic imaging techniques, pathologic assessment and controversial therapeutic management. In addition, the prognosis and survival of this rare condition were analyzed.