Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.

BACKGROUND: In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival. METHODS: In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448. FINDINGS: 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3-29·2] in the control group vs 17·0 months [9·4-30·1] in the cetuximab group; HR 1·04, 95% CI 0·87-1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0-12·5] in the control group vs 8·6 months [5·1-13·8] in the cetuximab group; HR 0·96, 0·82-1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5-27·4); KRAS mutant, 14·4 months (8·5-24·0); all wild-type, 20·1 months (11·5-31·7). INTERPRETATION: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended. FUNDING: Cancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.

Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.

BACKGROUND: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. METHODS: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1.162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. FINDINGS: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15.8 months (IQR 9.4-26.1) in arm A and 14.4 months (8.0-24.7) in arm C (hazard ratio [HR] 1.084, 80% CI 1.008-1.165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19.6 months (13.0-28.1) in arm A and 18.0 months (12.1-29.3) in arm C (HR 1.087, 0.986-1.198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400,000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0.96 (95% CI 0.80-1.15, p=0.66), versus 1.54 (1.17-2.03, p=0.0018) in patients with a raised platelet count (p=0.0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand-foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. INTERPRETATION: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. FUNDING: Cancer Research UK.

Malaria and anaemia among children in two communities of Kumasi, Ghana: a cross-sectional survey.

BACKGROUND: A survey in Kumasi, Ghana found a marked Plasmodium falciparum prevalence difference between two neighbouring communities (Moshie Zongo and Manhyia). The primary objective of this follow-up study was to determine whether this parasite rate difference was consistent over time. Secondary objectives were to compare prevalences of clinical malaria, anaemia, intestinal parasite infections, and malnutrition between these communities; and to identify potential risk factors for P. falciparum infection and anaemia. METHODS: A cross-sectional house-to-house survey of P. falciparum parasitaemia, clinical malaria, anaemia, anthropometric indices, and intestinal helminths was conducted in April-May 2005. Data collection included child and household demographics, mosquito avoidance practices, distance to nearest health facility, child's travel history, symptoms, and anti-malarial use. Risk factors for P. falciparum and anaemia (Hb < 11 g/dl) were identified using generalized linear mixed models. RESULTS: In total, 296 children were tested from 184 households. Prevalences of P. falciparum, clinical malaria, anaemia, and stunting were significantly higher in Moshie Zongo (37.8%, 16.9%, 66.2% and 21.1%, respectively) compared to Manhyia (12.8%, 3.4%, 34.5% and 7.4%). Of 197 children tested for helminths, four were positive for Dicrocoelium dendriticum. Population attributable risks (PAR%) of anaemia were 16.5% (P. falciparum) and 7.6% (malnutrition). Risk factors for P. falciparum infection were older age, rural travel, and lower socioeconomic status. Risk factors for anaemia were P. falciparum infection, Moshie Zongo residence, male sex, and younger age. CONCLUSION: Heterogeneities in malariometric indices between neighbouring Kumasi communities are consistent over time. The low helminth prevalence, and the twofold higher PAR% of anaemia attributable to P. falciparum infection compared to malnutrition, indicate the importance of malaria as a cause of anaemia in this urban population.

Atypical Polypoid Adenomyoma of the Uterus: An Immunohistochemical and Molecular Study of 21 Cases.

Atypical polypoid adenomyoma (APA) is an uncommon uterine lesion that commonly recurs after local excision and is occasionally associated with or precedes the development of atypical hyperplasia or endometrioid adenocarcinoma. Despite the fact that about 230 cases have been reported in the literature, only 2 studies of 6 and of 7 cases have investigated the molecular aspects; as such, molecular alterations that occur in APA remain largely unknown. We undertook a comprehensive immunohistochemical and molecular analysis of 21 cases of APA in 17 patients (including 4 recurrent/persistent lesions). The analyzed genes were PTEN and TP53 (by fluorescence in situ hybridization) and KRAS, BRAF, EGFR, and NRAS (all by polymerase chain reaction). Immunohistochemical staining was performed for PTEN, p53, mTOR, ß-catenin, HNF-1ß, and GLUT1 and for the mismatch-repair proteins MLH-1, MSH-2, MSH-6, and PMS-2. In most cases, there was nuclear expression of ß-catenin in squamous morules and expression of HNF-1ß, mTOR, and GLUT1 in the glandular component. All cases exhibited "wild-type" expression of p53. A common finding was loss of PTEN expression (6/19 cases). In 1 of these cases, loss of PTEN expression was accompanied by PTEN deletion. Mutation of the KRAS gene was found in 5/19 cases. Intact mismatch-repair protein expression was present in all cases, and TP53 abnormalities or mutations of EGFR, NRAS, or BRAF genes were not found. Given the association with atypical hyperplasia and endometrioid adenocarcinoma and the shared immunohistochemical and molecular features, we feel that, conceptually, APA is best regarded as analogous to a localized form of atypical hyperplasia.

Adenomyomatous Polyp of the Endometrium With Prominent Epithelioid Smooth Muscle Differentiation: Report of Two Cases of a Hitherto Undescribed Lesion.

A minor component of smooth muscle may be present in the stroma of benign endometrial polyps and 2 distinctive endometrial polypoid lesions, atypical polypoid adenomyoma and adenomyoma, are characterized by stroma with a predominant smooth muscle component. In this report, we describe 2 unusual endometrial polyps in 43- and 60-year-old women in which the stromal component was predominantly composed of smooth muscle with an epithelioid appearance, a phenomenon which, as far as we are aware, has not been previously reported.

Concordance between digital pathology and light microscopy in general surgical pathology: a pilot study of 100 cases.

AIM: (1) A pilot study to determine the accuracy of interpretation of whole slide digital images in a broad range of general histopathology cases of graded complexity. (2) To survey the participating histopathologists with regard to acceptability of digital pathology. MATERIALS AND METHODS: Glass slides of 100 biopsies and minor resections were digitally scanned in their entirety, producing digital slides. These cases had been diagnosed by light microscopy at least 1 year previously and were subsequently reassessed by the original reporting pathologist (who was blinded to their original diagnosis) using digital pathology. The digital pathology-based diagnosis was compared with the original glass slide diagnosis and classified as concordant, slightly discordant (without clinical consequence) or discordant. The participants were surveyed at the end of the study. RESULTS: There was concordance between the original light microscopy diagnosis and digital pathology-based diagnosis in 95 of the 100 cases while the remaining 5 cases showed only slight discordance (with no clinical consequence). None of the cases were categorised as discordant. Participants had mixed experiences using digital pathology technology. CONCLUSIONS: In the broad range of cases we examined, digital pathology is a safe and viable method of making a primary histopathological diagnosis.

Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, and HMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-ß.

Mesonephric adenocarcinomas are rare neoplasms that most commonly arise in the uterine cervix and exceptionally rarely in the uterine corpus. Although the morphologic features of these neoplasms are well described, there has been relatively limited investigation of the immunoprofile. We report a series of 8 mesonephric adenocarcinomas arising in the uterine cervix (7 cases) and corpus (1 case) and undertake a comprehensive immunohistochemical analysis. This includes markers that have not been investigated previously in mesonephric adenocarcinomas but that are commonly used in gynecologic pathology and may be undertaken when other, mainly Mullerian, adenocarcinomas are considered in the differential diagnosis. Linear array human papillomavirus (HPV) genotyping was also performed. Our results broadly confirm the immunohistochemical profile demonstrated in previous studies with the majority of mesonephric adenocarcinomas staining positively with CD10 (6 of 8), epithelial membrane antigen (8 of 8), vimentin (8 of 8), and calretinin (7 of 8). Estrogen receptor was positive in 2, carcinoembryonic antigen in 3, and inhibin in 4 cases. p16 was positive in 5 cases (1 diffuse and strong), despite all being HPV negative (in 1 case, there was insufficient DNA for HPV analysis). Novel findings in our study were the demonstration of nuclear positivity with PAX8 and HMGA2 in 7 cases, CA125 immunoreactivity in all 8 cases, and TTF1 and hepatocyte nuclear factor 1-ß staining in 3 cases. As PAX8, CA125, HMGA2, and hepatocyte nuclear factor 1-ß are commonly positive in a variety of Mullerian adenocarcinomas arising in the female genital tract, this may result in diagnostic confusion. All cases were WT1 negative.