Summary Background We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2 -amplified metastatic colorectal ...cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. Methods HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. Findings Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51–127), eight (30%, 95% CI 14–50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI −3 to 11) achieving a complete response, and seven (26%, 95% CI 9–43) achieving partial responses; 12 (44%, 95% CI 25–63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. Interpretation The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. Funding Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.
Summary Background Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR ...wild-type—which includes most patients—is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients. Methods We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m2 every 21 days or 35 mg/m2 on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov , number NCT00637910. Findings We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8–10·9) with docetaxel versus 5·4 months (4·5–6·8) with erlotinib (adjusted hazard ratio HR 0·73, 95% CI 0·53–1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4–3·8) with docetaxel versus 2·4 months (2·1–2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53–0·95; p=0·02). The most common grade 3–4 toxic effects were: low absolute neutrophil count (21 20% of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 14%), and asthenia (ten 10% vs six 6%). Interpretation Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours. Funding Agenzia Italiana del Farmaco.
Summary Background An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR ...tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. Methods From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m2 , intravenously, every 21 days, or docetaxel 75 mg/m2 , intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov , number NCT00989690. Findings 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8–10·9) in the chemotherapy group and 7·7 months (5·9–10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction =0·017 when adjusted for stratification factors; pinteraction =0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 95% CI 1·08–2·74, p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 0·77–1·46, p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 15% vs one <1% in the erlotinib group), whereas skin toxicity (one <1% vs 22 16%) was the most frequent in the erlotinib group. Interpretation Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. Funding Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.
Summary Background The density of tumour-infiltrating lymphocytes (TIL) has been proposed as an independent predictor of outcome in patients with colorectal cancer. However, the relative roles of TIL ...density, nodal status, and microsatellite instability (MSI) in predicting tumour progression to metachronous metastasis remain to be elucidated. The aim of this study was to assess the relationship between the density of CD3+ TIL and the postsurgical occurrence of distant-organ metastases in a large series of patients with deeply invading and MSI-typed colorectal cancer. Methods Per cent areas of immunoreactivity due to CD3+ TIL at the invasive margin of the tumour (CD3+ TILIM ) were measured by computer-assisted image analysis in 286 tissue specimens from pT3 or pT4 MSI-tested colorectal cancer. Tissue samples were taken from consecutive patients who underwent resection at the IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy, from January, 1997, to November, 2004, for colorectal cancer with no evidence of metastasis at diagnosis. Occurrence of metachronous metastasis, disease-specific survival (DSS), and disease-free survival (DFS), were assessed retrospectively in relation to per cent immunoreactivity. Findings CD3+ TILIM density was higher in MSI colorectal cancer than in mismatch repair-system-proficient tumours (6·53% vs 2·19%; p<0·0001). At Cox analysis, higher CD3+ TILIM densities, colonic site, and absence of nodal involvement were significantly associated with a lower risk of metachronous metastasis, but only the interaction between CD3+ TILIM density and N-stage was significant on multivariate analysis (p=0·002). On separate analysis of node-negative colorectal cancer, increasing percentage of CD3+ immunoreactive area progressively reduced the risk of metachronous metastasis (<1%, reference; 1–5%, HR 0·28, 95% CI 0·10–0·81, p=0·02; >5%, 0·06, 0·01–0·48, p=0·008). Conversely, no significant association was seen between CD3+ immunoreactive area and risk of metachronous metastasis in node-positive colorectal cancer. Accordingly, CD3+ TILIM density was associated with a better DSS (p=0·01) and DFS (p=0·006) only in patients with node-negative colorectal cancer. In primary tumours that had progressed to metachronous metastasis, stage III tumours had higher CD3+ TILIM densities than stage II tumours (p=0·0004). Interpretation Metachronous metastases are unlikely to arise from node-negative colorectal cancers with a high-density CD3+ TILIM , whereas high densities of CD3+ TILIM are not associated with the absence of postsurgical metastasis in patients with node-positive colorectal cancer. Our data suggest that densities of CD3+ TILIM cannot be used as an independent predictor of clinical outcome in patients with stage III colorectal cancer and, at least for now, the tumour-node-metastasis classification should remain the preferred prognostic system. Our findings are consistent with a relationship between nodal involvement and tumour immunoevasion. Funding MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca), Target Project Oncologia 2006, and Alleanza Contro il Cancro.
Objective The purpose of this study was to explore in greater depth the outcomes of the Italian randomized trial investigating the role of pelvic lymphadenectomy in clinical early stage endometrial ...cancer. In the attempt to identify the patients with poorer prognosis, the impact of age and body mass index were also thoroughly investigated by cancer-specific survival (CSS) analyses. Study Design Survival outcomes of trial patients were analyzed in relation to age (≤65 years and >65 years) in the 2 arms (lymphadenectomy and no lymphadenectomy) and in the whole population of the trial. Results Univariate and multivariable analyses of CSS and overall survival (OS) of patients showed that age >65 years is a strong independent poor prognostic factor (5-y OS 92.1% and 78.4% in ≤65 years and >65 years patients, respectively, P < .0001; 5-y CSS 93.8% and 83.5% in ≤65 years and >65 years patients, respectively, P = .003). Among women ≤65 years, node negative patients had 94.4% 5-y OS and 96.3% 5-y CSS vs 74.3% 5-y OS and 74.3% 5-y CSS for node positive patients ( P = .009 and P = .002, respectively), while among women >65 y, node negative patients had 75.7% 5-y OS and 83.6% 5-y CSS vs 74.1% 5-y OS and 83.3% 5-y CSS for node positive patients ( P = .55 and P = .58, respectively). Univariate and multivariable survival analyses in the whole trial population showed that older age, and higher tumor grade and stage were significantly associated to a worse prognosis. Conclusion Older women faced an intrinsic poorer survival whether or not they underwent lymphadenectomy, and, unexpectedly, irrespective of the presence of nodal metastasis. Only in older patients was obesity (body mass index >30) significantly associated with scarce prognosis.
The Thoracic Centers International coronavirus disease 2019 (COVID-19) Collaboration (TERAVOLT) registry found approximately 30% mortality in patients with thoracic malignancies during the initial ...COVID-19 surges. Data from South Africa suggested a decrease in severity and mortality with the Omicron wave. Our objective was to assess mortality of patients with thoracic malignancies with the Omicron-predominant wave and evaluate efficacy of vaccination.
A prospective, multicenter observational study was conducted. A total of 28 institutions contributed data from January 14, 2022, to February 4, 2022. Inclusion criteria were any thoracic cancer and a COVID-19 diagnosis on or after November 1, 2021. End points included mortality, hospitalization, symptomatic COVID-19 infection, asymptomatic COVID-19 infection, and delay in cancer therapy. Analysis was done through contingency tables and a multivariable logistic model.
We enrolled a total of 346 patients. Median age was 65 years, 52.3% were female, 74.2% were current or former smokers, 86% had NSCLC, 72% had stage IV at time of COVID-19 diagnosis, and 66% were receiving cancer therapy. Variant was unknown for 70%; for those known, Omicron represented 82%. Overall mortality was 3.2%. Using multivariate analysis, COVID-19 vaccination with booster compared with no vaccination had a protective effect on hospitalization or death (OR = 0.30, confidence interval: 0.15–0.57, p = 0.0003), whereas vaccination without booster did not (OR = 0.64, confidence interval: 0.33–1.24, p = 0.1864). Cancer care was delayed in 56.4% of the patients.
TERAVOLT found reduced patient mortality with the most recent COVID-19 surge. COVID-19 vaccination with booster improved outcomes of hospitalization or death. Delays in cancer therapy remain an issue, which has the potential to worsen cancer-related mortality.
Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, ...we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article.
For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920.
Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity.
With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials.
Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.
ABSTRACT Introduction Debate remains about prognostic factors in primary Merkel cell carcinoma (MCC). We investigated clinicopathological factors as determinants of survival in patients with MCC ...submitted to sentinel node biopsy. Methods Sixty-four consecutive patients treated for a primary MCC were identified from a prospectively maintained database at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Time to events outcome were described by product limit estimators and proportional hazards model was used to investigate the association between outcome and potential predictors. Results The most common site of primary tumor was lower limbs (56.3%). The size of primary lesion was ≤ 2 cm in 67.2% of cases. Presence of residual disease after the diagnostic surgical excision was observed in 28% of cases. All patients received sentinel node biopsy (SNB) and a SN positivity was detected in 26.6%. The median follow up was 78 months. Disease recurrence occurred in 17 patients (26.6%). In the SN negative group 10 recurrences occurred (21.3%), whereas 7 (41.2%) were found in SN positive one. Nine patients SN negative (19.1%) died of disease and 3 (17.6%) among SN positive. SN status was not associated with survival (p=0.78). Neither age, gender, size and site of primary tumor resulted predictors of patients’ outcome. The presence of residual tumor in the specimen of the wide local excision, after the diagnostic surgical excision, was the only variable associated with survival (p= 0.03). Conclusions Presence of residual tumor in the specimen of the wide local excision is the main prognostic factor in MCC patients.
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