Abstract Background Prognosis of diffuse malignant peritoneal mesothelioma (DMPM) has been recently improved by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). As with ...other peritoneal surface malignancies, the survival benefit is maximal when a complete surgical cytoreduction is achieved, but additional factors predicting long-term outcome are still poorly understood. We sought to investigate outcome and prognostic factors in patients with DMPM treated by complete cytoreduction and HIPEC. Methods From a prospective database, we selected 108 patients with DMPM undergoing complete cytoreduction (residual tumour nodules ⩽2.5 mm) and closed-abdomen HIPEC with cisplatin and doxorubicin or mitomycin-C. Twenty-seven patient-, tumour- and treatment-related variables were assessed by multivariate analysis with respect to overall (OS) and progression-free (PFS) survival. A panel of immunohistochemical markers was tested. Results Operative mortality was 1.9% and major morbidity 38.9%. Median follow-up was 48.8 months (95% confidence interval (CI) 37.1–60.6). Median OS and PFS were 63.2 months (95%CI 29.6–96.7) and 25.1 months (95%CI 5.1–45.1). The survival curve reached a plateau after 7 years, representing 19 actual survivors of 39 patients (43.6%) with potential follow-up ⩾7 years. Cytokeratin 5/6, calretinin, Wilms tumour-1 (WT-1), podoplanin and epithelial growth factor receptor (EGFR) were mostly positive. At multivariate analysis, epithelial histological subtype, negative lymph-nodes, ⩽10% Ki67-positive cells correlated with both increased OS and PFS. Positive podoplanin correlated to increased PFS. Conclusions After complete cytoreduction and HIPEC, prognosis of DMPM is primarily dependent on pathologic and biologic features. Patients with DMPM surviving ⩾7 years appeared to be cured. Cure rate was 43.6%. Proliferative index and podoplanin may be used for prognostic stratification.
Purpose: The use of tyrosine kinase receptor inhibitors is increasingly becoming a valuable therapeutic alternative in tumors carrying
activated tyrosine kinase receptors. In a previous study, we ...described a coexpression of KIT and stem cell factor (SCF) mRNA
in Synovial sarcomas, (SS) and in a limited number of cases, we demonstrated the presence of an activated receptor. Here,
in a wider number of cases, we investigated the expression level and phosphorylation status of two structurally related tyrosine
kinase receptors, KIT and platelet-derived growth factor receptor β (PDGFRβ), at the light of their role as possible targets
of tyrosine kinase receptors inhibitor molecules.
Experimental Design: Forty-three SS cases were analyzed for KIT and PDGFRβ expression/activation by immunoprecipitation/Western blotting experiments.
The cognate ligands, SCF and PDGFB, were detected by reverse transcription-PCR.
Results: KIT was observed in 48 and 41% (45% total) whereas PDGFRβ in 54 and 33% (45% total) of monophasic and biphasic SS cases,
respectively. With respect to the fusion transcript type SYTSSX1 and SYTSSX2, KIT was more expressed in SYTSSX1 carrying cases
(48 versus 38%), whereas PDGFRβ resulted more frequently expressed in SYTSSX2 ones (54 versus 37%). When expressed, the receptors were phosphorylated. Their ligands were detected in all of the activated cases.
Conclusions: About 70% of the cases express one of the two activated tyrosine kinase receptors with a mutually exclusive expression trend.
Coexpression is not frequent and seems to be restricted to monophasic subtype. These data indicate that a consistent fraction
of this tumor type could represent a good candidate for kinase inhibitor molecules effective on KIT and PDGFRβ where their
activation is sustained by an autocrine loop.
The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of ...patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection.
OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients’ death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974.
2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4–57·8) from cancer diagnosis and 44 days (28–329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 49·6%) and residual fatigue (96 41·0%). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p<0·0001), complicated COVID-19 (p<0·0001), and COVID-19 therapy (p=0·0002). With a median post-COVID-19 follow-up of 128 days (95% CI 113–148), COVID-19 sequelae were associated with an increased risk of death (hazard ratio HR 1·80 95% CI 1·18–2·75) after adjusting for time to post-COVID-19 reassessment, sex, age, comorbidity burden, tumour characteristics, anticancer therapy, and COVID-19 severity. Among 466 patients on systemic anti-cancer therapy, 70 (15·0%) permanently discontinued therapy, and 178 (38·2%) resumed treatment with a dose or regimen adjustment. Permanent treatment discontinuations were independently associated with an increased risk of death (HR 3·53 95% CI 1·45–8·59), but dose or regimen adjustments were not (0·84 0·35–2·02).
Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely affect survival and oncological outcomes after recovery. Adjustments to systemic anti-cancer therapy can be safely pursued in treatment-eligible patients.
National Institute for Health Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.
Abstract
The SARS-CoV-2 pandemic significantly affected oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncologic features to severity ...and mortality from COVID-19 and little guidance as to the role of anticancer and anti–COVID-19 therapy in this population. In a multicenter study of 890 patients with cancer with confirmed COVID-19, we demonstrated a worsening gradient of mortality from breast cancer to hematologic malignancies and showed that male gender, older age, and number of comorbidities identify a subset of patients with significantly worse mortality rates from COVID-19. Provision of chemotherapy, targeted therapy, or immunotherapy did not worsen mortality. Exposure to antimalarials was associated with improved mortality rates independent of baseline prognostic factors. This study highlights the clinical utility of demographic factors for individualized risk stratification of patients and supports further research into emerging anti–COVID-19 therapeutics in SARS-CoV-2–infected patients with cancer.
Significance:
In this observational study of 890 patients with cancer diagnosed with SARS-CoV-2, mortality was 33.6% and predicted by male gender, age ≥65, and comorbidity burden. Delivery of cancer therapy was not detrimental to severity or mortality from COVID-19. These patients should be the focus of shielding efforts during the SARS-CoV-2 pandemic.
This article is highlighted in the In This Issue feature, p. 1426
The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the ...prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe.
In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing.
As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 47·4% were women and 1822 52·6% were men, with a median age of 68 years IQR 57–77). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio OR 0·32 95% CI 0·19–0·61) and 28 days (0·34 0·16–0·79), complications due to COVID-19 (0·26 0·17–0·46), and hospitalisation due to COVID-19 (0·17 0·09–0·32), and had less requirements for COVID-19-specific therapy (0·22 0·15–0·34) and oxygen therapy (0·24 0·14–0·43) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten 25% of 40 patients vs 114 17% of 656) and at 28 days (11 27% of 40 vs 184 28% of 656) and similar rates of hospitalisation due to COVID-19 (18 43% of 42 vs 266 41% of 652) and complications from COVID-19 (13 31% of 42 vs 237 36% of 659) as those diagnosed during the alpha-delta phase.
Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19.
National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.
Trabectedin is an alkylating drug with a unique mechanism of action causing single-strand and double-strand DNA breaks that activate DNA damage-response pathways. Based on our preclinical data, we ...hypothesised that poly(ADP-ribose) polymerase 1 (PARP1) inhibitors might be an ideal partner of trabectedin and aimed to assess the safety, identify the recommended phase 2 dose, and explore preliminary signs of activity of trabectedin and olaparib combination treatment in patients with bone and soft-tissue sarcoma.
We did an open-label, multicentre, phase 1b study, recruiting patients from the national Italian sarcoma network aged 18 years and older with histologically confirmed bone and soft-tissue sarcoma progressing after standard treatments with Eastern Cooperative Oncology Group performance status of 1 or less. In a classic 3 + 3 design, patients received a 24 h infusion of trabectedin on day 1 and olaparib orally twice a day in 21-day cycles across six dose levels (trabectedin 0·675–1·3 mg/m2 every 3 weeks; olaparib 100–300 mg twice a day from day 1 to 21). Intermediate dose levels were permitted to improve safety and tolerability. The primary endpoint was determination of the recommended phase 2 dose (the maximum tolerated dose). Safety and antitumour activity were assessed in all patients who received at least one dose of the study drugs. We report the results of the dose-escalation and dose-expansion cohorts. The trial is still active but closed to enrolment, and follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT02398058.
Between Nov 17, 2014, and Jan 30, 2017, of 54 patients assessed for eligibility, we enrolled 50 patients: 28 patients in the dose-escalation cohort and 22 patients in the dose-expansion cohort. Patients received a median of four cycles of treatment (IQR 2–6; range 1–17 the patients who received the highest number of cycles are still on treatment) with a median follow-up of 10 months (IQR 5–23). Considering all dose levels, the most common grade 3–4 adverse events were lymphopenia (32 64% of 50 patients), neutropenia (31 62%), thrombocytopenia (14 28%), anaemia (13 26%), hypophosphataemia (20 40%), and alanine aminotransferase concentration increase (9 18%). No treatment-related life-threatening adverse events or deaths occurred. One (2%) patient interrupted treatment without progression without reporting any specific toxicity. Observed dose-limiting toxicities were thrombocytopenia, neutropenia for more than 7 days, and febrile neutropenia. We selected intermediate dose level 4b (trabectedin 1·1 mg/m2 every 3 weeks plus olaparib 150 mg twice a day) as the recommended phase 2 dose. Seven (14%; 95% CI 6–27) of 50 patients achieved a partial response according to Response Evaluation Criteria In Solid Tumors 1.1.
Trabectedin and olaparib in combination showed manageable toxicities at active dose levels for both drugs. Preliminary data on antitumour activity are encouraging. Two dedicated phase 2 studies are planned to assess activity of this combination in both ovarian cancer (EudraCT2018-000230-35) and soft-tissue sarcomas.
Italian Association for Cancer Research, Italian Sarcoma Group, Foundation for Research on Musculoskeletal and Rare Tumors, and Italian Ministry of Health.
Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST.
946 ...patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat.
At median follow-up of 760 days (IQR 644–859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0·82 95% CI 0·69–0·98; p=0·026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 16%
vs 282 60%) and treatment interruptions (189 40%
vs 302 64%) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58–172).
If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.
Rare primary malignant bone sarcomas (RPMBS) account for 5%-10% of primary high-grade bone tumors and represent a major treatment challenge. The outcome of patients with RPMBS enrolled in the ...EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S) is presented.
Inclusion criteria were as follows: age from 41 to 65 years and a diagnosis of high-grade spindle cell, pleomorphic, or vascular RPMBS. The chemotherapy regimen included doxorubicin 60 mg/m
, ifosfamide 9 g/m
, and cisplatin 90 mg/m
; postoperative methotrexate 8 g/m
was added in case of a poor histologic response. Version 2.0 of the Common Terminology Criteria for Adverse Events, Kaplan-Meier curves, log-rank tests, and univariate Cox regression models were used.
In total, 113 patients were evaluable for analysis. The median patient age was 52 years (range, 40-66 years), and 67 patients were men. Eighty-eight tumors were categorized as undifferentiated pleomorphic sarcomas (UPS), 20 were categorized as leiomyosarcomas, three were categorized as fibrosarcomas, and two were categorized as angiosarcomas. Eighty-three of 113 tumors were located in the extremities. Ninety-five of 113 patients presented with no evidence of metastases. After a median follow-up of 6.8 years (interquartile range IQR, 3.5-9.8 years), the 5-year overall survival rate for patients with localized disease was 68.4% (IQR, 56.9%-77.5%), and it was 71.7% (IQR, 58.1%-81.6%) for patients with UPS and 54.9% (IQR, 29.5%-74.5%) for patients with leiomyosarcoma. Grade III-IV hematologic toxicity was reported in 81% patients; 23% had grade II-III neurotoxicity, and 37.5% had grade I-II nephrotoxicity. Five-year overall survival was significantly better for patients with localized disease, for patients who obtained surgical complete remission, and when the primary tumor was located in the extremities.
The survival of patients who had RPMBS in the current series was similar to that of age-matched patients who had high-grade osteosarcoma treated according to the same protocol. An osteosarcoma-like chemotherapy may be proposed in patients who have RPMBS.
Tenosynovial giant cell tumour (TGCT) is a group of rare soft tissues neoplasia affecting synovial joints, bursae and tendon sheaths and is classified as localized type or diffuse type. The diffuse ...type (TGCT-D), also known as ‘pigmented villonodular (teno)synovitis’ is characterized by local aggressivity, with invasion and destruction of adjacent soft-tissue structures, and high local recurrence rate. Radical surgery remains the standard therapy while adjuvant radiotherapy may help to control local spread. Malignant TGCT is characterized by high rate of local recurrences and distant metastasis. Few cases of malignant TGCT and very few evidences on systemic therapies are described in the literature, so, to date, no systemic treatment is approved for this rare disease. We report the case of a malignant TGCT patient treated with many different systemic therapies, including chemotherapy and tyrosine-kinase inhibitors, and performed a review of the literature on the systemic treatment options of this rare tumour.
PDF
