Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: A Sarculator-based risk stratification analysis of the ISG-STS 1001 randomized trial.

BACKGROUND: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. METHODS: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%). RESULTS: The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105). CONCLUSIONS: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. LAY SUMMARY: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.

Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

BACKGROUND: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. METHODS: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. RESULTS: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01). CONCLUSIONS: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

Multimodality Treatment of Pediatric and Adult Patients With Ewing Sarcoma: A Single-institution Experience.

INTRODUCTION: The treatment of Ewing Sarcoma family of tumors is multimodal, both in children and adults. Axial location and metastases are classic prognostic factors. However, the worse prognosis in older patients is more controversial. METHODS: Retrospective analysis was performed of pediatric and adult patients treated with the 2001 SEOP protocol: 6 cycles of VIDE chemotherapy (CT). If no progression was observed, local (surgery and/or radiotherapy) and consolidation treatments were performed adjusted to prognosis: 8 cycles of VAC in standard-risk patients or 1 cycle of VAC and high-dose CT and autologous transplant in the case of increased risk.We analyzed induction CT toxicity, type of consolidation treatment, and disease-free (DFS) and overall (OS) survival by the Kaplan-Meier method, with a log-rank analysis of prognostic factors with regard to OS. RESULTS: Thirty-six patients were analyzed (2003 to 2011). Sixty percent were male, with a median age of 16 years (range, 7 to 57 y). The most frequent location was axial (43%), followed by extremities (34%), extraosseous (18%), and ribs (9%). Fifty-four percent of patients had metastases, of which, 58% were pulmonary.The median follow-up period was 36 months (5 to 101 mo). Median DFS was 25 months (16 to 34 mo) and median OS 29 months (19 to 40 mo), with a 3-year OS of 40%. Median OS from progression was 7 months (0.4 to 15 mo). Age <15 years and normal lactate dehydrogenase levels were associated with prolonged OS. CONCLUSIONS: Induction CT with the VIDE regimen was feasible in most patients, with a low risk for early progression. Hematological toxicity was substantial but manageable. Adult patients had a worse prognosis. Survival after progression was dismal.

Management of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practice.

CONTEXT: The combination of gemcitabine and erlotinib is a standard first-line treatment for unresectable, locally advanced or metastatic pancreatic cancer. We reviewed our single centre experience to assess its efficacy and toxicity in clinical practice. METHODS: Clinical records of patients with unresectable, locally advanced or metastatic pancreatic cancer who were treated with the combination of gemcitabine and erlotinib were reviewed. MAIN OUTCOME MEASURES: Univariate survival analysis and multivariate analysis were carried out to indentify independent predictors factors of overall survival. RESULTS: Our series included 55 patients. Overall disease control rate was 47%: 5% of patients presented complete response, 20% partial response and 22% stable disease. Median overall survival was 8.3 months). Cox regression analysis indicated that performance status and locally advanced versus metastatic disease were independent factors of overall survival. Patients who developed acne-like rash toxicity, related to erlotinib administration, presented a higher survival than those patients who did not develop this toxicity. CONCLUSIONS: Gemcitabine plus erlotinib doublet is active in our series of patients with advanced pancreatic cancer. This study provides efficacy and safety results similar to those of the pivotal phase III clinical trial that tested the same combination.

Neoadjuvant Chemotherapy in High-Grade Myxoid Liposarcoma: Results of the Expanded Cohort of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish Sarcoma Groups (PSG).

PURPOSE: A randomized trial was conducted to compare neoadjuvant standard (S) anthracycline + ifosfamide (AI) regimen with histology-tailored (HT) regimen in selected localized high-risk soft tissue sarcoma (STS). The results of the trial demonstrated the superiority of S in all STS histologies except for high-grade myxoid liposarcoma (HG-MLPS) where S and HT appeared to be equivalent. To further evaluate the noninferiority of HT compared with S, the HG-MLPS cohort was expanded. PATIENTS AND METHODS: Patients had localized high-grade (cellular component >5%; size ≥5 cm; deeply seated) MLPS of extremities or trunk wall. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). The trial used a noninferiority Bayesian design, wherein HT would be considered not inferior to S if the posterior probability of the true hazard ratio (HR) being >1.25 was <5%. RESULTS: From May 2011 to June 2020, 101 patients with HG-MLPS were randomly assigned, 45 to the HT arm and 56 to the S arm. The median follow-up was 66 months (IQR, 37-89). Median size was 107 mm (IQR, 84-143), 106 mm (IQR, 75-135) in the HT arm and 108 mm (IQR, 86-150) in the S arm. At 60 months, the DFS and OS probabilities were 0.86 and 0.73 (HR, 0.60 [95% CI, 0.24 to 1.46]; log-rank P = .26 for DFS) and 0.88 and 0.90 (HR, 1.20 [95% CI, 0.37 to 3.93]; log-rank P = .77 for OS) in the HT and S arms, respectively. The posterior probability of HR being >1.25 for DFS met the Bayesian monitoring cutoff of <5% (4.93%). This result confirmed the noninferiority of trabectedin to AI suggested in the original study cohort. CONCLUSION: Trabectedin may be an alternative to standard AI in HG-MLPS of the extremities or trunk when neoadjuvant treatment is a consideration.

Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups.

PURPOSE: To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall. PATIENTS AND METHODS: This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176). RESULTS: Between May 2011 and May 2016, 287 patients (UPS: n = 97 [33.8%]; HG-MLPS: n = 65 [22.6%]; SS: n = 70 [24.4%]; MPNST: n = 27 [9.4%]; and LMS: n = 28 [9.8%]) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank P = .323) and 0.76 and 0.66 (log-rank P = .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed. CONCLUSION: In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.

Controversies in the multimodality management of locally advanced rectal cancer.

Neoadjuvant radiotherapy previous to radical surgery, both as short-course radiotherapy and as long-course radiotherapy combined with 5-FU-based chemotherapy (LCRCT), is routinely used in the management of locally advanced rectal cancer, with consistent benefits in the reduction in the local relapse risk. Unfortunately, survival benefits have been elusive to demonstrate with this approach, especially in the setting of radical surgery in the form of total mesorectal excision (TME). Concerns about over-treating early-stage patients and about the possible long-term side effects have also cast more doubts in a blanket approach of treating all patients with neoadjuvant radiotherapy, especially with LCRCT. In this review of selected controversial topics in locally advanced rectal cancer, we examine the benefits and drawbacks for the use of both neoadjuvant approaches in the TME era, the role of the intensification of the neoadjuvant regimens with new chemotherapy agents and modifications of the radiotherapy regimen, the usefulness of adjuvant chemotherapy, especially after LCRCT and surgery, and the management of elderly and/or frail patients. Finally, we offer some future perspectives in the management of these patients.

Primary Mesenteric Undifferentiated Pleomorphic Sarcoma Masquerading as a Colon Carcinoma: A Case Report and Review of the Literature.

Undifferentiated pleomorphic sarcoma (UPS) is the most common sarcoma that appears in older patients, usually in the extremities and the retroperitoneum. Other locations are rare. By definition, in UPS, although the malignant cells tend to appear fibroblastic or myofibroblastic, they should not show differentiation towards a more specific line of differentiation. In this sense, we report the case of an 80-year-old patient with an initial clinical diagnosis of a locally advanced colonic neoplasm that was later confirmed as a primary mesenteric UPS. Primary mesenteric UPS are extremely rare with less than 20 cases reported. We also review the pathologic and radiologic diagnostic criteria and the natural history of these tumours.

Adjuvant chemoradiation in gastric cancer: long-term outcomes and prognostic factors from a single institution.

BACKGROUND: Adjuvant chemoradiotherapy (CRT) improves relapse-free (RFS) and overall survival (OS) in patients with resected gastric cancer. However, difficulties in standardizing an optimal surgical approach and a perceived higher toxicity compared with the perioperative approach have limited its widespread application in Europe. The aim of our study was to assess toxicity and long-term outcomes of adjuvant CRT at our institution. METHODS: A retrospective review (September 2001-January 2012) was completed of patients with resected gastric cancer who received adjuvant CRT (Macdonald regimen). Adverse events and completion rates, RFS and OS were estimated. Univariate and multivariate analyses of prognostic factors for OS were performed. RESULTS: Eighty-seven patients were included. Most had diffuse (52%) and locally advanced tumors (stage III-IV; 66.7%). D2 lymphadenectomy was performed in 80.5%. The most frequent grade 3-4 toxicities were gastrointestinal (28%) and stomatitis (20%), with 78.2% completing treatment. With a median follow-up of 115 months, 58.5% had relapsed, most of them distantly. Median RFS and OS were 9 and 24 months, respectively. Univariate analysis showed that performance status, stage and lymph node burden were significant factors for OS. In the multivariate study, only stage and lymph node burden remained as independent OS predictors. CONCLUSIONS: Our implementation of the Macdonald regimen achieved worse outcomes than those reported in the INT-0116 trial. The rate of distant relapse remains unacceptably high. Higher rate of positive lymph nodes and of diffuse tumors could explain some differences. The use of perioperative chemotherapy, especially in patients with a poorer prognosis, might improve these results.

Pleuropulmonary angiosarcoma involving the liver, the jejunum and the spine, developed from chronic tuberculosis pyothorax: Multidisciplinary approach and review of literature.

Pleuropulmonary angiosarcomas are very rare, with less than fifty cases reported in the literature. In most cases, the etiology is unknown but the presence of a chronic tuberculous pyothorax has been reported in several Asian case reports as a possible risk factor. We report the case of a Caucasian 68-year old man who presented with a pleuropulmonary angiosarcoma that arose from a chronic tuberculous pyothorax and which involved the ribs and the vertebrae, the psoas muscle, and the jejunum. The patient received adapted anti-tuberculosis treatment, embolization of the mass in the small bowel, palliative external beam radiotherapy on the spine and systemic chemotherapy with liposomal non-pegylated doxorubicin and ifosfamide. With this multidisciplinary approach the patient's symptoms were well controlled and he achieved a complete metabolic response after six cycles of chemotherapy. Unfortunately, the patient died after eight months from the beginning of chemotherapy due to an acute lung injury secondary to extensive bilateral interstitial infiltrates. Opportunistic pathogens or drug-induced lung toxicity were the most probable causes. Treatment with liposomal non-pegylated doxorubicin and ifosfamide could be a reasonable option in pleuropulmonary angiosarcoma but it should be validated in clinical trials. Chronic pyothorax seems to be a predisposing factor for the development of pleural angiosarcoma but further investigations are required to assess a causal association.

Long-term results with oral fluoropyrimidines and oxaliplatin-based preoperative chemoradiotherapy in patients with resectable rectal cancer. A single-institution experience.

INTRODUCTION: Neoadjuvant 5-FU-based chemoradiotherapy in resectable rectal cancer (RC) is a standard of treatment. The use of oral fluoropyrimidines and new agents such as oxaliplatin may improve efficacy and tolerance. MATERIAL AND METHODS: Between 1999 and 2009, 126 RC patients with T3-T4 and/or N+ disease were given three successive protocols: UFT (32), UFT-oxaliplatin (75) and capecitabine-oxaliplatin (19), alongside 45 Gy of radiotherapy; with surgery 4-6 weeks after. Adjuvant treatment was given in all patients. The primary objective was pathologic complete response (pCR). RESULTS: Preoperative therapy was well tolerated, with no toxic deaths and a 15% grade 3-4 toxicity rate. Eighty-five percent of patients received the full chemotherapy dose, 56% had an abdominoperineal resection, 6% reinterventions and 57% received the full adjuvant chemotherapy planned. The pCR rate was 13%. The downstaging rate was 80%; 8% had progression of disease. The relapse rate was 20%, with local relapse in 6%. By 5 years of followup, 92% of relapses had occurred. Median follow-up was 73 months, 5- and 10-year disease-free survival rates were 75% and 50%, and 5- and 10-year overall survival rates were 79% and 66% respectively. There was no benefit from the use of oxaliplatin regarding survival or pCR rates. Older patients had worse long-term outcomes. CONCLUSIONS: Neoadjuvant chemoradiotherapy with oral fluoropyrimidines and oxaliplatin is feasible and well tolerated. The risk of early progression is low. However, there was no added benefit with the use of oxaliplatin. There were no relapses in patients with pCR. The role of adjuvant chemotherapy is unclear.

Orbital and myocardial metastases of a primary pulmonary melanotic schwannoma.

We present the case of a 60-year-old man with a primary pulmonary melanotic schwannoma treated with surgery and who developed an orbital and myocardial relapse 2 years after the initial diagnosis. Melanotic schwannomas are rare pigmented tumours that tend to arise from the peripheral nerves near the midline. A primary lung presentation, as in our case, is extremely rare. In more than half of cases, the Carney triad of myxomas of the heart, skin and breast, spotty pigmentation and endocrine hyperactivity is present. A thorough pathological study is pivotal for a correct diagnosis. The main differential diagnosis is with metastases of malignant melanoma. The biological behaviour is unpredictable. Treatment should include radical surgery if possible; the role of chemotherapy and radiotherapy is uncertain due to the rarity of the tumour.