Treatment-related Fatalities Research Articles

A phase 2 trial of gemcitabine plus toripalimab for cisplatin-ineligible patients with recurrent or metastatic nasopharyngeal carcinoma

Cisplatin is a cornerstone chemotherapy for nasopharyngeal carcinoma (NPC); however, certain patients are ineligible for cisplatin-based regimens. This phase 2 trial (NCT04405622) evaluated the efficacy and safety of gemcitabine and toripalimab in previously untreated patients with recurrent or metastatic NPC who were either ineligible for cisplatin or had experienced severe adverse events from prior cisplatin-based treatments. Patients received gemcitabine (1,000mg/m2) and toripalimab (240mg) every three weeks for six cycles, followed by toripalimab monotherapy for up to two years. The primary endpoint was the incidence of grade ≥3 adverse events, while secondary endpoints included objective response rate (ORR) and overall survival (OS). Of 30 screened patients, 21 were enrolled. No treatment-related fatalities occurred, with the most frequent adverse events being headache and nausea. The ORR was 61.9%, coupled with a disease control rate of 100%. Overall, gemcitabine plus toripalimab demonstrated low toxicity and promising efficacy for this specific patient cohort.

Neoadjuvant tislelizumab with afatinib for locally advanced head and neck squamous cell carcinoma (neoCHANCE-1): An open-label, single-arm, phase 2 study.

6073 Background: For patients with locally advanced head and neck squamous cell carcinoma (HNSCC), even receiving surgery with adjuvant radiotherapy or chemoradiotherapy, those remain at high risk of recurrence or metastasis. Neoadjuvant immunotherapy has been used in HNSCC, but provides only modest pathological response. Given single agent activity and unique mechanism of action of immune checkpoint inhibitors and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), we aimed to evaluate the antitumour activity and safety of neoadjuvant PD-1 blockade with EGFR inhibition in locally advanced HNSCC. Methods: This open-label, single-arm, phase 2 trial was done at a a tertiary hospital in China. Eligible patients were aged 18 years or older and had resectable HNSCC disease, had an Eastern Cooperative Oncology Group performance status of 0–1, had at least one measurable target lesion according to the RECIST 1.1, had no prior antitumor therapy for HNSCC. Patients received neoadjuvant treatment with intravenous tislelizumab (200 mg) on the first day of each 3 week, with totally two cycles and orally afatinib (30 mg) starting on the first treatment day and ending on the day before surgery, with totally six weeks, and then patients proceeded to receive surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. Results: A total of 25 patients were enrolled completed the neoadjuvant therapy. Eight of 23 evaluable patients exhibited a major pathological response (MPR) (35%; 95% confidence interval [CI], 16%—57%), of which four had a complete pathological response of primary tumor (17%, 95%CI, 5%—39%). The overall response rate was 48% (12/25, 95%CI: 28%—69%) and disease control rate was 100% (25/25, 95%CI: 86%—100%). Common grade 3—4 adverse events included diarrhea (5/25 [20%]), hypokalemia (4/25 [16%]) and rash (3/25 [12%]). No treatment related fatalities were observed. Immunologically, post-neoadjuvant treatment demonstrated increased CD3, CD8, and CD56 expression within the tumor microenvironment. The increase of CD8 and CD56 expression level was significant higher in patients achieving MPR, along with elevated circulatory NK cells at baseline, compared to those in patients achieving non-MPR. Conclusions: This study underscores encouraging antitumor activity, manageable toxicity profile and promising immune activation elicited by neoadjuvant tislelizumab plus afatinib for HNSCC, which deserves further assessment. Clinical trial information: NCT05517330 .

Efficacy and safety of regorafenib plus ICIs as second-line treatment in advanced HCC post-frontline treatment failure: A real-world study from a single center.

e16141 Background: Tyrosine kinase inhibitor or bevacizumab (TKI/Bev) combined with immune checkpoint inhibitors (ICIs) currently represent the preferred frontline therapy for patients with Hepatocellular Carcinoma (HCC). Despite this, clinical evidence guiding therapeutic choice for patients unresponsive to this initial immunotherapy regimen remains scarce. This real-world study aimed to assess the efficacy and safety of regorafenib combined with ICIs in patients with HCC who have exhibited disease progress during treatment with TKI/Bev plus ICIs. Methods: This retrospective analysis encompassed a cohort of patients who transitioned to a combined regimen of regorafenib and immune checkpoint inhibitors (ICIs) after the progression of hepatocellular carcinoma (HCC) following treatment with tyrosine kinase inhibitors (TKIs) or a combination of bevacizumab and ICIs, from January 2019 to November 2023. Key efficacy metrics included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were systematically classified in accordance with the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). Results: A total of 37 patients were included; 56.8% were Child-Pugh A and 43.2% were Child-Pugh B. Treatment regimens prior to regorafenib and ICIs were lenvatinib plus ICIs in 83.8% of patients, sorafenib plus ICIs in three patients, apatinib plus ICIs, donafenib plus ICIs, and bevacizumab plus ICIs each in one patient. The ORR was 27.0% (10/37), and the DCR was 92.0% (28/37) according to mRECIST criteria. The median PFS was 7.8 months (95% CI, 6.0-9.6). The 6-month and 12-month PFS rates was 60.6% (95% CI, 46.4-79.2) and 40.0% (95% CI, 26.0%-61.6%). The median OS post-regorafenib and ICIs was 16.3 months, with 12-month and 24-month OS rates of 67.0% and 49.7%, respectively. The median OS since first-line treatment initiation was 35.8 months, with OS rates of 94.4% and 72.3% at 12-month and 24-month since first-line treatment initiation, respectively. Subgroup analysis indicated no statistical significance in median PFS between patients with lung metastasis and those without lung metastasis [3.9 months (95% CI, 3.0-4.8) vs 7.80 months (95% CI, 6.1-9.5); P=0.178], but there was a trend toward survival benefit in patients without lung metastasis. Grade 3-4 adverse events were reported in 16.22% of the patients, with no treatment-related fatalities. Conclusions: Regorafenib with ICIs is a promising and tolerable second-line treatment for advanced HCC after initial therapy failure.

Re-irradiation versus systemic therapy for the management of local-regionally recurrent head and neck cancer

PurposeThe optimal management of local-regionally recurrent head and neck cancer that is not amenable to surgical resection is uncertain. We sought to compare outcomes among patients treated with and without re-irradiation in this setting. Methods and MaterialsA review of institutional registries identified 65 patients with local-regionally recurrent squamous cell carcinoma of the head and neck who were ineligible for surgery. Forty patients (62 %) opted for re-irradiation with the remaining 25 patients (38 %) undergoing initial systemic therapy alone. All patients had measurable disease. Forty-three patients (66 %) were male and twenty-two (33 %) were female. The median age at the time of recurrence was 59 years (range, 39–84 years). The most common primary sites of disease were the oropharynx, (n = 25), oral cavity (N = 19), and nasopharynx (n = 11). The median interval from completion of prior radiation to the diagnosis of recurrent disease was 35 months (range, 2–102 months). ResultsRe-irradiation improved 2-year overall survival, (32 % versus 11 %), progression-free survival (31 % versus 7 %), and local–regional control (39 % versus 3 %) compared to systemic therapy alone (p < 0.05, for both). The likelihood of developing any new grade 3+ toxicity was significantly higher among patients treated by re-irradiation compared to those treated by systemic therapy (53 % vs. 28 %, p < 0.001). There were 3 treatment-related fatalities, all of which occurred in the re-irradiation group. The incidence of grade 3+ late toxicity was 48 % and 12 % for patients in the re-irradiation and systemic therapy cohorts, respectively (p < 0.001). ConclusionAlthough re-irradiation improved overall survival compared to systemic therapy for appropriately selected patients with local-regionally recurrent head and neck cancer, the relatively high risk of toxicity must be considered.

Therapeutic efficacy of rare earth carbonate with chemoradiotherapy in late-stage non-small cell lung cancer: a cohort prospective study.

To compare the therapeutic effects and adverse reactions of sterilizing rare earth carbonate combined with concurrent chemoradiotherapy and simple concurrent chemoradiotherapy in the treatment of late-stage non-small cell lung cancer (NSCLC), and to analyze the reasons for the differences. A total of 817 patients with pathologically diagnosed late-stage NSCLC from June 1, 2021 to December 30, 2022, in the affiliated hospital of Kunming University of Science and Technology, were selected. They were randomly divided into a control group of 394 people and an experimental group of 423 people. The control group was given concurrent chemoradiotherapy (cisplatin + etoposide), while the experimental group simultaneously took a low dose of sterilized rare earth carbonate (0.05mg/Kg). The χ² test and Fisher's test were used to compare the clinical pathological features, objective response rate (ORR), ECOG score, and adverse reactions of the two groups of patients, while survival analysis was used to compare the progression-free survival (PFS) of the two groups. Cox regression analysis was used to test factors related to prognosis. The differences in clinical pathological features between the two groups of patients were not statistically significant, with all P>0.05. The ORR of the control group was 45.18% (178/394), and the experimental group was 89.83% (380/423), with a statistically significant difference (P=0.001). After treatment, the ECOG score of the experimental group was lower than that of the control group, P<0.001. The adverse reaction grading of patients in both groups was below level 3 after treatment, and no treatment-related fatalities occurred. The risk of pulmonary infection and bone marrow suppression in the experimental group was lower than that in the control group. In late-stage NSCLC patients, compared with simple concurrent chemoradiotherapy, the combination of concurrent chemoradiotherapy and sterilizing rare earth carbonate can significantly improve the short-term therapeutic effect and prognosis of patients, with good safety.

Inotuzumab Ozogamicin in Lymphoid B Cell Malignancy：a Single Center Analysis in the Real World

Background : Recent developments in immunoconjugate usage has changed the landscape of lymphoid B-cell malignancy therapy. Historically, those who relapse from this condition have a dismal prognosis and limited treatment options. One recent development is the inotuzumab ozogamicin (INO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, which has the potential to reduce the overall toxicity of intensive regimens for ALL, as well as to show therapeutic effects in lymphoid B-cell malignancy. Aims and Methods: The study included B cell-acute lymphoblastic leukemia (B-ALL) (n=23), B/ myeloid mixed phenotype acute leukemia (MPAL) (n=1) and B-cell lymphoblastic lymphoma (B-LBL) (n=3) adult patients who received INO in our center from June 2022 to June 2023. Intravenous INO was given 1 or more doses at the dose of 0.6mg/m2, its clinical efficacy and adverse reactions were explored. Results: In our center, INO was strategically employed in various therapeutic scenarios: induction (n=2), maintenance/consolidation (n=6), minimal residual disease (MRD) clearance (n=5), and the management of relapsed/refractory lymphoid B-cell malignancies (n=14). Of the 27 patients, 14 were subjected to a combination regimen of INO and chemotherapy for recurrent and refractory lymphoid B-cell malignancy. The composition of these patients comprised of 4 individuals who experienced a relapse post-standard chemotherapy, 1 patient with a relapse post-allogeneic hematopoietic stem cell transplantation (allo-HSCT), 4 patients with a relapse post-autologous hematopoietic stem cell transplantation (auto-HSCT), and the remaining 5 patients were categorized as refractory cases. The median number of doses administered was 2 (1-3). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was observed in 9 out of 14 patients (64.3%) within a median duration of 30 (16-78)days. Partial response (PR) was noted in 2 of the 14 patients (14.3%), rendering the overall response rate (ORR) to be 78.6%. Negative MRD was observed in 7 out of 14 patients (50.0%). Of the 9 patients who achieved CR/CRi, 4 (44.4%) relapsed again with 2 fatalities. The remaining 2 patients attained negative MRD following a second allo-HSCT or INO retreatment. The two patients who achieved PR proceeded to receive chimeric antigen receptor T cell (CART) treatment, with one of them subsequently undergoing allo-HSCT after achieving CR. For the three non-responders (NR), one patient unfortunately passed away while the other two patients remained alive and were either participating in clinical trials or undergoing allo-HSCT after CART. For MRD clearance, it was successfully achieved in 4 out of 5 patients (80.0%)treated with INO within a median period of 45 (28-52)days. However, 2 patients reverted to MRD positivity and 1 died. The other four patients underwent allo-HSCT with neither mortality nor recurrence observed. Moreover, two patients (100%) were treated with a VICLP induction regimen combined with INO, with MRD negativity observed post-treatment. Regarding the remaining six patients, three patients were treated with INO as consolidation therapy due to high-risk factors or the intention to undergo auto-HSCT. Another 3 B-ALL patients treated with INO as maintenance therapy after auto-HSCT or after the remission of recurrence after transplantation. One patient unfortunately experienced a second recurrence four months following INO maintenance. The remaining five patients achieved and have since sustained negative MRD status, preceding INO treatment. Fortunately, no treatment-related fatalities or treatment discontinuation due to adverse events were observed. Notably, 19 out of 27 patients (70.4%) experienced Grade 3-4 hematological toxicity, while 1 out of 24 patients (4.2%) exhibited Grade 3 alanine aminotransferase (ALT) elevation. Veno-occlusive disease (VOD) was not observed. Furthermore, two patients developed septicemia, one each from Escherichia coli and Klebsiella pneumoniae, respectively. Conclusions: Given the well tolerance and improvement in response rates, InO may be an important treatment option not only for patients with relapsed/refractory lymphoid B-cell malignancy, but also for induction, maintenance and MRD clearance treatment. Key words: inotuzumab ozogamicin, acute lymphoblastic leukemia, hematopoietic stem cell transplantation, CD22

"Sandwich" protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.

Clinical outcomes of hepatocellular carcinoma patients after hepatectomy treated with TACE in combination with sorafenib: a propensity score matched analysis.

To assess the long-term effects of transarterial chemoembolization (TACE) combined with sorafenib versus TACE alone procedures in recurrent patients with unresectable hepatocellular carcinoma (HCC). A total of 381 recurrent patients treated with partial hepatectomy undergoing either TACE + sorafenib treatment or TACE alone were included in this retrospective research. To minimize bias brought on by confounding factors, propensity score matching (PSM) was used. The clinical effectiveness, complications, and negative responses of two groups were noted. Overall survival (OS) was the main result. The secondary outcome was time to target tumor progression (TTTP). The risk variables for OS were investigated using the Cox proportional hazards model. There were 32 individuals in each group following PSM. According to mRECIST (modified response evaluation criteria in solid tumors), patients receiving TACE + sorafenib had a significantly longer TTTP compared to patients receiving sorafenib alone (P=0.017). The median OS was 48.5 months with TACE plus sorafenib and 41.0 months with TACE alone. At 5 years, however, survival was comparable between groups (P=0.300). In the combination group, the most frequent side effect was hand-foot skin reaction (81.3%), whereas, in the monotherapy group, the most frequent side effect was fatigue (71.9%). In neither group were there any treatment-related fatalities. Although TACE plus sorafenib did not significantly lengthen OS compared to TACE alone, it did considerably enhance TTTP.

P-138 Real-world delivery, toxicity and outcomes of perioperative FLOT chemotherapy in resectable gastric/gastroesophageal adenocarcinoma: A population-based study

Perioperative docetaxel, oxaliplatin and fluorouracil/leucovorin (FLOT) has become the new standard of care for resectable gastric/ gastroesophageal adenocarcinoma since publication of the FLOT-AIO clinical trial. However, delivery, toxicity, and outcomes of this regimen in routine practice have not been widely studied. Data from Surveillance and Reporting group of Cancer Control Alberta was used to obtain data of all patients with resectable gastric and GEJ adenocarcinoma, who were treated with perioperative FLOT chemotherapy in the province of Alberta, Canada between August 1, 2017 and August 1, 2020. Charts were retrospectively reviewed for baseline demographics, cumulative doses and number of cycles received, chemotherapy-related toxicities and hospitalizations, extent of surgical resection achieved and disease-free and overall survival. Toxicities were graded using CTCAE v5 criteria. In total, 48 patients met inclusion criteria. Median age of patients was 60 and 54% (26/48) were male. Of those with reported pre-treatment ECOG and clinical stage, 94% (30/32) were ECOG ≤1 and 57% (21/37) clinical stage ≤2. Ninety-six percent (46/48) of patients completed 4 cycles of pre-operative FLOT and 94% (45/48) proceeded to surgery, while only 50% (24/48) completed 4 cycles of post-operative FLOT. Twenty-nine percent (14/48) of patients required hospitalization with a chemotherapy-related toxicity, most commonly from a gastrointestinal bleed (6/14) or infection (6/14). Pathological complete response was observed in 8.3% of patients (4/48). Fifty percent of patients (24/48) experienced a grade ≥3 chemotherapy-related toxicity. There were no treatment-related fatalities. Median overall survival and disease-free survival were 26.2 and 16.5 months respectively. In this real-world study, perioperative FLOT chemotherapy was feasible. Rates of treatment completion of all cycles, grade ≥3 toxicities and hospitalizations secondary to chemotherapy were high, but similar to those seen in the randomized trial. Median overall survival was considerably less than in the randomized trial, but this is likely due to short follow-up time. Further study is required to understand factors associated with completion of chemotherapy and overall survival in routine practice.

Acute and 28-Day Repeated Dose Subacute Toxicological Evaluation of Coroprotect Tablet in Rodents

Introduction: Ayurvedic medications are extensively used across the world for illness prevention and treatment. The components found in the Coroprotect tablet are Ashwagandha ext., Suddhashilajit ext., Giloyext., Dadim ext., Haridra ext., Saragavo ext., Brahmi ext., Papaya ext., Methiext., Punarnava ext., Kalmegh ext.etc. all are found to be safe and used in Ayurvedic system since many years. Objective: In Rodents, acute and subacute toxicity of coroprotect tablet was studied after a single and repeated 28-day oral dosage administration. Method: In acute toxicity testing, 2000 mg/kg single dose of coroprotect tablet have been employed, whereas doses of 100, 200, 400mg/kg have been utilized in subacute toxicity testing over a 28-day period in rodents. Result: With coroprotect tablet administration, no treatment-related fatalities or toxic signshave been identified in an acute toxicity investigation. There have been no significant variations in body weight changes, water/food intake, haematology, or clinical biochemistry content among the control and coroprotect tablet groups in the repeated dosage research. Between the control and coroprotect pill groups, no gross pathological abnormalities or differences in relative organ weights were found. With coroprotect tablet therapy, histopathological investigation indicated no abnormalities. Conclusion: In a repeated dosage toxicity study in rodents, the coroprotect tablet was determined to be safe at all dose levels.

Real-world evaluation of second line chemotherapy for patients with advanced non-small cell lung cancer harboring preexisting interstitial lung disease.

The optimal second and subsequent lines of chemotherapy for patients with non-small cell lung cancer (NSCLC) who have preexisting interstitial lung disease (ILD) are unclear. Hence, we examined the clinical efficacy and safety of second-line chemotherapy in such patients, including any exacerbation of preexisting ILD. The medical records of patients with NSCLC and preexisting ILD who received both first- and second-line chemotherapy were retrospectively reviewed. Twenty-four patients with a median age of 71years who were treated between April 2013 and March 2021 were included. The response rate after second-line chemotherapy with S-1 (n = 13), docetaxel (n = 8), pemetrexed (n = 2), or docetaxel plus ramucirumab (n = 1) was 12.5%, with a median progression-free survival (2nd line PFS) of 3.8months. The overall survival from a start of first-line chemotherapy (1st line OS) and post-progression survival (PPS) post-first-line chemotherapy were 18.7 and 9.7months, respectively. Spearman rank correlation and linear regression analyses showed that PPS was strongly correlated with 1st line OS (R = 0.85, P < 0.00001). Importantly, the 2nd line PFS was also significantly correlated with 1st line OS (R = 0.71, P = 0.0001). While second-line chemotherapy-related acute exacerbation of ILD was observed in 7 patients (29.2%), there were no treatment-related fatalities. Conslusions. Second-line chemotherapy has a strong positive impact on the OS of patients with NSCLC who have preexisting ILD. Given the findings of this study, second-line chemotherapy may be valuable in terms of prolonging long-term OS.

Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-up of an Open-Label Phase II Trial

Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-up of an Open-Label Phase II Trial

Clinical aspects of hymenoptera venom allergy and venom immunotherapy.

Hymenoptera venom allergy (HVA) is the most frequent cause of anaphylaxis in Europe, accounting for most of the severe reactions occurring in adults, and being the second cause of anaphylaxis in children. Prevention of further episodes in patients who developed a systemic reaction (SR) is based on the correct management of the allergic emergency, the referral to an allergist for a correct diagnosis, prescription of adrenaline auto-injectors (AAI) and specific venom immunotherapy (VIT), if recommended. Diagnosis is based on the classification of the type of reaction, confirmation of an IgE-mediated pathogenesis and the identification of the offending insect. The use of component resolved diagnostics may be helpful in case of poly-sensitization or negative allergy tests with a proven history of previous SRs. When a severe SR occurs, baseline serum tryptase levels should always be assessed. The prescription of AAI is recommended or suggested for untreated patients, patients undergoing VIT and after discontinuation of treatment, according to multiple evidence. VIT is the most effective treatment available for HVA patients, as confirmed by recent European guidelines. VIT has an early, sustained and persistent protective effect and modifies the natural course of the disease. Moreover, VIT proved to be safe and well tolerated. According to a recent systematic review, no treatment-related fatalities were recorded to date. Compared to AAI, VIT significantly improves the quality of life of HVA patients by reducing the anxiety and limitations in daily activities caused by the fear of stinging insects. The memory of a life-threatening experience is the most likely reason why adherence to VIT is higher compared to immunotherapy with inhalant allergens. Several risk factors in HVA have been identified that can influence not only the severity of sting reactions in untreated patents, but also the occurrence of side effects, treatment effectiveness and the risk of relapse after discontinuation of VIT. Patient and treatment-related risk factors must be considered while selecting the best candidates for VIT, the type and duration of treatment. In this paper we address the most important issues related to HVA and VIT that may have an impact on daily clinical practice.

Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease.

BackgroundMetastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M‐PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy.MethodsRetrospective analysis of outcomes data of UM patients receiving M‐PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively.ResultsA total of 51 patients received 134 M‐PHP procedures (median of 2 M‐PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow‐up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non‐hematologic grade 3‐4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9).ConclusionsM‐PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.

MRI-guided radiotherapy for head and neck cancer: initial clinical experience.

To report a single-institutional experience with the use of magnetic resonance imaging (MRI)-guided radiotherapy for cancers of the head and neck. Between October 2014 and October 2016, 18 patients with newly diagnosed cancers of the head and neck were prospectively enrolled on an institutional registry trial investigating the feasibility and efficacy of external-beam radiotherapy delivered using on-board MRI. All patients had biopsy-proven evidence of malignancy, measurable disease, and the ability to provide consent. None had previously received any treatment. Median dose was 70Gy (range 54-70Gy). MRI scans were obtained as part of an image-guided registration protocol for alignment prior to and during each treatment. Concurrent chemotherapy was administered to 14 patients (78%). Patient-reported outcomes were assessed using the University of Washington quality of life instrument. Seventeen of 18 patients completed the planned intensity-modulated radiotherapy (IMRT) treatment of which 15 (83%) had a complete response and 2 (11%) had a partial response based on initial post-therapy positron emission tomography (PET) at 3months. The 1-year estimates of progression-free survival, overall survival, and local-regional control were 95, 96, and 95%, respectively. There were no treatment-related fatalities. The incidence of grade 3+ acute toxicity was 44%. The proportion of patients rating their health-related quality of life as "very good" or "outstanding" at 6months and 1year after completion of radiation therapy was 60 and 70%, respectively. MRI-guided radiotherapy achieves clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Magnetic resonance imaging guided reirradiation of recurrent and second primary head and neck cancer

PurposeTo report a single-institutional experience using magnetic resonance imaging (MRI) guided radiation therapy for the reirradiation of recurrent and second cancers of the head and neck. Methods and materialsBetween October 2014 and August 2016, 13 consecutive patients with recurrent or new primary cancers of the head and neck that occurred in a previously irradiated field were prospectively enrolled in an institutional registry trial to investigate the feasibility and efficacy of MRI guided radiation therapy using a 0.35-T MRI scanner with a cobalt-60 radiation therapy source called the ViewRay system (ViewRay Inc., Cleveland, OH). Eligibility criteria included biopsy-proven evidence of recurrent or new primary squamous cell carcinoma of the head and neck, measurable disease, and previous radiation to >60 Gy. MRI guided reirradiation was delivered either using intensity modulated radiation therapy with conventional fractionation to a median dose of 66 Gy or stereotactic body radiation therapy (SBRT) using 7 to 8 Gy fractions on nonconsecutive days to a median dose of 40 Gy. Two patients (17%) received concurrent chemotherapy. ResultsThe 1- and 2-year estimates of in-field control were 72% and 72%, respectively. A total of 227 daily MRI scans were obtained to guide reirradiation. The 2-year estimates of overall survival and progression-free survival were 53% and 59%, respectively. There were no treatment-related fatalities or hospitalizations. Complications included skin desquamation, odynophagia, otitis externa, keratitis and/or conjunctivitis, and 1 case of aspiration pneumonia. ConclusionsOur preliminary findings show that reirradiation with MRI guided radiation therapy results in effective disease control with relatively low morbidity for patients with recurrent and second primary cancers of the head and neck. The superior soft tissue resolution of the MRI scans that were used for planning and delivery has the potential to improve the therapeutic ratio.

Defibrotide for the Treatment of Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with/without Multi-Organ Dysfunction Following Chemotherapy: Results from an Ongoing Expanded Access Program

IntroductionHepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Although VOD/SOS usually is thought of as a complication of HSCT, there is also a known risk in patients following chemotherapy in a non-HSCT setting. Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Endothelial cell (EC) damage is a critical factor in the pathophysiology of VOD/SOS. Preclinical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance. Defibrotide is approved for treatment of severe hepatic VOD/SOS in adult and pediatric patients in the European Union. In the United States, defibrotide is available as an investigational drug through an ongoing expanded-access protocol for treatment of hepatic VOD/SOS.MethodsIn the original protocol, patients were eligible if they had hepatic VOD/SOS by Baltimore criteria post-HSCT and MOD, defined by renal (tripling of creatinine levels or reduced creatinine clearance with or without dialysis) and/or pulmonary (need for oxygen supplementation with or without assisted ventilation) dysfunction. Symptoms of VOD/SOS were not considered adverse events (AEs) unless the event was considered serious. The protocol was later amended to include (1) post-chemotherapy patients with hepatic VOD/SOS; (2) patients with hepatic VOD/SOS without MOD, and (3) VOD/SOS per modified Seattle criteria. Enrolled patients received defibrotide 25 mg/kg/d in 4 divided doses for a recommended ≥21 days. Here, we describe efficacy and safety results with defibrotide for the subset of patients that developed VOD/SOS post-chemotherapy.ResultsOut of 642 patients who developed VOD/SOS and received ≥1 dose of defibrotide, 69 patients received chemotherapy without HSCT; 52% (n=36) had MOD, and 48% (n=33) did not. Median age was 8 years (range, <1 month-58.0 years), and 55 patients (80%) were ≤16 years (39 patients were children aged 2-11); 54% of patients were male. The most common primary diseases were acute lymphocytic leukemia (44%) and acute myelogenous leukemia (10%). Chemotherapeutic agents received by more than 30% of patients were vincristine, cyclophosphamide, cytarabine, doxorubicin, methotrexate and PEG-L-asparaginase. Antibody-drug conjugates linked to ozogamicin that are associated with development of VOD/SOS (gemtuzumab and inotuzumab) were received by 3 and 1 patient, respectively.The Kaplan-Meier estimated day +100 survival rate was 77.4% (95% confidence interval, 65.4%-85.7%). For patients with MOD and without MOD, the Kaplan-Meier estimated day +100 survival rates were 74.3% (56.4%-85.7%) and 80.9% (62.3%-90.9%), respectively.Overall, ≥1 AE was reported in 44 chemotherapy patients (63.8%). Of these, 14 (20.3%) had AEs assessed by the investigator as possibly, probably, or definitely related to defibrotide. Treatment-related AEs occurring in ≥2 patients were hypotension (4.3%), nausea (2.9%), vomiting (2.9%), and epistaxis (2.9%). Hemorrhagic AEs of any severity occurring in ≥2 patients were pulmonary (7.2%), epistaxis (5.8%), and gastric (2.9%). Serious AEs were reported in 26 patients (37.7%), most commonly multi-organ failure (7.2%), hypoxia (5.8%), and pulmonary hemorrhage (5.8%). AEs led to discontinuation in 4 patients (gastric, gastrointestinal and mouth hemorrhages, epistaxis, and hypotension). No treatment-related deaths were reported.ConclusionsDay+100 survival of 77.4% in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT (80% of which were pediatric, primarily children) is a clinically encouraging finding. Defibrotide treatment in this group of 69 patients developing VOD/SOS post-chemotherapy was generally well-tolerated, with only 5.8% of patients discontinuing due to an AE and no treatment-related fatalities. Enrollment to the study continues.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresKernan:Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis: Consultancy, Research Funding. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Limited-Stage Small-Cell Lung Cancer: An Age Limit for Combined Modality Therapy?

Limited-Stage Small-Cell Lung Cancer: An Age Limit for Combined Modality Therapy?

Intensive alternating 6-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma in children and adolescents: Impact on survival.

9566 Background: Both 5-year overall survival (OS) and event free survival (EFS) for pediatric rhabdomyosarcoma (RMS) has increased in the last 3 decades through multimodality, risk-adapted management. The reported EFS for high risk RMS in children treated at the NCI in Egypt during the 1990s was 50%. Using an intensive 6 drug alternating chemotherapy regimen in addition to local control measures was our aim to improve the outcome for this group of patients. Methods: Forty-six previously untreated patients, younger than 21 years of age, with localized high risk RMS received this regimen. High risk criteria included: (1) Localized tumors (T1) biopsied or incompletely resected, ortumors extending beyond the tissue or organ of origin (T2) completely or incompletely resected at any site (excluding orbit, uterus, vagina, and paratestis); (2)All node positive patients with primary tumor at any site; and (3) All RMS with alveolar histology at any site. Chemotherapy regimen comprised 27 weeks of alternating 6 drugs (carboplatin, doxorubicin hydrochloride, ifosfamide, actinomycin D, etoposide, vincristine). Local therapy (surgery, radiotherapy, or both) was offered at week 9. Results: Forty-six patients meeting high-risk criteria were recruited from September 2000 to November 2005. Median follow-up of survivors was 62 months. The 5-year OS and EFS for the whole group was 64% ± 10% and 47% ± 8% respectively. The EFS was significantly affected by: the size of the tumor (≤5 cm vs. &gt; 5 cm, p= 0.03), SIOP UICC clinical stage (p = 0.004), IRS stage (p = 0.01), lymph node status (p = 0.02), surgery vs. incisional biopsy (p=0.01) and overall duration of time in which therapy was delivered (p = 0.04). There was significant toxicity, mainly hematologic, but only one treatment related fatality. Conclusions: The use of intensified alternating 6-drug CT did not improve the EFS compared with historical control although it was feasible to be delivered safely in a variety of outpatient settings. Surgical resection of the tumor is essential. Delivering therapy in a timely fashion appears to impact outcome and future investigations will focus on impediments to administering chemotherapy as scheduled.

Phase II Study of Accelerated High-Dose Radiotherapy With Concurrent Chemotherapy for Patients With Limited Small-Cell Lung Cancer: Radiation Therapy Oncology Group Protocol 0239

To investigate whether high-dose thoracic radiation given twice daily during cisplatin-etoposide chemotherapy for limited small-cell lung cancer (LSCLC) improves survival, acute esophagitis, and local control rates relative to findings from Intergroup trial 0096 (47%, 27%, and 64%). Patients were accrued over a 3-year period from 22 US and Canadian institutions. Patients with LSCLC and good performance status were given thoracic radiation to 61.2 Gy over 5 weeks (daily 1.8-Gy fractions on days 1-22, then twice-daily 1.8-Gy fractions on days 23-33). Cisplatin (60 mg/m(2) IV) was given on day 1 and etoposide (120 mg/m(2) IV) on days 1-3 and days 22-24, followed by 2 cycles of cisplatin plus etoposide alone. Patients who achieved complete response were offered prophylactic cranial irradiation. Endpoints included overall and progression-free survival; severe esophagitis (Common Toxicity Criteria v 2.0) and treatment-related fatalities; response (Response Evaluation Criteria in Solid Tumors); and local control. Seventy-two patients were accrued from June 2003 through May 2006; 71 were evaluable (median age 63 years; 52% female; 58% Zubrod 0). Median survival time was 19 months; at 2 years, the overall survival rate was 36.6% (95% confidence interval [CI] 25.6%-47.7%), and progression-free survival 19.7% (95% CI 11.4%-29.6%). Thirteen patients (18%) experienced severe acute esophagitis, and 2 (3%) died of treatment-related causes; 41% achieved complete response, 39% partial response, 10% stable disease, and 6% progressive disease. The local control rate was 73%. Forty-three patients (61%) received prophylactic cranial irradiation. The overall survival rate did not reach the projected goal; however, rates of esophagitis were lower, and local control higher, than projected. This treatment strategy is now one of three arms of a prospective trial of chemoradiation for LSCLC (Radiation Therapy Oncology Group 0538/Cancer and Leukemia Group B 30610).