Platinum-based Induction Chemotherapy Research Articles

Supracricoid Partial Laryngectomy Versus Radiation Therapy for cT3N0M0 Glottic SCC: Outcomes in Candidates for Total Laryngectomy Responding Well to Induction Chemotherapy.

To evaluate whether supracricoid partial laryngectomy (SCPL) may be a viable alternative to radiation therapy (RT) for patients with glottic cT3N0M0 squamous cell carcinoma (SCC) who are surgical candidates for total laryngectomy (TL) and respond well to platinum-based induction chemotherapy. Retrospective case series review of 18 consecutive patients with cT3N0M0 glottic SCC, initially considered surgical candidates only for TL who showed a good response to platinum-based induction chemotherapy, managed at a French university teaching institution with either SCPL (n = 9) or RT (n = 9). The main endpoints were 10-year local control and laryngeal preservation. The secondary endpoints were 10-year survival, causes of death analysis, and univariate analysis of local control and survival. The 10-year actuarial local control, laryngeal preservation, survival rates were 77.8%, 88.9%, and 66.7% after SCPL, respectively, and 72.9%, 87.5%, and 33.3%, after RT without significant statistical differences. In univariate analysis none of the clinical variables under analysis were related to local control and survival. Our data suggest that SCPL may warrant further consideration as a treatment option for glottic cT3N0M0 SCC patients who respond well to platinum-based induction chemotherapy. However, additional prospective research is warranted given the retrospective, nonrandomized nature of the presented case series.

Adaptive radiotherapy (up to 74 Gy) or standard radiotherapy (66 Gy) for patients with stage III non-small-cell lung cancer, according to [18F]FDG-PET tumour residual uptake at 42 Gy (RTEP7–IFCT-1402): a multicentre, randomised, controlled phase 2 trial

Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose ([18F]FDG)-PET results. In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 intravenously on day 1 and 60 mg/m2 orally [or 30 mg/m2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 intravenously and vinorelbine 20 mg/m2 intravenously on day 1 and 40 mg/m2 orally (or 20 mg/m2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). A thoracic radiotherapy boost, based on interim [18F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. Programme Hospitalier de Recherche Clinique National 2014.

Maintenance therapy with anlotinib after induction therapy with platinum-based chemotherapy for advanced non-small-cell lung cancer: A pooled analysis of 2 single-arm trials.

Maintenance therapy could significantly improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Anlotinib is effective, tolerable, and convenient in administration as a third-line treatment for NSCLC. This study aimed to evaluate the efficacy and safety of maintenance therapy with anlotinib after platinum-based induction chemotherapy for patients with advanced NSCLC. This pooled analysis of 2 multicenter, open-label, single-arm, phase 2 clinical trials (ALTER-L014 and ALTER-L011) enrolled patients with locally advanced or metastatic NSCLC and without known sensitive mutations in China between September 2018 and January 2021. The primary outcome was progression-free survival. The secondary outcomes were objective response rate, disease control rate, overall survival, and safety. The data of 23 patients were pooled, with 15 from ALTER-L014 and 8 from ALTER-L011. At the cutoff date of June 13, 2021, the median progression-free survival since the start of maintenance therapy was 5.95 (95% confidence interval, 4.30-8.80) months. Nineteen patients had stable disease, 1 had a partial response and 3 had progressive disease. The objective response rate was 4.35%, while disease control rate was 86.96%. The median overall survival of the patients since the start of maintenance therapy was 18.60 (95% confidence interval, 6.87-22.80) months. The incidence of adverse events of grade ≥ 3 was 21.7%. Anlotinib might offer a new option for maintenance treatment in patients with locally advanced or metastatic NSCLC without known sensitive mutations after standard first-line platinum-based chemotherapy.

Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): Long-term patient-reported outcomes (PROs) in the phase 3 JAVELIN Bladder 100 trial.

581 Background: In the JAVELIN Bladder 100 trial, avelumab 1LM + best supportive care (BSC) significantly prolonged overall survival vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based induction chemotherapy, and health-related quality of life was maintained. We report long-term and exploratory PRO analyses in the overall avelumab + BSC arm (any treatment duration) and in the subgroup with ≥12 months of avelumab treatment. Methods: In JAVELIN Bladder 100 (NCT02603432), PROs were a secondary endpoint assessed at baseline, on day 1 of each 4-week cycle, at end of treatment/withdrawal, and up to 90 days post treatment. PRO instruments used were National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol 5 Dimensions 5 Levels (EQ-5D-5L). Descriptive and mixed-effect model analyses were conducted. Data were not evaluated in the BSC alone arm because few pts remained on study treatment at later time points. Results: At data cutoff (Jun 4, 2021), median follow-up in the avelumab arm (n=350) was 38.0 months (≥2 years in all pts), and median duration of treatment was 5.8 months. In pts treated for ≥12 months (n=118 [33.7%]), baseline characteristics were similar to those in the overall avelumab + BSC arm, except for a higher proportion with ECOG performance status of 0 (70.3% vs 60.9%) and lower proportion with visceral metastases (47.5% vs 54.6%). In both populations, completion rates for both PRO instruments among evaluable pts were >80% at all time points during treatment. On average, PRO scores remained stable throughout treatment, and no clinically relevant changes from baseline were reported (Table). Among pts treated for ≥12 months, ≈75% of evaluable pts reported no change or a decrease in being bothered by treatment side effects throughout 24 months of treatment. Conclusions: Prolonged avelumab 1LM treatment (≥12 months) was associated with stable PROs, indicating preservation in quality of life. The results further support the use of avelumab 1LM until progression or unacceptable toxicity as standard of care with level 1 evidence in pts with aUC who are progression-free after platinum-based chemotherapy. Clinical trial information: NCT02603432 . [Table: see text]

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib (CABO) and avelumab (Av) vs Av after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).

TPS714 Background: 1st-line induction platinum-based chemotherapy followed by switch maintenance Av is the current preferred standard of care in patients (pts) with aUC who do not progress after platinum-based chemotherapy. There is an significant need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitor. We hypothesized that CABO-Av combination would improve survival vs Av alone and have an acceptable safety profile as switch maintenance therapy in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for pts with locally advanced/metastatic UC (including cN3M0 only)) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adults are randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or Av and CABO 40 mg daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of anti-PD(L)1, no CNS metastases, no major surgery within 4 wks, no uncontrolled hypertension or cardiovascular disorders. Pts are stratified based on 1) best response to 1L chemotherapy: complete vs partial response vs stable disease and 2) presence vs absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of 1-sided alpha 0.025, power 80%, median OS 21 months (mo) with Av and hazard ratio 0.75, thus hypothesizing median OS 28 mo on CABO-Av. Key secondary endpoints include progression-free survival, safety, tolerability, and efficacy of CABO-Av vs Av alone based on RECIST 1.1 and iRECIST criteria (and PD-L1 status).Quality of life (QOL) are assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-Av vs Av alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test the correlation of established and new radiomic signatures with survival, adverse events and QOL and incorporate both radiologic and biologic features to assess their potential association with outcomes. This trial would be the first to systematically address whether adding the multitargeted TKI, CABO, to Av improves survival vs Av alone as 1L maintenance therapy. https://acknowledgments.alliancefound.org . Support: U10CA180821, U10CA180882; U24CA196171, U10CA180863 (CCTG); Clinical trial information: NCT05092958 .

Optimum cycles of induction chemotherapy in concurrent chemo-radiotherapy management of unresectable stage III non-small cell lung cancer: Results from a single institutional database.

Induction chemotherapy (IC) prior to concurrent chemo-radiotherapy is the recommended treatment for unresectable stage III non-small cell lung cancer (NSCLC). However, the optimum number of IC cycles for improved survival outcomes is still not known. Here, we assessed the efficacy of 2 or more cycles of IC for unresectable stage III NSCLC patients from our hospital. Data on unresectable stage III NSCLC patients treated with IC + concurrent chemo-radiotherapy at our hospital between 2018 and 2022 were retrieved and analyzed, and survival outcomes compared between IC = 2 and IC > 2 patients. Univariate and multivariate Cox regression, and Chi-square or Fisher exact test were used to assess prognosis and acute toxicity profiles. One hundred twenty-six patients were recruited; 90 for IC = 2 and 36 for IC > 2. Median follow-up time was 26 months [IQR 16-38]. Three-year overall survival was not statistically significant between the 2 groups (77.8% vs 75.0%, P = .453). Distant metastasis free survival, loco-regional recurrence free survival and progression free survival were also not significant, (90.0% vs 86.1%, P = .068), 97.8% vs 97.2%, P = .056), and (73.3% vs 66.7%, P = .446) respectively. Univariate and multivariate Cox regression analysis revealed smoking, T_stage, N_stage, and IC_regimen as independent prognostic factor for overall survival, while drinking and T_stage were risk factors for progression free survival. In summary, 2 cycles of platinum-based IC was effective for stage III unresectable NSCLC and adding more than 2 cycles did not offer extra survival benefits.

Efficacy of avelumab in the treatment of oncourological malignances. Results of registration studies and own experience

Background. In the JAVELIN Bladder 100 trial, 1st line maintenance with avelumab in combination with best supportive care significantly increased (9.2 months) overall survival compared to best supportive care in patients with locally advanced or metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy: 29.7 months versus 20.5 months, respectively. Trial results led to inclusion of avelumab into the international guidelines as a standard of care with the highest level of evidence. Combined therapy with avelumab + axitinib in patients with previously untreated metastatic renal cell carcinoma showed higher progression-free survival and objective response rate compared to sunitinib in all IMDC (International Metastatic Renal Cancer Database Consortium) groups. Avelumab + axitinib is one of the immuno-oncology combinations with proven effectiveness for progression-free survival and objective response rate.Aim. To evaluate the effectiveness of avelumab in treatment of oncological urological diseases in routine clinical practice. Materials and methods. At the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology - branch of the National Medical Research Radiology Center, 12 patients with locally advanced inoperable and metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy in combination with gemcitabine received maintenance avelumab therapy. Median follow-up was 10 months. Primary endpoints were overall survival from the start of avelumab maintenance therapy and safety.Combined therapy with avelumab + axitinib was administered in 18 patients with metastatic renal cell carcinoma. Median follow-up was 9 (3-16) months. Overall survival, progression-free survival, response rate and safety in the overall population and according to IMDC groups were evaluated.Results. At data cut-off (March 2023) with median follow-up of 10 months, overall survival was 100 %, progression-free survival was 66.7 % (among patients who received more than 3 infusions - 100 %). Progression-free survival was higher in patients with tumors of the lower urinary tract compared to upper (72.5 % versus 60 %), complete response to induction platinum-based chemotherapy compared to partial response and stable disease (100 % versus 66.7 %) and presence of metastases in the lymph nodes only compared to visceral and bone metastases (100 % versus 66.7 %). Adverse events were observed in 4 (66.7 %) patients.Among 18 patients who received avelumab + axitinib, complete response was observed in 2 (11.1 %) patients, partial response in 6 (33.3 %) patients, stable disease in 9 (50 %) patients, disease progression in 1 (5.6 %) patient. Response to therapy was observed in patients of all prognosis groups; for large (>5 cm) metastases in the lungs, soft tissues, lymph nodes and bones response was observed 3 months after treatment start. Overall survival for this follow-up duration was 100 %, progression-free survival was 96.4 ± 11.2 %. Adverse events were observed in 8 (44.4 %) patients, and in 6 (75 %) of them they were grade I—II and did not require infusion regimen correction or axitinib dose reduction.Conclusion. Avelumab maintenance therapy in the 1st line is the standard of care for patients with locally advanced and metastatic urothelial cancer without disease progression during 1st line platinum-based chemotherapy. Maintenance therapy allows to achieve better overall survival and progression-free survival irrespective of the choice of platinum regimen (cisplatin or carboplatin), response to platinum-based chemotherapy, number of chemotherapy cycles, tumor localization and advancement.Experience of the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology confirms results of the JAVELIN Bladder 100 trial on the effectiveness of avelumab maintenance therapy in routine clinical practice. Combination drug therapy with avelumab and axitinib in patients with metastatic renal cell carcinoma is an effective and safe treatment method which allows to achieve fast objective response and has good tolerability in patients irrespective of IMDC group or metastasis location. Effectiveness and favorable safety profile of avelumab + axitinib combination were proven in the context of routine clinical practice.

Chemo-Radio-Immunotherapy for NSCLC III: ESR/ATS Thresholds for DLCO Correlate with Radiation Dosimetry and Pneumonitis Rate

Durvalumab following chemoradiotherapy (CRT) for non-small cell lung cancer stage III has become the standard of care (SoC) in the past few years. With this regimen, 5-year overall survival (OS) has risen to 43%. Therefore, adequate pulmonary function (PF) after treatment is paramount in long-term survivors. In this respect, carbon monoxide diffusing capacity (DLCO), which represents the alveolar compartment, seems to be a suitable measure for residual lung capacity. The aim of the current analysis was to correlate DLCO with pneumonitis and radiation dose. One hundred and twelve patients with histologically confirmed NSCLC III treated between 2015/10 and 2022/03 were eligible for this study. Patients received two cycles of platinum-based induction chemotherapy followed by high-dose radiotherapy (RT). As of 2017/09, durvalumab maintenance therapy was administered for one year. The clinical endpoints were based on the thresholds jointly published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS). Pre-treatment DLCO of 60% was correlated to the incidence of pneumonitis, whereas the post-treatment DLCO decline of 10% was related to radiation dose. Patients with a pre-treatment DLCO < 60% had a higher probability of pneumonitis (n = 98; r = 0.175; p-value 0.042), which could be reproduced in the subgroup of patients who did not receive durvalumab (n = 40; r = 0.288; p-value 0.036). In these individuals, the decline in DLCO ≥ 10% depended significantly on the size of the lung volume receiving between 45% and 65% (V65-45%) of the total radiation dose (r = 0.354; p-value = 0.020) and V20 Total Lung (r = 0.466; corrected p-value = 0.042). The current analysis revealed that DLCO is a predictor for clinically relevant pneumonitis and a monitoring tool for post-treatment lung function as it correlates with radiation dose. This underlines the importance of peri-treatment lung function testing.

Acute and long-term toxicity in patients undergoing induction chemotherapy followed by thermoradiotherapy for advanced cervical cancer

Objectives To determine rates of vascular toxicity, acute kidney injury (AKI), chronic kidney disease (CKD) and survival in high-risk cervical cancer patients treated with platinum-based induction chemotherapy followed by thermoradiotherapy. Methods Between January 1999 and April 2017, patients with large primary tumors (>6cm) and/or para-aortic lymph node (LN) metastases >1 cm and/or para-iliac LN >2 cm were included. Patient and tumor characteristics, Common Toxicity Criteria v4.03 scores, laboratory tests and treatment data were retrieved from patient records. CT scans were reviewed for the presence of thrombo-embolic events (TEE). The study protocol was approved by the Medical Ethics Review Committee of Erasmus MC, Rotterdam (MEC2017-133). Results The 105 included patients had a mean age of 47.9 years (range 22–79) and a median follow-up time of 43 months (IQR 14–72). Median tumor size was 6.0 cm (range 2.6–11.5), 30% had a clinical FIGO stage ≥ IIIB and 42% had enlarged para-aortic LN. Cisplatin-based therapy was started in 86 patients (82%), of whom 30 (35%) switched to carboplatin and 47% of patients completed six cycles of platinum-based chemotherapy. All patients received external beam radiotherapy as planned, 98 patients (93%) underwent brachytherapy as planned or received an external boost, and 95 patients (90%) completed all five planned hyperthermia treatments. During cisplatin chemotherapy, 34 patients experienced AKI (39%). At last follow-up, 35% of patients had chronic renal toxicity (GFR 59 − 15/min/1.73 m2). At presentation, a TEE was present in 10 (10%) and another 23 (22%) patients experienced a TEE (18% venous, 4% arterial) during chemotherapy. Five-year overall survival was 58% (95% CI 47.8–68.6 SE 0.053). Conclusion Achieving a five-year overall survival of 58%, platinum-based induction chemotherapy followed by thermoradiotherapy is an effective treatment for advanced-stage high-risk cervical cancer. However, treatment is accompanied by an unacceptably high prevalence of chemotherapy-associated TEE and acute kidney injury, as well as chronic kidney disease. Future studies should investigate the role of carboplatin in reducing toxicity and the effect of thromboprophylaxis in high-risk patients.

SY17-4 Optimal treatment strategy for locally advanced nasopharyngeal cancer from the perspectives of Asian endemic region

In locoregionally advanced NPC, the addition of platinum-based induction chemotherapy and cisplatin concurrent chemotherapy to radiotherapy (RT) have been consistently associated with survival benefits. Trials of adjuvant chemotherapy have yielded mixed results. The role of plasma EBV DNA in guiding the choice of induction and adjuvant chemotherapy continues to be an area of active investigation. A positive randomized study of metronomic adjuvant chemotherapy using capecitabine has offered another alternative approach for future investigations.

Factors Associated With Choriocarcinoma Syndrome Development in Poor-Risk Patients With Germ Cell Tumors.

BackgroundGerm cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of poor-risk patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with a high mortality rate. Our retrospective study aimed to determine the risk factors of poor-risk GCTs susceptible to CS development.Patients and MethodsUsing a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated at the National Cancer Institute from 2000 to 2018. Ninety eligible patients with poor-risk GCTs based on IGCCCG classification were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation with CS development.ResultsNine (10%) of 90 patients developed CS in a median of 1 day (1–9 days) after chemotherapy administration. All patients died shortly after the chemotherapy start with a median of 4 days (3–35 days) due to ARDS development. In univariate analysis, metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss, hemoglobin ≤100 g/l, and NLR ≥3.3 at the time of presentation were associated with CS development. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS, compared to 0% with zero or one of these factors (p < 0.000001).ConclusionsIn our study, we identified factors associated with CS development. These factors might improve the risk stratification of the patients susceptible to CS and improve their outcome.

PD51-03 MOLECULAR CHARACTERISTICS OF METASTATIC TERATOMAS AND MATCHED PRIMARY TESTICULAR GERM CELL TUMORS

You have accessJournal of UrologyCME1 May 2022PD51-03 MOLECULAR CHARACTERISTICS OF METASTATIC TERATOMAS AND MATCHED PRIMARY TESTICULAR GERM CELL TUMORS Anna Savelyeva, Feng Wang, Lei Guo, John Lafin, Liwei Jia, Kirill Medvedev, Cheryl Lewis, Payal Kapur, Vitaly Margulis, Solomon Woldu, Xiaosong Meng, Nick Grishin, James Amatruda, Lin Xu, and Aditya Bagrodia Anna SavelyevaAnna Savelyeva More articles by this author , Feng WangFeng Wang More articles by this author , Lei GuoLei Guo More articles by this author , John LafinJohn Lafin More articles by this author , Liwei JiaLiwei Jia More articles by this author , Kirill MedvedevKirill Medvedev More articles by this author , Cheryl LewisCheryl Lewis More articles by this author , Payal KapurPayal Kapur More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , Solomon WolduSolomon Woldu More articles by this author , Xiaosong MengXiaosong Meng More articles by this author , Nick GrishinNick Grishin More articles by this author , James AmatrudaJames Amatruda More articles by this author , Lin XuLin Xu More articles by this author , and Aditya BagrodiaAditya Bagrodia More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002622.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Metastatic teratoma (MT) is a subtype of germ cell tumor (GCT) characterized by resistance to platinum-based chemotherapy. MT is treated via complete surgical excision, using retroperitoneal lymph node dissection (RPLND), following chemotherapy. Molecular characterization of post-chemotherapy MTs along with pre-chemotherapy testicular primary tumors could reveal 1) the mechanisms of MT development and differentiation, 2) molecular changes associated with platinum-resistance, 3) novel therapeutic options for patients with unresectable MTs. METHODS: We performed whole exome and transcriptome sequencing for 16 primary germ cell tumors and 18 metastatic teratomas, 11 were matched tumor/metastasis pairs. All MTs in our cohort were collected after induction platinum-based chemotherapy. We used VarScan for SNV analysis and PennCNV to detect genomic copy-number variations (CNVs). Metastatic Teratomas were compared to matched primary tumors and primary teratomas characterized by TCGA. RESULTS: Our analysis revealed that metastatic teratomas as well as their tumors of origin had low tumor mutation burden (0.65 and 0.47 accordingly). Amongst 583 SNVs detected in the study cohort, only two (KRAS p.Gly12Asp and KRAS p.Gly12Val) were previously described as oncogenic. Analysis of SNVs in proteins playing key roles in oncogenic signaling showed that TP53 and Ras pathways were the most affected in metastatic teratomas. The majority of metastatic teratomas possess gain of 3p11.1 and loss of 10q26.3, 16p11.2, 19p13.2, 19q12 and 22q12.3 loci. Within 3p11.1 we did not identify any well-known oncodrivers. However, 5 chromosomal loci with lost heterozygosity contained 16 previously annotated tumor suppressor genes: HTRA1, EBF3, FUS, PRKCB, NUPR1, PYCARD, ZNF668, ARMC5, YPEL3, DNMT1, DNAJB1, SMARCA4, GADD45GIP1, MIR199A1, TIMP3, TMPRSS6. Amongst those, GADD45GIP1 inhibition (growth arrest and DNA-damage-inducible, gamma interacting protein 1) is associated with cisplatin resistance development through mechanism of cellular senescence. CONCLUSIONS: Metastatic teratoma in our cohort is characterized by low tumor mutational burden and several recurring copy number changes. Molecular insight of metastatic teratoma may inform disease biology and treatment. Source of Funding: Dedman Scholar Award © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e843 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anna Savelyeva More articles by this author Feng Wang More articles by this author Lei Guo More articles by this author John Lafin More articles by this author Liwei Jia More articles by this author Kirill Medvedev More articles by this author Cheryl Lewis More articles by this author Payal Kapur More articles by this author Vitaly Margulis More articles by this author Solomon Woldu More articles by this author Xiaosong Meng More articles by this author Nick Grishin More articles by this author James Amatruda More articles by this author Lin Xu More articles by this author Aditya Bagrodia More articles by this author Expand All Advertisement PDF DownloadLoading ...

Carbon Monoxide Diffusing Capacity (DLCO) Correlates with CT Morphology after Chemo-Radio-Immunotherapy for Non-Small Cell Lung Cancer Stage III.

Introduction: Curatively intended chemo-radio-immunotherapy for non-small cell lung cancer (NSCLC) stage III may lead to post-therapeutic pulmonary function (PF) impairment. We hypothesized that the decrease in global PF corresponds to the increase in tissue density in follow-up CTs. Hence, the study aim was to correlate the dynamics in radiographic alterations to carbon monoxide diffusing capacity (DL) and FEV, which may contribute to a better understanding of radiation-induced lung disease. Methods: Eighty-five patients with NSCLC III were included. All of them received two cycles of platinum-based induction chemotherapy followed by high dose radiation. Thereafter, durvalumab was administered for one year in 63/85 patients (74%). Pulmonary function tests (PFTs) were performed three months and six months after completion of radiotherapy (RT) and compared to baseline. At the same time points, patients underwent diagnostic CT (dCT). These dCTs were matched to the planning CT (pCT) using RayStation® Model Based Segmentation and deformable image registration. Differential volumes defined by specific isodoses were generated to correlate them with the PFTs. Results: In general, significant correlations between PFTs and differential volumes were found in the mid-dose range, especially for the volume of the lungs receiving between 65% and 45% of the dose prescribed (V) and DL (). This volume range predicted DL after RT (p-value 0.03) as well. In multivariate analysis, DL (p-value 0.040) and FEV (p-value 0.014) predicted pneumonitis. Conclusions: The current analysis revealed a strong relation between the dynamics of DL and CT morphology changes in the mid-dose range, which convincingly indicates the importance of routinely used PFTs in the context of a curative treatment approach.

Relationship of PI3K-Akt/mTOR/AMPK signaling pathway genetic mutation with efficacy and prognosis in nasopharyngeal carcinoma.

Genetic mutation is one of the important causes for tumor genesis and development, but genetic mutation in nasopharyngeal carcinoma (NPC) has rarely been reported. This study explored the role of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR), and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in the efficacy and prognosis in patients with NPC. A total of 31 patients with advanced NPC, who came from the Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University/Hunan Provincial Cancer Hospital, were enrolled. All of the exons of 288 genes, introns of 38 genes and promoters or fusion breakpoint regions from the nasopharyngeal biopsy tissues before treatment were detected by the gene sequencing platform Illumina NextSeq CN500. The coding regions of 728 genes were carried out a high-depth sequencing of target region capture, and the 4 variant types of tumor genes (including point mutations, insertion deletions of small fragments, copy number variations, and currently known fusion genes) were detected. All of 31 patients received platinum-based induction chemotherapy combined with concurrent chemoradiotherapy and were followed up for a long time. The 3-year regional failure-free survival (RFFS) and disease-free survival (DFS) in patients with PI3K-Akt pathway mutation were significantly lower than those in unmutated patients (χ2=6.647, P<0.05). The 3-year RFFS and DFS in patients with mTOR pathway mutations were significantly lower than those in unmutated patients, and there was significant difference (χ2=5.570, P<0.05). The rate of complete response (CR) in patients with unmutated AMPK pathway was significantly higher than that in patients with mutation at 3 months after treatment (P<0.05), and the 3-year RFFS and DFS in patients with AMPK pathway mutation were significantly lower than those in unmutated patients (χ2=4.553, P<0.05). PI3K-Akt/mTOR/AMPK signaling pathway mutations and pre-treatment EB virus DNA copy numbers were independent prognostic factors for 3-year RFFS and DFS in patients with NPC (both P<0.05). The NPC patients with PI3K-Akt/mTOR/AMPK signaling pathway mutation have poor prognosis, and the detection of PI3K-Akt, mTOR, AMPK driver genes and signaling pathways by next-generation sequencing is expected to provide new idea for basic research and targeted therapy of NPC.

Molecular analysis of primary testicular germ cell tumor and matched metastatic teratomas.

425 Background: Metastastic teratoma (MT) is a unique germ cell tumor (GCT) subhistology characterized by resistance to platinum-based chemotherapy. Metastatic teratoma requires complete surgical excision, usually via retroperitoneal lymph node dissection (RPLND), following chemotherapy as a part of multidisciplinary GCT care. Molecular characterization of post-chemotherapy metastatic teratoma along with companion pre-chemotherapy testicular primary tumors could inform 1) the origin and differentiation site of metastatic teratomas, 2) mechanisms of platinum-resistance, 3) novel therapeutic options for patients with unresectable teratomas. Methods: We performed integrated molecular analysis for 16 primary germ cell tumors and 18 metastatic teratomas, 11 were matched tumor/metastasis pairs. All teratomas in our cohort were collected after induction platinum-based chemotherapy. In addition to SNV analysis, we conducted a chromosomal copy number gain and loss analysis for selected teratomas, matched primary tumors and primary teratomas from the TCGA. Results: Metastatic teratomas as well as their tumors of origin had low tumor mutation burden (0.65 and 0.47 accordingly). Amongst 583 SNVs detected in the study cohort, only two (KRAS p.Gly12Asp and KRAS p.Gly12Val) were previously described as oncogenic. Analysis of SNVs in proteins playing key roles in oncogenic signaling [1] showed that TP53 and Ras pathways were the most affected in metastatic teratomas. The majority of metastatic teratomas possess gain of 3p11.1 and loss of 10q26.3, 16p11.2, 19p13.2, 19q12 and 22q12.3 loci. Within 3p11.1 we did not identify any previously described oncodrivers. However, 5 chromosomal loci with lost heterozygosity contained 16 previously annotated tumor suppressor genes (15 protein coding and 1 microRNA, MIR199A1). Amongst those, GADD45GIP1 inhibition (growth arrest and DNA-damage-inducible, gamma interacting protein 1) is known for playing a role in cisplatin resistance through mechanism of cellular senescence [2]. Conclusions: Metastatic teratoma in our cohort is characterized by low tumor mutational burden, recurring copy number changes, and lack of recurring SNVs. Molecular insight of teratoma may inform disease biology and treatment.

Induction Chemotherapy Followed by Pleurectomy Decortication and Hyperthermic Intraoperative Chemotherapy (HITHOC) for Early-Stage Epitheliod Malignant Pleural Mesothelioma-A Prospective Report.

Malignant pleural mesothelioma (MPM) is an aggressive disease with poor prognosis and the current treatment for early-stage MPM is based on a multimodality therapy regimen involving platinum-based chemotherapy preceding or following surgery. To enhance the cytoreductive role of surgery, some peri- or intra-operative intracavitary treatments have been developed, such as hyperthermic chemotherapy, but long-term results are weak. The aim of this study was to report the post-operative results and mid-term outcomes of our multimodal intention-to-treat pathway, including induction chemotherapy, followed by surgery and Hyperthermic Intraoperative THOracic Chemotherapy (HITHOC) in the treatment of early-stage epithelioid MPM. Since 2017, stage I or II epithelioid MPM patients have been inserted in a surgery-based multimodal approach comprising platinum-based induction chemotherapy, followed by pleurectomy and decortication (P/D) and HITHOC with cisplatin. The Kaplan–Meier method was used to estimate overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). During the study period, n = 65 patients affected by MPM were evaluated by our institutional Multidisciplinary Tumour Board; n = 12 patients with stage I-II who had no progression after induction chemotherapy underwent P/D and HITHOC. Post-operative mortality was 0, and complications developed in n = 7 (58.3%) patients. The median estimated OS was 31 months with a 1-year and 3-year OS of 100% and 55%, respectively. The median PFS was 26 months with 92% of a 1-year PFS, whereas DFS was 19 months with a 1-year DFS rate of 83%. The multimodal treatment of early-stage epithelioid MPM, including induction chemotherapy followed by P/D and HITHOC, was well tolerated and feasible with promising mid-term oncological results.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma

BackgroundThe present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC).MethodsPatients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint.ResultsA total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011).ConclusionRadiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

Targeting DNA damage repair pathways in pancreas cancer.

Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15-25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.

Comparative study on hemato- and nephrotoxicity profile of weekly versus every 3-weekly cisplatin dosage during induction chemotherapy in locally advanced head neck squamous cell carcinoma

BackgroundCisplatin is a frontline anticancer drug routinely used as part of concurrent chemoradiation administered at 3-weekly (100 mg/m2) dose. However, its role as fractionated weekly dose has achieved favorable outcome in patients with locally advanced squamous cell carcinoma of head and neck (LA-SCCHN) during induction chemotherapy (IC). We therefore sought to compare the toxicity outcomes of patients with LA-SCCHN treated with platinum-based IC at a single institution study using split-dose cisplatin chemotherapy. We compared the hematological and renal toxicity profile between the weekly cisplatin (30 mg/m2) (group A) versus 3-weekly (100 mg/m2) (group B) dosage schedule in this setting.ResultsThe median age of the patients in groups A and B were 49.1 years and 48.27 years respectively with male:female ratio of 4:1. Most of the patients were of oropharyngeal cancers. Group A patients showed greater neutropenia (40.2%) than group B (20.6%). There was statistically significant fall in Hb% level in group A (13.9%) than in group B (11.9%). Renal profile showed greater rise in serum urea and serum creatinine (52.7%) in group B than in group A (52.29%) with statistically significant difference.ConclusionsSince toxicities induced by high-dose cisplatin are irreversible and reduce quality of life in patients, the weekly regimen may be preferred owing to less renal toxicity, lesser hospitalization and more feasible in situations with high patient load and limited resources.

Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial

BackgroundRadical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. MethodsWe performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FindingsBetween February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5–60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74–1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. ConclusionDE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer.The trial is registered: ISRCTN01483375.