A simulated trial with reinforcement learning for the efficacy of Irinotecan and Ifosfamide versus Topotecan in relapsed, extensive stage small cell lung cancer.

OBJECTIVES: Synthetic data may proxy clinical data. At the absence of direct clinical data, this study aimed to compare Irinotecan and Ifosfamide (II) with Topotecan in synthetic, recurrent small cell lung cancer (SCLC) patients within a simulated clinical trial. MATERIALS AND METHODS: Two simulation stages were conducted. Initially, 200 recurrent SCLC cases were simulated to replicate a previous phase 3 trial, testing the utility of Cox proportional hazards model and simulation methodology together, where patients were randomized to receive Cyclophosphamide, Adriamycin, Vincristine (CAV) or Topotecan. In the second stage, 600 recurrent SCLC patients were simulated and randomized to compare Topotecan versus II in terms of overall survival (OAS), using Reinforcement Learning (RL) and Cox proportional hazards model. RESULTS: CAV versus Topotecan comparison showed no statistical difference in overall survival (hazard ratio (HR): 0.89, 95% CI: 0.67-1.18, P = 0.418), aligning with the original clinical trial. For the Topotecan versus II comparison, the RL framework significantly favored the II arm (mean reward points: 193.43 versus - 251.82, permutation P < 0.0001). Likewise, II arm exhibited superior median OAS compared to Topotecan arm (11.12 versus 6.30 months). HR was 0.44 (95% CI: 0.38-0.52) with P < 0.0001, in favor of II. CONCLUSION: Artificial trial results for CAV versus Topotecan matched the original trial, confirming indifference of OAS. Additionally, II yielded superior overall survival compared to Topotecan in recurrent SCLC patients. These demonstrate the potential of RL and simulation in conjunction with Cox modelling for similar studies. However, definitive conclusions necessitate a randomized clinical trial between II and Topotecan in this patient cohort.

Camrelizumab in combination with doxorubicin, cisplatin, ifosfamide, and methotrexate in neoadjuvant treatment of resectable osteosarcoma: A prospective, single-arm, exploratory phase II trial.

BACKGROUND: The poor overall survival of osteosarcoma (OS) underscores the need to explore new therapeutic avenues. Tumor necrosis rate (TNR) after neoadjuvant chemotherapy predicts prognosis. AIMS: The study was to investigate safety and activity of neoadjuvant chemotherapy with camrelizumab (a humanized antibody against PD-1) in patients with resectable OS. MATERIALS & METHODS: We conducted a prospective, single-arm, exploratory phase II trial in OS patients. Eligible patients received camrelizumab combined with doxorubicin or liposomal doxorubicin, cisplatin, methotrexate, ifosfamide with mesna. Surgery was performed 12-14 days after neoadjuvant therapy and adjuvant therapy starting 2-3 weeks postoperatively. The primary endpoint was the rate of good tumor necrosis (TNR ≥90%) after neoadjuvant therapy, and the secondary outcomes were safety, 2-year progression free survival and 2-year overall survival. RESULTS: Seventy-five patients were recruited to the study. Subsequently, 64 patients completed neoadjuvant therapy and underwent surgery. Thirty-one patients (48.4%) have a good TNR to neoadjuvant therapy. With a median follow-up of 22.4 months (range 2.2-44.9 months), the estimated 2-year PFS was 69.6% and the estimated 2-year overall survival was 89.4%. Grade 3 or 4 treatment-related adverse events were noticed in 62.7% of the patients. Frequent grade 3 or 4 adverse events were decreased platelet count (45.3%), decreased white blood cell count (36%). No immune-related serious adverse events were observed. DISCUSSION: Our study had limitations. First, it was limited by its non-randomized design. Besides, stromal tumor-infiltrating lymphocytes was comprehensively analyzed in this study. CONCLUSIONS: This study demonstrated that amrelizumab combined with adriamycin, cisplatin, methotrexate, and ifosfamide in the neoadjuvant treatment of resectable OS was safe and tolerable. This combined therapeutic strategy may not increase TNR, but the long-term survival benefit remains to be followed up.

Long term survival in adult osteosarcoma patients treated with a two-drug regimen: Final results of the OSAD93 phase II study of the FSG-GETO.

RATIONALE: We report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. PATIENTS AND METHODS: This is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m2 and CDDP 100 mg/m2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. RESULTS: From Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16-63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3-4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. CONCLUSION: Though the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma.

Paclitaxel, Ifosfamide, and Cisplatin as Initial Salvage Chemotherapy for Germ Cell Tumors: Long-Term Follow-Up and Outcomes for Favorable- and Unfavorable-Risk Disease.

PURPOSE: Paclitaxel, ifosfamide, and cisplatin (TIP) is an established salvage regimen for germ cell tumors (GCT) on the basis of a phase II trial, but efficacy on a large patient cohort including patients with unfavorable risk features and long-term outcomes has not been reported. Herein, we report updated treatment efficacy and long-term follow-up with TIP. PATIENTS AND METHODS: Patients with GCT who received TIP after cisplatin-based chemotherapy were eligible. Favorable response (complete response or partial response with negative tumor markers), overall survival (OS) and progression-free survival (PFS) rates, relapse, and toxicity were determined. Disease was reclassified according to the International Prognostic Factor Study Group (IPFSG) score. RESULTS: Of the 104 patients, 87 had favorable risk factors and 17 had at least one unfavorable factor by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Ten patients were treated for a second gonadal primary GCT. With a median follow-up of 8.9 years, the 5-year PFS and OS rates were 66% (95% CI, 55 to 74) and 69% (95% CI, 59 to 77), respectively. Among 87 patients with favorable-risk disease, 69 (79%) achieved a favorable response with 5-year PFS and OS rates of 67% (95% CI, 56 to 76) and 72% (95% CI, 61 to 80), respectively. Among 17 patients with MSKCC unfavorable-risk disease, 13 (76%) achieved a favorable response with 5-year PFS and OS rates of 59% (95% CI, 33 to 78) and 56% (95% CI, 28 to 76), respectively. After IPFSG reclassification, 5-year PFS and OS rates for patients with ≤intermediate-risk disease were 75% (95% CI, 50 to 89) and 73% (95% CI, 55 to 85), respectively. CONCLUSION: TIP is an effective second-line regimen for patients with GCT. Similar outcomes were observed in patients with favorable- and unfavorable-risk disease. The randomized TIGER trial (ClinicalTrials.gov identifier: NCT02375204) comparing TIP with high-dose chemotherapy will determine the optimal second-line treatment approach.

Effectiveness and safety of primary prophylaxis with G-CSF for patients with Ewing sarcomas: a systematic review for the Clinical Practice Guidelines for the Use of G-CSF 2022 of the Japan Society of Clinical Oncology.

BACKGROUND: Multidrug chemotherapy for Ewing sarcoma can lead to severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, "Does primary prophylaxis with G-CSF benefit chemotherapy for Ewing sarcoma?" and CQ #2, "Does G-CSF-based intensified chemotherapy improve Ewing sarcoma treatment outcomes?". METHODS: A comprehensive literature search was conducted in PubMed, Cochrane Library, and Ichushi web databases, including English and Japanese articles published from 1990 to 2019. Two reviewers assessed the extracted papers and analyzed overall survival (OS), febrile neutropenia (FN) incidence, infection-related mortality, quality of life (QOL), and pain. RESULTS: Twenty-five English and five Japanese articles were identified for CQ #1. After screening, a cohort study of vincristine, ifosfamide, doxorubicin, and etoposide chemotherapy with 851 patients was selected. Incidence of FN was 60.8% with G-CSF and 65.8% without; statistical tests were not conducted. Data on OS, infection-related mortality, QOL, or pain was unavailable. Consequently, CQ #1 was redefined as a future research question. As for CQ #2, we found two English and five Japanese papers, of which one high-quality randomized controlled trial on G-CSF use in intensified chemotherapy was included. This trial showed trends toward lower mortality and a significant increase in event-free survival for 2-week interval regimen with the G-CSF primary prophylactic use compared with 3-week interval. CONCLUSION: This review indicated that G-CSF's efficacy as primary prophylaxis in Ewing sarcoma, except in children, is uncertain despite its common use. This review tentatively endorses intensified chemotherapy with G-CSF primary prophylaxis for Ewing sarcoma.

Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study.

BACKGROUND: The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. PATIENTS AND METHODS: The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. RESULTS: The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3-4 non-haematological toxicities. CONCLUSIONS: 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

Paclitaxel-Ifosfamide-based Therapy as Salvage Treatment in Platinum-resistant Recurrent/Metastatic Head and Neck Cancer.

BACKGROUND: Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy and safety of a paclitaxel and ifosfamide (TI) regimen in patients with R/M HNSCC whose disease had progressed following platinum-based therapy. PATIENTS AND METHODS: In this retrospective study, we included 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy, post platinum failure, between February 2020 and August 2023. Some patients received the TI regimen in combination with immunotherapy and/or cetuximab. Key metrics assessed included the objective response rate (ORR), disease control rate, and progression-free as well as overall survival. RESULTS: The study observed an ORR of 15.8% and a disease control rate of 36.8%. The median progression-free survival for the entire cohort was 3.3 months, and the median overall survival was 9.6 months. Notably, the combination of TI with immunotherapy yielded a higher ORR of 30.8%, compared to 14.3% with TI alone. The most prevalent grade 1-2 adverse events were anemia (81%), weight loss (68%) and hypernatremia (55%). CONCLUSION: The TI-based regimen demonstrated favorable efficacy and safety profile in treating R/M HNSCC. Enhanced outcomes may be attainable when combining it with immunotherapy. This study suggests that TI-based therapy could serve as a potential salvage option for this specific patient group.

Embryonal sarcoma of the liver in pediatric and young adult patients: A report from Children's Oncology Group study ARST0332.

BACKGROUND: Embryonal sarcoma of the liver (ESL) is a rare mesenchymal tumor most common in childhood; the optimal treatment approach is uncertain. The clinical features and outcomes of patients with ESL enrolled in a Children's Oncology Group (COG) clinical trial that evaluated a risk-based strategy for treating soft tissue sarcomas in patients aged <30 years were evaluated. METHODS: This subset analysis included patients with ESL enrolled in COG study ARST0332. Central review of records, pathology, and imaging confirmed the diagnosis, presenting features, and surgery extent and complications. All patients received dose-intensive ifosfamide/doxorubicin chemotherapy, with cycle timing dependent on surgery and radiotherapy. Tumor resection occurred before study entry or after four cycles of chemotherapy; radiotherapy for residual tumor was optional. RESULTS: Thirty-nine eligible/evaluable patients with ESL were analyzed. All tumors were >10 cm in diameter; four were metastatic. Tumor resection was performed upfront in 23 and delayed in 16. Positive surgical margins (n = 6) and intraoperative tumor rupture (n = 6) occurred only in upfront resections. Eight patients received radiotherapy. Estimated 5-year event-free and overall survival were 79% (95% confidence interval [CI], 65%-93%) and 95% (95% CI, 87%-100%), respectively. Positive margins increased the local recurrence risk. One of 13 patients with documented hemorrhagic ascites and/or tumor rupture developed extrahepatic intra-abdominal tumor recurrence. CONCLUSIONS: The treatment strategy used in ARST0332 achieved favorable outcomes for patients with ESL despite a substantial proportion having high-risk disease features. Deferring tumor resection until after neoadjuvant chemotherapy may decrease the risk of intraoperative tumor rupture and improve the likelihood of adequate surgical margins.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Salvage Therapy of Relapsed/Refractory Germ Cell Tumors: A Single-Center Experience.

INTRODUCTION: The optimal management of relapsed/refractory germ cell tumors remains unsettled. In this study, we aimed to evaluate the efficacy of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as salvage therapy in patients who progressed after at least one line of cisplatin-based chemotherapy. METHODS: We retrospectively reported the results of 133 patients who underwent HDCT and ASCT as salvage therapy from 2016 to 2021. Patients received 3 cycles of paclitaxel, ifosfomide and cisplatin (TIP) regimen as induction and 1 cycle of carboplatin 700 mg/m2 on days 1-3 plus etoposide 750 mg/m2 on days 1-3, followed by ASCT. Demographic and clinicopathological features of patients, the International Germ Cell Cancer Collaborative Group (IGCCCG) risk group at diagnosis, serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) levels before HDCT, treatment-related complications and survival outcomes were recorded. RESULTS: The median age of the patients was 31 (range 18-62). The median follow-up was 31.1 months (95% CI, 28.9-33.3 months). During the median follow-up period, 74 of the 133 patients were still alive, and 63 of these were in complete remission. The median progression-free survival (PFS) was 25.8 months (95% CI, 8.1-43.4 months). The 2-year PFS rate was 50.3% and the 2-year overall survival (OS) rate was 60.8%. Variables that remained statistically significant in multivariable analysis and were associated with poor prognosis were mediastinal primary tumor location, presence of brain metastases, and higher AFP and HCG levels at baseline. CONCLUSION: One course of HDCT and ASCT after induction with TIP is an effective and feasible treatment option for salvage treatment of relapsed/refractory germ cell tumors, with cure rates of up to 60%.

Recurrent Synovial Sarcoma with Breast and Pulmonary Nodule: A Case Report.

Synovial sarcoma is a mesenchymal tumour with partial epithelial differentiation. About 85-90% of SS occur in the extremities. We present a case of a 44-year-old woman diagnosed with recurrent synovial sarcoma with breast and pulmonary nodules. The primary treatment for synovial sarcoma is wide surgical excision, while chemotherapy is reserved for metastatic cases. In the first-line metastatic setting, combination treatment with adriamycin and ifosfamide is administered. Despite the unfavourable prognosis, the patient's extended survival is fortunately not the typical outcome. Keywords: case reports; chemotherapy; immunohistochemistry; synovial sarcoma.

Matched control analysis suggests that R-CHOP followed by (R)-ICE may improve outcome in non-GCB DLBCL compared with R-CHOP.

ABSTRACT: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score-matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score-matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.

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

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

Prospective validation of an equation based on plasma cystatin C for monitoring the glomerular filtration rate in children treated with cisplatin or ifosfamide for cancer.

We recently proposed an equation to estimate the glomerular filtration rate (GFR) in children with cancer based on plasma cystatin C and serum creatinine levels together with body weight (the "CysPed equation"). The current clinical study reports a prospective evaluation of this equation in 18 children treated by nephrotoxic chemotherapy. The CysPed equation resulted in less bias and greater precision compared to two equations previously proposed equations by Schwartz, with or without plasma cystatin C. Moreover, the decrease in GFR due to chemotherapy was clearly identified by the CysPed equation. This equation may be used to monitor the renal function in childhood cancer units.

Pleomorphic Liposarcoma Initially Presenting with Multiple Organ Involvement Including the Heart.

A 42-year-old man visited our hospital due to a gradually swelling subcutaneous mass on the back of the right shoulder. The biopsy specimen was diagnosed pathologically as pleomorphic liposarcoma. Systemic computed tomography and 18F-fluorodeoxyglucose positron emission tomography revealed multiple organ metastases, including involvement of the heart, skin, liver, bone, and lung. Six cycles of doxorubicin plus ifosfamide initially controlled the disease. However, newly developed lung metastases grew rapidly during subsequent cycles of chemotherapy, and the patient died 10 months after the initial diagnosis. The initial presentation of multiple organ involvement, including the heart, is a rare clinical manifestation of pleomorphic liposarcoma.

Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma.

INTRODUCTION: NUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated or squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports. METHODS: Patients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods. RESULTS: The study included 118 patients with NC. Median age was 34 (range: 1-82) years, 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%). Of 62 patients with nonmetastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher progression-free survival (12 mo: 59% [95% CI: 32-87] versus 37% [95% CI: 22-52], hazard ratio = 0.68 [0.32, 1.42], p = 0.3) but not overall survival (OS). Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (six of eight) and platinum had an ORR of 31% (11 of 36). Nevertheless, there was no difference in progression-free survival or OS. The 3-year OS of the entire cohort was 19% (95% CI: 10%-28%). Of the 11 patients alive greater than 3 years, all presented with nonmetastatic and operable or resectable disease. CONCLUSION: There is a numerically higher ORR for ifosfamide-based therapy compared with platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population.

A 51-Year-Old Woman with Advanced Peritoneal Mesothelioma and Stage 3b Chronic Kidney Disease Treated with Cytoreductive Surgery and Bidirectional Intraperitoneal Cisplatin and Ifosfamide Chemotherapy: A Case Report.

BACKGROUND Malignant mesotheliomas are rare, yet highly malignant tumors. Mesotheliomas are tumors that develop from mesothelial surfaces, with the pleura being the most common, followed by the peritoneum. The diagnosis of malignant peritoneal mesothelioma (MPM) is usually established when the disease is advanced, owing to the nonspecific clinical appearance and abdominal symptoms. Initially, MPM was treated with palliative systemic chemotherapy, with or without palliative surgery. However, cytoreductive surgery (CRS) combined with bidirectional intraoperative chemotherapy (BDIC) has recently emerged as a treatment option for MPM. BDIC creates a bidirectional chemotherapy gradient in the peritoneal tumor cells through the simultaneous use of intraperitoneal and intravenous chemotherapy. CRS, combined with BDIC (CRS-BDIC), allows the complete elimination of residual tiny tumor cells after complete removal of the visible tumor nodules. CASE REPORT Herein, we present a case of a 51-year-old woman with MPM and chronic kidney disease (CKD) stage 3b. Her treatment consisted of neoadjuvant chemotherapy and immunotherapy, followed by CRS-BDIC using intraperitoneal cisplatin and doxorubicin, and intravenous ifosfamide. The surgery was successful, with no immediate complications or decline in the patient's kidney function. On follow up 2 months later, the patient denies suffering any chemotherapy-related adverse effects, and her kidney profile remains stable. CONCLUSIONS In conclusion, nephrotoxicity, a known adverse effect of cisplatin and ifosfamide, might not be a contraindication for the use of these potentially nephrotoxic drugs in CRS-BDIC in patients with renal impairment.

Population Pharmacokinetics and Pharmacodynamics of Carfilzomib in Combination with Rituximab, Ifosfamide, Carboplatin, and Etoposide in Adult Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.

BACKGROUND: In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL. OBJECTIVE: This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients. PATIENTS AND METHODS: In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m2) on days 1, 2, 8, and 9, and standard doses of R-ICE on days 3-6 every 21 days (maximum of three cycles). Carfilzomib plasma concentrations up to 24 h postinfusion were measured by liquid chromatography coupled with tandem mass spectrometry. Proteasome activity (PD biomarker) in peripheral blood mononuclear cells was assessed on days 1-2 with sparse sampling. PK/PD models were developed using NONMEM v7.4.1 interfaced with Finch Studio v1.1.0 and PsN v4.7.0. Model selection was guided by objective function value, goodness-of-fit, and visual predictive checks. Stepwise covariate modeling was used for covariate selection. RESULTS: Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified. CONCLUSIONS: A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT01959698.

Perspectives of Cell Sensitivity/Resistance Assay in Soft Tissue Sarcomas Chemotherapy.

Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in targeted cancer therapies, cytostatic drug combinations remain the gold standard for STS chemotherapy. The lack of algorithms for personalized selection of STS chemotherapy leads to unhelpful treatment of chemoresistant tumors, causing severe side effects in patients. The goal of our study is to assess the applicability of in vitro chemosensitivity/resistance assays (CSRAs) in predicting STS chemoresistance. Primary cell cultures were obtained from 148 surgery samples using enzymatic and mechanical disaggregation. CSRA was performed using resazurin-based metabolic activity measurement in cells cultured with doxorubicin, ifosfamide, their combination and docetaxel, gemcitabine, and also their combination for 7 days. Both the clinical data of patients and the CSRA results demonstrated a higher resistance of some cancer histotypes to specific drugs and their combinations. The correlation between the CSRA results for doxorubicin and ifosfamide and clinical responses to the combination chemotherapy with these drugs was demonstrated via Spearman rank order correlation. Statistically significant differences in recurrence-free survival were also shown for the groups of patients formed, according to the CSRA results. Thus, CSRAs may help both practicing physicians to avoid harmful and useless treatment, and researchers to study new resistance markers and to develop new STS drugs.

[Advanced Bladder Cancer with Multiple Pulmonary Metastases Treated with Paclitaxel/Ifosfamide/Nedaplatin Therapy : Two Case Reports].

The standard treatment for advanced urothelial carcinoma includes platinum-based chemotherapy and programmed cell death protein 1 or programmed death ligand 1 inhibitors. However, urothelial carcinomas are often associated with both intrinsic and acquired resistance to these treatments. Paclitaxel, ifosfamide, and nedaplatin (TIN) chemotherapy has been proven to be effective as the second- or third-line treatment for platinum-resistant advanced urothelial cancer. Herein, we report two cases of patients with advanced bladder cancer resistant to platinum-based chemotherapy or pembrolizumab, who were treated with TIN chemotherapy. The first case was in a 66-year-old woman treated with gemcitabine and cisplatin (GC) chemotherapy followed by gemcitabine, paclitaxel, and cisplatin chemotherapy for multiple pulmonary metastases after radical cystectomy. Following reduction in pulmonary metastases after six courses of TIN treatment, metastasectomy and two courses of adjuvant TIN treatment were administered, with no recurrence for eight years. The other case was in a 70-year-old man treated with GC chemotherapy and pembrolizumab for invasive bladder cancer and multiple pulmonary metastases. We treated this patient with salvage pelvic exenteration. Pulmonary metastases significantly decreased after six courses of TIN chemotherapy. After a partial response for seven months; the patient died due to a novel cerebellar metastasis after six courses of TIN chemotherapy. Thus, we conclude that TIN chemotherapy can be considered as a third line treatment for advanced urothelial cancer resistant to platinum-based chemotherapy and pembrolizumab.