Cycles Of Induction Chemotherapy Research Articles

625. PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY CHEMORADIATION AND MINIMALLY INVASIVE SURGERY FOR LOCALLY ADVANCED CARCINOMA OF THE ESOPHAGUS

Abstract Background Most patients with esophageal cancer (EC) present locally advanced disease. Currently, multimodal strategies as neoadjuvant chemoradiotherapy or perioperative chemotherapy are employed, but still have high local and distant failures rates. This study evaluated the results of a phase II protocol with induction chemotherapy (IC) and concurrent chemoradiation (CR) before surgery for locally advanced carcinoma of the esophagus and esophagogastric junction (EGJ). The primary end point was to evaluate pathological complete remission (PCR) rate at surgical specimen. A PCR ≥ 30% was considered promising for further study. Methods Patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus and JEG, clinical stage T1b-3, N0-2, M0, PS 0-2, underwent two cycles of IC with carboplatin and paclitaxel followed by CR with the same agents and minimally invasive esophagectomy. At the screening, 14 days after the first cycle of IC and 6-8 weeks after the CR, metabolic responses were accessed by PET-CT and classified according the PERCIST criteria. Results One hundred and twenty-nine patients were accrued from January 2017 to April 2023. Forty-seven patients started the trial and 45 completed the neoadjuvant part of the protocol. Most patients were male (73.3%), the median age of was 55 years and AC was the most prevalent histological subtype (53.3%). Grade 3/4 toxicity during IC were infrequent and included neutropenia (12.5%), anemia (6.2%) and dysphagia (10.4%). Lymphopenia (10.7%) and dysphagia (6.5%) were the most common grade 3/4 toxicity during CR. All cases received the full radiotherapy dose of 45 Gy by IMRT technique. Thirty-seven patients underwent surgery and 31 had minimally invasive MacKeown esophagectomy with complete tumor resection (R0). Sixty-four percent of all included patients completed the neoadjuvant therapy and survived for 30 days after surgery. The most prevalent postoperative complications were anastomotic fistula (29%) and pneumonia (19%). Median hospital stay was 12 (7-56) days. Six patients (19.3%) had major postoperative morbidity (Clavien-Dindo ≥ IIIb), 4 were reoperated and one (3.2%) died during hospitalization. The median number of lymph nodes retrieved was 24. Eleven patients (33.5%) had pathological positive lymph nodes. The overall pathological complete response rate was 25.8%, 41.8% for SCC and 15.8% for AC. The early metabolic evaluation by PERCIST showed that 2 cases (4.4%) had progressive disease (PD), 26 (57.7%) stable disease (SD), 15 (33.3%) partial response (PR) and 2 (4.4%) complete response (CR). All the CR were SCC. The late metabolic response analysis showed that 1 (2.4%) patient had PD, 6 (14.6%) SD, 23 (56%) PR and 11 (27%) CR. On the basis of an intention-to-treat analysis, the median overall survival was 31.4 months, whereas the five-year overall survival was 31.2%. After curative surgery, 12 patients had recurrence disease. Six (19%) patients had recurrences at distant sites, 4 (12.9%) had loco-regional recurrence and 2 (6.4%) had both patterns. Conclusion This intensified neoadjuvant regimen was efficacious and safe in patients with locally advanced EC, but failed to reach the defined efficacy goal for further investigation, especially for AC.

Mecapegfilgrastim for the prophylaxis of chemotherapy-induced neutropenia in locally advanced nasopharyngeal carcinoma: A prospective phase II clinical study.

Induction chemotherapy of docetaxel plus cisplatin (TP) is myelosuppressive, leading to severe neutropenia and febrile neutropenia (FN). Herein, we aimed to investigate the efficacy and safety of mecapegfilgrastim in the prevention of neutropenia in patients with locally advanced nasopharyngeal carcinoma who received the TP regimen. A total of 30 treatment-naive patients with locally advanced nasopharyngeal carcinoma were included in this study. Mecapegfilgrastim 6 mg was injected 24-48 h after the completion of induction chemotherapy with the TP regimen. The incidence of grade ≥3 neutropenia during the three induction chemotherapy cycles was 6.7% (95% CI, 0.8%-22.1%). In the first cycle of chemotherapy, the incidence of grade ≥3 neutropenia was 3.3% (95% CI, 0.1%-17.2%). No FN or antibiotic usage was reported. All 30 patients completed the induction chemotherapy cycles. Mecapegfilgrastim effectively reduced the incidence of chemotherapy-induced neutropenia and FN in patients with locally advanced nasopharyngeal carcinoma.

Longitudinal tracing of on-treatment plasma Epstein-Barr virus DNA as a biomarker for real-time dynamic risk monitoring in patients with nasopharyngeal carcinoma: The EP-SEASON study.

136 Background: Plasma Epstein-Barr virus (EBV) DNA is a biomarker for nasopharyngeal carcinoma (NPC). However, whether longitudinal on-treatment EBV DNA tracing would inform real-time recurrence risk in NPC remains to be elucidated. To address this issue, we conducted EP-SEASON (NCT03855020), a prospective cohort study of longitudinal on-treatment EBV DNA in EBV-positive NPC patients. Methods: Non-metastatic NPC with detectable pretreatment EBV DNA that received standard sequential chemo-radiotherapy were recruited. Serial EBV DNA in blood specimens were collected across pretreatment, 3-week after each induction chemotherapy (IC), every-week during radiotherapy (RT), within 1-week and 1-3 months upon RT completion. EBV DNA extracted from plasma was quantified by a real-time quantitative polymerase chain reaction assay targeting the BamHI-W region of the EBV genome. Longitudinal changing patterns of EBV DNA and their clinical relevance were analyzed. Results: Between May 2019 and April 2021, a total of 1000 patients underwent per-protocol EBV DNA assessments and treatment; 248 and 752 patients received concurrent chemoradiotherapy (CCRT, subcochortno-IC) and IC plus CCRT (subcochortIC), respectively. Longitudinal changes and clearance rates of EBV DNA displayed unique patterns during IC and RT phases. Throughout IC and RT phases, the rate of EBV DNA clearance decreased with repeated IC cycles; interestingly, the rate re-rose upon the introduction of RT, and then dropped to low levels (<10%/week) after the 4th week of RT (post-RT4w). Patients in subcochortno-IC and subcochortIC also exhibited differential clearance patterns during RT, with the rate of clearance being higher in subcochortno-IC before the 2nd week of RT (post-RT2w). Notably, despite the prognostic significance of EBV DNA at each timepoint ( Pall < 0.05), longitudinal EBV DNA displayed a linkage changing map with dynamic recurrence risks: 3-year disease-free survival (DFS) rate steadily dropped with delayed EBV DNA clearance during IC; it re-rose at the 2nd RT week upon EBV DNA clearance, followed by a sharp decrease at the 4th RT week in subcochortIC. In contrast, 3-year DFS rate continuously decreased with delayed EBV DNA clearance in subcochortno-IC. Finally, we identified different phenotypes of whole-course circulating tumor DNA changing dynamics that showed distinct prognosis ( P < 0.05). Conclusions: Longitudinal on-treatment EBV DNA tracing could forecast real-time risks and facilitate risk-adapted decision-making in NPC.

Trends in the treatment of human papillomavirus-associated oropharyngeal carcinoma in Slovakia.

The optimal treatment of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) is currently a subject of clinical research. This questionnaire study investigated current trends in the treatment of HPV-associated (HPV+) OPC in Slovakia with the incorporation of deintensification of oncological treatment into routine clinical practice outside of clinical trials. The Slovak Cooperative Head and Neck Cancer Group (SCHNCG) developed a questionnaire aimed at identifying trends in the oncological treatment of HPV+ OPC intended for all radiation oncology (RO) facilities in Slovakia. Specialists in the field of RO responded to general questions about the character of their individual institutions as well as to 4 theoretical clinical scenarios (case reports) regarding the treatment of HPV+ OPC, focusing primarily on the applied dose of radiotherapy (RT), the extent of target volumes, and the type of concurrent chemotherapy (CHT). The questionnaire study involved 35 RO specialists from 14 institutions in Slovakia. Regarding primary chemoradiotherapy (CRT) in T1N1M0 HPV+ OPC, 16 respondents (45.7%) would consider de-escalation of the RT dose to <70 Gy. In the case of postoperative RT in pT1pN1M0 HPV+ OPC with negative resection margins (R0) and absent extracapsular extension (ECE), 4 physicians (11.4%) would consider de-escalation of the RT dose to <60 Gy in the tumor bed area, while the majority of the treating specialists (n=19, 54.3%) would omit concurrent CHT. In the case of primary RT in elderly patient with T2N1M0 HPV+ OPC, the same number of physicians (n=16, 45.7%) would consider de-escalation of the RT dose to <70 Gy, and 14 respondents (40.0%) would completely omit CHT. In a high-risk patient with T2N3M0 HPV+ OPC with a complete response after 3 cycles of induction chemotherapy (iCHT), none of the respondents would indicate a reduction in the RT dose to the area of the original tumor and lymphadenopathy to <60 Gy. The doses and extent of irradiated volumes in the treatment of HPV+ OPC in Slovakia vary among different institutions. The tendency to de-escalate RT doses and reduce doses of concurrent systemic therapy in Slovakia is high and there was also an observed trend to reduce the extent of radiation treatment fields.

Effect of Flow Cytometric MRD Detection at Different Time Points during AML Chemotherapy on Prognosis

To investigate the effect of flow cytometric minimal residual disease (MRD) detection at different time points during AML chemotherapy on prognosis. 130 adult primary AML patients diagnosed and standardized with chemotherapy from March 2018 to March 2022 were retrospectively analyzed, MRD was detected by flow cytometry, Kaplan-Meier curves was used for survival analysis and log-rank test was used for variance analysis, and univariate and multifactor influencing patient survival with COX proportional risk regression model analysis. Cumulative incidence rate (CIR) analysis with competing risk model and variance analysis using Fine-Gray. There were 81 CR1, 26 CR2, 14 PR, and 9 NR patients in 130 patients. OS of the CR1 group was higher than that in the CR2, PR,and NR groups. OS of the CR2 group was higher than that in the PR group, but there was no statistically difference compared to the NR group. There was no statistically difference in OS between the PR and NR groups. 107 patients in CR1 and CR2 were grouped according to MRD detected by flow cytometry, and after the first induction chemotherapy, for patients in the MRD- and MRD+ groups, the 4-year expected RFS rates were 65.3% and 27.9% respectively, the 4-year expected OS rates were 58.7% and 41.4% respectively, and the 4-year expected CIR were 34.7% and 69.7% respectively, with statistically significant differences between 2 groups (χ2=6.639, P =0.010; χ2=6.131, P =0.013 and χ2=6.637， P =0.010). After the second chemotherapy, for patients in the MRD- and MRD+ groups, the 4-year expected RFS rates were 50.8% and 37.9% respectively, the 4-year expected OS rates were 49.2% and 44.5% respectively, and the 4-year expected CIR were 49.2% and 59.5% respectively, with no statistically significant differences between 2 groups (χ2=1.475, P =0.225; χ2=2.432, P =0.119 and χ2=1.416， P =0.234). During consolidation therapy, for patients in the MRD - and MRD+ groups, the 4-year expected RFS rates were 51.9% and 29.6% respectively, the 4-year expected OS rates were 67.5% and 24.6% respectively, and the 4-year expected CIR were 48.1% and 70.4% respectively, with statistically significant differences between 2 groups (χ2=20.982, P < 0.001; χ2=17.794, P < 0.001 and χ2=19.879， P < 0.001). For patients with MRD- at all three time points and positive at either time point, the 4-year expected RFS rates were 69.9% and 33.3% respectively, the 4-year expected OS rates were 59.1% and 44.7% respectively, and the 4-year expected CIR were 30.1% and 65.1% respectively, with statistically significant differences between 2 groups (χ2=7.367, P =0.007; χ2=6.042, P =0.014 and χ2=7.662， P =0.006). Univariate analysis showed that karyotype at high risk of chromosome was an unfavorable factor affecting patients' RFS and OS, while 2 cycles of induction chemotherapy achieved CR, MRD- after the first induction chemotherapy and MRD- after the second induction chemotherapy was a protective factor affecting patients' RFS and OS. MRD- during consolidation therapy and MRD- at all three time points were all protective factors affecting patients' RFS, OS and CIR. Multivariate analysis showed that induction chemotherapy for 2 cycles achieved CR was a protective factor affecting patients' RFS and CIR, and MRD- during consolidation therapy was a protective factor affecting patients' RFS, OS and CIR. Early achievement of CR and MRD- in adult AML patients, especially MRD- during consolidation therapy, is a marker of good prognosis, and flow cytometry is the most commonly used method for MRD detection in AML patients.

Multidisciplinary treatment of giant thymoma, paving the way to complete surgical resection: a case report

BackgroundA multidisciplinary treatment approach is recommended for patients with extensive, advanced, or recurrent thymomas. However, detailed treatment strategies, such as chemotherapy regimens and optimal surgical procedures, are still under debate.Case presentationWe report a case of gigantic locally advanced thymoma. A 70-year-old male was referred to our hospital following the detection of abnormal chest shadows. Chest X-ray and computed tomography (CT) scans revealed a 21-cm mass in the anterior mediastinum, encircling the pulmonary hilum and extending into the left thoracic cavity. PET/CT showed increased 18F-fluorodeoxyglucose uptake at the tumor site. Based on a trans-percutaneous CT-guided needle biopsy, the tumor was diagnosed as a Type B2 thymoma at the clinical IIIA stage. The patient underwent four cycles of preoperative induction chemotherapy, including cisplatin, doxorubicin, and methylprednisolone (CAMP), resulting in a partial response; the tumor shrank to 12 cm and FDG uptake decreased. Considering the patient’s age and comorbidities, we performed total thymectomy, along with partial resections of the parietal, mediastinal and visceral pleura, pericardium, and left upper lobectomy. This approach achieved complete histological resection, mitigating the risk of recurrence. Pathological analysis confirmed a thymoma, ypT3 (lung) N0M0 stage IIIA, with no malignancy in the pericardial or pleural effusions. No recurrence was detected 9 months post-surgery.ConclusionsWe report a case of giant thymoma successfully treated with multidisciplinary strategy. Surgical treatment alone may not have achieved complete resection, but after inducing significant tumor shrinkage with preoperative CAMP therapy, we were able to achieve complete resection. This treatment strategy may be effective in large thymoma cases.

Atypical hemolytic uremic syndrome during induction chemotherapy in neuroblastoma, a rare phenomenon or common congenital predisposition?

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H(CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

Clinical prognostic factors to guide treatment strategy for HPV‑positive oropharyngeal cancer using treatment outcomes of induction chemotherapy: A real‑world experience.

The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains debatable, and suitable candidates for de-escalation treatment in these patients have not been fully identified. Therefore, the present study aimed to identify high-risk candidates for human papillomavirus (HPV)-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Patients diagnosed with stage III-IVA OPC and treated with a minimum of two cycles of IC followed by CRT, between 2004 and 2020, were retrospectively reviewed. All the patients were restaged according to the American Joint Committee on Cancer, 8th edition. The overall response rate and survival outcomes associated with clinical factors based on HPV status were analyzed using univariate and multivariate analyses. The present study analyzed 105 patients with a median age of 60 years (range, 40-76 years). Among 105 patients, 40 (38.1%) were HPV-negative and 65 (61.9%) HPV-positive. In all patients, survival outcomes were notably poorer in patients aged ≥60 years (P=0.006) and those who did not achieve complete response post-CRT (P<0.001), irrespective of the HPV status. The median relative dose intensity of IC was ≥80%, indicating adequate treatment, regardless of age. In contrast to patients with HPV-negative OPC, age ≥60 years (P=0.011) and T4 stage (P=0.019) emerged as substantial poor prognostic factors for survival outcomes in patients with HPV-positive OPC. Patients with HPV-positive OPC were categorized into three groups based on the number of clinical factors at diagnosis (such as age and T4 stage). The progression-free and overall survival showed significant stratification across each group as the number of high-risk factors increased despite IC and CRT. The findings indicated that patients with these high-risk factors require a cautious therapeutic strategy even when they are diagnosed with HPV-positive OPC, and the role of combined modality, including IC, will need to be investigated in a randomized trial to be routinely incorporated into clinical practice.

MDB-82. TRANSFUSION-RELATED IRON OVERLOAD MIMICKING METASTATIC DISEASE IN A PEDIATRIC PATIENT WITH MEDULLOBLASTOMA ON A RADIATION-DELAYING CHEMOTHERAPY REGIMEN

Abstract BACKGROUND Transfusion-related iron overload (TRIO) is a known complication of administering numerous packed red blood cell (pRBC) transfusions in pediatric oncology patients undergoing myelosuppressive therapy. Infant medulloblastoma regimens attempt to avoid or delay radiation and its adverse effects in this population, with intensive myelosuppressive chemotherapy. We report a case of TRIO first suspected as hepatic metastatic disease at time of CNS recurrence in a young patient with medulloblastoma after completion of a high-dose chemotherapy protocol. METHODS Case Report RESULTS A five-year-old male presented with four months of headaches, dizziness, imbalance, and emesis. MRI revealed a posterior fossa mass with near total resection of the mass confirming classic medulloblastoma, non-WNT, non-SHH. The patient received five cycles of induction chemotherapy. This was followed by a single cycle of high-dose chemotherapy (HDCSCR) with autologous stem cell rescue. During therapy, he received 26 pRBC transfusions to correct severe anemia. CNS recurrence occurred 19 months after therapy. Abdominal imaging revealed enlarging hepatic lesions concerning for metastases. Ferritin was 1,268 ng/mL (normal: 7-142 ng/mL) and MRI of liver revealed severe iron load with LIC of 11 mg Fe/g dry weight (dw) (normal: 0.4-2.2 mg Fe/g dw). Ultimately, hepatic lesions were thought to be non-cancerous, and he proceeded with craniospinal irradiation. He was diagnosed with TRIO. He underwent phlebotomy for 33 months with ferritin and MRI liver LIC within normal limits. CONCLUSION This case illustrates an occurrence of TRIO presenting as hepatic lesions concerning for metastatic disease during CNS recurrence in a patient who underwent an infant medulloblastoma regimen with HDCSCR. Our patient required phlebotomy for nearly 3 years to return ferritin and LIC to normal limits. Further investigation on the prevalence of TRIO in medulloblastoma survivors treated with radiation delaying/sparing protocols is necessary to improve outcomes and avoid end organ damage due to iron overload.

Can TTMV clearance predict recurrence in HPV HNSCC?

6066 Background: Patients with locally advanced (LA) HPV HNSCC are treated with various types of induction chemotherapy (IC) followed by standard (sd) or reduced (rd) chemoradiation (CRT). Tumor tissue-modified viral HPV DNA (TTMV) pairs with PET-CT in predicting an early detection of treatment failure in HPV-related HNSCC. Mid-treatment TTMV assessment in HPV-related HNSCC can help identify patients who are eligible to receive a lower dose of IC and/or CRT or those who may require close follow-up. Methods: Patients with LA HPV+ HNSCC with high-risk features (radiographic ECE, T4 primary, &gt;N2c) and &lt;20 pack-year (py) smoking history were treated with IC followed by rdCRT (56 Gy); sdCRT (70 Gy) was used in non-responders. 16/23 received IC with TPF, 1/23 TP, and 6/23 TP-PD1, and all patients received carboplatin weekly with their CRT. Regeneron trial patients who received TP-Cemiplimab (PD1) IC followed by sdCRT are also continuing adjuvant Cemiplimab alone for 6 months (NCT05376553). PET-CT-confirmed residual, recurrent, or metastatic diseases were defined as treatment failures; TTMV + patients only if PET-CT confirmed. Results: 23 subjects treated with IC followed by CRT between 2/4/21-1/26/24, who had pre- and post-treatment TTMV were included in our analysis. The median pre-IC TTMV was 8082 (27 – 90770). The median follow-up time from treatment start was 21 months. 9/23 patients had full clearance TTMV after 1 cycle of IC defined as rapid responders (RR). 11/23 patients still had positive TTMV after 1st cycle of IC were defined as slow responders (SR). 1 patient had no TTMV done after 1 cycle of IC but was elevated after 2nd IC; he was defined as SR. 2 patients had a positive pre-IC TTMV, but no TTMV was drawn during IC to see if RR. 1 of 2 patients was TTMV negative prior to CRT, and 2/2 had a 1st post IC negative TTMV done 1 week after CRT started. They were both included in the analysis but defined as unknown response status. TTMV testing was done for all 23 subjects after CRT; all were negative. All subjects have TTMV testing done during their surveillance visits. Among 9/23 RR, none developed a failure. Among 12/23 SR, 3 patients developed a failure: 1/3 was TTMV+ but PET-, being followed with TTMV and PET-CT; and 2/3 were confirmed failures, TTMV+ and PET+; 1 locoregional, 1 metastatic. 2 patients were not known to be a SR or RR and had no recurrence. Among 23 patients, NPV of TTMV to detect failure was 100%, but PPV was 96% (1/23). Conclusions: IC followed in rapid clearance of TTMV in 39% of patients, and all remained disease-free. 3/11 (27%) with persistently elevated TTMV after cycle 1 relapsed as of this time point. This small study was not large enough to be practice-changing. However, this is significantly hypothesis-generating and should be tested in a larger trial to help identify patients for de-escalation (RR) or closer surveillance (SR).

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: A retrospective study with a 5-year follow-up.

e18003 Background: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at the affiliated cancer hospital of Guizhou medical university. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a “MELODIE” multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n = 35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusions: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

A pilot study of post-consolidation chemoimmunotherapy for high-risk neuroblastoma (ANBL19P1): A report from the Children’s Oncology Group.

10004 Background: Post-consolidation anti-GD2 antibody-based immunotherapy has improved survival for newly diagnosed patients (pts) with high-risk neuroblastoma (HRNBL). However, nearly half of newly diagnosed pts relapse. Based upon the efficacy of anti-GD2 antibody dinutuximab given with chemotherapy (chemoimmunotherapy) in the relapse setting, we hypothesized that post-consolidation chemoimmunotherapy may further improve frontline outcomes. ANBL19P1 first assessed the feasibility of delivering chemoimmunotherapy after tandem high-dose chemotherapy with autologous stem cell transplant (ASCT). Methods: Pts &lt;31 years old with HRNBL who received 4-6 cycles of Induction chemotherapy +/- up to 4 cycles of post-Induction chemotherapy or chemoimmunotherapy, underwent tandem ASCT, had no evidence of progressive disease (PD), and met organ function criteria were eligible. Therapy, administered every 28 days, consisted of temozolomide and irinotecan on Days 1-5, dinutuximab on Days 2-5, and sargramostim on Days 6-12 during Cycles 1-5; isotretinoin on Days 8-21 during Cycles 1-6. Therapy was deemed feasible if the 95% confidence interval (CI) placed on the percentage of pts that completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks contained 75%, and if the interim monitoring rules for feasibility and excessive toxicity were not triggered. Event-free (EFS) and overall survival (OS) were determined from time of enrollment. Results: From 11/30/20-6/30/23, 40 eligible pts enrolled and started protocol therapy. 87.5% (n=35) were ≥18 months old and 97.5% (n=39) had INRG Stage M disease, at diagnosis. 87.5% (95% CI 73.9%, 94.5%) completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks, exceeding the feasibility benchmark of 75%. Feasibility and monitoring rules were not triggered. Five pts were removed from protocol therapy prior to Cycle 4 [physician determination (n=2), pt/parent refusal of further therapy (n=2), and PD (n=1)]. No unacceptable toxicities or deaths on protocol therapy were reported. Toxicities of interest are summarized (Table). One-year EFS and OS were 90.0±5.0% and 97.5±2.7%, respectively (median follow-up time for pts without event=1.2 years). Conclusions: Administration of post-consolidation chemoimmunotherapy in pts who underwent tandem ASCT is tolerable and met pre-defined feasibility criteria. The impact of this approach on survival outcomes will be studied in a future COG trial. Clinical trial information: NCT04385277 . [Table: see text]

Preliminary experience of ex-vivo expanded allogeneic universal donor TGFβi NK cell infusions in combination with irinotecan, temozolomide, and dinutuximab in patients with relapsed or refractory neuroblastoma: The Allo - STING trial.

10005 Background: Neuroblastoma (NBL) is the most common extra-cranial solid tumor in children and outcomes for children with relapsed/refractory (RR) NBL remain dismal. While the combination of chemoimmunotherapy (CIT) with the anti-GD2 antibody dinutuximab as per COG protocol ANBL1221 has improved responses, this regimen is still not curative. Dinutuximab can recruit NK cells for anticancer activity, however, NK cells are depleted in NBL patients undergoing chemotherapy. We devised a method to expand allogeneic NK cells ex vivo to improve effector function and render the NK cells resistant to TGFβ-induced suppression (TGFβi). These TGFβi NK cells are expanded from a universal donor (UD) pool, enabling multiple cycles of “off-the-shelf” high-dose therapy. We hypothesize that adoptive transfer of UD-TGFβi NK cells to patients with RR NBL sequentially following CIT is safe and improves outcomes compared to CIT alone. Methods: This Phase I/II study evaluates the safety and tolerability of UD-TGFβi NK cells in combination with CIT and compares anti-cancer efficacy to CIT alone. Eligibility includes age &lt; 30 years, RR or progressive NBL, and prior treatment with at least 4 cycles of induction chemotherapy. The treatment protocol consists of 21-day cycles of CIT as per COG protocol ANBL1221 with UD-TGFβi NK cells (1x108 cells/kg) infused on day 8. Up to six cycles of treatment are permitted. Overall response rates are defined using the Revised International NBL Response Criteria, with 95% confidence intervals compared to the results from ANBL1221. Progression-free and overall survival will be estimated by the Kaplan Meier method. Results: Four subjects (7 – 11 years) have been enrolled. All patients presented with high risk NBL: three with relapsed disease and one with refractory disease. All received at least one prior salvage therapy. Three patients have completed all 6 cycles of protocol therapy, and one remains on treatment. 20 NK cell infusions have been administered to date. All NK cell infusions occurred within the protocol specified window. One subject experienced grade 1 fever with two NK cell infusions. There have been no other adverse events attributable to the NK cells. Adverse events attributable to CIT were similar to those described in COG ANBL 1221. Treatment delays for cytopenias due to CIT occurred in two patients. Three patients achieved a partial response. A fourth patient attained prolonged stable disease (9 months) but experienced a skeletal recurrence. Conclusions: UD allo-TGFβi NK cells can be safely and feasibly administered to children with RR NBL after treatment with CIT, with early objective responses observed in the preliminary cohort of patients. Ongoing studies will assess markers of response, NK cell persistence, pharmacokinetics and pharmacodynamics. Clinical trial information: NCT04211675 .

Sequential chemoradiotherapy versus induction chemotherapy plus concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: A multicentre, open-label, non-inferiority, randomised, phase 3 trial.

6075 Background: Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) has been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable disease control. Now, distant metastasis was the main cause of failure. However, concurrent cisplatin is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and chemotherapy before or after radiotherapy decreases the risk of distant failure, it is worth exploring whether sequential chemoradiotherapy (SCRT) regimen could replace IC+CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from January 2018 to September 2021 in 6 centers in China. Patients aged 18–65 years with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive 2 cycles of IC with GP regimen (gemcitabine 1000mg/m2 d1,8 + cisplatin 25 mg/m2 d1-3, q21d) plus IMRT, followed by 2 cycles of adjuvant chemotherapy (AC) with the same regimen or IC with GP regimen for 2 cycles followed by IMRT plus concomitant weekly cisplatin (30 mg/m²). The primary endpoint was 3-year failure-free survival (FFS) with non-inferiority margin of 10% (HR&lt;1.6) and the incidence of grade ≥3 acute mucositis during radiotherapy. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 420 patients were randomly assigned to SCRT group (n = 210) or IC+CCRT group (n = 210). With a median follow-up of 47.0 months (IQR: 35.0-57.8), the 3-year FFS was 84.0% in SCRT group versus 79.8% in IC+CCRT group (log rank P=0.344), with an HR of 0.804 (95% CI, 0.510 to 1.266) and absolute difference of 4.2% (95% CI, -3.2 to 11.6). No significant differences were observed between groups in 3-year overall survival (97.4% vs. 94.5%; HR 0.413; 95% CI, 0.159 to 1.076; log rank P=0.061), locoregional control (91.7% vs. 88.8%; HR 0.767; 95% CI, 0.420 to 1.401; log rank P=0.386), or distant metastasis-free survival (93.6% vs. 91.5%; HR 0.756; 95% CI, 0.376 to 1.520; log rank P=0.430). Compared with IC+CCRT group, the SCRT group had significantly lower incidences of grade ≥3 acute nonhematological AEs due to the omission of concurrent chemotherapy (including acute mucositis 29.0% vs. 41.9%, P&lt;0.001; nausea 9.5% vs. 18.1%, P=0.011; and vomiting 3.8% vs. 9.5%, P=0.019), and higher incidences of grade ≥3 acute hematological AEs (including thrombocytopenia and leukopenia) due to the additional AC. Conclusions: For LA-NPC, SCRT was not inferior in 3-year FFS to IC+CCRT. It might be an alternative treatment for LA-NPC patients with fewer sever nonhematological AEs during IMRT. Clinical trial information: NCT03366415 .

Clinical prognostic factors to guide treatment strategy for HPV-positive oropharyngeal cancer from treatment outcomes of induction chemotherapy: A real-world experience.

e18014 Background: The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains a topic of debate and suitable candidates for de-escalation treatment in these patients have not been fully identified. This study aimed to identify high-risk groups for HPV-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Methods: Between 2004 and 2020, we reviewed patients with OPC diagnosed with stage III-IVA who underwent a treatment regimen comprising a minimum of two cycles of IC followed by CRT.In this study, all patients were re-staged according to the American Joint Committee on Cancer (AJCC) 8th edition, and we analyzed the overall response rate and survival outcomes associated with clinical factors based on HPV status by utilizing univariate and multivariate analyses. Results: This study analyzed 105 patients with a median age of 60 years (range: 40–76 years). Among 105 patients, 40 (38.1%) were HPV-negative, and 65 (61.9%) were HPV-positive. Through a median follow-up of 60.0 months (range, 5–60 months), no significant differences in progression-free survival (PFS) (p = 0.172) and overall survival (OS) (p = 0.064) were observed based on HPV status, regardless of no differences in relative dose intensity of IC and cumulative dose of radiation and cisplatin in CRT. In all patients, survival outcomes were notably poorer in patients aged ≥ 60 years ( p = 0.006) and those who did not achieve complete response (non-CR) post-CRT ( p &lt; 0.001), irrespective of HPV status. All have received sufficient IC with a median RDI of 80% or more in both age &lt; 60 years and age ≥ 60 years. Unlike HPV-negative OPC, where age and T stage showed no significant correlation, in HPV-positive OPC, age ≥ 60 years ( p = 0.011) and T4 stage ( p = 0.019) emerged as substantial poor prognostic factors for survival outcomes despite IC and CRT. Utilizing these results, we categorized HPV-positive OPC patients into three groups based on the number of clinical risk factors at diagnosis (age, T4 stage), the PFS and OS showed significant stratification across each group as the number of clinical risk factors increased. Conclusions: This study revealed that age and T stage significantly influenced on prognosis in HPV-positive OPC but not in HPV-negative OPC. Considering our result, HPV-positive OPC exhibiting these risk factors requires a careful treatment strategy, and combined treatments, including immunotherapy, may be considered to enhance treatment outcomes for these patients.

A prospective multicenter trial of dose escalation for weekly gemcitabine concurrent with intensity-modulated radiotherapy following cisplatin and gemcitabine induction chemotherapy in patients with locally advanced nasopharyngeal carcinoma.

6071 Background: Gemcitabine and cisplatin induction chemotherapy, followed by cisplatin-based concurrent chemoradiotherapy, constitutes the standard treatment for locally advanced nasopharyngeal carcinoma (LANPC). However, the substantial cumulative dosage of cisplatin used in this approach renders it intolerable for many patients due to advanced age or compromised renal function. Therefore, identifying alternative chemotherapeutic agents is crucial. Gemcitabine is a potent radiosensitizer with an overall favorable safety profile. Despite extensive research on the maximum tolerated dose (MTD) of concurrent gemcitabine chemotherapy in head and neck cancer, its MTD as a single-agent chemotherapy concurrently administered with intensity-modulated radiotherapy (IMRT) in LANPC remains uncertain. Methods: Patients diagnosed with stage III-IVa nasopharyngeal carcinoma were prospectively enrolled in three hospitals located within the largest NPC endemic area in southern China. After two cycles of cisplatin plus gemcitabine induction chemotherapy, patients underwent combined concurrent radiochemotherapy (70 Gy/6-7 weeks) with weekly gemcitabine. The initial dose level was set at 25mg/m2 and subsequently escalated in a sequential manner to higher doses of 50mg/m2, 100mg/m2, 200mg/m2, and 300mg/m2 etc. Our study employed a dose escalation strategy in which the dosage was incremented to the next group only if no more than one out of six patients experienced Dose-Limiting Toxicity (DLT), until DLT occurred in at least two patients. Patients underwent follow-up evaluations every three months. This study is registered with ClinicalTrials.gov under NCT04522050. Results: Between October 2018 and December 2023, a total of 39 Chinese patients were enrolled, 36 (27 males, 9 females) patients were considered evaluable. The incidence of DLT was observed in two out of six patients receiving a dosage level of 300 mg/m², with both cases presenting Grade 3 oral mucositis. Subsequently, the study was replicated using the same dosage level, resulting again in two instances of DLT: one case with Grade 3 radiation dermatitis and another case with oral mucositis. Consequently, a reduced dosage level of 200mg/m² was determined as MTD. No significant hematological toxicity or serious gastrointestinal adverse events were observed. Tumor response evaluation by MRI after twelve weeks of IMRT showed a complete response rate of 100%. To date, only two cases (5.56%) have been reported exhibiting tumor recurrence. Conclusions: The MTD for weekly gemcitabine with IMRT following induction chemotherapy in LANPC is determined to be 200 mg/m2. The DLT associated with this treatment regimen primarily consists of radiation dermatitis and/or oral mucositis. Clinical trial information: NCT04522050 .

Incorporation of PD-1 blockade into induction chemotherapy improved tumor response in patients with locoregionally advanced nasopharyngeal carcinoma in a retrospective patient cohort

ObjectiveTo investigate the short-term efficacy and safety of induction chemotherapy (IC) combined with anti-PD-1 immunotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MethodsA total of 217 patients diagnosed with LA-NPC at the First Affiliated Hospital of Nanchang University, including 67 who received IC combined with anti-PD-1 and 150 who received IC, were retrospectively enrolled. Efficacy was evaluated at the end of the IC cycles and one month after radiotherapy based on RECIST v1.1 criteria. Acute toxicities were graded based on the CTCAE v5.0 criteria. Quantitative variables were compared by unpaired t-tests, and categorical variables were evaluated by Fisher Freeman-Halton test or Pearson Chi-square test. ResultsAt the end of all induction therapy cycles, the objective response rate (ORR) of the IC + anti-PD-1 group was 88.1 % (59/67) as opposed to 70.0 % (105/150) in the IC group. Subgroup analysis showed that patients in both stage Ⅲ and ⅣA achieved a significant improvement in ORR with the inclusion of anti-PD-1 therapy. Patients with T3-4 or N2-3 category appeared to benefit more from anti-PD-1 compared to patients with T1-2 or N0-1 category. However, neither ORR nor the complete response (CR) rate was significantly different between the two treatment groups one month after the end of radiotherapy. In addition, the frequency of Grade 3–4 adverse events were also similar in both groups. ConclusionsIC combined with anti-PD-1 immunotherapy significantly improved the ORR of LA-NPC patients after induction therapy compared to IC alone.

Survival of Metastatic Human Papillomavirus (HPV)-Related Head and Neck Cancer Receiving Platinum-Based Triplet Induction Chemotherapy and Relevance of Circulating Tumor HPV DNA.

Objectives We aimed to examine the effectiveness of platinum-based triplet induction chemotherapy in metastatic squamous cell carcinoma of the head and neck (HNSCC) at diagnosis in terms of tumor human papillomavirus (HPV) status and the clinical relevance of circulating tumor HPV DNA (ctHPVDNA) during induction chemotherapy. Methods Twenty-one patients were included. ctHPVDNA was longitudinally quantified using optimized digital PCR in a subset of patients. Results HPV-related HNSCC patients (N=7) had a significantly better response to induction chemotherapy than HPV-unrelated HNSCC patients (N=14) (complete or partial response rate, 100% vs. 36%, P = 0.007). Following induction chemotherapy, more HPV-related HNSCC patients than HPV-unrelated patients received radiotherapy (86% vs. 36%, P = 0.06). With a median follow-up of 26 months in surviving patients, the two-year overall survival was 86% in HPV-related HNSCC patients and 43% in HPV-unrelated HNSCC patients (P = 0.04). In two patients, ctHPVDNA levels drastically decreased after the first cycle of induction chemotherapy but turned to continuous increase after the second cycle, suggesting the acquisition of drug resistance by the end of the second cycle. Radiographic imaging after induction chemotherapy failed to identify the drug resistance. In one patient, ctHPVDNA decreased gradually but remained detectable after induction chemotherapy despite no radiographic residual disease. ctHPVDNA became undetectable during radiotherapy. Conclusion HPV-related HNSCC patients with distant metastasis at diagnosis should be treated definitively. The ctHPVDNA level reflects real-time disease activity. ctHPVDNA monitoring during induction chemotherapy could help the decision-making of the therapeutic strategy.

Abstract PO2-03-05: Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study

Abstract Background: Immune checkpoint inhibitors(ICIs)have shown promising antitumor activity in triple negative breast cancer (TNBC) patients. Toripalimab, a novel PD-1 antibody, has been approved for the treatment in multiple solid tumors. However, the neoadjuvant use of toripalimab with chemotherapy has not been evaluated in TNBC patients. In addition, whether chemotherapy could sensitize the ICI treatment has not drawn conclusion yet. In this phase II trial, a sequential use of chemotherapy and anti-PD1 therapy was given in a neoadjuvant setting. The efficacy and safety of toripalimab were evaluated. Patients and methods: Female patients with histologically confirmed stage IIA to IIIC TNBC were included. Eligible patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks followed by toripalimab (240 mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was pathologic complete response (tpCR; ypT0/is ypN0) rate. Key secondary endpoints were breast pCR (bpCR; ypT0/is) rate, biomarker analysis, and safety. Results: Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 patients completed study treatment without progression and received surgery after study treatment. Overall, the percentages of patients with a tpCR and bpCR were 55.7% (39 of 70 patients) and 58.6 % (41 of 70 patients), respectively. For women with CD8–positive and negative tumors, the tpCR rates were 66.0% and 30.0% (P = 0.006), respectively. Significant upregulation of CD8 positive cells after 4 cycles of epirubicin-cyclophosphamide induction chemotherapy (P = 0.011) were shown in sequential biopsy samples. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 30 patients (42.9%), the most common of which were neutropenia (15.7%), leukopenia (14.3%) and alanine aminotransferase increase (4.3%). Most common immune-related AEs were hepatobiliary disorders (Grade 3, 7.2%), creatinine increase (all Grade 1-2, 2.8%) and hypothyroidism (all Grade 1-2, 2.8%). Conclusions: The addition of toripalimab to neoadjuvant chemotherapy is efficacious and safe in patients with locally advanced TNBC. Anthracycline-based chemotherapy could sensitize the ICI treatment with upregulated tumor immune response. The event-free survival results are expected with further follow up. Mechanisms of chemotherapy sensitization are still under investigation (ClinicalTrials.gov number: NCT04418154). Citation Format: Min He, Linxiaoxi Ma, Shuang Hao, Benlong Yang, Bingqiu Xiu, Ya-Yun Chi, Ruo-Hong Shui, Zhong-Hua Wang, Zhi-Ming Shao, Jiong Wu. Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-05.

Locally advanced nasopharyngeal carcinoma in adolescents treated with tomotherapy: Experience at King Faisal Specialist Hospital and Research Centre.

Nasopharyngeal carcinoma (NPC) is a rare disease worldwide; To the best of our knowledge, there is no established standard of care specifically tailored for the adolescent population. The majority of existing research relies on retrospective data analysis. Evaluate clinical features, treatment results, prognostic factors and late toxicities of locally advanced NPC patients treated with tomotherapy. Retrospective. Tertiary care hospital. Between January 2007 and January 2020, we treated patients with NPC, aged between 14 and 21 years, with concomitant chemoradiotherapy using tomotherapy at our institution. We prospectively collected details of clinical characteristics, treatment modalities, outcomes and prognostic factors of these patients and then analysed them retrospectively. 3-5 years overall survival (OS), 3-5 years locoregional control rate, 3-5 years disease-free survival (DFS), prognostic factors. 51 patients. There were 26 male and 25 female patients included in our study. The mean age was 16.5 years, 5 (9.8%) patients with stage III, and 46 (90.2%) with stage IVa according to the American Joint Committee on Cancer, 8th edition staging system. Most patients (98%) received two or more cycles of induction chemotherapy. All patients received concomitant chemoradiotherapy. The median total dose of radiotherapy delivered was 6600 cGy (range 4800-7000). With a median follow-up of 73 months (range 9-168 months), a 5-year locoregional control rate, 5-year OS and 5-year DFS rates were 100%, 86.8% and 71.7%, respectively. Five years later, disease control was 71.7%. Ten (19.6%) patients had disease recurrence in the form of distant metastases during the follow up. Helical tomotherapy has an excellent late toxicity profile without compromising clinical outcome for patients with NPC. Radiotherapy remains the mainstay of treatment of nasopharyngeal carcinoma to achieve remarkable local control rates. Single institution experience, small number of patients, and retrospective design.