Chemoradiotherapy Research Articles

Abstract B086: Patient-derived pancreatic tumor organoids as a tool to evaluate cancer stem cell populations and their role in therapeutic resistance

Abstract Introduction: Pancreatic ductal adenocarcinoma remains one of the most lethal forms of cancer with a five-year survival rate of less than 15%. Regardless of surgery eligibility, most patients receive systemic chemo-radiation therapy, which includes FOLFIRINOX or gemcitabine and nab-paclitaxel, often followed by radiation therapy (RT) with or without 5-FU. Unfortunately, patients’ tumors frequently develop resistance to these therapies, and it’s often unclear as to why. One potential source of resistance and recurrence is cancer stem cell (CSC) perseverance following treatment. Purpose: The purpose of this study was to characterize and treat three patient-derived pancreatic tumor organoids (IDs: 8510, 7800, and 11777) with RT and LD50 doses of relevant chemotherapy drugs to evaluate the treatment response. Furthermore, we sought to examine the impact of individual and combination treatments (i.e., chemo-RT) on the population of CSCs in these organoids. Methods: Organoids were cultured in 3D BME gel domes and grown in an NCI-recommended media formulation. Genome sequencing of 505 relevant genes was performed using a PGDx kit. The dose responses of three organoids to radiation (2-12 Gy) and several chemotherapy approaches were determined via MTT assay. CSCs were identified as those cells staining positive for markers SOX2 and OCT4. The population of CSCs before and after chemotherapy, RT, and combined chemo-RT were evaluated with immunofluorescence, western blotting, and flow cytometry. Results: The data revealed a variation in the responses of tumor organoids to treatments, as demonstrated by different LD50 doses. For instance, tumor organoid 8510 exhibited higher tolerance to 5-FU and FOLFIRINOX treatments compared to organoid 7800. Interestingly, organoid 11777 showed resistance to RT, unlike organoids 8510 and 7800. Clinical genomic sequencing revealed that organoid 11777 showed unique variants of several genes known to be involved with DNA repair, including PIM1, RAD54L, and SLX4, as well as mutations in the ARID1b and TGFBR2 genes. The latter two genes may have implications for radiation resistance and could explain the unique resistance of organoid 11777 to RT. Further investigation is warranted. Regarding the population of CSCs, the immunofluorescence data has confirmed the presence of SOX2 and OCT4 in these organoids, and the immunoblot data showed an upregulation of SOX2 and OCT4 in tumor organoids treated with radiation alone. Flow cytometry analysis confirmed that the percentage of CSCs increased following radiation treatment; however, the CSC population was slightly decreased following treatment with FOLFIRINOX and significantly decreased after combination treatment with FOLFIRINOX and RT. Conclusions: Patient-derived pancreatic tumor organoids can be used as a surrogate to provide molecular insights and therapeutic sensitivity profiles in individual patients. Additionally, while the data suggests a link between CSCs and RT resistance, the combination approach results in a more pronounced inhibition of the CSC population. Citation Format: Zachery L Keepers, Sanjit Roy, William Ryan, Binny Bhandary, Narottam Lamichhane, France Carrier, Ramaswamy K Iyer, Jason K Molitoris, William F Regine, Hem D Shukla. Patient-derived pancreatic tumor organoids as a tool to evaluate cancer stem cell populations and their role in therapeutic resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B086.

Rhabdomyosarcoma of the skull with EWSR1 fusion and ALK and cytokeratin expression: a case report.

Rhabdomyosarcoma (RMS) comprises of heterogeneous group of neoplasms that occasionally express epithelial markers on immunohistochemistry (IHC). We herein report the case of a patient who developed RMS of the skull with EWSR1 fusion and anaplastic lymphoma kinase (ALK) and cytokeratin expression as cytomorphologic features. A 40-year-old man presented with a mass in his forehead. Surgical resection was performed, during which intraoperative frozen specimens were obtained. Squash cytology showed scattered or clustered spindle and epithelioid cells. IHC revealed that the resected tumor cells were positive for desmin, MyoD1, cytokeratin AE1/ AE3, and ALK. Although EWSR1 rearrangement was identified on fluorescence in situ hybridization, ALK, and TFCP2 rearrangement were not noted. Despite providing adjuvant chemoradiation therapy, the patient died of tumor progression 10 months after diagnosis. We emphasize that a subset of RMS can express cytokeratin and show characteristic histomorphology, implying the need for specific molecular examination.

Return to work and self-reported swallowing following transoral robotic surgery for early-stage oropharyngeal squamous cell carcinoma: A retrospective cohort study

BackgroundTreatment de-intensification, including transoral robotic surgery (TORS), may outcomes in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). Early return to work (RTW) improves quality of life in oncology patients. Our objective was to compare the RTW time in OPSCC patients undergoing primary TORS or chemoradiotherapy (CRT). We investigated the role of treatment modality on self-reported swallowing function. MethodsAll patients were adults diagnosed with early-stage (T1–2, N0–2) OPSCC and treated via primary TORS or CRT. We performed 1:1 exact case matching based on tumor stage and subsite. We collected RTW outcomes for all patients. We also reported MD Anderson Dysphagia Index (MDADI) scores up to 24 months from the end of treatment. We performed statistical analyses and comparison of RTW and MDADI outcomes based on treatment group. ResultsOverall, 26 patients undergoing primary TORS and 25 undergoing primary CRT were included. We found a significant improvement in RTW in TORS patients compared to CRT (TORS: 54 days (1.8 months), IQR: 30.8; CRT: 164 days (5.4 months), IQR: 109; W=587, p = 9.28e-08) independent of HPV status, tonsillar subsite, and radiotherapy alone. Primary TORS had a 16.2-fold (95 % CI: 5.78–45.5) higher likelihood of returning to work than primary CRT patients. Primary TORS also had better MDADI scores within two years of treatment. ConclusionsIn OPSCC, primary TORS accelerated RTW and improved swallowing when compared to primary CRT. The potential economic advantage of returning to work sooner should be discussed when reviewing treatment options with patients.

Complement is increased in treatment resistant rectal cancer and modulates radioresistance

Resistance to neoadjuvant chemoradiation therapy (neo-CRT) is a significant clinical problem in the treatment of locally advanced rectal cancer. Identification of novel therapeutic targets and biomarkers predicting therapeutic response is required to improve patient outcomes. Increasing evidence supports a role for the complement system in resistance to anti-cancer therapy. In this study, increased expression of complement effectors C3 and C5 and increased production of anaphylatoxins, C3a and C5a, was observed in radioresistant rectal cancer cells. Modulation of the central complement effector, C3, was demonstrated to functionally alter the radioresponse, with C3 overexpression significantly enhancing radioresistance, whilst C3 inhibition significantly increased sensitivity to a clinically-relevant dose of radiation. Inhibition of C3 was demonstrated to increase DNA damage and alter cell cycle distribution, mediating a shift towards a radiosensitive cell cycle phenotype suggesting a role for C3 in reprogramming of the tumoural radioresponse. Expression of the complement effectors C3 and C5 was significantly increased in human rectal tumour tissue, as was expression of CFB, a component of the alternative pathway of activation. Elevated levels of C3a and C5b-9 in pre-treatment sera from rectal cancer patients was associated with subsequent poor responses to neo-CRT and poorer survival. Together these data demonstrate a role for complement in the radioresistance of rectal cancer and identify key complement components as potential biomarkers predicting response to neo-CRT and outcome in rectal cancer.

Safety and Efficacy of Conversion Therapy After Systemic Chemotherapy in Advanced Esophageal Cancer with Distant Metastases: A Multicenter Retrospective Observational Study.

Patients with esophageal squamous cell carcinoma (ESCC) with distant metastasis were treated with systemic chemotherapy. Recent advances in multimodal treatments have made conversion therapy a viable option for patients with incurable ESCC. We aimed to assess the safety and efficacy of conversion therapy for ESCC with distant metastases. Conversion therapy was defined as surgery or chemoradiotherapy (CRT) used to cure tumors that were previously considered incurable because of distant metastasis. We conducted a retrospective review of patients who underwent ESCC conversion therapy and assessed the treatment outcomes, including adverse events and survival rates. A total of 147 patients from 22 institutions were included. Systemic chemotherapy was initially administered to all patients. The most common M1 factor was the para-aortic lymph node, accounting for 55% of cases. Following the initial treatment, 116 patients underwent surgery, with 31 receiving CRT as conversion therapy. Postoperative complications in surgery patients included pneumonia (16%), anastomotic leakage (7%), and recurrent laryngeal nerve palsy (6%). During CRT, 18% of patients developed grade 3 or higher non-hematological toxicities. The 5-year overall survival (OS) rate was 31.7%. Pathological responders had significantly longer OS than non-responders (hazard ratio 0.493, p=0.012). The distribution of distant metastasis, regimen type, clinical response, and conversion therapy modality did not have a significant impact on OS. Conversion therapy can be safely performed for ESCC with distant metastasis and has a favorable prognosis.

Feasibility Study of Nivolumab in Combination with Carboplatin Plus Paclitaxel and Concurrent Thoracic Radiation in Patients with Untreated Unresectable Locally Advanced Non-Small Cell Lung Cancer.

Despite advancements in diagnosing and treating non-small cell lung cancer (NSCLC), the prognosis remains poor. Immune checkpoint inhibitors have shown promise in enhancing survival rates. Therefore, this study aimed to investigate the safety of nivolumab administration with concurrent chemoradiation therapy (CCRT) in patients with unresectable locally advanced NSCLC. Twelve patients with unresectable locally advanced NSCLC at Kansai Medical University Hospital and Izumi City General Medical Center were enrolled from May 2018 to September 2020. They received nivolumab (360 mg) tri-weekly twice, weekly carboplatin (AUC 2 min × mg/mL) and paclitaxel (40 mg/m2) for 6 weeks, and thoracic radiotherapy (60 Gy/30 fractions), followed by maintenance nivolumab therapy (360 mg, tri-weekly) for 6 months. The primary endpoint was incidence of dose-limiting toxicities (DLTs), and the secondary endpoints included safety, response rate, progression-free survival (PFS), overall survival (OS), 2-year survival rate, and treatment completion rate. Three patients completed the protocol. Nine discontinued due directly to interstitial pneumonia (three) and pneumonia (one). Ten patients (83.3%) experienced a grade 3 or higher event, of which three (25%) experienced a grade 4 or higher event, and of these, one (8.3%) experienced a grade 5 event. Three patients experienced DLTs. Concurrent nivolumab with CCRT was tolerated in unresectable locally advanced NSCLC, which offers potential treatment benefits.

The impact of preoperative treatments on the immune environment of rectal cancer.

To improve local disease control, the use of preoperative radiotherapy either alone or combined with chemotherapy has become standard practice in rectal cancer, but it is unclear how these treatments modify the antitumoral immune response. We aimed to evaluate tumor histopathologic features and the prognostic effect of host immune response in rectal cancer with variable treatment modalities. Ninety-five rectal cancers with short-course radiotherapy (SRT), 97 with long-course chemoradiotherapy (CRT), and 154 without preoperative treatments, were evaluated for histopathologic features including Crohn's-like reaction (CLR). CD3+ and CD8+ immunohistochemistry and tumor cells were analyzed from tumor tissue microarray samples to calculate T-cell densities and G-cross function values to estimate cancer cell-T-cell co-localization (proximity score). We found that lymphocyte densities were diminished after SRT, but CLR was scarcer after CRT. Proximity score and CLR density were prognostic for survival in cancer without preoperative treatments and could be combined into an enhanced prognostic score (immune grade). In the irradiated tumors, CLR density remained prognostic while the impact of T-cell infiltration was insufficient alone. In multivariable analysis, the immune grade proved to be an independent prognostic factor for survival. In conclusion, the immune contexture of rectal cancer harbors prognostic significance even after preoperative radiotherapy.

Mandibular Ameloblastoma: A Reported Case

Ameloblastoma is a benign aggressive odontogenic tumor which requires early diagnosis and appropriate treatment. It commonly affects the mandible and radical surgery is the gold standard treatment. We report the case of a patient with ameloblastoma in extremely advanced phase affecting the retromolar trigone who was treated with concomitant chemoradiation therapy. Mandibular ameloblastoma is not well documented in the literature. It is usually diagnosed at the later stage when optimal surgery cannot be performed. This case study aimed to demonstrate that radiation therapy is a real therapeutic alternative in the treatment of advanced and inoperable forms of ameloblastoma.

FP1.8 - Optimizing Rectal Cancer Treatment: Comprehensive response to Neoadjuvant therapy

Abstract Aims This study aimed to assess the outcomes and feasibility of a watch-and-wait strategy in patients with rectal cancer showing a complete response to neoadjuvant chemoradiotherapy (CRT). The primary objectives included evaluating the oncological results, disease-free interval, and survival rates in patients who underwent the watch-and-wait approach after a complete clinical response. Methods The study involved a retrospective analysis of last 10 years of rectal cancer patients enrolled in a complete responder surveillance program in an acute general hospital. Cohort characteristics, including age, performance status, tumor histology, distance from the anal verge, and treatment modalities, were documented. Results The median age was 74 (57-90), and the median performance status was 1, with the age at diagnosis being 69. All cohort members had a histologically confirmed rectal adenocarcinoma. The median tumor-to-anal-verge distance was 5 cm (1-10 cm). Neoadjuvant chemotherapy was administered to 55% of patients. All patients underwent long-course radiotherapy, and 35% received papillon contact brachytherapy. Total neoadjuvant therapy was received by 10%. The median follow-up involved approximately 9 colonoscopies. During follow-up, 25% of patients experienced recurrence, with a median disease-free interval of 3.5 years. Conclusion The findings of this study, in addition to ongoing prospective clinical trials and insights from databases such as EURECCA and OnCore, indicate that a watch-and-wait approach can be safe and effective for selected rectal cancer patients who have achieved a complete response to neoadjuvant CRT. This study highlights the significance of additional research to identify appropriate patients for this approach and to refine its implementation in rectal cancer management.

Radiomics analysis of cerebral blood flow suggests a possible link between perfusion homogeneity and poor glioblastoma multiforme prognosis

Objectives. This study investigates the association between cerebral blood flow (CBF) and overall survival (OS) in glioblastoma multiforme (GBM) patients receiving chemoradiation. Identifying CBF biomarkers could help predict patient response to this treatment, facilitating the development of personalized therapeutic strategies. Materials and Methods. This retrospective study analyzed CBF data from dynamic susceptibility contrast (DSC) MRI in 30 newly diagnosed GBM patients (WHO grade IV). Radiomics features were extracted from CBF maps, tested for robustness, and correlated with OS. Kaplan-Meier analysis was used to assess the predictive value of radiomic features significantly associated with OS, aiming to stratify patients into groups with distinct post-treatment survival outcomes. Results. While mean relative CBF and CBV failed to serve as independent prognostic markers for OS, the prognostic potential of radiomic features extracted from CBF maps was explored. Ten out of forty-three radiomic features with highest intraclass correlation coefficients (ICC > 0.9), were selected for characterization. While Correlation and Zone Size Variance (ZSV) features showed significant OS correlations, indicating prognostic potential, Kaplan-Meier analysis did not significantly stratify patients based on these features. Visual analysis of the graphs revealed a predominant association between the identified radiomic features and OS under two years. Focusing on this subgroup, Correlation, ZSV, and Gray-Level Nonuniformity (GLN) emerged as significant, suggesting that a lack of heterogeneity in perfusion patterns may be indicative of a poorer outcome. Kaplan-Meier analysis effectively stratified this cohort based on the features mentioned above. Receiver operating characteristic (ROC) analysis further validated their prognostic value, with ZSV demonstrating the highest sensitivity and specificity (0.75 and 0.85, respectively). Conclusion. Our findings underscored radiomics features sensitive to CBF heterogeneity as pivotal predictors for patient stratification. Our results suggest that these markers may have the potential to identify patients who are unlikely to benefit from standard chemoradiation therapy.

Locally advanced rectal cancer in a young adult affected with dyskeratosis congenita (Zinsser–Cole–Engman syndrome): a case report

BackgroundDyskeratosis congenita (DKC), also known as Zinsser–Cole–Engman syndrome, is a progressive genetic disease with a triad of reticulate skin pigmentation, nail dystrophy, and leukoplakia. Approximately 8–10% of patients with DKC develop malignancies, and cases of colorectal cancer with DKC in young people have been reported previously.Case presentationA 25-year-old man with DKC since approximately 10 years of age developed fever and lower abdominal discomfort. Diagnostic imaging revealed locally advanced rectal cancer with lymph node metastasis, direct invasion of the prostate, and pelvic abscess due to tumor microperforation (cT4bN2M0 cStage IIIC). Biopsy showed well to moderately differentiated ductal adenocarcinoma. Genetic testing was negative for RAS and BRAF gene mutations, and microsatellite instability (MSI) testing was also negative. After sigmoid colostomy, the patient was treated with total neoadjuvant therapy (TNT) with systemic chemotherapy (six courses of FOLFOX + panitumumab) followed by chemoradiation therapy (50.4 Gy with capecitabine). After TNT, the primary tumor and metastatic lymph nodes shrank. According to the findings of colonoscopy and magnetic resonance image (MRI), we diagnosed near complete response (near-CR) and decided to follow the patient without surgery by every 3 months re-evaluation. However, 5 months after TNT, tumor regrowth was detected on colonoscopy and imaging, and the patient underwent total pelvic exenteration. He developed paralytic ileus as a postoperative complication, and was discharged on the 38th postoperative day. Pathological examination revealed a residual tumor with invasion of the periprostatic tissue. There was no metastasis in the pararectal and lateral pelvic lymph nodes, but one extramural non-contiguous cancerous extension (tumor deposit) was observed (ypT4bN1cM0 ypStage IIIC). The patient has been free of recurrence for one year after surgery.ConclusionsDKC often develops into various tumors in the digestive system at an early age; therefore, appropriate surveillance may be required. In addition, considering that cancers in patients with DKC occur at a young age, fertility preservation and survivorship are also important, and adequate explanations and care should be provided to patients before and after treatment.

Surgical Outcomes Following Neoadjuvant Treatment for Locally Advanced and Borderline Resectable Pancreatic Ductal Adenocarcinoma.

To assess overall survival (OS), compare the effects of neoadjuvant treatment, and describe surgical outcomes for patients undergoing pancreatic resection following chemotherapy and/or chemoradiotherapy (CRT) for borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). We approach BR/LA PDAC using chemotherapy followed by selective CRT to the primary site of disease where either the surgical margin remains radiologically threatened following chemotherapy or as a further downstaging treatment. Retrospective study of patients between December 2005 and June 2023 at the Royal Marsden Hospital, London, United Kingdom. A total of 54 patients were included. The OS between R1 and R0 patients was significantly different: 7.5 versus 23 versus 42 versus 51 months for R1 chemo, R1 chemo and CRT, R0 chemo and R0 chemo, and CRT groups, respectively, P < 0.001. Similarly, 9 versus 18 versus 42 versus 41 months for N1 chemo, N1 chemo and CRT, N0 chemo and N0 chemo, and CRT groups, respectively, P = 0.0026. Multivariable Cox regression model demonstrated that perineural invasion (hazard ratio: 2.88, 95% confidence interval: 1.06-7.81; P = 0.038) and perivascular invasion (PVI) (HR: 2.76, 95% CI: 1.24-6.13; P = 0.013) were associated with significantly worse OS. Chemo and CRT conferred OS benefit compared to chemo only (7 vs 23 months, P = 0.004) in PVI-positive patients. Neoadjuvant chemotherapy followed by CRT compared to chemotherapy alone for resected BD and LA PDAC was demonstrated to significantly improve median OS, in particular, in patients with R1 resection margins, ypN1 nodal status, and perivascular invasion.

Prevailing Practices in Ototoxicity Monitoring in Individuals With Head and Neck Cancer Undergoing Radiotherapy and Chemoradiotherapy: A Scoping Review.

The aim of the current scoping review is to identify the studies reporting ototoxicity monitoring in individuals with head and neck cancer (HNC) undergoing radiation therapy and/or chemoradiation therapy across the world. The specific objectives were to identify and report the test protocol used, identify the most common timeline of follow-up, and identify barriers and facilitators influencing the implementation of the monitoring program. A comprehensive search was conducted across six electronic databases, including PubMed, Embase, Web of Science, Scopus, Google Scholar, and ProQuest. The scoping review method adhered to relevant guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) and frameworks. The database search was carried out by two independent researchers, and studies were selected based on specific inclusion and exclusion criteria. This scoping review identified 13 studies that fulfilled the inclusion criteria of this study. Only one study reported findings from the perspective of ototoxicity monitoring. Another study explicitly mentioned that ototoxicity monitoring was a standard of care in their hospital. Only one study reported using the relevant guidelines for monitoring ototoxicity. Specialized tests such as high-frequency audiometry, distortion product otoacoustic emissions, and vestibular tests were rarely used. Ototoxicity monitoring was influenced by awareness-related factors, technical factors, treatment-related factors, and organizational factors. Research on ototoxicity monitoring programs is in its early stages, highlighting the need for standardized practices and multidisciplinary collaboration to enhance health care services for HNC patients. A standardized approach, improved awareness, and the incorporation of patient perspectives are crucial to enhancing ototoxicity monitoring in HNC patients.

Parameters to assess the necessity of adjuvant therapy for early-stage oral squamous cell carcinoma.

One-third of head and neck squamous cell carcinomas are early-stage oral cavity squamous cell carcinomas (OCSCC). Despite a high curative rate, 20% of early-stage OCSCC patients do not achieve long-term survival. This study evaluates the role of adjuvant therapy (ADJ) in delaying disease progression and prolonging survival. This single-institute retrospective cohort study enrolled 481 early-stage OCSCC patients, 16% (78/481) of whom received ADJ. It was reported according to the STROBE guidelines. Cox proportional hazards regression and Kaplan-Meier survival curves were employed to identify suitable candidates for ADJ. The 5-year locoregional recurrence-free survival (LR-RFS) and overall survival rates were 73.2% and 84.9%, respectively. Positive margins and advanced depth of invasion (DOI) were independent predictors of LR-RFS. For patients with positive margins, adjuvant chemoradiotherapy (CRT) was superior to adjuvant radiotherapy alone in improving LR-RFS (hazard ratios for adjuvant CRT vs. none, 0.042; adjuvant radiotherapy alone vs. none, 0.702). Excluding positive margins, advanced DOI was the most critical factor in assessing the need for ADJ. Positive margins and advanced DOI were more appropriate criteria than EORTC 22931/RTOG 9501 for evaluating adjuvant CRT. Adjuvant CRT was indicated for patients with positive margins and advanced DOI to improve survival outcomes.

Comparative Study on Symptomatic Response and Toxicity of Concurrent Chemo-Radiotherapy and Radiotherapy Alone in the Treatment of Cervical Cancer

This prospective observational study was carried out to compare the symptomatic response and acceptable toxicity in concurrent chemo-radiotherapy and radiotherapy alone in the treatment of cervical cancer. A total of 60 patients (30 patients in arm A &amp; 30 patients in arm B) who have biopsy proven cervical carcinoma with no history of previous treatment were selected from the Department of radiotherapy Rajshahi Medical College Hospital, Rajshahi &amp; in the department of Radiation &amp; Oncology, National Institute of Cancer Research &amp; Hospital. All patients in both arms received external beam radiation with 50Gy in 25 daily fractions over five weeks. Followed by three insertions (one insertion per week) of Intracavitary brachytherapy each 700 cGy. Patients in arm-A received Inj. Cisplatin 40mg/m2 in IV infusion on the first day of each treatment per week in addition to radiotherapy. In this study it was observed that a significant symptomatic improvement was found in arm-A after treatment than arm-B and no severe unwanted reaction was noted in most of the patients. Systematic toxicity developed in both groups and comparatively more in arm-A (chemo radiation) but that was not statistically significant and well managed with conservative treatment. Regarding performance status patients treated with concurrent chemo radiation showed better performance status than the patient treated with radiotherapy alone. In this study it was observed that patients of carcinoma cervix treated with concurrent chemo radiotherapy was effective for symptomatic improvement and feasible with acceptable toxicity for advanced cancer of the uterine cervix than those with radiation alone.

A retrospective evaluation of therapeutic efficacy and safety of chemoradiotherapy in older patients (aged ≥ 75 years) with limited-disease small cell lung cancer: insights from two institutions and review of the literature.

The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreover, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC. From April 2007 to June 2021, consecutive older patients (aged ≥ 75 years) with stage I to III SCLC who received concurrent or sequential CRT at two institutions were retrospectively evaluated for efficacy and toxicity of CRT. A total of 32 older patients underwent concurrent (n = 19) or sequential (n = 13) CRT for LD-SCLC. The median ages of the patients in the concurrent and sequential CRT groups were 77 (range: 75-81) years and 79 (range: 76-92) years, respectively. The median number of chemotherapeutic treatment cycles was four (range, 1-5), and the response rate was 96.9% in all patients (94.7% in concurrent and 100% in sequential CRT groups). The median progression-free survival (PFS) and median overall survival (OS) for all patients were 11.9 and 21.1 months, respectively. The median PFS was 13.0 and 9.0 months in the concurrent CRT and sequential CRT groups, respectively, with no statistically significant difference (p = 0.67). The median OS from the initiation of CRT was 19.2 and 23.5 months in the concurrent and sequential CRT groups, respectively (p = 0.46). The frequencies of Grade ≥ 3 hematological adverse events were as follows: decreased white blood cell count, 20/32 (62.5%); decreased neutrophil count, 23/32 (71.9%); anemia, 6/32 (18.8%); decreased platelet count, 7/32 (21.9%); and febrile neutropenia, 3/32 (9.4%). Treatment-related deaths occurred in one patient from each group. Although hematological toxicities, particularly reduced neutrophil count, were severe, CRT showed favorable efficacy in both concurrent and sequential CRT groups. However, concurrent CRT may not be feasible for all older patients with LD-SCLC; accordingly, sequential CRT may be considered as a treatment of choice for these patients. Further prospective trials are warranted to identify optimal treatment strategies for this patient group.

Dynamics of Daily Glioblastoma Evolution During Chemoradiation Therapy on the 0.35T Magnetic Resonance Imaging-Linear Accelerator

Glioblastoma changes during chemoradiation therapy are inferred from magnetic resonance imaging (MRI) before and after treatment but are rarely investigated due to logistics of frequent MRI. Using a combination MRI-linear accelerator (MRI-linac), we evaluated changes during daily chemoradiation therapy. Patients with glioblastoma were prospectively imaged daily during chemoradiation therapy on 0.35T MRI-linac and at 3 timepoints with and without contrast on standalone high-field MRI. Tumor or edema (lesion) and resection cavity dynamics throughout treatment were analyzed and compared with standalone T1 postcontrast (T1+C) and T2 volumes. Of 36 patients included in this analysis, 8 had cavity only, 12 had lesion only, and 16 had both cavity and lesion. Of these, 64% had lesion growth and 46% had cavity shrinkage during treatment on MRI-linac scans. The average MRI-linac migration distance was 1.3 cm (range, 0-4.1 cm) for lesion and 0.6 cm (range, 0.1-2.1 cm) for cavity. Standalone versus MRI-linac volumes correlated strongly with R2 values: 0.991 (T2 vs MRI-linac cavity), 0.972 (T1+C vs MRI-linac cavity), and 0.973 (T2 vs MRI-linac lesion). There was a moderate correlation between T1+C and MRI-linac lesion (R2 = 0.609), despite noncontrast MRI-linac inability to separate contrast enhancement from surrounding nonenhancing tumor and edema. From pretreatment to posttreatment in patients with all available scans (n = 35), T1+C and MRI-linac lesions changed together-shrank (n = 6), grew (n = 12), or unchanged (n = 8)-in 26 (74%) patients. Another 9 patients (26%) had growth on MRI-linac, although the T1+C component shrank. In no patient did T1+C lesion grow while MRI-linac lesion shrank. Anatomic changes are seen in patients with glioblastoma imaged daily on MRI-linac throughout the chemoradiation therapy course. As surgical resection cavities shrink, margins may be reduced to save normal brain. Patients with unresected or growing lesions may require margin expansions to cover changes. Limited volume glioblastoma boost trials could consider triggered gadolinium contrast administration for evaluation of adaptive radiation therapy when lesion growth is seen on noncontrast MRI-linac.

Efficacy and Safety of Nimotuzumab in Combination with Radiotherapy or Chemoradiotherapy for Local Advanced Head and Neck Cancer: A Systematic Review and Meta-analysis.

The present meta-analysis aimed to evaluate the efficacy and safety of adding nimotuzumab to radiotherapy (RT) or chemoradiotherapy (CRT). Prospective randomized controlled studies at EMBASE, PubMed, and the Cochrane Library from January 1, 2010, to October 1, 2022, were searched. Data on the overall survival (OS), progress-free survival (PFS), disease-free survival (DFS), complete response rate (CRR), objective response rate (ORR), and all grade adverse events were collected from the enrolled publications. OS was the primary measurement indicator. Pooled analysis was performed with relative risks (RRs), hazard risks (HRs), and their corresponding 95% confidence intervals (CIs) in the software Stata SE 16.0. Six randomized controlled studies were included in the analysis of the overall pooled effect. As compared to the control group, the nimotuzumab intervention group exhibited improved OS by 21% (pooled HR=0.79,95% CI: 0.64-0.98, P=0.028), along with PFS up to 31% (HR=0.69, 95% CI: 0.55-0.86, P=0.001) and DFS up to 29% (HR=0.71, 95% CI: 0.56-0.91, P=0.006), increased CRR as 50% (RR=1.50, 95% CI:1.09-2.04; P=0.012), and ORR as 35% (RR=1.35, 95% CI:1.04-1.73; P=0.022). Regarding safety, nimotuzumab in combination with RT or CRT did not increase the incidence of all grade adverse events (pooled-RD=-1.27, 95% CI:-2.78-0.23, P=0.099). The present meta-analysis has demonstrated that nimotuzumab, in combination with RT or CRT, could provide survival benefits and increase response rates. Its safety profile has been found to be controllable.

Dose-Response Relationships Between Radiation Exposure, Bone Marrow Function as Measured by 18F-Fluorothymidine Positron Emission Tomography, and Lymphocyte Counts During Chemoradiation for Non-Small Cell Lung Cancer

Purpose18F-Fluorothymidine(FLT)-PET enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/CT scans before and during chemoradiation (CRT) for non-small cell lung cancer (NSCLC) were repurposed to investigate dose-response effects of radiation on BM proliferation. Methods and materialsTwenty-six NSCLC patients underwent platinum-based CRT to 60Gy in 30 fractions with FLT-PET/CT scans at baseline, week 2 (20Gy) and week 4 (40Gy). FLT uptake in BM was isolated using Medical Image Merge software. Week 2 and week 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (SUVmax and visual parameters) were analyzed using generalized-linear and restricted cubic-spline models. Percentage volumes of total BM without appreciable FLT uptake (“ablated”) on week 2 and week 4 FLT-PET scans were calculated by comparisons with baseline scans. ResultsThoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3Gy by week 2. In all cases BM FLT SUVmax declined rapidly as radiation dose increased. BM proliferation significantly decreased by more than 95% after ≥3-4Gy at 2 weeks and ≥4-5Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. Median percentage of total BM ablated was 13.1% (range 5.6-20.3) at 2 weeks and 15.7% (range 9.2 - 24.1) at 4 weeks. Mean lymphocyte counts fell from baseline of 2.01×109/L to 0.77 week 2, and 0.60 week 4. Lymphocyte decline strongly correlated with percentage of total BM ablated by week 4 (y=-46 -1.64 x, R2adj = 0.34, p=0.001). ConclusionsBM ablation associated with low dose-radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ-at-risk and reducing the BM volume exposed to ≥3Gy may help preserve lymphocytes essential for effective adjuvant immunotherapy.

Long-term survival and post-hoc analysis of toripalimab plus definitive chemoradiotherapy for oesophageal squamous cell carcinoma: insights from the EC-CRT-001 phase II trial

In the EC-CRT-001 phase II study, the combination of toripalimab (an anti-programmed death-1 antibody) and definitive chemoradiotherapy (CRT) has shown promising efficacy in patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Here, we reported the long-term outcomes and post-hoc exploratory analyses. This single-arm, phase II trial enrolled 42 patients diagnosed with unresectable stage I-IVA ESCC was conducted at Sun Yat-sen University Cancer Center between November 2019 and January 2021. Treatment consisted of chemotherapy (weekly 50mg/m2 of paclitaxel and 25mg/m2 of cisplatin for five cycles), concurrent radiotherapy (50.4Gy in 28 fractions), and toripalimab (240mg every 3 weeks for up to 1 year). The primary endpoint was clinical complete response (CR) rate at 3 months after CRT completion. The 3-year overall survival (OS) and progression-free survival (PFS) rates were evaluated. Additionally, the exploratory objectives included analysing recurrence patterns, assessing the associations between immune-related adverse events (irAEs) and efficacy, and identifying potential predictors for irAEs. The trial was registered with ClinicalTrials.gov (NCT04005170). With a median follow-up of 44.3 months (IQR 40.8-46.1), the 3-year OS and PFS rates were 44.8% (95% CI 31.9-62.8) and 35.7% (95% CI 23.8-53.6), respectively. Patients who failed to achieve a clinical complete response (CR) demonstrated significantly worse OS (hazard ratio [HR]=13.73, 95% CI 4.43-42.54, P<0.0001) and PFS (HR=32.08, 95% CI 8.57-120.10, P<0.0001). Disease recurrence occurred in 23 of 42 patients (55%), with recurrences being earlier and more frequent in the non-CR group compared to the CR group. Patients experiencing irAEs showed a significantly higher CR rate (72% vs. 39%, P=0.082) and better PFS (HR=0.43, 95% CI 0.19-0.93, P=0.027) than those without irAEs. GON4L mutation was associated with a lower incidence of irAEs (P=0.036). The updated survival outcomes confirmed the efficacy of toripalimab plus definitive CRT in locally advanced ESCC. Moreover, the development of irAEs may predict a more favourable prognosis. National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Sci-Tech Project Foundation of Guangzhou.