Results of the study of factors predicting the risk of the development of grade III radiation-induced mucositis during radiation or chemoradiation therapy in patients with oral cavity and oropharynx cancer.

BACKGROUND: Today, a number of methods and ways of prevention and treatment of radiation- -induced mucositis of the oral cavity and oropharynx have been developed, but the represented approaches are still not effective enough. Therefore, to increase the effectiveness of the prevention and treatment of radiation-induced mucositis, it is necessary to approach this problem comprehensively and individually, and to evaluate the factors affecting the development of mucositis. MATERIALS AND METHODS: In this single-center prospective controlled non-randomized clinical trial, the results of clinical observation of the development of complications of radiation and chemoradiation therapy in 105 patients with a newly diagnosed squamous cell cancer of the oral cavity and oropharynx were analyzed. Factors affecting the risk of the development of grade III radiation-induced mucositis including the age, gender of the patients, their general condition before the treatment according to World Health Organisation scales, type of the treatment and its doses, additional use of immunotherapy with alpha/beta defensins, characteristic signs of the tumor process and all indices of the immune status of the patients before the treatment have been analyzed. RESULTS: The method of construction and analysis of one-factor logistic regression models, where 24 indices were analyzed as factorial features, showed that the reduction of the risk of the development of grade III radiation-induced mucositis is predicted by several factors: immunotherapy, gender, serum concentrations of IgG and IgA. A decrease (P < 0.001) in the risk of the development of grade III radiation-induced mucositis was revealed if immunotherapy with alpha/beta defensins (with a total dose of 40 mg) was included into the treatment scheme (relative odds (RO) 0.05; 95% reference interval (RI) 0.02-0.18), in comparison with patients of the groups where it was not present or this immune agent was used in a total dose of 60 mg (P = 0.001, RO 0.06; 95% RI 0.01-0.30). The next factorial sign was gender, namely the risk of the development of grade III radiation-induced mucositis was lower for men (P = 0.003; RO 0.15; 95% RI 0.04-0.53) compared to women. An increase (P = 0.024) in the risk of the development of grade III radiation-induced mucositis with an increase in the initial level of IgG serum concentration was revealed, (RO 1.08; 95% RI 1.01-1.16) for each 1 mg/mL, as well as an increase (P = 0.044) in the possibility of the appearance of grade III radiation-induced mucositis with an increase in the serum concentration of IgA (RO 1.23; 95% RI 1.01-1.50) for every 1 mg/mL also before the beginning of the treatment. Multifactorial analysis has also confirmed that the risk of the development of grade III radiation-induced mucositis increases (P = 0.008) with a high serum IgG concentration before the treatment or with an increase in this index during therapy (RO 1.13; 95% RI 1.03-1.09) for every 1 mg/mL (when standardized by other risk factors). It was determined that when standardizing according to other factors (gender, IgG level), the risk of the development of grade III radiation-induced mucositis in the use of the immune agent alpha/beta defensins in a total dose of 40 mg per course decreases (P < 0.001; RO 0.08; 95% RI 0.02-0.27) compared to patients with oral cavity and oropharynx cancer who were not treated with immunotherapy. The risk of the development of grade III radiation-induced mucositis also decreases (P = 0.001) in the use of immunotherapy in a higher dose, i.e. 60 mg per course (RO 0.03; 95% RI 0.004-0.24 compared to patients whose treatment did not include immunotherapy (when standardized by other factors). CONCLUSION: As a result of this controlled clinical study, some factors were determined in addition to the radiation as those affecting the risk of the development of grade III radiation-induced mucositis in patients with oral cavity and oropharynx cancer during special treatment. These factors comprise the inclusion of immunotherapy with alpha/beta defensins into the specific treatment; gender, and baseline levels of serum IgG and IgA concentrations suggest a pattern in which the higher the serum IgG and IgA concentrations are before the start of the treatment, the greater is the likelihood of severe radiation-induced mucositis degree during special therapy. The results of the study of humoral state of the immune system in patients with oral cavity and oropharynx cancer before the beginning of chemoradiation therapy can be used as prognostic risk factors for the development of severe gamma-irradiation-induced mucositis of the oropharyngeal area, as well as an indication for the use of immunotherapeutic agents (in particular, alpha/beta defensins) that are able to polarize the immune response towards type 1 T-helpers through their immunomodulatory action.

Survival outcomes and failure patterns for oropharyngeal cancers treated with simultaneous integrated boost in intensity modulated radiotherapy (SIB-IMRT) and concurrent chemotherapy.

BACKGROUND: Intensity modulated radiotherapy (IMRT) has become a standard radiotherapy treatment delivery option owing to the advantages it offers in terms of target coverage and organ sparing. Furthermore, the ability to introduce different fractionation for different targets lets us deliver higher doses to the high-risk areas and lower doses to the elective volumes at the same sitting, referred to as simultaneous integrated boost (SIB). In the current study, we intended to retrospectively analyze the clinical outcomes and patterns of the failure of oropharyngeal cancers treated with SIB-IMRT and concurrent chemotherapy at our centre and analyze the factors contributing to poorer outcomes. MATERIAL AND METHODS: Data of oropharyngeal cancer patients treated with SIB-IMRT and concurrent chemotherapy were retrieved from the institutional database. Patient demographic details, histopathological features, staging, treatment details, failure patterns and outcomes were documented. All potential factors were evaluated for outcomes. Radiation was delivered by using the SIB-IMRT technique. High-risk planning target volume (PTV) received 66 Gy in 2.2 Gy/fraction, intermediate and low-risk PTV received 60 Gy and 54 Gy, respectively. Primary endpoint was to assess local control (LC), regional control (RC) and loco-regional control (LRC) rates and secondary end point was to evaluate the survival outcomes - overall survival (OS) and cancer-specific mortality. All survival analyzes were performed using the Kaplan-Meier method. RESULTS: A total of 169 cases were included in the final analysis. The median age was 55 years (range 20-78) with 95.3% males. The base of tongue was the most common primary site. Around 54% cases were node negative with 38% patients having stage IV disease. The local control rates for N0 vs. N+ cases were 74.1 vs. 62.3% (P = 0.046), respectively. Similarly, the 4-year RC rates for N0 vs. N+ cases were 94.4 vs. 83.5% (P = 0.024), respectively. On multivariate analysis, only 4-year RC rates showed significant difference between the two (P = 0.039). No differences were found between T stages in LRC and OS. The 4-year LRC rates for stages 1, 2 vs. 3, 4 were non-significant (69.2 vs. 66.3%; P = 0.178). The 4-year OS rate was 81.3%. The 4-year LC and LRC rates were 67.8 and 89.5%, respectively. There were 54 local and 17 regional failures. The median time to failure was 13 months (range 3.6-82.9). CONCLUSION: SIB-IMRT provides comparable outcomes for oropharyngeal cancers. OS and loco-regional recurrences were significantly worse for nodal positive disease.

Risk factors for nausea and vomiting requiring the daily administration of 5-HT3 receptor antagonists in radiotherapy combined with temozolomide for high-grade glioma.

Radiotherapy combined with temozolomide (TMZ+RT) is the primary treatment for high-grade glioma. TMZ is classified as a moderate emetic risk agent and, thus, supportive care for nausea and vomiting is important. In Nagoya University Hospital, all patients are treated with a 5-hydroxy-tryptamine 3 receptor antagonist (5-HT3RA) for the first 3 days. The daily administration of 5-HT3RA is resumed after the 4th day based on the condition of patients during TMZ+RT. Therefore, the present study investigated risk factors for nausea and vomiting in patients requiring the daily administration of 5-HT3RA. Patients with high-grade glioma who received TMZ+RT between January 2014 and December 2019 at our hospital were included. Patients were divided into two groups: a control group (patients who did not resume 5-HT3RA) and resuming 5-HT3RA group (patients who resumed 5-HT3RA after the 4th day), and both groups were compared to identify risk factors for nausea and vomiting during TMZ+RT. There were 78 patients in the control group (68%) and 36 in the resuming 5-HT3RA group (32%). A multivariate analysis of patient backgrounds in the two groups identified age <18 years, PS 2 or more, and occipital lobe tumors as risk factors for nausea and vomiting. Nausea and vomiting were attenuated in 30 patients (83%) in the resuming 5-HT3RA group following the resumption of 5-HT3RA. The results obtained highlight the importance of extracting patients with these risk factors before the initiation of therapy and the early resumption or daily administration of 5-HT3RA according to the condition of each patient.

Prognostic Value of Novel CARWL Score in Stage IIIC Non-Small-Cell Lung Cancer Patients Undergoing Concurrent Chemoradiotherapy.

Objectives: We explored the prognostic utility of the unique combination of C-reactive-protein-to-albumin ratio (CAR) and significant weight loss (WL > 5%) over the preceding 6 months, namely, the CARWL score, in stage IIIC non-small-cell lung cancer (NSCLC) patients who underwent concurrent chemoradiotherapy (CCRT). Methods: For each patient, the CAR was calculated using C-reactive protein and albumin measurements obtained on the first day of CCRT: CAR = C-reactive protein ÷ albumin. The availability of an ideal CAR cutoff that may categorize patients into two distinct progression-free (PFS) and overall survival (OS) outcomes was explored by employing receiver operating characteristic (ROC) curve analysis. Patients were additionally divided into two groups based on their status of significant WL according to the well-recognized Delphi criteria. Then, the CARWL score was created by combining all feasible combinations of the CAR and significant WL groupings. The potential links between pretreatment CARWL groups and the post-CCRT OS and PFS outcomes were determined as the primary and secondary endpoints. Results: This retrospective cohort study comprised a total of 651 stage IIIC NSCLC patients. ROC curve analysis indicated that rounded 3.0 was the ideal CAR cutoff (area under the curve (AUC): 70.1%; sensitivity: 67.8%; specificity: 65.9%), which categorized the patients into CAR < 3.0 (N = 324) and CAR ≥ 3.0 (N = 327) groups. There were 308 (47.3%) and 343 (52.7%) patients without and with significant WL, respectively. The created CARWL groups were CARWL-0: CAR < 3.0 and WL ≤ 5.0%; CARWL-1: CAR < 3.0 and WL > 5.0%, or CAR ≥ 3.0 and WL ≤ 5.0%; and CARWL-2: CAR > 3.0 and WL > 5.0%. The Kaplan-Meier curves showed that the PFS (14.2 vs. 11.4 vs. 7.5 months; P < 0.001) and OS (37.3 vs. 23.6 vs. 12.8 months; P < 0.001) durations were gradually and significantly lowered from the CARWL-0 to CARWL-2 groups. The CARWL score's significant impacts on PFS and OS outcomes were found to be independent of the other variables in the multivariate analysis (P < 0.001, for each). Conclusions: Our findings indicate that the novel CARWL score, which accounts for pretreatment CAR and significant WL during the preceding 6 months, can reliably stratify newly diagnosed stage IIIC NSCLC patients into three groups with significantly different PFS and OS after definitive CCRT.

[The application of induction chemotherapy in the treatment of locally advanced head and neck squamous cell carcinoma].

Standard treatment for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) whose larynx could not be preserved surgically consists mainly of concurrent chemoradiotherapy (CCRT). Induction chemotherapy (ICT) followed by radiotherapy or chemoradiotherapy is also an alternative option. However, whether ICT could provide survival benefits for patients with LAHNSCC, besides its role in laryngeal preservation and selecting the treatment modality, is still controversial. The article summarizes the current position of ICT for LAHNSCC and discusses the standard regimen of ICT, its role in larynx preservation, its ability to predicting the result of chemoradiotherapy, clinical outcomes regarding the survival benefits after ICT, its role in the treatment deintensification for human papillomavirus-positive LAHNSCC and its application in the era of immunotherapy.

[Analysis of tumor regression after concurrent radiochemotherapy for locally advanced hypopharyngeal carcinoma].

Objective: To investigate the pathological characteristics of tumor regression and the expression level of chemoradiotherapy resistance-related molecular markers after preoperative concurrent radiochemotherapy in patients with locally advanced hypopharyngeal carcinoma. Methods: The clinical data of 44 patients with locally advanced hypopharyngeal carcinoma who underwent preoperative concurrent radiochemotherapy in the Department of Head and Neck Surgery of Shandong Otolaryngology Hospital from August 2016 to August 2020 were retrospectively analyzed. All patients received preoperative concurrent chemotherapy and radiotherapy. After radiochemotherapy, electronic laryngoscopy and imaging examination were performed to assess the tumor regression status. After 4 weeks, surgical resection was performed, and the specimens of the primary focus were processed as continuous pathological sections. After operation, HE staining and TdT-mediated dUTP nick-end labeling (TUNEL) method were used to detect the distribution characteristics and apoptosis of the remaining cancer focus, and immunohistochemistry was performed to determine the proliferation of the remaining cancer focus and the expression of radiation resistance-related molecular markers [signal transducer and activator of transcription 3 (STAT3), hypoxia-inducible factor-1alpha (HIF-1α), sex determining region Y-box 2 (SOX2), and P53]. Results: A total of 44 patients were included, all of whom were male, with a mean age of (58.3±3.5) years. There were 40 cases of pyriform sinus carcinoma and 4 cases of posterior pharyngeal wall carcinoma. Twenty-nine cases were in stage T3 and 15 cases were in stage T4. There were 6 stage Ⅲ cases and 38 stage Ⅳ cases. According to the response evaluation criteria in solid tumors (RECIST), 13 patients achieved complete response (CR), 22 patients had partial response (PR), and 9 patients achieved stable disease (SD) after concurrent radiochemotherapy. The primary lesion resection methods included 19 cases of hypopharyngeal circumferential resection and 2 cases of total laryngectomy and partial hypopharyngeal resection. Twenty-three cases underwent supracricoid cartilage subtotal laryngectomy cricoid tongue fixation (CHP). Among 22 patients with PR, 10 had large PR (remission rate ≥70%) and 12 had small PR (remission rate <70%). The residual tumor was found in 30 patients (68.2%) after resection of all primary lesions by HE staining of pathological sections, of which 3 patients (3/13) with CR had residual cancer, all of which were focal residues. In large PR patients, residual cancer was detected in 6 cases (6/10), scattered in 4 cases, and focal residual in 2 cases, respectively. Large residual tumors were detected in small PR and SD patients. TUNEL method did not show any sign of apoptosis in 30 specimens with residual cancer focus, and the positive expression rate of Ki-67 was less than 10%. The expression of STAT3 (3.40±2.49 vs 5.23±3.02, t=-2.932, P=0.007) in 19 cases (63.3%) and HIF-1α (3.73±2.66 vs 6.97±3.05, t=-4.45, P<0.001) in 22 cases (73.3%) of residual cancer were significantly higher than those before radiochemotherapy. Other molecular markers showed no significant changes. All patients were followed up for 3 years. The 2-year survival rate was 59.3%, and the 3-year survival rate was 54.1%. Conclusions: Preoperative radiochemotherapy can make some patients with locally advanced hypopharyngeal carcinoma achieve complete or significant remission in clinical evaluation, but pathological detection still shows some residual cancer lesions with enhanced anti-apoptosis ability and decreased proliferation activity.

Chemoradiotherapy versus radiotherapy in high risk salivary gland cancer.

OBJECTIVE: The aim of this study was to investigate the potential survival benefits associated with chemoradiotherapy (CRT) as opposed to radiotherapy (RT) in patients with resected high-risk salivary gland cancer (SGC), with a specific focus on determining whether these benefits are influenced by the number of high-risk variables. METHODS: Patients who underwent surgical treatment for high-risk SGC were retrospectively enrolled and categorized into either CRT or RT groups. The impact of adjuvant therapy on locoregional control (LRC) and overall survival (OS) was assessed using a multivariable Cox model. RESULTS: A total of 152 patients were included following propensity score-matching. In comparison to RT, CRT did not demonstrate a significant survival advantage in terms of LRC (p = 0.485, HR: 1.14, 95%CI: 0.36-4.22) and OS (p = 0.367, HR: 0.99, 95%CI: 0.17-3.87) in entire population. But among patients with T3/4 stage, high-grade tumors, and 5 or more positive lymph nodes, the addition of chemotherapy to RT significantly (p = 0.042) correlated with a 15% reduction in the risk of cancer recurrence (95%CI: 4-54%). Conversely, in other subgroups with varying combinations of high-risk variables, CRT did not provide additional survival benefits for LRC and OS compared to RT. CONCLUSION: Adjuvant chemotherapy may be considered in conjunction with RT specifically in cases where there is a presence of T3/4 stage, high-grade tumors, and 5 or more metastatic lymph nodes in high-risk SGC.

Trends in the treatment of advanced pancreatic cancer.

Pancreatic cancer (PC) has the poorest prognosis among digestive cancers; only 15-20% of cases are resectable at diagnosis. This review explores multidisciplinary treatments for advanced PC, emphasizing resectability classification and treatment strategies. For locally advanced unresectable PC, systemic chemotherapy using modified FOLFIRINOX and gemcitabine with albumin-bound paclitaxel is standard, while the role of chemoradiation is debated. Induction chemotherapy followed by chemoradiation may be a promising therapy. Conversion surgery after initial chemotherapy or chemoradiotherapy offers favorable survival, however criteria for conversion need further refinements. For metastatic PC, clinical trials using immune checkpoint inhibitors and molecular targeted therapies are ongoing. Multidisciplinary approaches and further research are crucial for optimizing treatment and improving outcomes for advanced PC.

Total pelvic exenteration extended to pelvic bones with subsequent VRAM flap reconstruction in patient with recurrent anal squamous cell carcinoma following chemoradiotherapy.

Anal squamous cell carcinoma, typically associated with human papillomavirus infection, remains a rare malignancy. This article outlines a case of local recurrence in a male patient with a history of HIV and hepatitis C virus infection, previously treated with chemoradiotherapy. Extensive tumour involvement called for total pelvic exenteration extended to anterior osteomuscular compartment and genitalia. The surgical approach involved multidisciplinary collaboration and detailed preoperative planning using three-dimensional reconstruction. Key surgical considerations comprised the following: achieving tumour-free margins (R0 resection), extensive osteotomies and intricate pelvic floor reconstruction with prosthetic mesh and flap reconstruction. The procedure successfully yielded an R0 resection, maintaining adequate lower limb functionality. Our case report underscores the benefits of pelvic exenteration in locally advanced or recurrent pelvic tumours, invariably following careful patient selection and exhaustive preoperative studies.

Additional chemoradiotherapy for superficial esophageal squamous cell carcinoma after near-circumferential or full-circumferential noncurative endoscopic submucosal dissection: a retrospective study.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a potentially efficient therapeutic intervention for superficial esophageal cancer. Additional treatment such as chemoradiotherapy (CRT) or esophagectomy is recommended in cases of muscularis mucosa invasion with positive resection margins or lymphovascular invasion or submucosal layer invasion, which are considered noncurative ESD, due to an increased risk of lymph node metastasis. However, the adequacy of additional CRT after near-circumferential or full-circumferential noncurative ESD has not been fully discussed. In this study, we retrospectively evaluated the efficacy and toxicity of additional CRT for superficial esophageal squamous cell carcinoma (SCC) after near-circumferential or full-circumferential noncurative ESD, which was defined as a mucosal defect measuring ≥ 3/4 of the esophageal circumference. METHODS: We retrospectively evaluated 24 patients who received additional CRT for superficial esophageal SCC after near-circumferential or full-circumferential noncurative ESD between 2012 and 2018. Elective nodal irradiation (ENI) was performed in all patients and boost irradiation (BI) was performed after ENI in 4 patients with positive resection margins. The prescription doses of ENI and BI were 41.4 Gy in 23 fractions and 9 Gy in 5 fractions, respectively. Concurrent chemotherapy (a combination of cisplatin or nedaplatin and 5-fluorouracil) was administered to all patients. RESULTS: The 3-year and 5-year overall survival rates were 92% and 78%, respectively, while the 3-year and 5-year progression-free survival rates were 83% and 70%, respectively. Grade 2 esophageal stenosis occurred in 8 (33%) patients. There was no case of Grade 3 or worse esophageal stenosis. Among them, 4 (17%) patients developed stenosis before additional CRT, which persisted after the completion of additional CRT. The remaining 4 (17%) patients developed de novo stenosis within 5 months following the completion of additional CRT. One patient (4%) still requires regular bougie dilation. Grade 3 and Grade 4 acute toxicity, including anemia, neutropenia, thrombocytopenia, and esophagitis occurred in 1 (4%) and 0 (0%), 6 (25%) and 1 (4%), 1 (4%) and 0 (0%), and 1 (4%) and 0 (0%) patients, respectively. One (4%) patient who underwent salvage CRT for the out-of-field lymph node recurrence died with acute myeloid leukemia. CONCLUSIONS: Additional CRT is a viable treatment option even in patients who have undergone near-circumferential or full-circumferential noncurative ESD. Esophageal stenosis after additional CRT following near-circumferential or full-circumferential noncurative ESD is manageable and acceptable.

Predictive value of circulating lymphocyte subsets and inflammatory indexes for neoadjuvant chemoradiotherapy response in rectal mucinous adenocarcinoma patients: A machine learning approach.

INTRODUCTION: In this study, we aimed to evaluate the predictive value of circulating lymphocyte subsets and inflammatory indexes in response to neoadjuvant chemoradiotherapy (NCRT) in patients with rectal mucinous adenocarcinomas (MACs). METHODS: Rectal MAC patients who underwent NCRT and curative resection at Fujian Medical University Union Hospital's Department of Colorectal Surgery between 2016 and 2020 were included in the study. Patients were categorized into good and poor response groups based on their pathological response to NCRT. An independent risk factor-based nomogram model was constructed by utilizing multivariate logistic regression analysis. Additionally, the extreme gradient boosting (XGB) algorithm was applied to build a machine learning (ML)-based predictive model. Feature importance was quantified using the Shapley additive explanations method. RESULTS: Out of the 283 participants involved in this research, 190 (67.1%) experienced an unfavorable outcome. To identify the independent risk factors, logistic regression analysis was performed, considering variables such as tumor length, pretreatment clinical T stage, PNI, and Th/Tc ratio. Subsequently, a nomogram model was constructed, achieving a C-index of 0.756. The ML model exhibited higher prediction accuracy than the nomogram model, achieving an AUROC of 0.824 in the training set and 0.762 in the tuning set. The top five important parameters of the ML model were identified as the Th/Tc ratio, neutrophil to lymphocyte, Th lymphocytes, Gross type, and T lymphocytes. CONCLUSION: Radiochemotherapy sensitivity is markedly influenced by systemic inflammation and lymphocyte-mediated immune responses in rectal MAC patients. Our ML model integrating clinical characteristics, circulating lymphocyte subsets, and inflammatory indexes is a potential assessment tool that can provide a reference for individualized treatment for rectal MAC patients.

Current State of Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

ABSTRACT: In locally advanced rectal cancer, neoadjuvant treatment has evolved from no preoperative treatment to the addition of radiation and systemic therapy and ultimately total neoadjuvant therapy. Total neoadjuvant therapy is the completion of preoperative radiation or chemoradiation and chemotherapy before surgery in order to maximize tumor response and improve survival outcomes. This review summarizes the literature of the neoadjuvant approaches related to locally advanced rectal cancer and highlights the nuances of selecting the appropriate treatment.

Nonoperative Management for Rectal Cancer.

ABSTRACT: The treatment paradigm for rectal cancer has been shifting toward de-escalated approaches to preserve patient quality of life. Historically, the standard treatment in the United States for locally advanced rectal cancer has standardly comprised preoperative chemoradiotherapy coupled with total mesorectal excision. Recent data challenge this "one-size-fits-all" strategy, supporting the possibility of omitting surgery for certain patients who achieve a clinical complete response to neoadjuvant therapy. Consequently, patients and their physicians must navigate diverse neoadjuvant options, often in the context of pursuing organ preservation. Total neoadjuvant therapy, involving the administration of all chemotherapy and radiation before total mesorectal excision, is associated with the highest rates of clinical complete response. However, questions persist regarding the optimal sequencing of radiation and chemotherapy and the choice between short-course and long-course radiation. Additionally, meticulous response assessment and surveillance are critical for selecting patients for nonoperative management without compromising the excellent cure rates associated with trimodality therapy. As nonoperative management becomes increasingly recognized as a standard-of-care treatment option for patients with rectal cancer, ongoing research in patient selection and monitoring as well as patient-reported outcomes is critical to guide personalized rectal cancer management within a patient-centered framework.

Treatment of Locally Recurrent Rectal Cancer: A Review.

ABSTRACT: Up to 10% of patients with locally advanced rectal cancer will experience locoregional recurrence. In the setting of prior surgery and often radiation and chemotherapy, these represent uniquely challenging cases. When feasible, surgical resection offers the best chance for oncologic control yet risks significant morbidity. Studies have consistently indicated that a negative surgical resection margin is the strongest predictor of oncologic outcomes. Chemoradiation is often recommended to increase the chance of an R0 resection, and in cases of close/positive margins, intraoperative radiation/brachytherapy can be utilized. In patients who are not surgical candidates, radiation can provide symptomatic relief. Ongoing phase III trials are aiming to address questions regarding the role of reirradiation and induction multiagent chemotherapy regimens in this population.

Point/Counterpoint #1: Chemotherapy Alone Is a Sufficient Preoperative Treatment for Rectal cancer.

ABSTRACT: For decades, the standard neoadjuvant therapy regimen for locally advanced rectal cancer consisted of chemoradiation, surgical resection, and consideration of adjuvant systemic therapy. Additional data have emerged suggesting neoadjuvant systemic therapy as a reasonable alternative to chemoradiation in selected patients. In addition, a total neoadjuvant therapy approach integrating both chemotherapy and chemoradiation results in superior cancer outcomes and the potential for consideration of nonoperative management in patients with a clinical complete response. Despite a multitude of therapeutic pathways for the management of rectal cancer, what is clear, however, is the importance of a multidisciplinary approach with shared patient and provider decision-making.

Efficacy and Safety Analysis of Recombinant Human Endostatin (Endostar) Combined With Chemoradiotherapy for Locally Advanced Cervical Cancer: A 2-Center Retrospective Study.

BACKGROUND: This study aims to assess the efficacy and safety of Endostar in the management of locally advanced cervical cancer. METHODS: This retrospective, 2-center study enrolled 41 patients with locally advanced cervical cancer between June 2017 and December 2020. The patients were subjected to a combination of Endostar and chemoradiotherapy until they experienced disease progression or an unacceptable level of toxicity. The patients in the Endostar combined chemoradiotherapy (E + CRT) and CRT groups were matched 1:1 based on clinical features, including age, disease stage, and pathological type. The therapeutic efficacy and safety outcomes were compared between the 2 groups. RESULTS: Early treatment response: the CR rates in E + CRT and CRT groups were 48.8% and 26.8%, respectively (χ2 = 4.20, P < .05). The ORR and DCR were not significantly different between the 2 groups. Long-term efficacy: there was no significant difference in the 1-year and 2-year PFS rates and OS rates between 2 groups. However, in patients with stage IIB, subgroup analyses revealed a significant difference in PFS between the 2 groups (P < .05). Prognostic factors: stage, Eastern Cooperative Oncology Group (ECOG) score, and tumor size were independent predictive factors for PFS, while ECOG score and tumor size were those of OS in patients with locally advanced cervical cancer. Safety: The incidence of grade III-IV myelosuppression was significantly lower in E + CRT group than in CRT group (P < .05). CONCLUSIONS: The combination of Endostar and concurrent CRT exhibited greater efficacy in treating locally advanced cervical cancer with no severe adverse reactions, when compared to simple CRT. It is expected that this approach will evolve into a new treatment alternative for patients with locally advanced cervical cancer.

GWO+RuleFit: rule-based explainable machine-learning combined with heuristics to predict mid-treatment FDG PET response to chemoradiation for locally advanced non-small cell lung cancer.

Objective.Vital rules learned from fluorodeoxyglucose positron emission tomography (FDG-PET) radiomics of tumor subregional response can provide clinical decision support for precise treatment adaptation. We combined a rule-based machine learning (ML) model (RuleFit) with a heuristic algorithm (gray wolf optimizer, GWO) for mid-chemoradiation FDG-PET response prediction in patients with locally advanced non-small cell lung cancer.Approach.Tumors subregions were identified using K-means clustering. GWO+RuleFit consists of three main parts: (i) a random forest is constructed based on conventional features or radiomic features extracted from tumor regions or subregions in FDG-PET images, from which the initial rules are generated; (ii) GWO is used for iterative rule selection; (iii) the selected rules are fit to a linear model to make predictions about the target variable. Two target variables were considered: a binary response measure (ΔSUVmean ⩾ 20% decline) for classification and a continuous response measure (ΔSUVmean) for regression. GWO+RuleFit was benchmarked against common ML algorithms and RuleFit, with leave-one-out cross-validated performance evaluated by the area under the receiver operating characteristic curve (AUC) in classification and root-mean-square error (RMSE) in regression.Main results.GWO+RuleFit selected 15 rules from the radiomic feature dataset of 23 patients. For treatment response classification, GWO+RuleFit attained numerically better cross-validated performance than RuleFit across tumor regions and sets of features (AUC: 0.58-0.86 vs. 0.52-0.78,p= 0.170-0.925). GWO+Rulefit also had the best or second-best performance numerically compared to all other algorithms for all conditions. For treatment response regression prediction, GWO+RuleFit (RMSE: 0.162-0.192) performed better numerically for low-dimensional models (p= 0.097-0.614) and significantly better for high-dimensional models across all tumor regions except one (RMSE: 0.189-0.219,p< 0.004).Significance. The GWO+RuleFit selected rules were interpretable, highlighting distinct radiomic phenotypes that modulated treatment response. GWO+Rulefit achieved parsimonious models while maintaining utility for treatment response prediction, which can aid clinical decisions for patient risk stratification, treatment selection, and biologically driven adaptation. Clinical trial: NCT02773238.

Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial.

BACKGROUND: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients. METHODS: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores. CONCLUSIONS: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Pegylated recombinant human granulocyte colony-stimulating factor for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy: a prospective study.

BACKGROUND: This study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy. METHODS: In this prospective, single-center, single-arm study, we enrolled patients (18-70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48-72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3-4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2-4, time to complete radiotherapy, and safety. RESULTS: Overall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3-4 neutropenia was 28.8%, with an average duration of grade 3-4 neutropenia persistence of 3.85 days (1-7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2-4, respectively. The incidences of grade 3-4 neutropenia for cycles 1-4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41-56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient. CONCLUSION: PEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

Short-term OS as a surrogate endpoint for 5-year OS in nasopharyngeal carcinoma in non-endemic area.

PURPOSE: To address this evidence gap and validate short-term OS at less than 5 years as a reliable surrogate endpoint for 5-year OS. METHODS: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on non-metastatic NPC patients diagnosed between 2010 and 2015. Patients were categorized into radiotherapy and chemoradiotherapy groups. RESULTS: This retrospective study examined 2,047 non-metastatic NPC patients. Among them, 217 received radiotherapy, and 1,830 received chemoradiotherapy. Our analysis results indicated that the 4-year OS may serve as a reliable surrogate endpoint for patients with AJCC clinical stage I (80 vs. 78%, P = 0.250), regardless of the treatment received. Specifically, in the radiotherapy group, patients with stage I, T0-T1, and N0 NPC showed similar OS rates at 4 and 5 years (83 vs. 82%, P = 1.000; 78 vs. 76%, P = 0.250; 78 vs. 77%, P = 0.500, respectively). Similarly, patients with stage II-IV, T2-T4, and N1-3 NPC showed no significant difference in OS rates between 3 and 5 years (57 vs. 51%, P = 0.063; 52 vs. 46%, P = 0.250; 54 vs. 46%, P = 0.125, respectively) in the radiotherapy group. In the chemoradiotherapy group, only the 3-year OS rate did not significantly differ from that at 5 years in stage I patients (79vs. 72%, P = 0.063). CONCLUSIONS: Our study suggests that short-term surrogate endpoints may be valuable for evaluating 5-year OS outcomes in NPC patients in non-endemic areas.