Locoregional Relapse-free Survival Research Articles

Clinicopathological Outcomes in Patients With Locally Advanced Rectal Cancer Undergoing Preoperative Short-Versus Long-course Chemoradiotherapy With Delayed Surgery.

We aimed to compare the clinicopathological outcomes in patients with locally advanced rectal cancer after short- or long-course concurrent chemoradiotherapy (CCRT) followed by delayed surgery. The records of 94 patients with cT3-4N0-2M0 rectal cancer who received CCRT between 2010 and 2017 were reviewed. Short-course radiotherapy (RT) was delivered with a median total dose of 25 Gy in five fractions (n=27), and long-course RT was delivered with a median total dose of 50.4 Gy in 28 fractions (n=67). The following concurrent chemotherapy regimens were administered: 5-fluorouracil plus leucovorin in 58 and capecitabine in 24; in 12 cases agents were unknown. The median interval between CCRT and surgery was 8 weeks. Adjuvant chemotherapy was administered after surgery in 80 patients (5-fluorouracil plus leucovorin, n=54; capecitabine, n=9; other, n=14; and unknown, n=3). Propensity-score matching analysis was conducted. The median follow-up duration was 4.3 years. There were no statistically significant differences between the short- and long-course RT groups in sphincter preservation (85.2% vs. 92.5%, p=0.478), pathological complete remission (18.5% vs. 14.9%, p=0.905), downstaging (44.4% vs. 26.9%, p=0.159), and negative circumferential resection margin (92.6% vs. 89.6%, p=0.947) rates. No differences were found in survival outcomes between the short- and long-course groups at 3 years (overall survival: 91.8% vs. 88.1%, p=0.790; disease-free survival, 75.2% vs. 72.5%, p=0.420; locoregional relapse-free survival, 90.5% vs. 98.4%, p=0.180; and distant metastasis-free survival, 79.6% vs. 73.5%, p=0.490). Similar results were observed after PSM. Clinically, short-course CCRT may be a feasible alternative to long-course CCRT in patients with locally advanced rectal cancer.

Concurrent chemotherapy using taxane plus cisplatin versus cisplatin alone in high-risk nasopharyngeal carcinoma patients with suboptimal response to induction chemotherapy.

Detectable Epstein-Barr virus (EBV) DNA levels and unsatisfactory tumor response to induction chemotherapy (IC) could be used to guide the risk-adapted treatment strategy of locoregionally advanced nasopharyngeal carcinoma (LANPC) before concurrent chemoradiotherapy. We aim to compare the efficacy and safety of concurrent chemotherapy using taxane plus cisplatin [double-agent concurrent chemotherapy (DACC) group] with those of cisplatin alone [single-agent concurrent chemotherapy (SACC) group] in high-risk LANPC. Overall, 197 LANPC patients with detectable EBV DNA or stable disease (SD) after IC were retrospectively included. Potential confounders between the DACC and SACC groups were adjusted by propensity score matching. Short-term efficacy and long-term survival were assessed in the two groups. Although the objective response rate of the DACC group was marginally higher than that of the SACC group, the difference was not significant (92.7% versus 85.3%, p = 0.38). Concerning long-term survival, DACC did not show superiority to SACC after patient matching: 3-year progression-free survival: 87.8% versus 81.7%, p = 0.80; overall survival: 97.6% versus 97.3%, p = 0.48; distant metastasis-free survival: 87.8% versus 90.5%, p = 0.64, and; locoregional relapse-free survival: 92.3% versus 86.9%, p = 0.77. The incidence of grade 1-4 hematological toxicities was significantly higher in the DACC group. Due to the small sample size, we do not have sufficient evidence that concurrent chemotherapy using taxane plus cisplatin provides additional survival benefits in LANPC patients with an unfavorable response (detectable EBV DNA levels or SD) after IC. But concurrent taxane and cisplatin chemotherapy is associated with a higher rate of hematologic adverse events. Further clinical trials will be required to establish evidence and identify more effective treatment modalities for high-risk LANPC patients.

Prognostic Value of Lymph Node Necrosis at Different N Stages in Patients with Nasopharyngeal Carcinoma.

Background: Lymph node necrosis (LNN), including retropharyngeal nodal necrosis and cervical nodal necrosis, which is related to radiotherapy/ chemotherapy resistance, is a common phenomenon in nasopharyngeal carcinoma (NPC). This study was to assess the prognostic value of LNN at different N stages in NPC patients. Materials and Methods: In total, 1,665 newly diagnosed NPC patients at stage TxN1-3M0 from two centers were enrolled. Univariate and multivariate models were constructed to assess the association between LNN and long-term survival outcomes. The propensity score matching method was performed to balance treatment groups for baseline characteristics. Results: Of the 1,665, 540 patients (540/1665, 32.4%) were diagnosed with LNN, of which 54.1% (292/540) patients were at stage N1, 31.3% (169/540) at stage N2, and 14.6% (79/540) at stage N3. Univariate and multivariate analyses indicated LNN as an independent predictor for progression‑free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) in stage N1-3 patients (all P<0.001). When patients were analyzed according to stage, similar findings were observed for N1 patients (all P<0.001); for N2 patients, LNN independently predicted PFS (P=0.003), OS (P=0.011), and DMFS (P=0.004), and for stage N3, LNN only independently predicted LRRFS (P=0.019). 123 pairs of patients who received induction chemotherapy plus concurrent chemoradiotherapy or only concurrent chemoradiotherapy were matched, adding induction chemotherapy improved 5-year OS, PFS and LRFFS, but the results were not statistically significant. Conclusions: In NPC patients, LNN could independently predict poor prognosis at all N1-3 stages and at each N stage (N1 to N3). The value of adding induction chemotherapy to concurrent chemoradiotherapy in patients with LNN still requires further prospective studies.

Short-term efficacy and long-term survival of nasopharyngeal carcinoma patients with radiographically visible residual disease following observation or additional intervention: A real-world study in China.

To explore the short- and long-term outcomes in patients with nasopharyngeal carcinoma (NPC) with magnetic resonance imaging (MRI)-detected residual disease at 3 months post-treatment who received intervention either promptly (0 month) or following observation (after an additional 3 months). A total of 272 patients with residual disease at 3 months post-treatment (observation [observation for additional 3 months]: 122, intervention [prompt intervention]: 150) were analyzed. Univariate and multivariate analyses were performed to examine the survival. Adverse events were analyzed in all patients. Patients in the observation group had a lower 3-year overall survival (77.1% vs. 85.2%), progression-free survival (10.2% vs. 18.1%), and locoregional relapse-free survival (10.2% vs. 20.6%) (all p< .05), but not distant metastasis-free survival (83.8% vs. 78.4%, p= .189), whereas patients in the intervention group achieved higher complete remission (CR) rates (43.3% vs. 21.2%, p= .003). Patients who achieved CR after prompt intervention had a better survival rate than those who achieved observation-CR or non-CR (p< .001). Multivariate analyses revealed that a wait-and-see policy was an independent prognostic factor for impaired survival (p< .001). No significant differences of acute or late toxicities were observed between the two groups. Patients with NPC with MRI-detected residual disease 3 months post-radiotherapy should be encouraged to undergo prompt intervention rather than adopting a passive wait-and-see policy.

Role of postoperative chemoradiotherapy in head and neck cancer without positive margins or extracapsular extension: a propensity score-matching analysis

BackgroundThe aim of this work was to determine whether patients with intermediate-risk head and neck squamous cell carcinoma (HNSCC) can benefit from postoperative chemoradiotherapy (POCRT).MethodsPatients without extracapsular extension (ECE) or positive margins (PMs) who received POCRT or postoperative radiotherapy (PORT) at our center were retrospectively (December 2009 to October 2018) included for analysis, in particular, using a propensity score-matching method.ResultsAfter matching, 264 patients were enrolled, including 142 (41.2%) patients with pT3-4, 136 (38.3%) patients with pN2-3, 68 (21.1%) patients with perineural invasion, and 45 (12.8%) patients with lymphatic/vascular space invasion. With a median follow-up of 52 months, 3-year overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) rates were 72.4%, 79.3%, 83.5% and 62.5%, respectively. pN2-3 was an independent risk factor for OS (p < 0.001), DFS (p < 0.001), LRFS (p < 0.001) and DMFS (p = 0.002), while pT3-4 was a poor prognostic factor for DMFS (p = 0.005). Overall, patients receiving POCRT had no significant differences from those receiving PORT in OS (p = 0.062), DFS (p = 0.288), LRFS (p = 0.076) or DMFS (p = 0.692). But notably, patients with pN2-3 achieved better outcomes from POCRT than PORT in 3-year OS (p = 0.050, 63.9% vs. 47.9%) and LRFS (p = 0.019, 74.6% vs. 54.9%). And patients with pT3-4 also had higher 3-year LRFS (p = 0.014, 88.5% vs. 69.1%) if receiving POCRT.ConclusionsAmong all intermediate-risk pathological features, pN2-3 and pT3-4 were independent unfavorable prognostic factors for patients with HNSCC without PMs or ECE. POCRT can improve the survival outcomes of patients with pN2-3 or pT3-4.

The feasibility of reduced-dose radiotherapy in childhood nasopharyngeal carcinoma with favorable response to neoadjuvant chemotherapy

BackgroundTo assess the feasibility of adjusting radiation dose (RD) in childhood NPC with favorable tumor response after neoadjuvant chemotherapy (NAC). Patients and methodsUsing an NPC-specific database, children and adolescents (≤18 years) with locoregionally advanced NPC (CA-LANPC) were retrospectively analyzed. Enrolled patients were those who received favorable tumor response after 2–4 cycles of NAC followed by concurrent chemoradiotherapy. Survival outcomes and treatment-related toxicities were compared for the standard RD on primary tumors (PT-RDstandard, 66–72 Gy) and the reduced RD on primary tumors (PT-RDreduced, 60–65.9 Gy). ResultsA total of 132 patients were included, and the median follow-up time was 75.2 months (IQR, 53.2–98.7 months) for the entire cohort. The PT-RDreduced group had a significantly decreased incidence of severe mucositis (51.3 % vs 32.1 %; P = 0.034) when compared to the PT-RDstandard group. The total incidence of severe sequela in the PT-RDstandard group were significantly higher than those in the PT-RDreduced group (31.8 % vs 13.7 %; P = 0.029). In the propensity-matched analysis, the PT-RDreduced group resulted in parallel 5-year survival with the PT-RDstandard group from the matched cohort (disease-free survival, 82.7 % vs 80.3 %, P = 0.841; overall survival, 91.7 % vs 91.3 %, P = 0.582; distant metastasis-free survival, 87.5 % vs 82.8 %, P = 0.573; and locoregional relapse-free survival, 95.6 % vs 97.3 %, P = 0.836). In multivariate analysis, the impact of PT-RDreduced on all survival end points remained insignificant. ConclusionsChemoradiotherapy with RD at levels of 60–65.9 Gy may be a reasonable strategy for CA-LANPC with favorable tumor response after NAC.

Radiation dose escalation for locally advanced nasopharyngeal carcinoma patients with local and/or regional residual lesions after standard chemoradiotherapy: a non-randomized, observational study

BackgroundTo assess the effectiveness and toxicity of radiation dose escalation for locally advanced nasopharyngeal carcinoma (LA-NPC) in patients with local and/or regional residual lesion(s) after standard treatment.MethodsFrom November 2011 to November 2020, 259 LA-NPC patients who had local and/or regional residual lesion(s) after induction chemotherapy followed by concurrent chemoradiotherapy (IC + CCRT) from our hospital were included. The total dose of primary radiotherapy (RT) was 68.1–74.25 Gy (median, 70.4 Gy). The boost doses were 4.0–18.0 Gy (median, 9 Gy), 1.8–2.0 Gy/fraction.ResultsFor all patients, the 5-year local relapse-free survival was 90.2%, regional relapse-free survival was 89.1%, locoregional relapse-free survival (LRRFS) was 79.5%, distant metastasis-free survival (DMFS) was 87.9%, failure-free survival (FFS) was 69.0%, and overall survival (OS) was 86.3%. LRRFS, DMFS, FFS, and OS in patients with age ≤ 65 versus > 65, plasma Epstein-Barr virus-deoxyribonucleic acid ≤ 500 versus > 500, T1–2 versus T3–4, N0–1 versus N2–3, and stage III versus stage IV showed no statistically significant differences. The interval between primary RT and boost was not a prognostic factor for LRRFS, DMFS, FFS, and OS. Males had a lower 3-year FFS rate than females (72.9% vs. 83.7%, P = 0.024). LA-NPCs with locally and regionally residual lesion(s) had the worst 3-year DMFS and OS rates compared with locally or regionally residual lesion(s) (77.7% vs. 98.8% vs. 87.4%, P = 0.014; 75.9% vs. 94.5% vs. 82.4%, P = 0.002).ConclusionBoost radiation was an option for LA-NPCs with locally and/or regionally residual lesions after receiving IC + CCRT. It warrants further prospective study.Trial registration: Retrospectively registered.

Distinct Failure Patterns in Hypopharyngeal Cancer Patients Receiving Surgery-Based Versus Radiation-Based Treatment

BackgroundTo cure advanced hypopharyngeal squamous cell carcinoma (HPSCC), primary operation followed by adjuvant (chemo-)radiotherapy (OP-CRT) or definitive chemoradiation (CCRT) are the two primary options. This study aimed to compare the failure patterns and long-term survival outcomes of HPSCC patients treated with these two strategies.Patients and MethodsFrom 2007 to 2015, 198 pathologically confirmed HPSCC patients receiving either OP-CRT or CCRT were retrospectively reviewed. Failure patterns and survival outcomes stratified by the 7th American Joint Committee on Cancer staging system and treatment modalities were compared.ResultsOne hundred and eighty-nine patients (95.4%) were stage III/IV and 62 patients (31.3%) received OP-CRT. Median follow-up duration was 4.9 years. Compared with CCRT, OP-CRT provided better 3-year local relapse-free survival for T3 (93 vs 48%, p < 0.0001), T4a (88 vs 37%, p = 0.0005) and better 3-year regional relapse-free survival for N2b+2c (93 vs 60%, p < 0.0001). Of note, for stage IVA subjects, OP-CRT provided better 3-year loco-regional relapse-free survival (85 vs 37%, p < 0.0001), marginal poor 3-year distant metastasis-free survival (62 vs 79%, p = 0.06), but comparable 3-year OS (52 vs 44%, p = 0.37) and 5-year OS (44 vs 31%, p = 0.15) compared with CCRT.ConclusionsFor patients with advanced HPSCC, although OP-CRT and CCRT provided similar overall survival, failure patterns were distinct. OP-CRT provided better loco-regional control but was more likely to encounter distant metastases than CCRT. The detailed analysis of failure patterns will pave the way to improve this devastating disease.

Identifying optimal candidates for postoperative adjuvant therapy among regional persistent/recurrent nasopharyngeal carcinoma patients after neck dissection

PurposeTo analyze the clinical outcomes of patients with regional persistent/recurrent nasopharyngeal carcinoma (NPC) who received neck dissection, and to evaluate the clinical benefit of postoperative adjuvant therapy (PAT) based on patients’ positive lymph node counts (PLNs), extracapsular spread (ECS) and preoperative plasma EBV DNA levels.MethodsFrom 2003 to 2017, 342 patients with regional persistent/recurrent NPC were included in this study. All patients were treated with neck dissection and 76 patients received PAT. Progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS) were compared between groups using propensity score matching (PSM).Results152 patients without PAT treatment and 76 patients with PAT treatment were selected by the PSM. There was no significant difference in 2-year PFS (52.4% vs. 61.3%, P = 0.371), 2-year OS (91.9% vs. 90.5%, P = 0.097) or 2-year LRFS (66.3% vs. 67.9%, P = 0.872) between the two groups. However, the application of PAT brought survival benefits to patients in terms of 2-year DMFS (76.5% vs. 84.7%, P = 0.020). PLN, ECS and preoperative EBV DNA level remained independent risk factors for poorer PFS. Accordingly, patients were divided into low-risk and high-risk groups using receiver operating characteristic (ROC) curve; the 2-year PFS rates for two risk groups were 73.4% and 59.1% (P < 0.0001) respectively. The results showed that low-risk patients didn’t benefit from the addition of PAT. However, the 2-year DMFS rate was significantly improved in high-risk PAT-treated patients than those treated by neck dissection alone (83.7% vs. 71.7%, P = 0.023).ConclusionsPLNs, ECS and preoperative EBV DNA level are associated with the prognosis of patients with regional persistent/recurrent NPC. High-risk patients identified by PLNs, ECS and preoperative EBV DNA level may benefit from the addition of PAT after neck dissection.

Postoperative Radiotherapy can Improve the Disease-Free Survival of EGFR Wild Type Patients with pN2 NSCLC after Complete Resection and Adjuvant Chemotherapy

<h3>Purpose/Objective(s)</h3> Recently published phase III trials showed that postoperative radiotherapy (PORT) did not improve the survival of patients with pN2 non-small-cell lung cancer (NSCLC) after complete resection. However, the effect of PORT for pN2 NSCLC with different EGFR status remains unclear. <h3>Materials/Methods</h3> From 2010 to 2019, consecutive patients with pN2 NSCLC after complete resection and adjuvant chemotherapy who had detection of EGFR status were retrospectively analyzed. PORT was administered using IMRT at 2 Gy per fraction up to 50 Gy over 5 weeks. Patients were categorized into 4 groups according to EGFR status and treatment: Group 1 (EGFR wild type with PORT), Group 2 (EGFR wild type without PORT), Group3 (EGFR-mutated with PORT), Group 4 (EGFR-mutated without PORT). The Kaplan-Meier method and log-rank test were used to evaluate the disease-free survival (DFS), overall survival (OS), locoregional relapse free survival (LRFS), and distant metastasis free survival (DMFS). <h3>Results</h3> Totally 575 patients were enrolled. 264 patients (45.9%) were EGFR wild type, including 96 with PORT and 168 without PORT. 311 patients (54.1%) were EGFR-mutated, including 109 with PORT and 202 without PORT. The median DFS was 28.4 months in Group 1 and 17.3 months in Group 2 (HR 0.70, 95% CI 0.52-0.96, p=0.032). The median OS was not reached in Group 1 and Group 2 (HR 0.75, 95%CI 0.46-1.21, p=0.263). LRFS was statistically higher in Group 1 than Group 2 (HR 0.64, 95%CI 0.43-0.96, p=0.041). However, no significant difference was shown in DMFS (HR 0.75, 95%CI 0.54-1.04, P=0.097). Group 3 and Group 4 showed median DFS of 20.2 months and 25.7 months (HR 1.113, 95% CI 0.84-1.53, p=0.402), respectively. The median OS was not reached in either Group 3 or Group 4 (HR 0.64, 95% CI 0.33-1.21, p=0.201). LRFS was not significantly different (HR 0.83, 95% CI 0.53-1.31, p=0.45) in Group3 vs Group4, neither was DMFS (HR 1.15, 95%CI 0.85-1.57, p=0.73). <h3>Conclusion</h3> For completely resected pN2 NSCLC, PORT can improve DFS and LRFS in EGFR wild type patients. However, PORT may not prolong survival in EGFR-mutated patients. Prospective randomized clinical trials are needed for validation.

Timing of additional neoadjuvant chemotherapy in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy and total mesorectal excision

BackgroundIn locally advanced rectal cancer (LARC), the optimal sequence of neoadjuvant chemotherapy in relation to neoadjuvant chemoradiotherapy and before total mesorectal excision is unknown.MethodsA total of 426 LARC patients, treated with neoadjuvant chemoradiotherapy followed by total mesorectal excision, between January 2010 and December 2018, were studied retrospectively. Patients were divided into induction and consolidation chemotherapy groups. Overall, disease-free, locoregional relapse-free, and distant metastasis-free survival rates for the 2 groups were compared. Multivariate analysis hazard ratios (HR) with 95% confidence intervals (CI) to identify survival predictors.ResultsMedian follow-up was 37 (range, 7–162) months. The 3-year overall, disease-free, locoregional relapse-free, and distant metastasis-free survival rates were 93.8%, 71.6%, 93.5%, and 74.4%, respectively. For those receiving either induction or consolidation chemotherapy, 3-year disease-free survival rates were 82.5% and 67.7%, respectively (P = 0.021), distant metastasis-free rates were 85.4% and 70.8%, respectively (P = 0.024), and both overall and locoregional relapse-free survival rates did not differ significantly. Absence of neural invasion was an independent predictor of disease-free (HR = 0.49, 95% CI 0.25–0.97, P = 0.04) and distant metastasis-free (HR = 0.49, 95% CI 0.25–0.98, P = 0.04) survival. Both ypTN stage III (vs.0-II) and consolidation (vs. induction) chemotherapy were independent predictors of disease relapse (HR = 1.95, 95% CI 1.47–2.58, P < 0.001; HR = 1.68, 95% CI 1.01–2.79, P = 0.046; respectively) and distant metastasis (HR = 2.04, 95% CI 1.51–2.76, P < 0.001; HR = 1.75, 95% CI 1.03–2.99, P = 0.04; respectively).ConclusionsLARC patients receiving neoadjuvant chemoradiotherapy and total mesorectal excision had better disease-free and distant metastasis-free survival, with induction rather than consolidation neoadjuvant chemotherapy.

Clinical Outcome-Related Cancer Pathways and Mutational Signatures in Patients With Unresectable Esophageal Squamous Cell Carcinoma Treated With Chemoradiotherapy

Definitive chemoradiotherapy (dCRT) is a standard-of-care for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). However, even in individuals treated with the same dCRT regimen, differences in the local control rate and radiation-induced thoracic toxicity exist (radiation-induced esophagitis [RIE]). Here, we describe a comprehensive genomic evaluation of pretreatment tumor tissue samples from 183 patients with ESCC using targeted sequencing of 474 cancer-related genes. The association between endpoints (progression-free survival [PFS], overall survival, locoregional relapse-free survival, distant metastasis-free survival), toxicity (RIE) and genomic features, including altered pathways and the mutational signature, was analyzed. An independent cohort of 84 stage II-III patients with ESCC was used for validation. Gene alterations in the cell cycle pathway were identified in 87% of cases. Other frequently altered pathways included PI3K-AKT (45.9%), NOTCH (38.3%), NRF2 (36.6%), RKT-RAS (28.4%), and homologous recombination repair (HRR; 20.2%). HRR pathway alterations correlated with shortened PFS (mutation vs wild-type: 9.00 vs 14.40 months, hazard ratio, 2.10; 95% confidence interval, 1.29-3.44), while altered RTK-RAS pathways were correlated with worse overall survival in patients with ESCC treated with chemoradiotherapy (mutation vs wild-type: 23.70 vs 33.50 months; hazard ratio, 1.65; 95% confidence interval, 1.01-2.69). Furthermore, enrichment of apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures (signatures 2 and 13) was identified in ESCC tumors with altered HRR pathways. High APOBEC signatures and an altered HRR pathway were correlated with poor prognoses in dCRT-treated ESCC. Moreover, the APOBEC signature and/or the presence of HRR pathway alterations were associated with poor PFS and overall survival, which was validated in an independent whole exome sequence cohort. Notably, the altered HRR pathway was also associated with high-grade RIE toxicity in patients with ESCC. Collectively, our results support the use of comprehensive genomic profiling to guide treatment and minimize RIE in patients with ESCC.

Tumor Grade Predicts for Calcitonin Doubling Times and Disease-Specific Outcomes After Resection of Medullary Thyroid Carcinoma.

Background: Tumor grade is a new validated prognostic factor for medullary thyroid cancer (MTC). Calcitonin doubling time can predict MTC recurrence. We aimed to describe the association of tumor grade with calcitonin doubling and its effect on disease-specific outcomes times after resection. Methods: A retrospective analysis of MTC patients who underwent resection at a single tertiary-care cancer center between 1986 and 2017 were evaluated. Tumors were designated as high-grade MTC if two head and neck pathologists identified mitotic index ≥5 per 2 mm2, tumor necrosis, or a Ki67 proliferative index ≥5% within the tumor. Calcitonin doubling time was calculated using a validated calculator with at least three consecutive levels. Using Cox proportional hazards models, outcomes evaluated included locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: Among 117 patients, 95 were low grade and 22 high grade. Median follow-up was 70.2 months. High-grade patients demonstrated significantly faster calcitonin doubling times when compared with low-grade patients (8.51 ± 3.22 months vs. 38.42 ± 11.19 months; p < 0.001). In addition, most high-grade patients (66.7%) had calcitonin doubling times less than 1 year compared with fewer low-grade patients (1.0%; p < 0.001). High- and low-grade patients were further stratified by those who had calcitonin doubling times less than or greater than 2 years-a previously validated prognostic cutoff point. For patients with calcitonin doubling times less than 2 years, 70% were high grade, while 30% were low grade (p < 0.001). On multivariate analysis comparing grade and calcitonin doubling times, high-grade patients had significantly worse LRFS (hazards ratio [HR] 4.77 [confidence interval; CI 1.19-8.81]), DMFS (HR 7.25 [CI 2.36-22.28]), and OS (HR 6.04 [CI 1.85-19.72]; p < 0.05 for all), while calcitonin doubling times less than 2 years had worse DMFS (HR 7.22 [CI 1.05-49.75]). High-grade patients with calcitonin doubling times less than 2 years had associated worse LRFS and OS (both p < 0.05) compared with low-grade patients. Conclusions: The majority of high-grade MTC patients have calcitonin doubling times less than 2years. Close monitoring should be advocated for patients assessed to have high-grade tumors as they are at risk for poor disease-specific outcomes and structural recurrence.

The impairment of induction chemotherapy for stage II nasopharyngeal carcinoma treated with intensity-modulated radiotherapy with or without concurrent chemotherapy: A propensity score-matched analysis.

To explore the efficacy of induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) in stage II nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Totally, 450 eligible patients with staged II NPC on the basis of the 8th edition of the AJCC/UICC TNM staging system were eventually included from January 2010 to September 2020. The one-to-one propensity score-matched (1:1 PSM) analysis was employed to balance variables. We conducted univariate and multivariate analysis of survival to identify prognostic factors and demonstrated the findings in the matching cohort. In total, 141 pairs were selected by 1:1 PSM. IC + CCRT group in the matched data decreased 5-year progression-free survival (PFS, 75.5% vs. 88.0%, p=0.032) and distant metastasis-free survival (DMFS, 86.0% vs. 96.5%, p=0.009). There was no significant difference in 5-year overall survival (OS, 93.8% vs. 95.6%, p=0.192) and locoregional relapse-free survival (LRRFS, 87.1% vs. 94.3%, p=0.169) compared with RT/CCRT. Multivariate analysis indicated that IC + CCRT was associated with significantly poor PFS (p=0.024) and DMFS (p=0.010). High neutrophil-to-lymphocyte ratio (>4.1) was negatively associated with OS (p=0.034), PFS (p=0.017) and DMFS (p=0.001). Adding IC to CCRT or IMRT alone has decreased PFS and DMFS, therefore, IC should not berecommended in stage II NPC patients. No significant differences in OS and LRRFS were observed in stage II disease.

Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma

Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT). To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT. This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022. Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]). The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms). Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation. Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy. ClinicalTrials.gov Identifier: NCT02633202.

Prognostic significance of AKR1C4 and the advantage of combining EBV DNA to stratify patients at high risk of locoregional recurrence of nasopharyngeal carcinoma

BackgroundDistinguishing patients at a greater risk of recurrence is essential for treating locoregional advanced nasopharyngeal carcinoma (NPC). This study aimed to explore the potential of aldo–keto reductase 1C4 (AKR1C4) in stratifying patients at high risk of locoregional relapse.MethodsA total of 179 patients with locoregionally advanced NPC were grouped by different strategies; they were: (a) divided into two groups according to AKR1C4 expression level, and (b) classified into three clusters by integrating AKR1C4 and Epstein-Barr virus (EBV) DNA. The Kaplan–Meier method was used to calculate locoregional relapse-free survival (LRFS), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The Cox proportional hazards model was used to determine potential prognostic factors, and a nomogram was generated to predict 3-year and 5-year LRFS.ResultsA significant difference in the 5-year LRFS was observed between the high and low AKR1C4 expression groups (83.3% vs. 92.7%, respectively; p = 0.009). After integrating AKR1C4 expression and EBV DNA, the LRFS (84.7%, 84.5%, 96.9%, p = 0.014) of high-, intermediate-, and low- AKR1C4 and EBV DNA was also significant. Multivariate analysis indicated that AKR1C4 expression (p = 0.006) was an independent prognostic factor for LRFS. The prognostic factors incorporated into the nomogram were AKR1C4 expression, T stage, and EBV DNA, and the concordance index of the nomogram for locoregional relapse was 0.718.ConclusionsIn conclusion, high AKR1C4 expression was associated with a high possibility of relapse in NPC patients, and integrating EBV DNA and AKR1C4 can stratify high-risk patients with locoregional recurrence.

Nedaplatin-based chemotherapy or cisplatin-based chemotherapy combined with intensity-modulated radiotherapy achieve similar efficacy for stage II-IVa nasopharyngeal carcinoma patients

This retrospective study compared the efficacy and safety of nedaplatin-based chemoradiotherapy and cisplatin-based chemoradiotherapy in stage II-IVa nasopharyngeal carcinoma (NPC) patients. Patients treated with cisplatin-based or nedaplatin-based chemoradiotherapy between January 2012 and December 2015 were evaluated. Survival was estimated by the Kaplan‒Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. A cohort of 538 NPC patients was enrolled. There were no significant differences in the 5-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), or distant metastasis-free survival (DMFS) between the cisplatin and nedaplatin groups. During the whole treatment course, patients in the cisplatin group had higher incidences of grade 3‒4 vomiting and anorexia, while patients in the nedaplatin group had higher incidences of grade 3‒4 leucopenia and mucositis. In terms of late toxicities, patients in the cisplatin group had a higher incidence of xerostomia. In multivariate analysis, T stage, N stage, and clinical stage were prognostic factors for OS, PFS, and DMFS. In subgroup analyses, nedaplatin-based chemotherapy achieved comparable treatment outcomes in specific populations stratified by age, sex, ECOG PS score and clinical stage. Cisplatin and nedaplatin are effective choices for stage II-IVa NPC patients, with a different spectrum of side effects.

Locoregional Recurrence and Survival Outcomes in Breast Cancer Treated With Modern Neoadjuvant Chemotherapy: A Contemporary Population-based Analysis

BackgroundData guiding radiotherapy (RT) decisions after neoadjuvant chemotherapy (NAC) is largely retrospective, based on older treatment approaches without molecular subtype information. This study evaluated outcomes in breast cancer patients treated with modern NAC by molecular subtype and locoregional treatment. Materials and MethodsThere were 949 patients diagnosed between 2005 and 2016 treated with NAC followed by surgery ± locoregional radiotherapy (LRRT). Outcomes were 7-year locoregional relapse-free survival (LRRFS), breast cancer-specific survival (BCSS), and overall survival (OS). ResultsMedian follow-up was 6.5 years, 92% had cT2-4 and 72% cN1-3 disease. Subtypes were: 21% Luminal A, 18% Luminal B, 35% Her2+, and 21% triple-negative breast cancer (TNBC). Combined taxane and anthracycline-based NAC was used in 91.7% of cases. All patients with Her2+ disease received anti-Her2 therapy. After NAC, the majority (84.9%) underwent mastectomy, and received LRRT (86.1%). Only 11% had mastectomy without RT. Pathologic complete response (pCR) rates were 2.5% for Luminal A, 14.4% Luminal B, 27% TNBC, and 35.1% Her2+. Overall, adjuvant LRRT was associated with improved outcomes but was most significant for improved LRRFS in TNBC (92.5% vs. 68.5%, P < .001; Her2+ 95.4% vs. 93.6%, P = .81; Luminal A 97.4% vs. 100%, P = .49; Luminal B 89.7% vs. 100%, P = .17). On multivariable analysis, factors associated with reduced LRRFS were grade 3 histology (HR 4.96, P = .009) and no pCR (HR 7.0, P = .0008). Predictors of lower BCSS and OS were age >50, grade 3, cT3-4, lack of pCR, LRRT omission, and TNBC and Her2+ subtypes. ConclusionIn this analysis of patients treated with modern NAC, pCR rates varied by molecular subtype. Patients who did not receive LRRT, particularly those with TNBC, had lower survival compared to those treated with LRRT. These findings support the need for prospective studies to evaluate the safety of de-escalating RT after NAC.

Accelerated Partial Breast Irradiation with Intraoperative Radiotherapy Is Effective in Luminal Breast Cancer Patients Aged 60 Years and Older.

Adjuvant whole breast irradiation (AWBI) improves local control and survival in breast cancer patients after breast-conserving surgery. Between 2010 and 2017, 823 patients ≥ 60 years with ER-positive, Her-2 negative, clinically N0 breast cancer underwent breast-conserving surgery (BCS) at the West Pomeranian Oncology Center. Intraoperative radiotherapy (IORT) with kV photons was applied to 199 (24.2%) patients according to the IORT protocol, and AWBI only was applied to 624 (75.8%). IORT patients in cases with lymph node metastasis, lobular type presence, extensive in situ components, lymphatic vessel invasion, or resection margin < 2 mm, additionally underwent AWBI. Median follow-up was 74 months. There were two (1%) breast relapses in the IORT protocol group and one (0.2%) in the AWBI-only group. In each group, one axillary lymph node relapse was diagnosed (0.5% and 0.2%, respectively). There were two local relapses in the IORT-only group, and they were treated further with BCS and AWBI. Although locoregional relapse-free survival differed between the AWBI-only and IORT protocol groups (98.5% vs. 99.7%, p = 0.048), the local control, distant metastasis-free survival, and breast cancer-specific survival were similar. IORT is a reasonable option to avoid AWBI in ER-positive, Her-2 negative, cN0 women with breast cancer aged ≥ 60 years.

Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head-Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy.

Microenvironmental conditions control the entrance and thriving of cytotoxic lymphocytes in tumors, allowing or preventing immune-mediated cancer cell death. We investigated the role of tumor-infiltrating lymphocyte (TIL) density in the outcome of radiotherapy in a series of squamous cell head–neck tumors (HNSCC). Moreover, we assessed the link between markers of hypoxia and TIL density. One-hundred twenty-one patients with HNSCC treated prospectively with radical radiotherapy/chemo-radiotherapy were analyzed. The assessment of TIL density was performed on hematoxylin and eosin biopsy sections before radiotherapy. TIL density ranged from 0.8 to 150 lymphocytes per ×40 optical field (median 27.5). Using the median value, patients were grouped into two categories of low and high TIL density. Early T-stage tumors had a significantly higher TIL density (p < 0.003), but we found no association with N-stage. Overexpression of HIF1α, HIF2α, and CA9 was significantly linked with poor infiltration by TILs (p < 0.03). A significant association of high TIL density with better disease-specific overall survival and improved locoregional relapse-free survival was noted (p = 0.008 and 0.02, respectively), which was also confirmed in multivariate analysis. It is concluded that HNSCC phenotypes that allow for the intratumoral accumulation of lymphocytes have a better outcome following radical radiotherapy/chemo-radiotherapy. Intratumoral-activated HIF- and CA9-related pathways characterize immunologically cold tumors and may be used as targets for therapeutic interventions.