Twenty-year experience with salvage total laryngectomy: lessons learned.

OBJECTIVE: The purpose of this study was to evaluate the outcome of salvage total laryngectomy and identify areas for further improvement. METHOD: A retrospective analysis of all patients who underwent salvage total laryngectomy between January 1999 and December 2018 was performed. RESULTS: Thirty-one patients were identified. The most common primary tumour site was the glottis (83.8 per cent). Early stage (T1-T2) disease was identified in 83.9 per cent of cases. Overall survival at 2 and 5 years post-salvage total laryngectomy was 71 per cent and 45 per cent, respectively. Disease-free survival at 2 and 5 years post-salvage total laryngectomy was 65 per cent and 42 per cent, respectively. The rate of post-salvage total laryngectomy pharyngocutaneous fistula was 29 per cent. CONCLUSION: More than half of patients will not survive beyond five years after salvage total laryngectomy. Regional recurrence was the most common form of failure and death. From this study, elective lateral and central neck dissection is advocated in patients with early laryngeal cancer who present with an advanced recurrence.

Adjuvant Versus Early Salvage Radiation Therapy for Men at High Risk for Recurrence Following Radical Prostatectomy for Prostate Cancer and the Risk of Death.

PURPOSE: Adjuvant compared with early salvage radiation therapy (sRT) following radical prostatectomy (RP) has not been shown to reduce progression-free survival in randomized controlled trials. However, these trials might have missed a benefit in men with adverse pathology at RP given that these men were under-represented and immortal time bias might have been present; herein, we investigate this possibility. METHODS: We evaluated the impact of adjuvant versus early sRT on all-cause mortality (ACM) risk in men with adverse pathology defined as positive pelvic lymph nodes (pN1) or pGleason score 8-10 prostate cancer (PC) and disease extending beyond the prostate (pT3/4). We used a treatment propensity score to minimize potential treatment selection bias when estimating the causal effect of adjuvant versus early sRT on ACM risk and a sensitivity analysis to assess the impact that varying definitions of adverse pathology had on ACM risk adjusting for age at RP, PC prognostic factors, site, and the time-dependent use of post-RP androgen deprivation therapy. RESULTS: After a median follow-up (interquartile range) of 8.16 (6.00-12.10) years, of the 26,118 men in the study cohort, 2,104 (8.06%) died, of which 539 (25.62%) were from PC. After excluding men with a persistent prostate-specific antigen, adjuvant compared with early sRT was associated with a significantly lower ACM risk among men with adverse pathology at RP when men with pN1 PC were excluded (0.33 [0.13-0.85]; P = .02) or included (0.66 [0.44-0.99]; P = .04). CONCLUSION: Adjuvant radiation therapy should be considered in men with pN1 or pGleason score 8 to 10 and pT3/4 PC given the possibility that a significant reduction in ACM risk exists.

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017. METHODS: In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months. RESULTS: Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies. CONCLUSIONS: This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority. TRIAL REGISTRATION NUMBER: NCT02267603.

Resultados oncológicos del tratamiento de rescate en pacientes con carcinomas de hipofaringe / Oncological results of salvage treatment in patients with hypopharyngeal carcinoma

INTRODUCCIÓN Y OBJETIVOS: El objetivo del presente estudio es analizar las variables relacionadas con la posibilidad de llevar a cabo una cirugía de rescate con intención radical en pacientes con carcinomas de hipofaringe con una recidiva local del tumor, así como evaluar el rendimiento oncológico de este tipo de cirugías. MÉTODOS: Estudio retrospectivo de 96 pacientes con carcinoma de hipofaringe con una recidiva local del tumor. RESULTADOS: Sólo 27 pacientes (28,1%) fueron considerados candidatos a cirugía de rescate. Las variables relacionadas con que el paciente fuese tratado con una cirugía de rescate fueron el tratamiento no quirúrgico inicial y un intervalo libre de enfermedad superior a los seis meses. Los 69 pacientes no candidatos a tratamiento quirúrgico de rescate fallecieron como consecuencia de la evolución del tumor en un periodo inferior a los 2,5 años. La supervivencia específica a los cinco años para los pacientes tratados con una cirugía de rescate fue del 39,5%. La única variable que se relacionó de forma significativa con la supervivencia específica fue el estatus de los márgenes de resección. Los pacientes con una recidiva tumoral extensa (rT3-4) o con una afectación ganglionar simultánea tuvieron una peor supervivencia, pero sin que las diferencias alcanzasen la significación estadística. CONCLUSIÓN: Sólo un 28,1% de los pacientes con carcinomas de hipofaringe con una recidiva local del tumor fueron considerados candidatos a tratamiento de rescate quirúrgico con intención radical. De los pacientes tratados con una cirugía de rescate, la supervivencia específica a los cinco años fue del 39,5%

INTRODUCTION AND OBJECTIVE: The aim of this study is to analyse the variables related to the feasibility of salvage surgery with radical intention in patients with a local recurrence of hypopharyngeal carcinoma, and to evaluate the oncological performance of this type of surgery. METHODS: Retrospective study of 96 patients with hypopharyngeal carcinoma with local tumour recurrence RESULT: Only 27 patients (28.1%) were considered for surgical salvage treatment. The variables related to feasibility of salvage surgery were non-surgical initial treatment of the tumour and a disease-free interval greater than 6 months. All 69 patients non-candidates for salvage surgery died as a result of tumour progression in a period of less than 2.5 years. The 5-year disease-specific survival rate for the patients treated with salvage surgery was 39.5%. The only variable significantly related to disease-specific survival was the status of the resection margins. Patients with extensive tumour recurrence (rT3-T4) or with simultaneous nodal involvement had a lower survival rate, but the differences did not reach statistical significance. CONCLUSION: Only 28% of the patients with hypopharyngeal carcinoma with local recurrence of the tumour were eligible for salvage surgery with radical intention. The patients treated with salvage surgery had a 5 -year disease-specific survival of 39.5%

Cyberknife® hypofractionated stereotactic radiosurgery (CK-hSRS) as salvage treatment for brain metastases.

PURPOSE: The introduction of hypofractionated stereotactic radiosurgery (hSRS) extended the treatment modalities beyond the well-established single-fraction stereotactic radiosurgery and fractionated radiotherapy. Here, we report the efficacy and side effects of hSRS using Cyberknife® (CK-hSRS) for the treatment of patients with critical brain metastases (BM) and a very poor prognosis. We discuss our experience in light of current literature. METHODS: All patients who underwent CK-hSRS over 3 years were retrospectively included. We applied a surface dose of 27 Gy in 3 fractions. Rates of local control (LC), systemic progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related complications were rated using the Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: We analyzed 34 patients with 75 BM. 53% of the patients had a large tumor, tumor location was eloquent in 32%, and deep seated in 15%. 36% of tumors were recurrent after previous irradiation. The median Karnofsky Performance Status was 65%. The actuarial rates of LC at 3, 6, and 12 months were 98%, 98%, and 78.6%, respectively. Three, 6, and 12 months PFS was 38%, 32%, and 15%, and OS was 65%, 47%, and 28%, respectively. Median OS was significantly associated with higher KPS, which was the only significant factor for survival. Complications CTCAE grade 1-3 were observed in 12%. CONCLUSION: Our radiation schedule showed a reasonable treatment effectiveness and tolerance. Representing an optimal salvage treatment for critical BM in patients with a very poor prognosis and clinical performance state, CK-hSRS may close the gap between surgery, stereotactic radiosurgery, conventional radiotherapy, and palliative care.

Improved outcome of children with relapsed/refractory acute myeloid leukemia by addition of cladribine to re-induction chemotherapy.

BACKGROUND: The preferred salvage treatment for children with relapsed/refractory acute myeloid leukemia (R/R-AML) remains unclear. The combination of cladribine/Ara-C/granulocyte-colony stimulating factor and mitoxantrone (CLAG-M) shown promising results in adult R/R-AML. We aim to investigate the efficacy and safety of CLAG-M versus mitoxantrone/etoposide/cytarabine (MEC) or idarubicin/etoposide/cytarabine (IEC) in R/R-AML children. METHODS: Fifty-five R/R-AML children were analyzed. The overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) at 3-year were documented. Karyotype or mutations status were summarized as different risk groups. RESULTS: The ORR was achieved in 80% (16/20) and 51% (18/35) of patients after one-cycle of CLAG-M and MEC/IEC treatment (p < 0.001). The CLAG-M group's OS (66.8% ± 16.2% vs. 40.4% ± 10.9%, p = 0.019) and PFS (52.6% ± 13.7% vs. 34.9% ± 9.1%, p = 0.036) at 3-year was significantly higher than the MEC/IEC group. In high-risk patients, 33.3% experienced progression of disease (PD) and 22.2% dead in CLAG-M group, while 50% experienced PD and 43.8% dead in MEC/IEC. When it comes to low-risk group, none of them in CLAG-M experienced PD or death, while up to 50% of patients received MEC/IEC suffered PD, and all of them died eventually. Similar results were also found in the intermediate-risk group. Surprisingly, the presence of FLT3-ITD was associated with poor outcome in both groups. The most common adverse events were hematologic toxicities, and the incidence was similar in both group. CONCLUSIONS: CLAG-M group demonstrated effective palliation along with acceptable toxicity in R/R-AML patients. However, patients with FLT3-ITD may benefit less from CLAG-M, owing to higher PD rate and all-cause mortality than other patients.

Oncological and Functional Outcomes of Primary and Salvage Total Laryngectomy.

OBJECTIVES: To evaluate and compare the oncological and functional outcomes of total laryngectomies (TL) performed as first line treatment or for salvage after failure of conservative approaches for treating advanced laryngeal carcinoma (LSCC). STUDY DESIGN: A retrospective cohort study. METHODS: A cohort of 217 patients who underwent TL was divided according to whether the procedure was for primary treatment of their LSCC (101 patients) or for recurrences after conservative surgery or chemo-radiotherapy (116 patients). RESULTS: The overall survival rate and disease-specific survival rate were significantly higher in the primary TL group than in the salvage TL group (P = .04 and P = .01, respectively). The recurrence rate was significantly higher and the disease-free survival (in months) was shorter for patients who had salvage TL than for those who had primary TL (P = .00 and P = .01, respectively). The salvage TL group also included significantly more cases of postoperative pharyngo-cutaneous fistula needing salivary stent positioning, and experienced significantly longer hospital stays than the primary TL group (P = .04 and P = .03, respectively). CONCLUSION: Oncological and functional outcomes of primary TL were significantly better than after salvage TL. If salvage TL was performed after conservative surgery had failed, the oncological and functional results were better than after the failure of organ-preserving protocols. This could justify a first attempt at conservative surgery for intermediate-advanced LSCC in selected cases, reserving chemo-radiotherapy only for patients unsuitable for surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E569-E575, 2021.

Outcomes of Primary Versus Salvage Surgery for Sinonasal Malignancies: A Population-Based Analysis.

OBJECTIVES/HYPOTHESIS: There exists a lack of consensus on the optimal sequence of treatment for many sinonasal malignancies (SNMs). This study compares the overall survival (OS) outcomes for primary surgery (PS) versus salvage surgery (SS) in SNM patients across stage, histology, and primary site. STUDY DESIGN: Retrospective database review. METHODS: The National Cancer Database was queried for all SNM cases treated with multimodal surgical and nonsurgical therapy between 2004 and 2015. Logistic regression identified predictors of SS. Cox proportional hazards models evaluated predictors of mortality, and Kaplan-Meier log-rank test assessed OS outcomes. RESULTS: Our SNM cohort consisted of 3,011 patients (PS = 2,804; SS = 207). SS patients had significantly longer postoperative hospital stays (P = .009) and increased rates of 30-day (P < .001) and 90-day mortality (P < .001) compared to PS. On multivariate logistic regression, predictors of undergoing SS included sinonasal undifferentiated carcinoma histology (odds ratio = 2.72; 95% confidence interval [CI]: 1.16-6.66; P = .024). On multivariate Cox proportional hazards analyses among SS patients, late-stage disease (hazard ratio [HR] = 4.80; 95% CI: 1.46-15.8; P = .01) and positive surgical margins (HR = 2.31; 95% CI: 1.29-4.13; P = .005) portended significantly worse OS. In the propensity score-matched cohort controlling for stage and histology, PS had significantly improved OS compared to SS (P = .007). Compared to SS, PS also had improved OS in subgroup analyses for patients with late-stage disease (P = .026) and squamous cell carcinoma histology (P = .006). CONCLUSIONS: In our SMN cohort, PS resulted in improved OS outcomes compared to SS independent of stage and histology. Consideration may be given to primary surgical resection for SMN whenever feasible, though a targeted, individualized approach is warranted. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E710-E718, 2021.

Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

BACKGROUND: FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression. METHODS: We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate, progression-free survival (2nd PFS) and overall survival (2nd OS) during treatments after progression were assessed. The RECIST response in first line and the oxaliplatin and irinotecan-free interval (OIFI) were investigated as potential predictors of benefit from FOLFOXIRI ± bev reintroduction. RESULTS: Longer 2nd PFS was reported in patients receiving FOLFOXIRI ± bev reintroduction compared to doublets ± bev or other treatments (6.1 versus 4.4 and 3.9 months, respectively, P = 0.013), and seems limited to patients achieving a response during first line (6.9 versus 4.2 and 4.7 months, respectively, P = 0.005) and an OIFI ≥ 4 months (7.2 versus 6.5 and 4.6 months, respectively, P = 0.045). CONCLUSIONS: First-line FOLFOXIRI/bev does not impair the administration of effective second-line therapies. First-line response and longer OIFI seem associated with improved response and 2nd PFS from FOLFOXIRI ± bev reintroduction, without impacting 2nd OS.

Análisis de supervivencia de los pacientes con cáncer de próstata con factores patológicos desfavorables tratados con prostatectomía radical y radioterapia de rescate tras la recidiva y persistencia bioquímica / Survival analysis of patients with prostate cancer and unfavorable risk factors treated with radical prostatectomy and salvage radiotherapy after biochemical recurrence and persistence

OBJETIVO: Analizar la supervivencia de los pacientes con cáncer de próstata (CP) con factores pronósticos desfavorables (FPD) tratados con PR y radioterapia de rescate (RTR) tras recidiva bioquímica (RB) y persistencia bioquímica (PB). MATERIAL Y MÉTODO: Análisis retrospectivo de 446 pacientes con al menos uno de los siguientes FPD: score de Gleason ≥ 8, estadio patológico ≥ pT3 y/o márgenes quirúrgicos positivos (MQ+). El criterio de RB fue la elevación del PSA por encima de 0,4 ng/ml. Evaluación de supervivencia mediante Kaplan-Meier y log-rank. Para identificar factores de riesgo con posible influencia en la respuesta a RTR y la supervivencia causa-específica (SCE) se usó análisis uni y multivariable (regresión de Cox). RESULTADOS: Mediana de seguimiento: 72 (rango 37-122) meses, mediana de tiempo hasta RB: 42 (rango 20-112) meses. El 36,3% presentaron RB. Presentaron respuesta bioquímica a la RTR 121 (74,7%) pacientes. La supervivencia libre de recaída (SLR) después de la RTR a los 3, 5, 8 y 10 años fue del 95,7, del 92,3, del 87,9 y del 85%, la SG a los 5, 10 y 15 años fue del 95,6, del 86,5 y del 73,5%. La SCE a los 5, 10 y 15 años fue del 99,1, del 98,1 y del 96,6%, respectivamente. Solo el tiempo hasta la RB < 24 meses (HR = 2,55, p = 0,01) se comportó como un factor predictor independiente de SLR después de RTR. CONCLUSIONES: La PR solo consigue control de la enfermedad a los 10años en aproximadamente la mitad de los casos. El tratamiento multimodal secuencial (PR + RTR cuando precise) aumenta este control bioquímico hasta > 87%, lográndose una larga SCE. Los pacientes con un tiempo hasta recidiva > 24 meses respondieron mejor al tratamiento de rescate

OBJECTIVE: Survival analysis of patients with prostate cancer (PCa) with adverse prognostic factors (APF) treated with radical prostatectomy (RP) and salvage radiotherapy (SRT) after biochemical recurrence (BR) or biochemical persistence (BP). MATERIALS AND METHODS: Retrospective analysis of 446 patients with at least one of the following APF: Gleason score ≥ 8, pathologic stage ≥ pT3 and/or positive surgical margins. BR criteria used was PSA level over 0.4 ng/ml. A survival analysis using Kaplan-Meier was performed to compare the different variable categories with log-rank test. In order to identify risk factors for SRT response and cancer specific survival (CSS) we performed univariate and multivariate analyses using Cox regression. RESULTS: Mean follow up: 72 (IQR 27-122) months, mean time to BR: 42 (IQR 20-112) months, mean PSA level at BR: 0.56 (IQR 0.42-0.96). BR was present in 36.3% of the patients. Biochemical response to SRT was observed in 121 (75.7%) patients. Recurrence-free survival (RFS) rates after SRT at 3, 5, 8 and 10 years were 95.7%, 92.3%, 87.9%, and 85%; overall survival (OS) rates after 5, 10 and 15 years was 95.6%, 86.5% and 73.5%, respectively. CSS rates at 5, 10 and 15 years were 99.1%, 98.1% and 96.6%. Only time to BR < 24 months (HR = 2.55, P = .01) was identified as an independent risk factor for RFS after SRT. CONCLUSIONS: In these patients, RP only controls the disease in approximately half of the cases. Multimodal sequential treatment (RP+SRT when needed) increases this control, achieving high CSS rates and biochemical control in over 87% of the patients. Patients with time to recurrence > 24 months responded better to rescue treatment

A novel nomogram to predict survival in patients with recurrent nasopharyngeal carcinoma after salvage endoscopic surgery.

OBJECTIVES: To develop and validate a nomogram to predict survival in patients with recurrent nasopharyngeal carcinoma (NPC) after salvage endoscopic surgery. MATERIALS AND METHODS: A total of 229 eligible patients with recurrent NPC were divided into training (n = 115) and validation (n = 114) cohorts. A multivariate Cox proportional risk regression model was used to identify significant prognostic factors for overall survival (OS) in the training cohort. A nomogram was then developed based on the regression model. The performance of the nomogram was assessed with regard to discrimination and calibration. Patients were divided into low-risk or high-risk groups based on the risk scores derived from the nomogram. Furthermore, decision curve analysis (DCA) was used to assess the clinical utility of the nomogram. RESULTS: Six significant predictors were identified: diabetes mellitus, body mass index (BMI), neutrophil-to-lymphocyte ratio (NLR), T stage, lymph node metastasis, and tumor necrosis. The nomogram incorporating these six predictors demonstrated favorable discrimination and calibration in the training cohort, with a C-index of 0.746 (95% confidence interval [CI] 0.656-0.836), which was subsequently confirmed in the validation cohort (C-index 0.768 [95% CI 0.675-0.861]). Furthermore, the nomogram successfully distinguished patients into low- and high-risk groups. DCA indicated that the nomogram was clinically useful. CONCLUSIONS: The novel nomogram demonstrated its potential as an individual tool to predict survival in patients with recurrent NPC after salvage endoscopic surgery.

Role of high-dose salvage radiotherapy for oligometastases of the localised abdominal/pelvic lymph nodes: a retrospective study.

BACKGROUND: Abdominal/pelvic lymph node (LN) oligometastasis, a pattern of treatment failure, is observed occasionally, and radiotherapy may work as salvage therapy. The optimal prescription dose, however, is yet to be determined. This study assessed the efficacy of high-dose radiotherapy. METHODS: The medical records of 113 patients at 4 institutes were retrospectively analysed who had 1 to 5 abdominal/pelvic LN oligometastases and were treated with definitive radiotherapy between 2008 and 2018. The exclusion criteria included non-epithelial tumours, uncontrolled primary lesions, palliative intent, and re-irradiation. The prescription dose was evaluated by using the equivalent dose in 2 Gy fractions (EQD2). Patients receiving EQD2 ≥ 60 Gy were placed into the high-dose group, and the remaining others the low-dose group. Kaplan-Meier analyses were performed to evaluate overall survival (OS), local control (LC), and progression-free survival (PFS). Univariate log-rank and multivariate Cox proportional hazards model analyses were performed to explore predictive factors. Adverse events were compared between the high-dose and low-dose groups. RESULTS: The primary tumour sites included the colorectum (n = 28), uterine cervix (n = 27), endometrium (n = 15), and ovaries (n = 10). The rate of 2-year OS was 63.1%, that of LC 59.7%, and that of PFS 19.4%. On multivariate analyses, OS were significantly associated with solitary oligometastasis (hazard ratio [HR]: 0.48, p = 0.02), LC with high-dose radiotherapy (HR: 0.93, p < 0.001), and PFS with long disease-free interval (HR: 0.59, p = 0.01). Whereas high-dose radiotherapy did not significantly improve 2-year OS in the entire cohort (74.8% in the high-dose vs. 52.7% in the low-dose; p = 0.08), it did in the subgroup of solitary oligometastasis (88.8% in the high-dose vs. 56.3% in the low-dose; p = 0.009). As for Late grade ≥ 3 adverse event, ileus was observed in 7 patients (6%) and gastrointestinal bleeding in 4 (4%). No significant association between the irradiation dose and adverse event incidence was found. CONCLUSIONS: As salvage therapy, high-dose radiotherapy was recommendable for oligometastasis in the abdominal/pelvic LNs. For solitary oligometastasis, LC and OS were significantly better in the high-dose group.

Pattern-of-failure and salvage treatment analysis after chemoradiotherapy for inoperable stage III non-small cell lung cancer.

BACKGROUND: Loco-regional and distant failure are common in inoperable stage III non small-cell lung cancer (NSCLC) after chemoradiotherapy (CRT). However, there is limited real-world data on failure pattern, patient prognosis and salvage options. METHODS: We analysed 99 consecutive patients with inoperable stage III NSCLC treated with CRT between 2011 and 2016. Follow up CT scans from date of the first-site failure were matched with the delivered radiation treatment plans. Intra-thoracic loco-regional relapse was defined as in-field (IFR) vs. out-of-field recurrence (OFR) [in- vs. outside 50Gy isodose line in the involved lung], respectively. Extracranial distant (DMs) and brain metastases (BMs) as first site of recurrence were also evaluated. Using the Kaplan-Meier method, impact of salvage surgery (sS), radiotherapy (sRT), chemotherapy (sCT) and immunotherapy (sIO) on patient survival was assessed. RESULTS: Median follow-up was 60.0 months. Median PFS from the end of CRT for the entire cohort was 7.5 (95% CI: 6.0-9.0 months) months. Twenty-six (26%) and 25 (25%) patients developed IFR and OFR. Median time to diagnosis of IFR and OFR was 7.2 and 6.2 months. In the entire cohort, onset of IFR and OFR did not influence patient outcome. However, in 73 (74%) patients who survived longer than 12 months after initial diagnosis, IFR was a significant negative prognostic factor with a median survival of 19.3 vs 40.0 months (p < 0.001). No patients with IFR underwent sS and/or sRT. 18 (70%) and 5 (19%) patients with IFR underwent sCT and sIO. Three (12%) patients with OFR underwent sS and are still alive with 3-year survival rate of 100%. 5 (20%) patients with OFR underwent sRT with a median survival of 71.2 vs 19.1 months (p = 0.014). Four (16%) patients with OFR received sIO with a numerical survival benefit (64.6 vs. 26.4 months, p = 0.222). DMs and BMs were detected in 27 (27%) and 16 (16%) patients after median time of 5.8 and 5.13 months. Both had no impact on patient outcome in the entire cohort. However, patients with more than three BMs showed significantly poor OS (9.3 vs 26.0 months; p = 0.012). CONCLUSIONS: After completion of CRT, IFR was a negative prognostic factor in those patients, who survived longer than 12 months after initial diagnosis. Patients with OFR benefit significantly from salvage local treatment. Patients with more than three BMs as first site of failure had a significantly inferior outcome.

Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel-ramucirumab.

INTRODUCTION: For energy production, cancer cells maintain a high rate of glycolysis instead of oxidative phosphorylation converting glucose into lactic acid. This metabolic shift is useful to survive in unfavorable microenvironments. We investigated whether a positive glycolytic profile (PGP) in gastric adenocarcinomas may be associated with unfavorable outcomes under an anticancer systemic therapy, including the anti-angiogenic ramucirumab. MATERIALS AND METHODS: Normal mucosa (NM) and primary tumor (PT) of 40 metastatic gastric adenocarcinomas patients who received second-line paclitaxel-ramucirumab (PR) were analyzed for mRNA expression of the following genes: HK-1, HK-2, PKM-2, LDH-A, and GLUT-1. Patients were categorized with PGP when at least a doubling of mRNA expression (PT vs. NM) in all glycolytic core enzymes (HK-1 or HK-2, PKM-2, LDH-A) was observed. PGP was also related to TP53 mutational status. RESULTS: Mean LDH-A, HK-2, PKM-2 mRNA expression levels were significantly higher in PT compared with NM. 18 patients were classified as PGP, which was associated with significantly worse progression-free and overall survival times. No significant association was observed between PGP and clinical-pathologic features, including TP53 positive mutational status, in 28 samples. CONCLUSIONS: Glycolytic proficiency may negatively affect survival outcomes of metastatic gastric cancer patients treated with PR systemic therapy. TP53 mutational status alone does not seem to explain such a metabolic shift.

The role of surgical intervention for isolated breast cancer liver metastasis: Results of case-control study with comparison to medical treatment.

BACKGROUND: Combined with systemic therapy, the surgical intervention for breast cancer liver metastases (BCLM) is increasingly accepted but lacks convincing evidence. The aim of this study was to evaluate the disease control efficacy of hepatic surgery in isolated BCLM patients. METHODS: Between 2012 and 2017, metastatic breast cancer patients with isolated liver metastasis and regular follow-up were identified. Cohort design was conducted to compare the progression-free survival (PFS) between the surgical and nonsurgical BCLM patients. Univariate analysis and multivariate Cox regression survival analyses were performed to identify significant prognostic factors. RESULT: In all, 148 isolated BCLM patients were enrolled and 95 participants received hepatic surgery for metastatic lesions. With median follow-up of 36.47 months, there was no significant difference between hepatic surgical group and nonsurgical group for PFS (median PFS: 11.17 months vs 10.10 m, P = .092). Based on the multivariate analysis, the disease-free interval (DFI) was an independent prognostic factor for isolated BCLM patients. Among the surgical group, BCLM patients who had ideal response after first salvage systemic treatment experienced the best long-term survival (median PFS: 14.20 months). CONCLUSION: For isolated BCLM patients with ideal response in first-line medical treatment, surgical intervention (hepatectomy, radiofrequency ablation) combining with systemic treatment could bring improved progression-free survival compared to sole systemic treatment, indicating that hepatic surgery may be considered as a therapeutic choice for selected isolated BCLM patients in clinical practice.

Retrospective analysis of salvage surgery for local progression of brain metastasis previously treated with stereotactic irradiation: diagnostic contribution, functional outcome, and prognostic factors.

BACKGROUND: Stereotactic irradiation (STI) is a primary treatment for patients with newly diagnosed brain metastases. Some of these patients experience local progression, which is difficult to differentiate from radiation necrosis, and difficult to treat. So far, just a few studies have clarified the prognosis and effectiveness of salvage surgery after STI. We evaluated the diagnostic value and improvement of functional outcomes after salvage surgery. Based on these results, we reconsidered surgical indication for patients with local progression after STI. METHODS: We evaluated patients with brain metastases treated with salvage surgery for local progression from October 2002 to July 2019. These patients had undergone salvage surgery based on magnetic resonance imaging findings and/or clinical evidence of post-STI local progression and stable systemic disease. We employed two prospective strategies according to the eloquency of the lesions. Lesions in non-eloquent areas had been resected completely with a safety margin, utilizing a fence-post method; while lesions in eloquent areas had been treated with minimal resection and postoperative STI. Kaplan-Meier curves were used for the assessment of overall survival. Prognostic factors for survival were analyzed. RESULTS: Fifty-four salvage surgeries had been performed on 48 patients. The median age of patients was 63.5 years (range 36-79). The median interval from STI to surgery was 12 months. The median overall survival was 20.2 months from salvage surgery and 37.5 months from initial STI. Primary cancers were lung 31, breast 9, and others 8. Local recurrence developed in 13 of 54 lesions (24%). Leptomeningeal dissemination occurred after surgery in 3 patients (5.6%). Primary breast cancer (breast vs. lung: HR: 0.17), (breast vs. others: HR: 0.08) and RPA class 1-2 (RPA 1 vs. 3, HR:0.13), (RPA 2 vs 3, HR:0.4) were identified as good prognostic factors for overall survival (OS) in multivariate analyses. The peripheral neutrophil-to-lymphocyte ratio (NLR) of ≤3.65 predicted significantly longer OS (median 25.5 months) than an NLR > 3.65 (median 8 months). CONCLUSION: We insist that salvage surgery leads to rapid improvement of neurological function and clarity of histological diagnosis. Salvage surgery is recommended for large lesions especially with surrounding edema either in eloquent or non-eloquent areas.

Local control by salvage stereotactic body radiotherapy for recurrent/residual hepatocellular carcinoma after other local therapies.

Background: To clarify local control by salvage stereotactic body radiotherapy (SBRT) for recurrent/residual hepatocellular carcinoma (HCC) compared with initial definitive SBRT for local treatment-naïve HCC.Material and methods: We retrospectively investigated HCC patients that received SBRT between July 2005 and December 2017. We classified HCC tumors as the initial definitive SBRT group (Arm-1; initial definitive SBRT, Arm-2; initial definitive planned SBRT following transarterial chemoembolization (TACE)) and salvage SBRT group (Arm-3; salvage SBRT for recurrent/residual tumors after TACE, Arm-4; salvage SBRT for recurrent/residual tumors after radiofrequency ablation (RFA), Arm-5; salvage SBRT for recurrent/residual other than Arm-3 or Arm-4). Local control was evaluated by mRECIST.Results: We reviewed 389 HCC tumors of 323 patients treated by 35-40 Gy/5 fr. The median follow-up time for local recurrence of tumors was 34.8 months (range, 6.5-99.2). The cumulative local recurrence rates at 3 years of Arm-1-5 were 1.4% (95% CI, 0.3-4.4%), 5.0% (95% CI, 1.6-11.5%), 12.4% (95% CI, 5.7-21.9%), 14.8% (95% CI, 3.3-34.3%) and 7.3% (95% CI, 1.9-18.0%), respectively. The cumulative local recurrence rates at 3 years of initial definitive treatment and salvage treatment groups were 2.8% (95% CI, 1.1-5.6%) and 11.1% (95% CI, 6.3-17.3%), respectively (p=.004). On multivariate analysis, salvage treatment and the tumor diameter were significant risk factors of local recurrence (p = .02, p < .001 respectively). Estimated overall survival at 3 years for all patients in initial definitive treatment and salvage treatment groups were 71.5% (95% CI, 63.4-78.1%) and 66.1% (95% CI, 56.4-74.2%), respectively (p = .20). No treatment-related death caused by SBRT was observed.Conclusions: This analysis showed local control of salvage SBRT for recurrent/residual HCC was significantly worse than that of initial definitive SBRT for local treatment-naïve HCC. However, local control of salvage SBRT was relatively good, and salvage SBRT is one of the favorable treatment options for recurrent/residual HCC.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Role of Gamma Knife Radiosurgery in Small Cell Lung Cancer: A Multi-Institutional Retrospective Study of the International Radiosurgery Research Foundation (IRRF).

BACKGROUND: Despite a high incidence of brain metastases in patients with small-cell lung cancer (SCLC), limited data exist on the use of stereotactic radiosurgery (SRS), specifically Gamma Knife™ radiosurgery (Elekta AB), for SCLC brain metastases. OBJECTIVE: To provide a detailed analysis of SCLC patients treated with SRS, focusing on local failure, distant brain failure, and overall survival (OS). METHODS: A multi-institutional retrospective review was performed on 293 patients undergoing SRS for SCLC brain metastases at 10 medical centers from 1991 to 2017. Data collection was performed according to individual institutional review boards, and analyses were performed using binary logistic regression, Cox-proportional hazard models, Kaplan-Meier survival analysis, and competing risks analysis. RESULTS: Two hundred thirty-two (79%) patients received SRS as salvage following prior whole-brain irradiation (WBRT) or prophylactic cranial irradiation, with a median marginal dose of 18 Gy. At median follow-up after SRS of 6.4 and 18.0 mo for surviving patients, the 1-yr local failure, distant brain failure, and OS were 31%, 49%, and 28%. The interval between WBRT and SRS was predictive of improved OS for patients receiving SRS more than 1 yr after initial treatment (21%, <1 yr vs 36%, >1 yr, P = .01). On multivariate analysis, older age was the only significant predictor for OS (hazard ratio 1.63, 95% CI 1.16-2.29, P = .005). CONCLUSION: SRS plays an important role in the management of brain metastases from SCLC, especially in salvage therapy following WBRT. Ongoing prospective trials will better assess the value of radiosurgery in the primary management of SCLC brain metastases and potentially challenge the standard application of WBRT in SCLC patients.

Disease course after the first recurrence of head and neck squamous cell carcinoma following (chemo)radiation.

PURPOSE: Recurrent head and neck squamous cell carcinoma (HNSCC) after chemoradiation is a challenging clinical problem. Salvage surgery (SS) is often extensive and mutilating. Oncological outcomes of SS are relatively well known, but little is published about the course of disease after the first recurrence, especially in patients without salvage possibilities. The aim of this study was to analyze the course of disease in patients with recurrent HNSCC after chemoradiation. METHODS: We retrospectively analyzed and descriptively reported the disease course in 198 patients with recurrent HNSCC after chemoradiation in the time period after the first recurrence. We scored any type of event, salvage treatment, systemic treatment and overall survival (OS). RESULTS: Of the 198 patients with recurrent HNSCC, salvage surgery was attempted in 104 (53%). SS was more frequently given in patients with recurrent laryngeal cancer, isolated regional failure (p < 0.001) and HPV-positive disease (p = 0.09). The 2-year OS of the whole group was 31% and was significantly different by tumor site, type of failure and SS. HPV-positive disease and salvaged recurrences were significantly predictive for better survival. One third of that salvaged patients was still alive without second recurrence. Median survival in patients that received any palliative systemic treatment without surgery, compared to those were no treatment was given, was 6 and 3 months, respectively (p = 0.006). CONCLUSIONS: Main factors influencing the course of disease in recurrent HNSCC are the possibilities for SS and HPV-status. Therefore, SS should always be considered and discussed. In patients without possibilities for SS, overall survival is 3-6 months.