Patterns Of Treatment Failure Research Articles

Safety of Dienogest and Other Hormonal Treatments for Endometriosis in Real-World Clinical Practice (VIPOS): A Large Noninterventional Study.

IntroductionEndometriosis is a common gynecologic disease associated with a significant burden on women’s health and healthcare systems. Currently approved hormonal treatments for endometriosis can be effective in controlling symptoms, but may have clinically relevant side effects that limit their long-term use. Dienogest 2 mg (Visanne; Bayer AG, Berlin, Germany) is a 19-nortestosterone derivative that significantly reduces menstrual bleeding, dysmenorrhea, premenstrual pain, dyspareunia, and pelvic pain in women with endometriosis. Although dienogest 2 mg has demonstrated efficacy in clinical trials, data regarding long-term and real-world use are limited.MethodsTo our knowledge, the Visanne Post-approval Observational Study (VIPOS) is the largest real-world, noninterventional study performed examining the safety of dienogest and other hormonal treatments for the management of endometriosis in routine clinical practice. Patients self-reported medical and gynecologic history and symptoms and treatment information. Primary clinical outcomes were clinically validated and subject to independent blinded adjudication. Loss to follow-up was minimized through active contact with participating women at 6 months post-enrollment and annually thereafter to ensure almost all clinically relevant outcomes were captured.Planned OutcomesVIPOS planned to enroll approximately 25,000 women initiating a new treatment for endometriosis, including those prescribed dienogest 2 mg/day and other hormonal medications for endometriosis (approved or nonapproved), from approximately 1000 centers in six European countries. The main clinical outcomes of interest for follow-up are anemia requiring medical intervention, de novo or clinically worsening depression, and treatment-failure patterns that result in drug discontinuation. Additional analyses will characterize the baseline risk factors of medically managed patients with endometriosis and assess treatment utilization patterns. VIPOS was designed to provide real-world information on endometriosis treatment and associated clinical outcomes, while not affecting the prescribing physician’s decisions or the classification of patient diagnoses.Trial RegistrationEuropean Union Electronic Register of Post-Authorisation Studies (EU PAS) no. 1613, Clinicaltrials.gov: NCT01266421.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-020-01331-z) contains supplementary material, which is available to authorized users.

Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

AbstractThe BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.

Treatment failure patterns of adjuvant gefitinib therapy and minimal residual disease detection in resected EGFR-mutant non-small cell lung cancer: author's reply.

We appreciate the remarks on our recent ADJUVANT publication of comparing spatial and temporal recurrence patterns between gefitinib and VP (vinorelbine plus cisplatin) chemotherapy in selected stage II–IIIA NSCLC patients with activating EGFR mutations. The recurrent model is very important for early non-small cell lung cancer (NSCLC) treated with curative procedure that could guide making future treatment strategy to cure disease. In our manuscript we built a new analytical method based on hazard ratios that showed the unique spatial-temporal recurrent patterns. In gefitinib group, we observed that recurrence risk increased at a constant rate 12 months post- surgery. It could be inferred that gefitinib could not kill tumor cells in these patients. The highest peak occurred at 30 months post-surgery. All of these indicated adjuvant EGFR TKI prolongs and reduces the recurrence or metastasis at space and timing for completely resected N1– N2 NSCLC (1).

Patterns of failure in patients with cutaneous head and neck melanoma

IntroductionThe incidence of head and neck melanoma is increasing. Various factors influence prognosis. ObjectiveWe sought to investigate the subgroup of patients with head and neck melanoma who fail primary treatment and to define the patterns of failure. MethodsThe database of a tertiary medical center was reviewed for patients diagnosed and surgically treated for cutaneous head and neck melanoma in 1995–2014. Regional disease failure was defined as disease confirmed in positive SLNB at first assessment or at recurrence. ResultsThe cohort included 141 patients followed for a median duration of 6.8 years (range 1–20 years). Median tumor thickness was 2.1 mm (range 0.5–12 mm). Ulceration was documented in 38 patients (26.9%). Sentinel lymph node biopsy (SLNB) was positive in 18 patients (12.8%). Total disease failure rate was 32.6% with similar rates of regional (n = 26, 18.4%) and distal (n = 22, 15.6%) failure. Most patients (86.3%) with systemic recurrence had a negative SNLB as did 6/26 patients (23%) with regional failure. Forty-three patients (30.4%) died during follow-up, half of them (23 patients, 16.3%) of melanoma. On multivariate analysis, Breslow thickness was the only significant predictor of outcome. ConclusionsThe pattern of treatment failure in patients with head and neck melanoma relate predominantly to Breslow thickness. The high false-negative rate of SNLB and the relatively high rate of systemic failures in patients with negative SNLB indicate a low predictive value of this procedure. Efforts to detect systemic disease during follow-up need to be intensified.

Prognostic significance of lymphovascular invasion in patients with salivary duct cell carcinoma of the head and neck

The purpose of this study was to evaluate the treatment outcomes of patients who underwent surgery with curative intention after the diagnosis of salivary duct cell carcinoma (SDC) in the head and neck area and to analyse the prognostic factors and treatment failure pattern. Fifty-nine patients treated between March 2003 and December 2018 were enrolled in the study. The mean follow-up period was 45.5 months (range 12–189 months). The 5-year overall survival rate was 54.7% and the 5-year disease-free survival rate was 56.8%. Nineteen recurrences occurred during the study period: four loco-regional recurrences and 15 distant metastases. During the study period, 10 patients died of disease relapse and 5 patients died of other medical caused. On univariate analysis, lymphovascular invasion (LVI) (P=0.031) showed the most significant correlation with mortality. On multivariate Cox regression analysis, LVI showed the most significant correlation with patient survival (P = 0.027). LVI was the most significant prognostic factor related to the 5-year overall survival rate of SDC patients. The development of novel therapeutic agents is necessary to improve the survival rate of these patients with LVI.

Outcomes of definitive radiotherapy for early laryngeal cancer in terms of survival and patterns of failure.

Early laryngeal cancer treated with definitive radiotherapy or surgery has a high cure rate. This study evaluated the patterns of treatment failure and long-term results of early laryngeal cancers treated with definitive radiotherapy. From January 2002 to December 2014, a total of 242 patients with early-stage laryngeal cancers were treated with radical radiotherapy. All patients had squamous cell carcinoma of the larynx (92 per cent male and 8 per cent female). Median follow-up was 4.5 years. The majority of patients were smokers (57.4 per cent). Local failure was seen in 12.5 per cent of stage I patients and 22.8 per cent of stage II patients. The 5-year overall survival and disease specific survival were 84 per cent and 91 per cent, respectively. In summary, radiotherapy is a suitable treatment modality for patients with early-stage laryngeal cancer, with an overall locoregional control rate of 84 per cent. Patients who fail radiotherapy may still undergo salvage laryngectomy.

A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study.

Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS. In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m2 per dose intravenously on days 1-3 and five cycles of doxorubicin 37·5 mg/m2 per dose intravenously on days 1-2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164. Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9-7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0-93·8) and 96·2% (93·2-99·2) in the low-risk group; 65·0% (58·2-71·8) and 79·2% (73·4-85·0) in the intermediate-risk group; and 21·2% (11·4-31·1) and 35·5% (23·6-47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group). Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed. National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.

Clinical characteristics, treatment, and survival outcome in pediatric patients with atypical teratoid/rhabdoid tumors: a retrospective study by the Japan Children's Cancer Group.

The prognosis of atypical teratoid/rhabdoid tumors (ATRTs) has improved in recent years with the use of multimodal therapy, mainly in cases not involving metastatic disease. The authors wanted to obtain historical control data and evaluate the suitable treatments in Japanese children with ATRTs that were proven negative for INI-1 immunostaining. The authors retrospectively collected clinical information on 38 pediatric patients with ATRTs treated from 2005 to 2016 and analyzed the data for this series. The median age of the patient population was 1.3 years, and the male/female ratio was approximately 2:1. Twenty-three patients (60.5%) had metastases. The effects of treatment on prognosis were analyzed for 34 patients after exclusion of 4 patients who could not receive curative treatment. At a median follow-up of 40.9 months, the mean (± SD) progression-free survival (PFS) and overall survival (OS) were 66.6% ± 8.3% and 45.9% ± 8.7% at 2 years and 44.2% ± 9.9% and 34.2% ± 8.9% at 5 years, respectively. The metastasis stage at diagnosis (M0-1 vs M2-4) (HR 2.68, 95% CI 1.08-6.65; p = 0.0338) and gross tumor resection (yes vs no) (HR 3.49, 95% CI 1.01-12.1; p = 0.0481) were prognostic factors for PFS but not for OS. Postoperative chemotherapy was performed in all 34 cases. High-dose chemotherapy was performed in 19 (55.8%) of 34 patients and showed a positive impact on OS (HR 0.31, 95% CI 0.11-0.86; p = 0.0254); the most commonly used regimen was a double-conditioning regimen of thiotepa plus melphalan. Local radiotherapy had a positive impact on both PFS and OS; however, craniospinal irradiation (CSI) performed in 12 patients as the primary therapy was associated with a poor outcome. Disseminated recurrence within 12 months from diagnosis was the most common pattern of treatment failure regardless of CSI. There has been an improvement in outcomes for pediatric ATRT patients since the introduction of multimodal therapy in Japan, mainly in patients without metastases. Even if selection bias is taken into consideration, CSI did not contribute to an improved prognosis. Novel treatment approaches are required for pediatric ATRT patients with metastases.

The Association Between the Development of Radiation Therapy, Image Technology, and Chemotherapy, and the Survival of Patients With Nasopharyngeal Carcinoma: A Cohort Study From 1990 to 2012

Previous studies demonstrated that the radiation therapy, image technology, and the application of chemotherapy have developed in the last 2 decades. This study explored the survival trends and treatment failure patterns of patients with nonmetastatic nasopharyngeal carcinoma (NPC) treated with radiation therapy. Furthermore, we evaluated the survival benefit brought by the development of radiation therapy, image technology, and chemotherapy based on a large cohort from 1990 to2012. Data from 20,305 patients with nonmetastatic NPC treated between 1990 and 2012 were analyzed. Patients were divided into 4 calendar periods (1990-1996, 1997-2002, 2003-2007, and 2008-2012). Overall survival (OS) was the primary endpoint. Magnetic resonance imaging has replaced computed tomography as the most important imaging technique since 2003. Conventional 2-dimensional radiation therapy, which was the main radiation therapy technique in our institution before 2008, was replaced by intensity modulated radiation therapy later. An increasing number of patients have undergone chemotherapy since 2003. The 5-year OS across the 4 calendar periods increased at each TNM stage with progression-free survival (PFS) and locoregional relapse-free survival (LRFS) showing a similar trend, whereas distant metastasis-free survival showed small differences. Multivariate analyses showed that the application of intensity modulated radiation therapy and magnetic resonance imaging were independent protective factors in OS, PFS, LRFS, and distant metastasis-free survival. Chemotherapy benefited patients in OS, PFS, and LRFS. The main pattern of treatment failure shifted from recurrence to distant metastasis. The development of radiation therapy, image technology, and chemotherapy increased survival rates among patients with NPC because of excellent locoregional control. Distant failure has become the greatest challenge for NPC treatment.

Radiation therapy for extrahepatic bile duct cancer: Current evidences and future perspectives

Extrahepatic bile duct cancer (EBDC) is a rare malignancy that involves neoplastic changes extending from both hepatic ducts to the common bile duct. The treatment of choice is surgical resection, but the predominant pattern of initial treatment failure is locoregional recurrence. Accordingly, adjuvant radiotherapy has been administered after surgical resection based on these rationales. At this time, there is minimal evidence supporting adjuvant radiotherapy, because there have been no phase III trials evaluating its benefit. Relatively small retrospective studies have tried to compare outcomes associated with EBDC treated with or without radiotherapy. We aimed to review studies investigating adjuvant radiotherapy for resected EBDC. Because less than one-third of EBDC cases are amenable to curative resection at diagnosis, other locoregional treatment modalities need to be considered, including radiotherapy. The next aim of this review was to summarize reports of definitive radiotherapy for unresectable EBDC. Patients with advanced EBDC often experience biliary obstruction, which can lead to jaundice and progress to death. Biliary stent insertion is an important palliative procedure, but stents are prone to occlusion after subsequent ingrowth of the EBDC. Radiotherapy can be effective for maintaining the patency of inserted stents. We also reviewed the benefit of palliative radiotherapy combined with the biliary stent insertion. Lastly, we discuss the existing gaps in the evidence supporting radiotherapy in the management of EBDC.

Patterns of treatment failure in patients undergoing adjuvant or definitive radiotherapy for vulvar cancer.

Knowledge of the detailed pattern of failure can be useful background knowledge in clinical decision making and potentially drive the development of new treatment strategies by increasing radiotherapy dose prescription to high-risk sub-regions of the target. Here, we analyze patterns of recurrence in patients with vulvar cancer treated with radiotherapy according to original planning target volumes and radiation dose delivered. We analyzed dose-planning and post-treatment recurrence scans from patients with vulvar cancer treated at two institutions from January 2009 through October 2014. We delineated the recurrences and merged the dose-planning and recurrence scans for each patient by using deformable co-registration. We estimated the center of each recurrence on the merged scans with the goal of relating them to the original dose plan. We evaluated 157 patients who received radiotherapy for vulvar cancer. Median age was 68 years (range 29-91). Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA-IVB were included. Twenty-nine patients had recurrent disease; 156 patients had squamous cell carcinoma and one patient had adenosquamous carcinoma of the vulva. Among the 157 patients, 37 patients with recurrent disease had recurrence scans available for review, for a total of 80 recurrence sites; 53% of the recurrences were located in the region to which the highest dose (60-70 Gy) had been prescribed. Patients who received definitive radiotherapy developed failure primarily in the high-dose region (80.5%), whereas patients who received adjuvant radiotherapy had a more scattered failure pattern (p<0.0001). Among the latter group, 29.5% failed in the high-dose region. Patients who received definitive versus adjuvant radiotherapy had different failure patterns, indicating that separate approaches are needed to improve both adjuvant and definitive radiotherapy for vulvar cancer.

Predictors of distant metastasis in parotid acinic cell carcinoma

BackgroundDistant metastasis (DM) is a common treatment failure pattern in acinic cell carcinoma (AciCC) of the major salivary glands; therefore, the main goal of this study was to analyse the predictors of DM in parotid AciCC.MethodsConsecutive patients with surgically treated parotid AciCC who were followed for at least 5 years were retrospectively reviewed. Data regarding age, sex, TNM stage, pathologic characteristics, surgical treatment, and follow-up examinations were collected and analysed. The primary end-point was DM control (DMC); the DMC survival was calculated from the date of surgery to the date of event or the latest follow-up examination and analysed by the Kaplan-Meier method. Independent prognostic factors were evaluated by the Cox proportional hazards method.ResultsA total of 144 patients were included. Positive intraparotid nodes (IPNs) were noted in 34 (31.8%) patients. High-grade transformation was noted in 12 (8.3%) patients. A total of 83 (57.6%) patients underwent neck dissection, and neck node metastasis was proven in 37 (44.6%, 37/83) patients. The 10-year DMC rate was 86%. The Cox model analysis confirmed IPN metastasis (1.854 [1.061–4.144], p = 0.011) and high-grade transformation (4.219 [1.948–15.553], p < 0.001) as independent predictive factors of the DMC survival.ConclusionIPN metastasis and high-grade transformation are independent prognostic factors of the DMC survival.

The results of nasopharyngeal cancer patients treated by simultaneous integrated boost technique and concomitant chemotherapy

Background/aim To assess the efficacy and side effects of concurrent weekly chemotherapy and radiotherapy with simultaneous integrated boost (SIB) technique for nasopharyngeal cancer (NPC). Materials and methods A total of 51 consecutive patients with diagnosis of NPC were treated between February 2010 and December 2015. The median dose for PTV70 (range: 60–82) was given in 33 fractions (range: 31–35). Forty-five of the patients received concomitant weekly chemotherapy between 3–7 cycles (median 6). Eleven patients received neoadjuvant and thirty-nine patients received adjuvant chemotherapy. ResultsAt a median follow-up 43 months (range: 2–76) the estimated 5-year overall survival and disease-free survival were 74.6% and 62.6%, respectively. ConclusionIn radiotherapy of advanced NPC, generally a considerable amount of normal head and neck tissues might have to be irradiated in addition to gross tumor volume, involved node, and elective neck irradiation. Together with chemoradiotherapy, poor oral hygiene and inadequate nutritional support result in excessive morbidity. Despite loco-regional success of concurrent chemoradiotherapy, distant metastasis is still the major pattern of treatment failure in the intensity modulated radiotherapy era. We need to improve our adjuvant chemotherapy regimens or develop new drugs.

Concurrent chemoradiation with paclitaxel versus cisplatin in locally advanced head and neck cancer patients - A prospective comparative study

Background: External beam radiotherapy with concurrent chemotherapy has become the mainstay of treatment for locally advanced head and neck cancers. Objective: The objective of this study was to compare paclitaxel to cisplatin as an agent for concurrent chemoradiation in locally advanced squamous cell carcinoma of head neck region in terms of toxicities and response to treatment. Materials and Methods: Biopsy-proven Stage III and Stage IVA head and neck squamous cell cancer patients were included in the study. The study arm patients received concurrent dose of paclitaxel 20 mg/m2 I/V 1 h infusion 4 h before radiation, repeated weekly for 6 cycles. Patients in the control arm received concurrent dose of cisplatin 30 mg/m2 I/V 1 h infusion 4 h before radiation, repeated weekly for 6 cycles. Patients of both arms received a total dose of 66 Gy external beam radiation, 200 cGy/day, 5 fractions in a week in 6.5 weeks treated on a Theratron 780E Cobalt-60 teletherapy unit. Results: Acute Grades III and IV renal toxicity and nausea were reported significantly more number of cases in cisplatin arm in comparison to paclitaxel arm. There was no statistically significant difference observed in the groups in terms of treatment response and failure pattern (χ2 = 3.63, df = 1, level of significance 0.05). On follow-up, up to 6 months, 51.85% of cases are disease free in the control arm and 50.66% of cases in the study arm. Conclusion: Low-dose weekly paclitaxel concurrent with external beam radiation therapy given in conventional fractionation is comparable to concurrent cisplatin in locally advanced head and neck squamous cell carcinoma in terms of efficacy. There is lower incidence of severe renal toxicity and vomiting with concurrent paclitaxel than with cisplatin.

Extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy for cervical cancer with para-aortic lymph nodes metastasis.

This study was conducted to evaluate the efficacy and toxicity of extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy in patients with cervical cancer with positive para-aortic lymph nodes (PALN). From September 2007 to December 2014, a total of 59 patients who had cervical cancer with para-aortic lymph node metastasis were treated with concurrent chemoradiotherapy at our institution. A dose of 45-50.4 Gy in 25-28 fractions with extended-field intensity-modulated radiation therapy was prescribed to planning target volume, and a dose of 30-36 Gy in 5-6 fractions was prescribed to Point A with high-dose-rate brachytherapy. A concurrent first-line cisplatin-based chemotherapy regimen was used. The median duration of follow-up was 32.1 months (range, 3.2-103.7 months). The 2- and 3-year overall survival, disease-free survival and local control rates were 69.0 and 52.8%, 45.0 and 41.3% and 83.4 and 81.0%, respectively. Distant metastasis was the major pattern of treatment failure, which occurred in 26 patients (44.1%). The incidence of Grade 3 or greater acute hematologic, gastrointestinal and genitourinary toxicity was 50.9, 1.7 and 3.4%, respectively. Only one patient had both Grade 3 late gastrointestinal and genitourinary toxicity. The study found that extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy was safe and effective in patients who had cervical cancer with positive PALN.

Analysis of clinical efficacy, failure pattern and prognostic factors of comprehensive treatment for malignant mucosal melanoma of head and neck

Objective To evaluate the clinical efficacy, failure pattern and prognostic factors of the malignant mucosal melanoma of the head and neck (MMHN) in a single center. Methods The treatment pattern, clinical efficacy, failure pattern and prognostic factors of 194 M0 MMHN patients admitted to our institution from 1982 to 2017 were retrospectively analyzed. Results The 5-year overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS) and distant metastasis-free survival (DMFS) were 41.4%, 57.8%, 76.5% and 46.5%, respectively. The failure rate was calculated as 74.6%(141/189). Among them, 40%(56/141) had distant metastasis as the first pattern of treatment failure, 37%(52/141) had local relapse, 15%(21/141) had regional relapse, 5%(7/141) had concurrent distant metastasis and local/regional relapse and 3%(5/141) had concurrent local and regional relapse. Multivariate analysis demonstrated that surgical margins (P=0.001) and adjuvant radiotherapy (P=0.000) were the independent prognostic factors for LRFS. Conclusions Surgery combined with radiotherapy can yield relatively high LRFS in the comprehensive treatment of MMHN.Distant metastasis is the major failure pattern. Key words: Head neck neoplasmsm/radiotherapy; Melanoma/radiotherapy; Prognosis

The Unique Spatial-Temporal Treatment Failure Patterns of Adjuvant Gefitinib Therapy: A Post Hoc Analysis of the ADJUVANT Trial (CTONG 1104)

IntroductionAdjuvant gefitinib therapy prolonged disease-free survival in patients with resected early-stage EGFR-mutation positive NSCLC in the ADJUVANT study (CTONG 1104). However, treatment failure patterns after gefitinib therapy are less well characterized. MethodsOverall, 222 stage N1–N2, EGFR-mutant NSCLC patients received gefitinib or vinorelbine plus cisplatin (VP) treatment. Tumor recurrences or metastases occurring during follow-up were defined as treatment failure; sites and data of first treatment failure were recorded. A post hoc analysis of treatment failure patterns which was estimated by Kaplan-Meier and hazard rate curves in modified intention-to-treat patients was conducted. ResultsThere were 114 recurrences and 10 deaths before recurrence across 124 progression events. Spatial distribution analysis showed that the first metastasis site was most frequently the central nervous system in the gefitinib group (29 of 106 [27.4%]), extracranial metastases were most frequent in the VP group (32 of 87 [36.8%]). Temporal distribution analysis showed lower tumor recurrence with gefitinib than with VP 0 to 21 months post-surgery. However, recurrence with gefitinib showed a constant rate of increase 12 months post-surgery. The first peak of extracranial metastasis appeared during 9 to 15 months with VP and 24 to 30 months with gefitinib. The highest peak for central nervous system metastases post-surgery occurred after 12 to 18 months with VP and 24 to 36 months with gefitinib. ConclusionsAdjuvant gefitinib showed advantages over VP chemotherapy in treatment failure patterns especially in extracranial metastasis. Adjuvant tyrosine kinas inhibitors may be considered as a treatment option in resected stage N1–N2 EGFR-mutant NSCLC but longer duration should be explored.

Single Institution Experience of Gastrointestinal Involvement of Diffuse Large B- Cell Lymphoma: Presentation, Outcomes and Patterns of Treatment Failure

IntroductionExtranodal (EN) involvement of the gastrointestinal (GI) tract in diffuse large B-cell lymphoma (DLBCL) presents heterogeneously across different anatomic sites and often occurs at initial diagnosis. Rituximab, anthracycline-based combination chemotherapy, radiation, and surgery have all been studied separately and in various combinations. However, given the variability in how patients may present in these contexts, there remains no consistent standard of care or pattern of treatment failure. We hypothesized these patients have different outcomes than those lacking this EN site of involvement.MethodsWe conducted a single-institution, retrospective analysis of consecutive cases who presented at initial diagnosis with DLBCL involving the GI tract including the esophagus, stomach, small intestine, or portion of large intestine. We performed a search in the University of Virginia Pathology database to identify all patients age >/= 18 years with DLBCL involving the GI tract and excluded those without additional clinical information available for review. A total of 51 patients were identified and we retrospectively collected data on demographics, date of diagnosis, involvement of extranodal sites, stage, International Prognostic Index (IPI) score, treatment, response to treatment, relapse, and survival at last follow-up.ResultsOf the 51 DLBCL patients, 65% of patients were male and 82% were Caucasian. Median age was 65 years (range 22-92). Three patients had HIV infection and no patients had active hepatitis B or C. Sites included gastric (51%), colon (27%), small bowel (12%), esophagus (4%), and rectum (2%); 4% had multiple GI sites involved. Forty-nine percent of patients presented with abdominal pain. Other common presentations included gastric/bowel perforation (12%), GI bleed (12%), gastric/small bowel obstruction (12%). Three cases (6%) were discovered on a screening colonoscopy. Forty-three percent of patients presented as stages I-IIIE versus 57% presented as stage IVE. Fifty-five percent were IPI 0-2 while 45% were IPI 3-5. Six patients (12%) had CNS involvement at presentation. Median follow-up was 20 months (range 26 days to 17 years). Six patients were lost to follow-up prior to assessment of response, and 4 had treatment discontinued early (3 due to grade 5 infection, 1 for GI perforation leading to death). One patient was still undergoing treatment.Forty patients were available to assess for response to treatment. The majority were treated with R-CHOP (57%) or DA-R-EPOCH (29%). Sixty-eight percent (n=27) had a complete response (CR), 22.5% (n=9) a partial response (PR), and 10% (n=4) were primary refractory. Of the 27 CRs, 13 (48%) had presented as stage 1-3 and 14 (52%) had presented as stage 4; 16 (59%) had an IPI score of 0-2 and 11 (41%) had an IPI score of 3-5. Of the four patients who had primary refractory disease, 3 had multiple EN sites involved at diagnosis, including 2 with CNS involvement. Of those who had a response (including CR or PR), median duration of response was 1 year (range 4 months to 13 years). Eleven patients (28%) had a relapse: 3 in the CNS, 5 in the GI tract (3 at the same site of initial involvement, 1 with a different GI site involved, and 1 with a different GI site in addition to systemic disease), and 3 in lymph nodes alone. Time to relapse ranged 1 month to 13 years with a median of 8.4 months. Fifty-seven percent of patients were alive at time of last follow-up. Median Overall survival (OS) was 5.7 years and Median Progression Free Survival (PFS) was 5.6 years (Figure 1).ConclusionThere is limited data on how patients with DLBCL involving the GI tract initially present and respond to therapy. This study encompassing almost twenty years of experience at a single institution, suggests that though patients present at all stages and as low risk vs high risk IPI, outcomes are poor compared to prior studies, especially when additional extranodal sites are involved. Duration of response can be substantial, however relapses are common and may present years later indicating ongoing follow-up is imperative. [Display omitted] DisclosuresPortell:AbbVie: Research Funding; Amgen: Consultancy; Kite: Research Funding; TG therapeutics: Research Funding; BeiGene: Research Funding; Genentech/Roche: Consultancy, Research Funding; Acerta: Research Funding; Infinity: Research Funding. Williams:Sandoz: Consultancy; Pharmacyclics: Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Juno: Consultancy.

Nodal Oligorecurrent Prostate Cancer: Anatomic Pattern of Possible Treatment Failure in Relation to Elective Surgical and Radiotherapy Treatment Templates

BackgroundPatients with biochemical recurrence following primary prostate cancer (PCa) treatment often experience relapse in the lymph nodes (LNs). Both salvage LN dissection (sLND) and elective nodal radiotherapy (ENRT) are potential treatment options. ObjectiveTo describe anatomic patterns of nodal oligorecurrent PCa in relation to different surgical and radiotherapy templates. Design, setting, and participantsPatients with biochemical recurrence following primary PCa treatment were eligible for 18F-choline positron emission tomography/computed tomography (CT). Patients with five or fewer LN recurrences (N1/M1a) were eligible for the current retrospective analysis. Outcome measurements and statistical analysisAll LN recurrences were mapped on a reference patient CT, as well as different surgical templates (limited to superextended) and an adapted version of the PIVOTAL ENRT template, blinded for the recurrences. Descriptive statistics were used to report recurrences in relation to the different templates and to compare LN coverage between templates. Results and limitationsIn total, 158 LN recurrences (N1: 88; M1a: 70) in 82 patients (median age: 67yr; prostate-specific antigen [PSA]: 3.1ng/ml; PSA doubling time of 7.8mo at the time of clinical recurrence) were mapped. In 49% of patients, recurrences were exclusively located in the true pelvis, followed by the common iliac LN (10%), retroperitoneal/inguinal LN (10%), or a combination (31%). There was up to 40% volume overlap between ENRT and the surgical templates. Theoretically, with ENRT more patients are fully covered (p<0.02) and the total number of covered lesions is higher (p<0.001) when compared to all types of sLND, except for superextended sLND, which is comparable to ENRT (patient-level: p=0.6; lesion-level: p=0.09). With 22% of all 158 lesions located outside all templates (N1: 7%; M1a: 15%), at least 31% of all 82 patients would not be salvaged using any of the templates. ConclusionsMore than half of nodal recurrences are located outside the true pelvis. Limited or standard extended sLND is considered insufficient as a salvage treatment approach and is thus not recommended for use. To maximize treatment outcomes for nodal recurrences, ENRT or superextended sLND should be preferred. Patient summaryWe compared two possible treatment options, elective nodal radiotherapy and salvage lymph node dissection, for patients with prostate cancer recurrence limited to five or fewer lymph nodes and reported the nodal distrubution. Radiotherapy and surgery cover different areas with possible different outcomes.

Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma

Craniospinal irradiation (CSI) is a crucial component of treatment for medulloblastoma (MB), a brain tumor clinically stratified into prognostically distinct molecular subgroups. Preclinical models of clinically relevant CSI offer the potential to study radiation dose and volume effects in these subgroups and to identify subgroup-specific combination adjuvant therapies, particularly for very-high-risk MB in which treatments are often unsuccessful. The commercially available Small Animal Radiation Research Platform equipped with a motorized variable collimator was used for image-guided CSI. Mice were implanted in brain cortices with patient-derived orthotopic xenografts (PDOXs) of very-high-risk Group 3 (G3) or Sonic Hedgehog (SHH) MB and were treated with fully fractionated CSI at 2Gy/fraction for a cumulative 36Gy. Radiation therapy dose response effects on tumor burden and overall survival were assessed. The pattern of treatment failure was determined using bioluminescence and then confirmed histologically. Acute toxicity was appraised by body weight measurements and blood work. We established an accurate and efficient preclinical protocol to administer CSI reproducibly to mice harboring MB. CSI improved the survival of mice bearing very-high-risk G3 or SHH MB PDOXs. However, radiation therapy dose responses across models suggested significant radio-responsiveness to conventionally fractionated CSI ≥20Gy. CSI was well tolerated; mice had no significant changes in body weight, and acute leukopenia developed but resolved soon after therapy completion. Our protocol for preclinical CSI delivery was effective and well tolerated, and it can be readily integrated into preclinical pipelines for MB and other central nervous system-seeding tumors.