Initial Site Of Failure Research Articles

Patterns of Failure in Immunosuppressed Patients With Cutaneous Squamous Cell Carcinomas of the Head and Neck

Chronic immunosuppression is a well-known risk factor for the development of cutaneous malignancies and is also associated with a more aggressive disease phenotype. Prior retrospective studies have demonstrated that cutaneous squamous cell carcinomas of the head and neck (cSCC-HN) which arise in immunosuppressed patients have a 3-4-fold or greater risk of locoregional disease recurrence compared with similar tumors in immunocompetent patients. In this study, we retrospectively examined a cohort of immunosuppressed patients with cSCC-HN to better understand the response to therapy and patterns of recurrence.We retrospectively reviewed medical records of patients with cSCC-HN who had undergone either bone marrow transplant (BMT) or solid organ transplantation (SOT) at the University of Minnesota between 2011 - 2020. Patient and tumor-related variables including patient demographics, tumor grade and stage, type of immunosuppression, treatment techniques and site of first recurrence were recorded. All statistical analysis was conducted using JMP Pro 15.2.We identified a total of 174 patients treated for cSCC-HN with a history of either BMT (n = 25) or SOT (n = 149) with a median follow-up of 53.9 months [range: 1.4-118.8 months]. Of the patients who had available documentation of clinical stage and tumor grade, the majority (89%) had well or intermediate grade tumor and clinical T1 or T2 tumors (85%). Mohs micrographic surgery (MMS) was the most frequently utilized treatment modality (n = 137) followed by WLE +/- elective neck dissection. A total of 30 patients received radiotherapy with 13 patients also receiving chemotherapy. Fifty-four patients developed recurrent disease. Isolated local recurrence was the most common site of initial failure (65%) followed by regional failure (18%), distant failure (11%) and combined local and regional failure (6%). Eleven of the 30 patients receiving radiotherapy developed recurrent disease with the majority developing distant metastases (n = 6) followed by local recurrence (n = 5). No patient receiving radiotherapy developed regional nodal failure. The 12- and 24-month rates of local disease control following radiotherapy in the primary setting were 93% and 90%, respectively.Patients with cSCC-HN in the setting of chronic immunosuppression have significantly worse treatment outcomes compared with immunocompetent patients. Despite a preponderance of early stage and low or intermediate grade disease within our selected patients, we observed high rates of disease recurrence with local recurrence predominating as the most common site of failure. This study highlights the need for consideration of therapeutic interventions in this patient population.

Risk factors of brain metastases as initial failure in completely resected stage IIIA(N2) non-small cell lung cancer.

BackgroundThis study aimed to identify the risk factors of brain metastases (BM) as the initial site of failure in patients with completely resected stage IIIA (N2) non-small-cell lung cancer (NSCLC).MethodsFrom January 2005 and June 2012, the clinical data of 357 patients with completely resected stage IIIA (N2) NSCLC were reviewed in this study. Kaplan-Meier analysis was used to identify the incidence of BM as the initial site of failure and survival. To assess the risk factors of BM, the log-rank test and Cox regression were used for univariate analysis and multivariate analysis, separately.ResultSeventy-three (20.4%) patients developed BM; 60 patients had BM as their initial site of failure. The 1-, 3-, and 5-year risk for patients developing BM as the initial site of failure was 9.1%, 27.4% and 35.4%, respectively. Univariate analysis showed adenocarcinoma histology (P=0.000), number of regional LN >4 (P=0.018), multiple N2 stations (P=0.027), multiple region of LN involvement (P=0.010) were significantly associated with an increased risk of developing BM as the initial site of failure. Multivariate analysis showed adenocarcinoma (P=0.001; HR =0.150; 95% CI, 0.047–0.479), multiple regions of LN involvement (P=0.015; HR =2.010; 95% CI, 1.146–3.524) were significantly associated with the high risk of developing BM as the initial site of failure. In patients with adenocarcinoma and multiple regions of LN involvement, the 5-year actuarial risk of BM as the initial failure was 47.6%, respectively.ConclusionsAdenocarcinoma and multiple regions of LN involvement were independent risk factors for BM as the initial failure in completely resected stage IIIA (N2) NSCLC. Prospective clinical trials are needed to verify the effect of PCI in the highest-risk subset we identified.

Definitive Photon or Proton Radiotherapy for Oligo-recurrences at the Regional Lymph Nodes after Surgery in Patients with Non-Small Cell Lung Cancer

To evaluate outcomes of definitive radiotherapy (RT) for oligo-recurrences at the regional lymph nodes after surgery in patients with non-small cell lung cancer (NSCLC). Between January 2003 and December 2016, 33 patients were selected from our database for this analysis. The selection criteria were as follows: a) lymph node recurrence at the hilar, the mediastinum, and the supraclavicular fossa after surgery, b) no recurrence/metastasis at other than the lymph nodes, and c) receiving photon or proton RT ≥ 60 Gy/GyE. Twenty-two patients were men, and the median age was 68 years (range, 51 – 80 years). The pathological stage according to UICC 7th classification was Stage I in 14, II in 5, III in 12, IV in 1, and unknown in 1. Twelve patients had squamous cell carcinoma, 15 had adenocarcinoma, and the remaining 6 had others. The median time from the surgery to the recurrence was 14.8 months (range, 2.2 – 61.0 months). Thirty (91%) patients underwent positron emission tomography/computed tomography before RT. Their rN stages were rN1 in 3, rN2 in 20, and rN3 in 10. The lymph node metastasis at the single and multiple stations were observed in 15 and 18 patients, respectively. The elective nodal irradiation was performed in 30 patients, and 17 received proton RT. Concurrent chemotherapy was administered in 10 patients. The median follow-up time from the first day of salvage RT was 35.2 months (range, 5.9 - 89.6 months) for all patients. The 3-year overall survival, progression-free survival, and distant metastasis-free survival rates after RT were 63.8%, 45.1%, and 53.6%, respectively. In 18 (54%) of 33 patients, disease recurrences occurred and initial failure sites were observed at regional lymph node in 10 (in-field: n = 4, out-field: n = 6), at distant organs in 6, and both of them in 2 patients. The 3-year control within the irradiated field and regional control rates were 79.7%, and 63.3%, respectively. Concurrent chemotherapy improved the 3-year regional control rate compared with RT alone (87.5% vs 53.9%, p = 0.039). Proton RT had a tendency to improve the 3-year regional control rate compared with photon RT (76.6% vs 50.0%, p = 0.084). No Grade 4 or severe acute and late non-hematologic toxicity developed, but Grade 3 esophagitis and esophageal stricture were observed in each patient. Definitive RT for NSCLC patients with oligo-recurrence at the regional lymph nodes after surgery is considered to be an effective treatment option with high local control rate.

Patterns of Failure and Need for Biliary Intervention among Patients with Biliary Tract Cancers Treated with Definitive Surgery and Adjuvant Chemoradiation

Adjuvant chemoradiation therapy (CRT) after surgical resection of biliary tract cancers (BTC) has been shown to improve patient outcomes. However, there are limited data regarding patterns of failure after adjuvant chemotherapy and CRT with modern treatment regimens. In this study, we sought to characterize patterns of failure and need for biliary intervention after adjuvant CRT for gallbladder carcinoma (GBC) and cholangiocarcinoma (CCA). We present a retrospective analysis of 80 patients with GBC (n=29), extrahepatic CCA (n=30), perihilar CCA (n=13), or intrahepatic CCA (n=8). All patients underwent curative-intent resection with adjuvant CRT at a single institution from 2007–2017. Median CRT dose was 50.4 Gy (range: 36–65 Gy), which was administered with concurrent 5-FU-based chemotherapy. All but two patients received adjuvant chemotherapy. Tumor genomic mutation profiling was available for 30 patients (38%). Kaplan-Meier method was used to calculate rates of overall survival (OS) and locoregional failure (LRF), and log rank method was used to compare groups. Biliary interventions included ERCP with and without biliary stenting and percutaneous biliary tube placement. Study variables included age, performance status, site of primary disease, margin status, stage, receipt of oncologic resection, lymph node (LN) positivity, presence of lymphovascular invasion (LVI), tumor differentiation, and KRAS and TP53 mutational status. The median follow-up time was 30.5 months, and the median OS was 35.0 months. Among the entire cohort, 34% had T1/T2 disease, 40% were LN positive, and 53% underwent margin-negative (R0) resection. The overall rates of LRF and OS at 2 years were 21% and 62%, respectively. LRF was the initial site of failure in 16/80 patients (20%), and 19 patients (24%) had any LRF. On univariate analysis, only LN positivity (p=0.02) was positively associated with LRF. Site of primary disease (GBC vs. CCA), stage, LVI, and tumor mutation profile were not associated with LRF. Margin status was also not associated with LRF (2-year LRF: 18% vs. 29% in R0 vs. margin-positive (R1) resections, respectively, p=0.76). Among all patients, 23 (29%) required subsequent biliary intervention. Biliary intervention was required in 63% (12/19) of patients with LRF, compared to 18% (11/61) of patients without LRF. Of the 12 patients with LRF who required biliary intervention, 4 (33%) went on to die from biliary complications. Despite adjuvant CRT, there are high rates of LRF among patients with BTC, including GBC. Lymph node positivity may increase the risk of LRF. R1 resection was not associated with higher rates of LRF, suggesting that CRT may partially mitigate the risk of LRF in this high-risk group. LRF results in high rates of subsequent biliary interventions and can yield significant morbidity. Novel strategies should be considered to further improve upon rates of LRF.

Effects of Adjuvant Radiotherapy in Patients With Synovial Sarcoma.

To analyze the treatment outcomes and the effects of adjuvant radiotherapy (RT) in patients with synovial sarcoma (SS). The medical records of 103 patients treated with definitive surgery for SS, with/without RT, from August 1982 to July 2013 were reviewed retrospectively. The median age of the patients was 33 years (range, 5 to 72 y). The most frequent tumor location was the extremities (79 patients, 77%). Seventy-five patients (73%) received adjuvant RT and 26 (25%) did not. The median dose of adjuvant RT was 61.2 Gy (range, 45 to 66.6 Gy). The median follow-up period was 5.4 years (range, 0.2 to 31.0 y). The 5- and 10-year overall survival rates were 77 % and 65%, respectively. The progression-free survival (PFS) rates at 5 and 10 years were 52% and 43%, respectively. The most common site of initial failure was the lung (24 patients), followed by local recurrence (14 patients). The 5-year local-recurrence-free survival (LRFS) and distant-metastasis-free survival (DMFS) rates were 80% and 63%, respectively. On multivariate analysis, a mitosis count of <10 per 10 high-power fields (HPF) was a significant predictor of better overall survival, PFS, LRFS, and DMFS (P=0.004, <0.001, 0.025, and <0.001, respectively). Adjuvant RT was an additional prognostic factor for better PFS and LRFS (P=0.006 and 0.028, respectively). A positive/uncheckable resection margin was associated with poor prognosis for DMFS (P=0.011). There was no significant difference in LRFS between the higher and lower RT dose groups (<63 Gy group, 89%; ≥63 Gy group, 88%; P=0.772). The lung and primary site were frequent sites of failure in patients treated with definitive surgery for SS. Adjuvant RT improved LRFS and PFS. Frequent mitotic figures (≥10 mitoses per 10 HPF) were the worst prognostic factor for these patients.

Abstract 754: Selective ALK inhibitor alectinib (CH5424802/RO5424802) with potent antitumor activity in models of crizotinib resistance, including intracranial metastases

Abstract Purpose: EML4-ALK has been implicated as a driver oncogene and a therapeutic target in non-small cell lung cancer (NSCLC). The clinical efficacy of the ALK inhibitor crizotinib has been demonstrated in ALK fusion-positive NSCLC; however, resistance to crizotinib certainly occurs through ALK secondary mutations in clinical use. In addition, brain metastases are frequent sites of initial failure in patients because crizotinib has poor penetration of the central nervous system. This study aimed to clarify the efficacy of ALK inhibitor alectinib (CH5424802/RO5424802) in models of crizotinib-resistant ALK mutant tumors and intracranial tumors. Experimental Design: The antitumor activity of alectinib was evaluated in subcutaneous xenograft tumor models of Ba/F3 cells expressing mutated EML4-ALK, and in intracranial tumor implantation models of EML4-ALK-positive NSCLC NCI-H2228. Results: Alectinib had kinase inhibitory activity against some ALK mutations, including G1269A, and blocked tumor growth driven by a mutant of EML4-ALK in vitro and in vivo. In intracranial tumor implantation mouse models, alectinib resulted in regression of NCI-H2228 tumor in brain and provided a survival benefit. Alectinib is not a substrate for P-glycoprotein efflux transporter in vitro and showed a high brain-to-plasma ratio in rat. Additionally, alectinib led to tumor size reduction in the subcutaneous NCI-H2228 xenograft tumor that had failed to regress fully during treatment with crizotinib. Conclusions: Alectinib was effective against most EML4-ALK mutations and showed potent efficacy against intracranial ALK-positive tumor. Thus, alectinib might provide therapeutic opportunities for crizotinib-treated patients with ALK secondary mutations and brain metastases. Citation Format: Tatsushi Kodama, Toshiyuki Tsukaguchi, Masami Hasegawa, Miyuki Yoshida, Kenji Takanashi, Osamu Kondoh, Hiroshi Sakamoto. Selective ALK inhibitor alectinib (CH5424802/RO5424802) with potent antitumor activity in models of crizotinib resistance, including intracranial metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 754. doi:10.1158/1538-7445.AM2014-754

Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.

The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors. We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell. Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration. We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.

Limited Margins Using Modern Radiotherapy Techniques Does Not Increase Marginal Failure Rate of Glioblastoma

We investigate the patterns of failure in the treatment of glioblastoma (GBM) based on clinical target volume (CTV) margin size, dose delivered to the site of initial failure, and the use of temozolomide and intensity-modulated radiotherapy (IMRT). Between August 2000 and May 2010, 161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide. Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique. Patterns of failure and time to progression and overall survival were compared based on CTV margin, use of temozolomide, and use of IMRT. Kaplan Meier analysis was used to estimate survival times, and χ test was used for comparison of cohorts. For patients treated with 5-, 10-, and 15- to 20-mm CTV, 79%, 77%, and 86% experienced failures in the 60 Gy volume, respectively. Forty-eight percent, 55%, and 66% of patients with 5-, 10-, and 15- to 20-mm CTV experienced failures in the 46 Gy volume, respectively. There was no statistical difference between patients treated with 5-, 10-, 15- to 20-mm margins with regard to 60 Gy failure (P=0.76), 46 Gy failure (P=0.51), or marginal failure (P=0.73). Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume. There was no increased likelihood of marginal failures in patients receiving IMRT (P=0.97). Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.

Consolidation whole abdomen irradiation following adjuvant carboplatin-paclitaxel based chemotherapy for advanced uterine epithelial cancer: feasibility, toxicity and outcomes

BackgroundTo evaluate feasibility and preliminary outcomes associated with sequential whole abdomen irradiation (WAI) as consolidative treatment following comprehensive surgery and systemic chemotherapy for advanced endometrial cancer.MethodsWe conducted a retrospective analysis of patients treated at our institution from 2000 to 2011. Inclusion criteria were stage III-IV endometrial cancer patients with histological proof of one or more sites of extra-uterine abdomen-confined disease, treated with WAI as part of multimodal therapy. Endpoints were feasibility, acute toxicity, late effects, recurrence-free survival (RFS) and overall survival (OS). Twenty patients were identified. Chemotherapy consisted of 3 to 6 cycles of a platinum-paclitaxel regimen in 18 patients. WAI was delivered using conventional technique to a median total dose of 27.5 Gy.ResultsNo grade 4 toxicities occurred during chemotherapy or radiotherapy. No radiation dose reduction was necessary. Three patients developed small bowel obstruction, all in the context of recurrent intraperitoneal disease. Kaplan-Meier estimates and 95% confidence intervals for RFS and OS at one year were 63% (38–80%) and 83% (56-94%) and at 3 years 57% (33-76%) and 62% (34-81%), respectively. On univariate Cox analysis, stage IVB and serous papillary (SP) histology were found to be statistically significantly (at the p = 0.05 level) associated with worse RFS and OS. The peritoneal cavity was the most frequent site of initial failure.ConclusionsConsolidative WAI following chemotherapy is feasible and can be performed without interruption with manageable acute and late toxicity. Patients with endometrioid adenocarcinoma, especially stage FIGO III, had favorable outcomes possibly meriting prospective evaluation of the addition of WAI following chemotherapy in selected patients. Patients with SP do poorly and do not routinely benefit from this approach.

Recurrence patterns of advanced non-small cell lung cancer treated with gefitinib

Background Gefitinib is widely used in the treatment of advanced non-small cell lung cancer (NSCLC). However, only a small number of reports have described initial failure sites in patients treated with gefitinib. The aim of this study was to investigate survival, recurrence sites, and treatment after recurrence in these patients. Methods A retrospective review was conducted of all patients with stage III/IV NSCLC treated with gefitinib in Peking Union Medical College Hospital from October 2002 to September 2011. Patient characteristics, initial failure sites, associated clinical factors, and subsequent therapy were included in the analysis of prognostic factors. Results A total of 316 patients were identified The median progress free survival (PFS) and overall survival (OS) times were 238 days and 468 days, respectively. The median survival time after progression was 145 days. The sites of initial failure were lung (62.34%), bone (17.72%), central nerve system (CNS, 16.14%), liver (9.49%), and others (7.19%). Patients with single-site progression or multi-site progression were 81.01% and 18.99%, respectively. Progression-free survival time was associated with lung and bone failure. Additionally, the median survival time after progression was lower in patients with multi-site progression and liver progression. Other initial failure sites displayed no relationship with survival, including CNS failure. Subsequent therapy may affect survival after progression. In patients receiving continuous epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, radiotherapy, and re-treatment with EGFR-TKIs, survival time after progression was prolonged compared with the best supportive care. Conclusions Our data suggest that patients receiving gefitinib should be closely monitored regarding lung metastasis during follow-up. Liver metastases and multi-site progression were poor prognostic factors. After failure with gefitinib, patients may benefit from radiotherapy, chemotherapy, continuous EGFR-TKI therapy and re-treatment with EGFR-TKIs.

Strength and fracture behavior of graphene grain boundaries: effects of temperature, inflection, and symmetry from molecular dynamics

We present a molecular dynamic simulation on the mechanical strength and fracture behavior of graphene grain boundaries (GBs). The intrinsic strength, critical failure strain, and failure mechanism of graphene GBs mainly rely on the temperature and inflection angle, whereas the Young's modulus does not vary significantly with either temperature or boundary configuration. The overall intrinsic strengths of inflected GBs can be correlated with infection angle by a linear term, which is irrelevant to the system temperature. The initial failure sites of GBs locate either on the boundary line or inside the domain at high temperature.

Patterns of Failure as a Function of Clinical Target Volumes in Patients With GBM Treated With Radiation Therapy (RT), Temozolomide, and Bevacizumab

While the practice at our institution is to utilize the pre-operative MRI T2 hyperintense volume for planning RT of glioblastoma (GBM), others utilize the post-operative T2 volume acquired at various times following surgery. This study examined the difference in the size and relative location of these target volumes and compared the site of initial failure in relation to these volumes in patients initially treated with RT and concurrent temozolomide (TMZ) and bevacizumab (BVZ).

Initial failure site according to primary treatment with or without para-aortic lymphadenectomy in endometrial cancer

ObjectiveThe objective of this study was to compare the initial failure sites in patients with endometrial cancer who underwent surgical treatment including pelvic lymphadenectomy with or without para-aortic lymphadenectomy. MethodsA retrospective chart review was carried out for 657 endometrial cancer patients with no residual disease after initial treatments including lymphadenectomy at two tertiary centers between 1987 and 2004. Surgical treatment at one institute included pelvic lymphadenectomy (PLX) without para-aortic lymphadenectomy (PALX), while surgical treatment including PLX+PALX was routinely performed at the other institute. We identified patients with recurrence and evaluated initial failure sites. Rates of recurrence in the respective sites were compared according to the type of lymphadenectomy. ResultsOf the 657 patients, 103 (15.7%) suffered recurrence. There was no significant difference between the rate of intrapelvic recurrence in the PLX alone group and that in the PLX+PALX group (4.7% vs. 2.9%, p=0.22). The rate of extrapelvic recurrence in the PLX alone group was significantly higher than that in the PLX+PALX group (16.1% vs. 6.2%, p<0.0001), and the rate of para-aortic node (PAN) recurrence in the PLX alone group was also significantly higher than that in the PLX+PALX group (5.1% vs. 0.6%, p=0.0004). In the analysis of patients who received adjuvant chemotherapy, the rate of PAN recurrence in the PLX alone group was significantly higher than that in the PLX+PALX group (9.5% vs. 1.3%, p=0.0036). ConclusionPAN recurrence was a failure pattern peculiar to the PLX alone group. Adjuvant chemotherapy might not be able to replace surgical removal as a treatment for metastatic lymph nodes.

Nonsurgical management of oropharyngeal, laryngeal, and hypopharyngeal cancer: The Fox Chase Cancer Center experience

Oropharyngeal, laryngeal, and hypopharyngeal cancer treatment has changed at our institution, but survival outcomes have not been evaluated. We approached the evaluation by a retrospective single-institution cohort study. Review of 180 patient records from 1993 to 2004 revealed that the number of patients with oropharyngeal cancer treated nearly doubled, whereas the number of patients with laryngeal and hypopharyngeal cancers declined (p = .006). Since 2000, concurrent chemotherapeutic regimens rather than radiation alone became the dominant treatment approach, with associated improvements in recurrence-free and overall survival (p = .009 and p = .006, respectively). Stratification by tumor site, however, revealed the survival of patients with oropharyngeal cancer improved markedly, whereas the survival of patients with laryngeal cancer did not change. In the multivariate analysis, T classification (p = .0001) and chemotherapy use (p = .0001) were associated with improved survival. The recurrence-free survival of nonsmokers was better than that for former or current smokers (p = .01), but was accounted for by earlier T classification on presentation in the multivariate analysis (p = .0001). The predominant initial site of failure remained at the primary site for oropharyngeal cancer (14 of 17 relapses or 82%), but not laryngeal cancer (3 of 7 relapses or 42%). As a result, an increasing number of patients with recurrent oropharyngeal cancer, and a decreasing number of recurrent laryngeal cancer patients were evaluated for salvage surgery. Patients with oropharyngeal recurrences, however, were less likely to undergo surgery with curative intent (p = .02) and were less likely to achieve locoregional control after disease recurrence. The survival of patients with oropharyngeal and hypopharyngeal cancers treated at our institution has improved over the last 15 years, which is likely related to changes in treatment and tumor biology. The improvement was not observed in patients with laryngeal cancer. A subset of patients with oropharyngeal cancer remain subject to local failure and disease-related death.

Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall‐cell lung cancer

We investigated the risk of central nervous system (CNS) failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in Korean patients with nonsmall-cell lung cancer (NSCLC) METHODS: We retrospectively evaluated the pattern of disease progression of 287 advanced NSCLC patients who were treated with gefitinib or erlotinib. Patients whose best tumor response was complete response, partial response, or stable disease (> or =90 days) were classified into the group receiving clinical benefit with these drugs. The clinical benefit group had a higher incidence of CNS failure as an initial progression, compared with the non-clinical benefit group (26% vs 4%; P < .001). Isolated CNS failure was also more frequent in the clinical benefit group than in the non-clinical benefit group (13% vs 1%; P < .001). In a multivariate analysis, clinical benefit with EGFR-TKIs significantly increased the risk of isolated CNS failure, with an adjusted hazard ratio of 10.9 (95% confidence interval [CI], 1.4-29.1, P = .01). In patients with isolated CNS failure, the median time from initial intracranial failure to extracranial failure was 9.9 months (95% CI, 1.9-21.9 months) and to death was 12.9 months (95% CI, 3.3-22.5 months). The CNS was frequently the initial failure site after clinical benefit with EGFR-TKIs in Korean NSCLC patients. Patients with isolated CNS failure showed durable extracranial control after cranial progression. A role for close surveillance of the CNS during EGFR-TKI treatment or prophylactic measures appears worthy of further study in these patients.

Radical hysterectomy for FIGO stage I–IIB adenocarcinoma of the uterine cervix

A retrospective analysis was carried out to identify risk factors for survival and relapse in patients with FIGO stage I–IIB cervical adenocarcinoma (AC), who underwent radical hysterectomy, and to compare outcome and spread pattern with those of squamous cell carcinoma (SCC). One hundred and twenty-three FIGO stage I–IIB patients with AC and 455 patients with SCC, who all underwent primary radical hysterectomy, were reviewed. Among the patients with AC, Cox model identified tumour size (95% CI: 1.35–30.71) and node metastasis (95% CI: 5.09–53.44) as independent prognostic factors for survival, and infiltration to vagina (95% CI: 1.15–5.76) and node metastasis (95% CI: 6.39–58.87) as independent prognostic factors for relapse. No significant difference was found in survival or relapse between the AC and SCC groups, after adjusting for other clinicopathological characteristics using Cox model. No significant difference was found in the positive rates of lymph nodes or location of initial failure sites between the two groups, but ovarian metastatic rate was significantly higher in patients with pathologic stage IIB AC (P=0.02). Positive node is a common independent prognostic factor for survival and relapse of patients with AC. FIGO stage I–IIB patients with AC or SCC, who underwent radical hysterectomy, have similar prognosis and spread pattern, but different ovarian metastasis rates.

Intensity Modulated Radiotherapy for Squamous Cell Carcinoma of the Hypopharynx and Larynx: Clinical Outcomes and Patterns of Failure

Limited clinical data exists in the use of intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx (HP) and larynx (LX). This study reports the clinical outcomes and patterns of failure in patients treated with IMRT for squamous cell cancers (SCC) of these sites. Between 9/2001 and 12/2007, 42 patients with newly diagnosed SCC of the HP (23) and LX (19) were treated with IMRT with curative intent at Stanford University Medical Center. Six patients were treated in the postoperative setting with uninvolved surgical margins, 5 received post-operative radiotherapy with involved margins or gross residual disease, and 31 underwent definitive radiotherapy. Seventeen patients received concurrent cisplatin-based chemotherapy, 13 received non-cisplatin based regimens with or without Cetuximab, 6 received Cetuximab monotherapy and 6 received no systemic therapy. Treatment plans were designed to provide a median dose of ≥66 Gy at 2.2 Gy/fraction to >95% of the gross tumor volume (GTV) in the definitive setting and to post-operative cases with positive margins, and a median dose of 60 Gy at 2 Gy/fraction in the post-operative setting with clear margins. Median follow-up was 14 months among surviving patients (range, 5-64 months). In patients with local or regional failure, imaging studies delineating the site of failure were co-registered to the treatment planning CT when available to aid in determining site of failure in relation to the treatment plan. Five patients developed a locoregional failure or had persistent disease, with a median time to failure of 12.1 months. Three local failures occurred entirely within the high-dose region, 1 of whom had synchronous bony metastatic disease, and 2 occurred in irradiated regional nodes, 1 of whom had synchronous distant metastasis. No marginal misses were observed. Seven patients developed distant metastasis as the initial site of failure. The 2-year Kaplan-Meier estimates of locoregional control, freedom from distant metastasis, overall survival, and disease-free survival (DFS) were 82%, 79%, 62%, and 57%, respectively. On univariate analysis, HP primaries had a statistically significant lower DFS than LX primaries. T-classification, overall stage, histologic grade, and age did not predict for DFS. IMRT provided excellent LRC for patients with SCC of the HP and LX. Pattern of failure analysis showed that locoregional relapses occurred in the high-dose volumes, suggesting that target volume delineation was adequate but further dose-escalation may be needed. HP tumors faired worse than LX tumors, suggesting that these patients may warrant more aggressive treatment.

Management of Regional Lymph Nodes in Localized Vulvar Carcinoma

‡,§ ‡ § Purpose: To evaluate the impact of postoperative radiotherapy on loco-regional failure in patients with vulvar carcinoma and to determine the treatment strategy for inguinal lymph nodes. Materials and Methods: Sixty-six patients who received treatment for primary vulvar carcinoma at Seoul National University Hospital, from October 1979 through June 2004, were retrospectively analyzed. Sixteen patients were excluded from the analysis due to the following reasons: distant metastases in two patients; palliative intent for six patients; previous radiotherapy given to the pelvis in three patients; follow-up loss after surgery for four patient; insufficient medical records for one patient. Of 50 eligible patients, 35 were treated with surgery alone (S), ten were treated with surgery followed by radiotherapy (S+RT), and five were treated with radiotherapy alone. Results: The 5-year overall survival (OS) and disease-free survival (DFS) rates of all patients were 91% and 78%, respectively. Twelve patients (26%) experienced treatment failures and the sites of initial failure were as follows: a primary site in eight patients; regional lymph nodes in three patients; the lung in one patient. Although risk factors for failure were more common in the S+RT group than the S group of patients (p ＜0.05), the DFS rates were similar for the two groups (5-year DFS rates, 78% vs. 83%, p=0.66). The incidences of occult lymph node metastases was 10%. Ten of 31 patients with clinically negative lymph nodes did not received inguinal lymph node dissection, but no patient experienced regional failure. Conclusion: Postoperative radiotherapy may have a potential benefit for patients with risk factors for failure. The omission of inguinal dissection or elective radiotherapy to the inguinal lymph nodes may be considered in low-risk patients with clinically negative lymph nodes.

A Phase II Study of Concurrent Carboplatin and Paclitaxel and Thoracic Radiotherapy for Completely Resected Stage II and IIIA Non-small Cell Lung Cancer

To determine the feasibility of combining concurrent carboplatin/paclitaxel and thoracic radiotherapy (TRT) for completely resected stage II and IIIA non-small cell lung cancer. Eligibility stipulated gross total resections with involved lymph nodes (N1 or N2), pathologic stage II or IIIA non-small cell lung cancer. TRT consisted of 50.4 Gy in 28 fractions with a boost of 10.8 Gy for extranodal extension (ENE) or 16.2 Gy for involved surgical margins. Chemotherapy was administered every 3 weeks: carboplatin (area under the curve of 5) and paclitaxel (175 mg/m2) during TRT for two cycles, with doses increased to an area under the curve of 7.5 and 225 mg/m2, respectively, for two cycles after TRT. Cox multivariate regression analysis was used to confirm independent predictors of outcome among clinical and treatment-related factors: age, T stage, N stage, presence of ENE, presence of involved surgical margins, histopathology. Between April 1997 and March 2001, 42 patients were enrolled. Two patients were deemed ineligible due to having T4 disease, leaving 40 patients for analysis. Ninety-two percent (37/40) of patients had T1 or T2 disease; 60% (24/40) had N2 disease. Nine patients (22.5%) had ENE and 15% (six patients) had involved surgical margins. At a median follow up of 37 months (range, 3-103; median, 68 months for living patients), the 2- and 5-year Kaplan-Meier estimates of local regional control, freedom from distant metastasis, freedom from brain metastasis, and overall survival were 92% and 88%, 77% and 59%, 87% and 71% and 72% and 44%, respectively. Fourteen patients developed distant metastasis as the initial site of failure, eight of whom had brain metastasis. Brain metastasis was the only site of failure in four of the eight patients. Multivariate regression analysis demonstrated that the only independent predictor of overall survival was histology (p = 0.02). Patients with adenocarcinoma had a 5-year overall survival of 28% versus 68% for all other cell types. There were no independent predictors of distant metastases or brain metastases on multivariate regression analysis. Treatment was tolerated reasonably well: 92% of patients (37/40) received the planned doses of TRT; 67% of patients (27/40) received all four cycles of chemotherapy. Five patients developed grade 3 esophagitis, and three patients experienced grade 3 pneumonitis. Two patients experienced grade 5 toxicity. One was treatment related due to a patient who developed grade 3 esophagitis who developed an aspiration pneumonia that progressed to acute respiratory distress syndrome. Our results support the Radiation Therapy Oncology Group 97-05 findings and suggest that with new and better tolerated chemotherapy regimens the strategy of concurrent TRT and chemotherapy after completely resected stage II and IIIA non-small cell lung cancer should be further explored.

High-risk surgical stage 1 endometrial cancer: analysis of treatment outcome.

PurposeTo report the relapse and survival rates associated to treatment for patients with stage IC, grade 2 or grade 3 and IB grade 3 diseases considered high risk patients group for relapse.Materials and methodsFrom January 1993 to December 2003, 106 patients with endometrial cancer stage I were managed surgically in our institution. Based on data from the medical records, 106 patients with epithelial endometrial cancer met the following inclusion criteria: stage IC grade 2 or 3 and IB grade 3 with or without lymphovascular invasion. Staging was defined according to the FIGO surgical staging system. Postoperative adjuvant radiotherapy consisted of external beam pelvic radiation, vaginal brachytherapy alone or both. The median age was 65 years (range, 32–83 years), lymph node dissection was performed in 45 patients (42.5%) and 14 patients (13.2%) received vaginal brachytherapy only, and 92 (86.8%) received combined vaginal brachytherapy and external beam radiotherapy. The median dose of external beam radiotherapy administered to the pelvis was 4500 cGy (range 4000 – 5040). The median dose to vaginal surface was 2400 cGy (range 2000 – 3000). Predominant pathological stage and histological grade were IC (73.6%) and grade 3 (51.9%). The lymphovascular invasion was present in 33 patients (31.1%) and pathological stage IC grade 2 was most common (48. 1%) combination of risk factors in this group.ResultsWith a follow up median of 58.3 months (range 12.8 – 154), five year overall survival and event free survival were 78.5% and 72.4%, respectively. Locoregional control in five year was 92.4%. Prognostic factors related with survival in univariate analyses were: lymphadenectomy (p = 0.045), lymphovascular invasion (p = 0.047) and initial failure site (p < 0.0001). In multivariate analyses the initial failure in distant sites (p < 0.0001) was the only factor associated with poor survival. Acute and chronic gastrointestinal and genitourinary toxicity grades 3 were not observed.ConclusionIn conclusion, our results showed that the stage IC, grade 2, 3 and IB grade 3 endometrial cancer was associated with significantly increased risk of distant relapse and endometrial carcinoma-related death independently of salvage treatment modality.