Tumor regression grading after preoperative hyperfractionated radiotherapy/chemoradiotherapy for locally advanced rectal cancers: interim analysis of phase III clinical study.

We investigated the tumor regression grading (TRG) as a prognostic marker for disease-free survival (DFS) in patients with advanced rectal cancer treated within phase III randomized study (ClinicalTrials.gov Identifier: NCT01814969). The study is still recruiting prospective trial of preoperative hyperfractionated radiotherapy (HART) compared with concomitant hyperfractionated radiotherapy with co-administration of chemotherapy based on 5-FU (HART-CT) in patients with T2/N+ or T3/any N resectable rectal cancer. This preplanned interim analysis examined the pathological outcome in the group of 136 patients who were randomly assigned to HART (n=69) and HART-CT (n=67). The pelvis was irradiated twice a day (28 fractions of 1.5 Gy), with a minimal interfraction interval of 8 h to a total dose of 42 Gy over 18 days (HART) or mentioned scheme with concurrent chemotherapy: 5-FU 325 mg/m2 (bolus) on days 1-3 and days 16-18 (HART-CT). Surgery was performed 6-7 weeks after HART/HART-CT. Postoperative 5-FU-based chemotherapy was given to ypN positive patients. The TRG was recorded using the following 4-point scale: TRG0 (pCR) denoted no cancer cells; TRG1 was diagnosed when a few cancer foci had been seen in less than 10% of a tumor mass; TRG2 denoted cancer cells seen in 10-50% of a tumor mass; in order to diagnose TRG3, cancer cells had to be seen in more than 50% of a tumor mass. Multivariable analysis was performed using Cox regression models and Cox proportional hazard model was used in the survival analysis. The crude rate of patients with any serious acute 3 toxicity during the follow-up was 16% vs. 25% for HART and HART-CT. Twenty-two patients (16%) presented with postoperative complications. Anterior resection was performed in 52% vs. 62% for HART and HART-CT respectively (p=0.06). Of the 136 patients evaluable for pathologic response, there were 3 (4%) vs. 9 (13%), 16 (23%) vs. 24 (36%), 40 (58%) vs. 30 (45%), and 10 (15%) vs. 4 (6%) patients with TRG 0, 1, 2, and 3, respectively in HART vs. HART-CT, the difference was statistically significant p=0.002. The addition of 5-FU infusion to HART was not associated with statistically significant improved loco-regional relapse-free survival (LRC), metastasis-free survival (MFS), and DFS. Significant differences in the tumor regression grading (TRG) were found. Both LRC and DFS of rectal cancer patients treated with HART vs. HART-CT had favorable outcomes in the HART-CT arm. Also, the sphincter preservation rate tended to favor HART-CT.

The assessment of risk factors for long-term survival outcome in ypN0 patients with rectal cancer after neoadjuvant therapy and radical anterior resection.

BACKGROUND: The main negative prognostic factors in patients with rectal cancer after radical treatment include regional lymph node involvement, lymphovascular invasion, and perineural invasion. However, some patients still develop cancer recurrence despite the absence of the above risk factors. The aim of the study was to assess clinicopathological factors influencing long-term oncologic outcomes in ypN0M0 rectal cancer patients after neoadjuvant therapy and radical anterior resection. METHODS: A retrospective survival analysis was performed on a group of 195 patients. We assessed clinicopathological factors which included tumor regression grade, number of lymph nodes in the specimen, Charlson comorbidity index (CCI), and colorectal anastomotic leakage (AL). RESULTS: In the univariate analysis, AL and CCI > 3 had a significant negative impact on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). After the division of ALs into early and late ALs, it was found that only patients with late ALs had a significantly worse survival. The multivariate Cox regression analysis showed that CCI > 3 was a significant adverse risk factor for DFS (HR 5.78, 95% CI 2.15-15.51, p < 0.001), DSS (HR 7.25, 95% CI 2.25-23.39, p < 0.001), and OS (HR 3.9, 95% CI 1.72-8.85, p = 0.001). Similarly, late ALs had a significant negative impact on the risk of DFS (HR 5.05, 95% CI 1.97-12.93, p < 0.001), DSS (HR 10.84, 95% CI 3.44-34.18, p < 0.001), and OS (HR 4.3, 95% CI 1.94-9.53, p < 0.001). CONCLUSIONS: Late AL and CCI > 3 are the factors that may have an impact on long-term oncologic outcomes. The impact of lymph node yield on understaging was not demonstrated.

Assessment of the risk of permanent stoma after low anterior resection in rectal cancer patients.

BACKGROUND: One of the most severe complications of low anterior rectal resection is anastomotic leakage (AL). The creation of a loop ileostomy (LI) reduces the prevalence of AL requiring surgical intervention. However, up to one-third of temporary stomas may never be closed. The first aim of the study was to perform a retrospective assessment of the impact of LI on the risk of permanent stoma (PS) and symptomatic AL. The second aim of the study was to assess preoperative PS risk factors in patients with LI. METHODS: A total of 286 consecutive patients who underwent low anterior rectal resection were subjected to retrospective analysis. In 101 (35.3%) patients, diverting LI was performed due to low anastomosis, while in the remaining 185 (64.7%) patients, no ileostomy was performed. LIs were reversed after adjuvant treatment. Analyses of the effect of LI on symptomatic AL and PS were performed. Among the potential risk factors for PS, clinical factors and the values of selected peripheral blood parameters were analysed. RESULTS: PS occurred in 37.6% and 21.1% of the patients with LI and without LI, respectively (p < 0.01). Symptomatic ALs were significantly more common in patients without LI. In this group, symptomatic ALs occurred in 23.8% of patients, while in the LI group, they occurred in 5% of patients (p < 0.001). In the LI group, the only significant risk factor for PS in the multivariate analysis was preoperative plasma fibrinogen concentration (OR = 1.007, 97.5% CI 1.002-1.013, p = 0.013). CONCLUSIONS: Although protective LI may reduce the incidence of symptomatic AL, it can be related to a higher risk of PS in this group of patients. The preoperative plasma fibrinogen concentration can be a risk factor for PS in LI patients and may be a useful variable in decision-making models.

Blood serum proteins as biomarkers for prediction of survival, locoregional control and distant metastasis rate in radiotherapy and radio-chemotherapy for non-small cell lung cancer.

BACKGROUND: Several studies have documented that blood biomarkers can improve basic prognostic models in radiotherapy and radio-chemotherapy for non-small cell lung cancer. The current study evaluated the prognostic impact of six markers focusing on their utility in homogenous subsets, compared to the significance in a large heterogeneous group. METHODS: Blood samples of 337 patients who were referred for curative or palliative external beam thoracic radiotherapy for non-small cell lung cancer were collected. The concentration of osteopontin (OPN), vascular endothelial growth factor (VEGF), erythropoetin (EPO), high mobility group box 1 protein (HMGB1), insulin-like growth factor 1 (IGF-1) and platelet-derived growth factor (PDGF) in serum were measured by ELISA assay and the prognostic potential was assessed using univariable and multivariable survival models. RESULTS: Multivariable analysis revealed that out of several variables studied six dichotomized features: namely: cigarette smoking, lack of chemotherapy, palliative doses of radiotherapy, high OPN concentration, advanced T stage and high VEGF concentration had a highly significant (p < 0.005) and independent influence on overall survival in the group of 337 patients. In a subset of patients treated with curative radio-chemotherapy or radiotherapy (N = 148) tumor pathology, EPO concentration and VEGF concentration, significantly and independently influenced overall survival. In a subset of patients with squamous cell cancer (N = 206) OPN had a highly significant impact on overall survival. In contrast, in a subset of patients with nonsquamous histology (N = 131) only VEGF had a significant influence on survival. CONCLUSIONS: Blood serum proteins appear to be clinically useful prognosticators of overall survival in radio-chemotherapy and radiotherapy for non-small cell lung cancer. In unselected heterogeneous groups, dichotomized concentrations of OPN and VEGF emerged among the strongest independent prognosticators of overall survival. VEGF and EPO concentration (dichotomized) were found to be independent prognostic factors among the patients treated with curative doses of radiotherapy. The utility of OPN as a prognostic marker appeared restricted to the patients with squamous histology.

Hypofractionated stereotactic radiotherapy for large or involving critical organs cerebral arteriovenous malformations.

BACKGROUND: The treatment of large arteriovenous malformations (AVMs) or AVMs involving eloquent regions of the brain remains a challenge. For inoperable lesions, observation, volume-staged radiosurgery or hypofractionated stereotactic radiotherapy (HFSRT) are proposed. The aim of our study was to assess the safety and efficiency of HFSRT for large AVMs located in eloquent areas of the brain. MATERIALS AND METHODS: An analysis of records of 49 patients irradiated for cerebral AVMs with a mean dose of 19.9 Gy (12-28 Gy) delivered in 2-4 fractions with planned gap (at least one week) between fractions. Actuarial obliteration rates and annual bleeding hazard were calculated using Kaplan-Meier survival analysis and life tables. RESULTS: Annual bleeding hazard rates were 4.5% and 1.6% after one and two years of the follow-up, respectively. Actuarial total obliteration rates were 7%, 11%, and 21% and total response rate (total and partial obliterations) 22%, 41%, and 55% after one, two and three years of the follow-up, respectively. There was a trend towards larger total obliteration rate in patients irradiated with fraction dose ≥ 8 Gy and total dose > 21 Gy for lesions of volume ≤ 8.18 cm(3) which was not observed in case of partial obliterations. CONCLUSIONS: HFSRT results with relatively low obliteration rate but is not associated with a significant risk of permanent neurological deficits if both total and fraction doses are adjusted to size and location of the lesion. Predictive factors for total and partial obliterations can be different; this observation, however, is not firmly supported and requires further studies.

Evaluation of risk factors for postoperative complications in rectal cancer patients.

<b>Introduction:</b> The complications of surgical treatment for rectal cancer, particularly anastomotic leaks after anterior resection, are a significant clinical problem. We retrospectively analysed preoperative factors that may affect the occurrence of complications. <br><b>Meterial and Methods:</b> A total of 392 rectal cancer patients were included in a retrospective analysis. A total of 257 anterior resections (AR) and 135 abdominoperineal resections (APR) were performed. The risk factors for early postoperative complications were analysed by logistic regression and receiver operating characteristic curves. <br><b>Results:</b> The significant risk factors for severe complications (grade 3B and higher on the Clavien-Dindo scale) in the multivariate analysis were neutrophil to lymphocyte ratio > 5 (P = 0.047) in the AR group, age of the patients (P = 0.031) in the APR group, and coronary artery disease in both groups (P = 0.03, P = 0.011, respectively). There were no risk factors for anastomotic leaks in the AR group before the analysis was divided into early and late leaks. In the univariate analysis, the statistically significant risk factors for early leaks were preoperative neutrophil to lymphocyte ratio > 5 and peripheral blood platelet count, while late leaks were associated with coronary artery disease; however, in the multivariate analysis, these factors were not statistically significant. <br><b>Conclusions:</b> The risk factors for severe postoperative complications were neutrophil to lymphocyte ratio > 5, advanced age of the patients and coronary artery disease. The different risk factors for early and late anastomotic leaks after anterior resection may indicate their different aetiologies.

Randomised clinical trial on 7-days-a-week postoperative radiotherapy vs. concurrent postoperative radio-chemotherapy in locally advanced cancer of the oral cavity/oropharynx.

OBJECTIVE: To compare the efficacy and tolerance of 7-days-a-week accelerated postoperative radiotherapy (p-CAIR) vs postoperative radio-chemotherapy (p-RTCT). METHODS: Between September 2007 and October 2013, 111 patients were enrolled and randomly assigned to receive 63 Gy in 1.8 Gy fractions 7-days-a-week (n = 57, p-CAIR) or 63 Gy in 1.8 Gy fractions 5-days-a-week with concurrent cisplatin 80-100 mg per square meter of body-surface area on days 1, 22 and 43 of the radiotherapy course (p-RTCT). It represents approximately 40% of the intended trial size, that was closed prematurely due to slowing accrual. Only high-risk patients with squamous cell cancer of the oropharynx/oral cavity, considered fit for concurrent treatment were enrolled. RESULTS: The rate of locoregional control (LRC) did not differ significantly between treatment arms (p = 0.18, HR = 0.56), 5 year LRC tended, however, to favour p-RTCT (81%) vs p-CAIR (62%). There was no difference in overall survival between treatment arms (p = 0.90, HR = 1.03).The incidence and severity of acute mucosal reactions and late reactions did not differ significantly between treatment arms. Haematological toxicity of p-RTCT was, however, considerably increased compared to p-CAIR. CONCLUSION: Concurrent postoperative RTCT tended to improve locoregional control rate as compared to p-CAIR. This, however, did not transferred into improved overall survival. Postoperative RTCT was associated with a substantial increase in haematological toxicity that negatively affected treatment compliance in this arm. ADVANCES IN KNOWLEDGE: To our knowledge, this is the first trial that compares accelerated radiotherapy and radio-chemotherapy in postoperative treatment for oralcavity/oropharyngeal cancer.

Randomized clinical trial on 7-days-a-week postoperative radiotherapy for high-risk squamous cell head and neck cancer.

PURPOSE: To evaluate the normal tissue reactions and loco-regional control rates (LRC) in patients treated with 7-days-a-week postoperative continuous irradiation (p-CAIR) compared to conventionally fractionated 5-days-a-week postoperative radiotherapy (CF). MATERIALS/METHODS: Between 2001 and 2004, 279 patients with high-risk squamous cell cancer of the larynx (158 pts.) or cancer of the oral cavity/oropharynx (121 pts.) were enrolled. They were stratified according to the primary cancer site (larynx vs. others) and the treating center and randomized to receive 63 Gy in fractions of 1.8 Gy given 5-days-a-week (140 pts: CF) or 7-days-a-week (139 pts: p-CAIR). RESULTS: The acute and late toxicity was considered acceptable, although the proportion of patients with confluent mucositis was higher in p-CAIR compared to CF (60.0 vs. 33.3%). The actuarial 3-year LRC were 64 vs. 70% for CF and p-CAIR, respectively, p=0.32. A statistically significant improvement in 3-year LRC in p-CAIR arm appeared in a subset of the patients with cancer of the oropharynx/oral cavity (74% p-CAIR vs. 53% CF, p=0.02). By contrast, there was no improvement in LRC in a subset of the patients with cancer of the larynx (p=0.46). CONCLUSION: An improvement in LRC attributable to acceleration of postoperative radiotherapy appeared restricted to the patients with cancer of the oropharynx/oral cavity. In patients with cancer of the larynx acceleration of postoperative radiotherapy did not have any beneficial effect.

[Risk of distant metastases after postoperative radiation therapy for locally advanced laryngeal cancer]. / Ocena ryzyka przerzutów odleglych u chorych na raka krtani napromienianych pooperacyjnie.

PURPOSE: To evaluate the prognostic factors for the risk of distant metastases after postoperative radiotherapy for laryngeal cancer. MATERIAL AND METHODS: Medical records of 267 patients cancer treated between 1997 and 2003 were analyzed. All pts had locally advanced squamous cell laryngeal cancer treated with surgery and postoperative radiotherapy. Metastasis Free Survival was analyzed using Kaplan-Meier method. A multivariate Cox proportional hazard model and logistic regression model was used to evaluated influence of the following variables on MFS and the ultimate risk of metastases: age, sex, localization, TN stage, HGB before and at the end radiotherapy, total radiation dose, dose per fraction, overall treatment time, interval surgery-radiation time, pathological margins and positive nodes in surgical specimen. RESULTS: The crude incidence of distant metastases was 12% (33/267 pts). One year, 3-year, 5-year actuarial metastases free survival were 95%, 85% and 84% respectively. The lungs and bones were the most common sites of metastases (58% and 33% respectively), whereas metastases to liver (6%) and brain (3%) were rare. Localization of cancer (glottic vs. supraglottic) and number of positive lymph nodes at pathological staging significantly and independently affected MFS. CONCLUSIONS: Number of positive lymph nodes in pathological specimen and site of primary cancer (glottic vs. supraglottic) significantly and independently predict a risk of distant metastases in combined modality treatment for laryngeal cancer.

The prognostic value of hemoglobin concentration in postoperative radiotherapy of 835 patients with laryngeal cancer.

PURPOSE: To investigate the prognostic value of hemoglobin (Hb) concentration in patients with laryngeal cancer treated with postoperative radiotherapy (pRT). METHODS AND MATERIALS: The records of 835 patients who underwent pRT between 1980 and 2003 were reviewed. Most patients (526 of 835 patients; 63%) were in advanced clinical stages (T3-T4) and 371 of 835 patients (44%) were node positive. Total laryngectomy had been performed in 676 of 835 patients (81%). Median Hb concentration before (Hb0) and after pRT (Hb1) was the same (13.3 g/dl). However, individual differences between Hb1 and Hb0 (dHb) varied within a broad range (-8.8; 5.0 g/dl). Univariate and multivariate analyses were performed to identify variables significantly associated with locoregional control (LRC), metastases-free survival, and overall survival. RESULTS: Patients with dHb greater than 0 had significantly improved 5-year LRC compared with those with dHb of 0 or less (80% vs. 72%, p = 0.01). Conversely, when categorized, neither Hb0 nor Hb1 had a significant influence on LRC. In multivariate analysis, dHb remained a prognostic factor for LRC (p = 0.01) among the other variables, which included overall radiation treatment time and nodal status. None of the Hb-related variables significantly influenced metastases-free or overall survival. CONCLUSION: Individual change in Hb concentration during the course of pRT (dHb) rather than Hb level before or after pRT appeared as an independent prognostic factor for LRC in this set of patients.

Pre-operative hyperfractionated concurrent radiochemotherapy for locally advanced rectal cancers: a phase II clinical study.

OBJECTIVE: The study was prospectively designed as a single-arm, single-institution prospective trial of pre-operative concomitant hyperfractionated radiotherapy (HART) with co-administration of chemotherapy based on 5-fluorouracil (5FU) in patients with T2/N+ or T3/any N resectable mid-low primary rectal cancer. The aim of the study was to assess the safety and efficacy of accelerated HART with concurrent 5FU-based chemotherapy in patients with locally advanced rectal cancer. METHODS: Patients with resectable locally advanced (≥T3 or N+) rectal cancer were eligible. The patients received total dose 42 Gy in 28 fractions of 1.5 Gy, two times daily, with at least 8 h of interval, with concurrent chemotherapy: 325 mg m-2 of 5FU (bolus) on Days 1-3 and Days 16-18 (except for cN0 patients for whom only one cycle on Days 1-3 was prescribed). The primary end point included tolerance, post-operative complication rate and pathological response rate. The secondary end points included locoregional relapse-free survival, metastasis-free survival and overall survival. RESULTS: Out of 53 enrolled patients; 2 did not undergo surgery. Of the 51 patients evaluable for pathological response, there were 8 (15.6%), 20 (39.3%), 18 (35.3%) and 5 (9.8%) patients with tumour regression grade 0, 1, 2 and 3, respectively. Downstaging of the primary tumour and lymph nodes was observed in 22 (43%) and 25 (49%) patients, respectively. The primary tumour ypCR (ypT0) rate was 15% (8/51). The nodal ypCR rate for cN+ patients was 60% (21/35). The total ypCR (ypT0N0M0) rate was 11% (6/51). Toxicity included: Grade 3 diarrhoea (4/51, 7.8%), Grade 2 diarrhoea (22/51, 43.1%), Grade 2 leukopenia (7/51, 13.7%), Grade 2 neutropenia (6/51, 11.7%) and Grade 1 thrombocytopenia (3/51, 5.9%). No Grade 4 toxicity was reported. Nine patients (18%) presented with post-operative complications (during the 3 months after surgery). There were 6 locoregional relapses (11.8%) and distant metastasis occurred in 11 patients (21.6%). The 2-year cumulative locoregional relapse-free survival, metastasis-free survival and overall survival was 87%, 79% and 89%, respectively. CONCLUSION: The proposed pre-operative HART with co-administration of 5FU had acceptable toxicity profile and provided satisfactory rate of ypCR. This created rationale to initiate a Phase III randomized study that was registered under ClinicalTrials.gov Identifier: NCT01814969. Advances in knowledge: The results of this research show that responders to pre-operative radiochemotherapy have favourable outcome. Tumour regression grade as prognostic clinical feature holds the promise of better classifying patients at high risk of local and systemic recurrence and this issue may be an interesting objective for future research.

[The difference of larynx cancer stage evaluation between clinical and pathological examinations]. / Róznica w ocenie stopnia zaawansowania raka krtani w badaniu klinicznym i histopatologicznym.

PURPOSE: Comparison of stage larynx carcinoma and estimation of hazard dissemination lymph nodes in preoperative clinical and postoperative histological examination according to the TNM staging system. MATERIAL AND METHODS: The group of 100 patients with previously untreated squamous cell carcinoma of larynx was analysed. The material consisted of: 89 man and 11 women of age 39 to 78 year old (average 56). There were 51 patients with supraglottic carcinoma, 39 with glottic carcinoma, 4 with subglottic carcinoma and 6 patients had all larynx occupied. The anaplastic degree checks out brought following results: G1--17 cases, G2--54, G3--13 and 16 cases were not estimated. The diseases stage was defined preoperatively and postoperatively. The number and risk lymph nodes metastases were correlated with the diameter and topographical distribution. RESULTS: The following of clinical examination were estimated: T2--49 patients, T3--40, T4--11. On the case of postoperative histological examination following stages were found: pT2--29, pT3--34, pT4--37. According to clinical nodal staging we found: N0--70, N1--13, N2a--4, N2b--6, N2c--6, N3--1. The postoperative nodal stage verification showed: N0--64, N1--11, N2a--4, N2b--17, N2c--4, N3--0. The harmony of clinical and pathological tumor stage was found in 62 cases and 38 patients were more advanced in pathological examination. In 62 cases the agreement between clinical and pathological N stage was found. In other 38 cases we found different N stage. In group with clinical enlarge lymph nodes 91% cases were metastases. The topographical distribution of the nodal metastases is determined. The most occupied group of lymph nodal are: upper cervical nodes--44%, the mid jugular nodes--31%, submaxillary nodes--14%, low jugular nodes--6%, perilaryngeal--5%. The risk of nodal metastases with diameter to 1 cm is 9% (659 lymph nodal), to 2 cm 15% (48 nodal), above 3 cm (8 nodal) 100%. CONCLUSION: The agreement of larynx carcinoma T stage in clinical examination is considerably incompatible with postoperative pathological examination. In postoperative examination a bigger rate of higher larynx cancer stage was found. The clinical regional lymph node examination is in good agreement with postoperative histological examination. Hazard metastases to lymph nodal is increased in diameter nodal in larynx lesions.

Randomized clinical trial on continuous 7-days-a-week postoperative radiotherapy for high-risk squamous cell head-and-neck cancer: a report on acute normal tissue reactions.

BACKGROUND AND PURPOSE: To analyse acute mucosal reactions in patients treated with continuous accelerated postoperative irradiation (p-CAIR) compared to conventionally fractionated postoperative radiotherapy (p-CF). PATIENTS AND METHODS: The patients were randomly assigned to receive 63 Gy in 1.8 Gy fractions 7-days-a-week given over a period of 5 weeks (n=88), or 63 Gy in 1.8 Gy fractions given 5-days-a-week over 7 weeks (n=87). It represents 65% of an overall trial size. Acute mucosal reactions were scored using modified Dische system. Polychotomous logistic regression was used to estimate the influence of the selected variables on maximum grade of mucositis, and percent of the body weight loss during radiotherapy. RESULTS: The average maximum Dische score and percent of the patients with confluent mucositis were higher in patients treated with p-CAIR, compared to p-CF (13.3 vs. 10.8 and 54 vs. 27%). Polychotomous logistic regression analysis revealed that fractionation scheme and tumour site have significantly influenced maximum Dische score. Tumour site (laryngeal vs. other) had even stronger influence on maximum Dische score than fractionation scheme. The average residual Dische score 8 weeks after radiotherapy was higher in p-CAIR compared to p-CF (2.1 vs. 1.4), and was, most frequently, related to persistent mucosal erythema (70 vs. 57% of pts.). No severe consequential toxicity of radiotherapy was observed, so far, in the trial. CONCLUSIONS: While the incidence, intensity and duration of mucosal reactions was higher in p-CAIR than in p-CF the accelerated treatment can be considered tolerable with respect to acute toxicity. In both arms of the trial slight or moderate mucosal erythema was the most frequent acute side effect, which did not completely subside within 8 weeks after irradiation.