Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II–III trial

BackgroundPlatinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3–4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy.Materials and methodsPatients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level).Results414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56–0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF.ConclusionsIC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy.Clinical Trial NumberNCT01086826, www.clinicaltrials.gov     

Complications after breast cancer surgery in patients treated with concomitant preoperative chemoradiation: a case–control analysis

Background Nearly 60% of breast cancer cases in Mexico are in advanced stages. At our institution, concomitant preoperative chemoradiation is being used in patients with advanced breast cancer. In the present study, we evaluated the postoperative wound complications and risk factors associated. Patients and methods The study included breast cancer patients from January 2000 to December 2002 treated with concomitant preoperative chemoradiation and mastectomy. Wound complication rates were described along with a nested case–control analysis to evaluate risk factors for postoperative major wound complications. Results We evaluated 360 patients treated with preoperative chemoradiation. About 165 patients (45.8%) developed a wound complication (infection and/or flap necrosis); 60 (16.6%) patients had a surgical site infection (SSI) and 61 (16.9%), flap necrosis; 44 (12.2%) developed both complications, and 25 (6.9%) experienced late dehiscence after suture removal. Epidermolysis, seroma, and hematoma ocurred in 93 (25.8%), 80 (22.2%), and 12 patients (3.3%), respectively. Case–control analysis was conducted in 335 patients. After logistic regression analysis, the sole variable found associated with SSI and/or flap necrosis was epidermolysis (OR = 8.81, 95% CI = 4.52–17.18). Although not significant and of lesser magnitude, adjusted risk estimates of overweight, age >50 years, and type of mastectomy showed the same trend. Conclusions Postoperative wound complications were not different from those observed in non-radiated patients, but its rate was higher. Epidermolysis was associated with SSI and/or flap necrosis. Careful surgical technique should be encouraged.     

Phase II study of preoperative radiotherapy and concomitant weekly intravenous oxaliplatin combined with oral capecitabine for stages II–III rectal cancer

Introduction

A prospective phase II study was conducted to assess the clinical activity and tolerability of oxaliplatin, capecitabine, and radiotherapy (RT) for neoadjuvant therapy of stages II?CIII rectal cancer.

Materials and methods

Patients with histologically confirmed stages II?CIII (T3?CT4 and/or N+) resectable rectal adenocarcinoma were eligible. Capecitabine was administered at 825?mg/m² twice daily for 5?days/week and oxaliplatin at 50?mg/m² on day 1 weekly for 5?weeks starting the first day of RT (before RT). RT consisted of a total dose of 45?Gy delivered in 25 fractions of 1.8?Gy, 5?days per week, for 5?weeks.

Results

A total of 46 patients were included (35 male, 10 female, median age 62?years). TNM Stage was T3 in 43 patients and T4 in 2. Twenty-eight patients had suspected nodal involvement. The intended chemoradiation treatment was completed in 94?% patients. Grade 3/4 toxicity included lymphocytopenia (6 patients), diarrhea (4 patients), emesis (2 patients), asthenia (3 patients), anorexia (1 patient), and hepatic toxicity (1 patient). Grade 1 neurotoxicity occurred in 18 patients, Grade 2 neurotoxicity in 3, and Grade 1 palmoplantar erythrodysesthesia in 2. Forty-two patients underwent surgery (complete resection 95?%, sphincter-saving operation 55?%). The overall pathologic response rate was 83?%, with a pathologic complete response (pCR) rate of 11.9?% (95?% CI 4.0?C25.6).

Conclusions

The pCR rate observed with oxaliplatin plus capecitabine and RT did not reach the pre-specified criteria of efficacy in this trial, which is in line with recent results of randomized phase III trials.     

Radiothérapie mammaire locorégionale et traitement concomitant par trastuzumab

The overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2) is observed in 15 % of breast cancers and associated with poor prognosis in terms of overall survival. Trastuzumab is an anti-HER2 targeted therapy, leading to a specific inhibition of the molecular mechanisms triggered by this receptor. In an adjuvant setting, trastuzumab and radiotherapy have each proved their oncologic efficacy in the management of the breast tumours presenting this molecular profile. However, both treatments expose to an increased risk of toxicities, particularly cardiovascular ones. Moreover, the radiosensitizing effect of trastuzumab has been proved in vitro and in vivo. Hence, in clinical practice, the benefit/risk ratio of a concurrent treatment remains to be defined.This literature review has for purposes to describe the rationale making conceivable the administration of trastuzumab concurrently with locoregional breast radiotherapy, and to remind the results of the clinical studies having assessed this therapeutic association.     

Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I–II study

BackgroundThe prognosis of pancreaticobiliary tumors is poor. The aim was to assess the feasibility of radiotherapy (RT) and concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma.Patients and methodsTwenty-two patients with locally advanced pancreatic (n = 17) or biliary tract cancer (n = 5) were included. They received two cycles of gemcitabine/oxaliplatin followed by 5 weeks of RT in combination with a weekly fixed dose gemcitabine and an escalating dose of oxaliplatin from 40 up to 70 mg/m². National Cancer Institute—Common Toxicity Criteria 3.0 was used to score weekly the treatment-related toxicity.ResultsThe patients treated at a dose of 40 mg/m² of oxaliplatin had no dose-limiting toxicity. At 50 mg/m², two patients developed grade 4 thrombocytopenia. Nine patients received 60 mg/m², one developed grade 4 thrombocytopenia. Grade 4 thrombocytopenia in two patients and grade 3 diarrhea in one patient were observed with 70 mg/m². Median time to progression was 8 months and median overall survival was 17 months.ConclusionsRT in combination with gemcitabine and oxaliplatin is feasible in patients with locally advanced pancreaticobiliary cancer. The reported time to progression underlines the potential activity of this regimen. The dose of 60 mg/m² of oxaliplatin can be considered as the recommended dose.     

Node-negative T1-T2 anal cancer: Radiotherapy alone or concomitant chemoradiotherapy?

Purpose

To evaluate the influence of concomitant chemotherapy on loco-regional control (LRC) and cancer-specific survival (CSS) in patients with T1-T2 N0 M0 anal cancer treated conservatively by primary radiotherapy (RT).

Materials and methods

Between 1976 and 2008, 146 patients with T1 (n = 29) or T2 (n = 117) N0 M0 anal cancer were treated curatively by RT alone (n = 71) or by combined chemoradiotherapy (CRT) (n = 75) consisting of mitomycin C ± 5-fluorouracil. Univariate and multivariate analyses were performed to assess patient-, tumor- and treatment-related factors influencing LRC and CSS.

Results

With a median follow-up of 62.5 months (interquartilerange, 26-113 months), 122 (84%) patients were locally controlled. The five-year actuarial LRC, CSS and overall survival for the population were 81.4% ± 3.6%, 91.9% ± 2.6%, and 75.4% ± 3.9%, respectively. The five-year LRC and CSS for patients treated with RT alone and with CRT were 75.5% ± 6.0% vs. 86.8% ± 4.1% (p = 0.155) and 88.5% ± 4.5% vs. 94.9% ± 2.9% (p = 0.161), respectively. In the multivariate analysis, no clinical or therapeutic factors were found to significantly influence the LRC and CSS, while the addition of chemotherapy was of borderline significance (p = 0.065 and p = 0.107, respectively).

Conclusions

In the management of node negative T1-T2 anal cancer, LRC and CSS tend to be superior in patients treated by combined CRT, even though the difference was not significant. Randomized studies are warranted to assess definitively the role of combined treatment in early-stage anal carcinoma.     

Pathological lymph node involvement at surgery is a significant predictive factor of recurrence in locally advanced breast cancer treated with concomitant epirubicin–docetaxel neoadjuvant chemotherapy: a cohort study

Background  Neoadjuvant chemotherapy (NAC) is the standard therapy for locally advanced breast cancer. Recently, several studies have revealed that clearance of axillary lymph node involvement is an independent factor for survival irrespective of the response of the primary lesion. However, in daily practice, it is difficult to fully examine every lymph node that has been surgically sampled, in view of pathology laboratory workload and cost. Therefore, in the present study, we adopted the more clinically relevant categorization of evaluating postoperative axillary lymph node status and retrospectively studied its significance in predicting patients’ survival. Methods  The study cohort consisted of 35 locally advanced breast cancer patients who are treated with concomitant epirubicin–docetaxel. The clinicopathological factors used for analysis were as follows: ERα, PgR, p53, HER2, pathological response (in the primary tumor), and axillary lymph node status at surgery. With regard to axillary lymph node status, we categorized patients into two groups: those with pathological lymph node involvement at surgery (pLNI) and those without. Using multivariate analysis, we evaluated the significance of these factors in predicting disease-free survival after surgery. Results  The median follow-up period was 23.4 months (range 4.3–45.4). Multivariate analysis showed significantly reduced disease-free survival associated with pLNI (P = 0.005). Conclusions  pLNI is an excellent prognostic factor for locally advanced breast cancer patients treated with concomitant epirubicin–docetaxel. Use of our criteria may enable large numbers of oncologists to participate in new studies of high-risk cohorts who are refractory to NAC.     

Did the addition of concomitant chemotherapy to radiotherapy improve outcomes in hypopharyngeal cancer? A population-based study

BackgroundFor oncologists and for patients, no site-specific clinical trial evidence has emerged for the use of concurrent chemotherapy with radiotherapy (ccrt) over radiotherapy (rt) alone for cancer of the hypopharynx (hpc) or for other human papilloma virus–negative head-and-neck cancers.MethodsThis retrospective population-based cohort study using administrative data compared treatments over time (1990–2000 vs. 2000–2010), treatment outcomes, and outcomes over time in 1333 cases of hpc diagnosed in Ontario between January 1990 and December 2010.ResultsThe incidence of hpc is declining; the use of ccrt that began in 2001 is increasing; and the 3-year overall survival for all patients remains poor at 34.6%. No difference in overall survival was observed in a comparison of patients treated in the decade before ccrt and of patients treated in the decade during the uptake of ccrt.ConclusionsThe addition of ccrt to the armamentarium of treatment options for oncologists treating head-and-neck patients did not improve outcomes for hpc at the population level.     

Muscle-invasive bladder cancer in elderly-unfit patients with concomitant illness: can a curative radiation therapy be delivered?

AIMS AND BACKGROUND: There is no standard treatment for elderly-unfit patients with muscle-invasive bladder cancer. Pelvic irradiation alone is an usual approach in this instance, and some reports have demonstrated that curative radiotherapy is feasible in elderly patients. To our knowledge, no data exist about the feasibility of a curative treatment in elderly patients with concomitant illness and a Charlson Comorbidity Index (an index of comorbidity that includes age) greater than 2. The main purpose of the present study was to establish the feasibility of irradiation in a cohort of elderly patients in poor general condition. METHODS: The records of 45 elderly-unfit patients (median age, 75 years; range, 70-85), with a comorbid Charlson score >2, treated with curative dose, planned continuous-course, external beam radiotherapy for muscle-invasive bladder cancer were reviewed. The patients were treated to a median total dose of 60 Gy (range, 56-64), with an average fractional dose of 190 +/- 10 cGy using megavoltage (6-15 MV). All patients were treated with radiation fields encompassing the bladder and grossly involved lymph nodes with a radiographic margin of at least 1.5 cm. RESULTS: No treatment-related mortality and clinically insignificant acute morbidity was recorded. No patient was hospitalized during or after the irradiation because of gastrointestinal or urogenital side effects. In one patient a week rest from therapy was necessary due a febrile status. Median survival was 21.5 months; overall 3- and 5-year survival was 36% and 19.5%, respectively. CONCLUSIONS: Elderly-unfit patients with comorbidities and >70 years of age can be submitted to radical pelvic irradiation. The results observed in this retrospective analysis have encouraged us to use non-palliative radiotherapy doses in these patients with muscle-invasive bladder cancer.     

Birt–Hogg–Dubé syndrome and the skin

Birt-Hogg-Dubé syndrome (MIM #135150) is characterized by the development of benign skin tumours called fibrofolliculomas, pulmonary cysts that may lead to pneumothorax and a high risk of developing kidney cancer. BHD is caused by mutations affecting the highly conserved protein folliculin (FLCN), which probably has a role in intracellular transport. Most of the research effort directed towards BHD has focused on understanding how loss of FLCN causes kidney cancer. The cutaneous manifestations have received comparatively little attention. Although understandable, it is unfortunate, as the fibrofolliculomas are highly accessible and thus potentially are an excellent system for trying to understand the basic pathobiology of BHD. Also, patients can be very much burdened by the cosmetic consequences of having hundreds of facial skin tumours. Our lack of insight into what drives fibrofolliculoma growth translates into a very limited therapeutic arsenal. Thus, paying attention to fibrofolliculomas has both basic science and practical benefits. In this review, we will discuss the state of the art regarding our understanding of fibrofolliculoma pathogenesis and indicate future directions for research.     

HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy – a phase III study

Background and purpose

The aim of this randomised trial was to investigate whether hyperthermia (HT) combined with interstitial brachytherapy (ISBT) has any influence on local control (LC), disease-free survival (DFS), or acute and late side effects in patients with advanced cervical cancer.

Materials and methods

After radiochemotherapy, consecutive patients with cervical cancer (FIGO stage II–III) were randomly assigned to two treatment groups, either ISBT alone or ISBT combined with interstitial hyperthermia (ISHT). A total of 205 patients were included in the statistical analysis. Once a week, HT, at a temperature above 42.5 °C, was administered for 45 min before and during the HDR BT.

Results

The median follow-up time was 45 months (range 3–72 months). An effect of hyperthermia was not detected for disease-free survival (DFS) (log-rank test: p = 0.178) or for local control (LC) (p = 0.991). According to Cox’s analysis, HT did not significantly influence failure or interactions with potential prognostic factors for LC or DFS. Statistical differences were not observed for the distribution of early and late complications between the HT and non HT groups.

Conclusions

ISHT is well-tolerated and does not affect treatment-related early or late complications. Improvements in DFS and LC were not observed following the addition of ISHT to ISBT.     

Matrix Metalloproteinase-9 Expression in the Normal Mucosa–Adenoma–Dysplasia–Adenocarcinoma Sequence of the Colon

It has been proposed that matrix metalloproteinases (MMPs) play a role in tumor invasion. We determined protein expression of matrix metalloproteinase-9 (MMP-9) in colorectal cancer (CRC), corresponding normal mucosa and colorectal adenomas. For confirmation of immunohistochemical results MMP-9 TaqMan RT-PCR analysis was performed. Expression of MMP-9 was determined on paraffin embedded biopsy sections by immunohistochemistry in 31 CRC patients (from cancer tissue and corresponding normal mucosa) and in 30 patients with adenoma (nine adenomas with high grade of dysplasia). MMP-9 immunostaining was determined semi-quantitatively. For Taqman RT-PCR analyses normal mucosa (n = 5), adenoma without (n = 6) and with high grade dysplasia (n = 7) and CRC (n = 10) were investigated. Statistical analysis with ANOVA, LSD test and correlation analysis were performed. P value of <0.05 was considered significant. The MMP-9 expression in CRC was significantly higher compared to adenomas or the normal mucosa (P = 0.001). Significantly higher expression of MMP-9 has been observed in adenomas with high grade dysplasia compared to other adenomas or normal colon (P < 0.001). Diffuse strong MMP-9 expression was present in tumor as well as in stromal cells. In adenoma samples, dysplastic epithelial cells showed moderate intensive cytoplasmic MMP-9 expression, with a clear-cut differentiation between dysplastic and non-dysplastic areas. Staining intensity correlated with the grade of CRC. We demonstrate a significantly higher expression of MMP-9 in adenoma with high grade dysplasia-CRC sequence as compared to normal tissue. The over-expression of MMP-9 strongly suggests its association with colorectal carcinogenesis.     

The role of amifostine on late normal tissue damage induced by pelvic radiotherapy with concomitant gemcitabine: an in vivo study

In this in vivo study, we aimed to assess the radioprotective effect of amifostine on late normal tissue damage induced by gemcitabine concomitant with pelvic radiotherapy by histopathological and quantitative methods. Fifty-six male Wistar albino rats were randomly divided into seven experimental groups as follows: (I) gemcitabine, (II) radiation + gemcitabine, (III) radiation + gemcitabine + amifostine, (IV) radiation + amifostine, (V) sham radiation, (VI) amifostine, (VII) radiation. Irradiation was given to pelvic region with a dose of 25 Gy in 5 fractions. Amifostine was given for 30 min; gemcitabine was administered 24 h before the first fraction of radiotherapy. All animals were killed at the end of 4th month. Pathological examination was performed and the tissue collagen content was measured in bladder and rectal tissues. Fifty-one animals that were alive at the end of the follow-up period were analyzed. Thirty-five animals (68.6%) revealed grades I–III late effect in histopathological examination. We observed grade III colitis in 1 animal (radiation + gemcitabine) and bladder fibrosis in 4 animals (radiation and radiation + gemcitabine groups). There was no significant difference between any groups for bladder cystitis and fibrosis by Kruskal–Wallis method. Colitis was seen significantly lower in the radiation + gemcitabine + amifostine group (P = 0.0005). The collagen contents in the bladder and rectum of radiation and radiation + gemcitabine groups were markedly increased as compared to the sham group. This effect was reversed in the groups which received amifostine in addition to radiation and radiation + gemcitabine groups, but this difference was not significant. This study demonstrated that amifostine may have a beneficial effect in limiting rectal colitis from the radiosensitizing effect of gemcitabine.     

Pancreatic cancer–Endosonography

EUS is the most sensitive imaging procedure for the detection of small solid pancreatic masses and is accurate in determining vascular invasion of the portal venous system. Even compared to the new CT-techniques EUS provides excellent results in preoperative staging of solid pancreatic tumors. Compared to helical CT-techniques EUS is less accurate in detecting tumor involvement of superior mesenteric artery. EUS staging and EUS-guided FNA can be performed in a single-step procedure, to establish the diagnosis of cancer. There is no known negative impact of tumor cell seeding due to EUS-FNA. Without FNA EUS and additional methods are not able to reliably distinguish between inflammatory and malignant masses.     

C–X–C ligand 10 and C–X–C receptor 3 status can predict tamoxifen treatment response in breast cancer patients

To investigate the expression levels of CXCL10 and CXCR3 in tumors from breast cancer patients randomized to adjuvant tamoxifen treatment or no endocrine treatment, in order to further study the connection to prognosis and prediction of tamoxifen treatment outcome. Immunohistochemistry on tissue microarrays from 912 breast cancer patients randomized to tamoxifen or no endocrine treatment. CXCR3 status was found to be a prognostic tool in predicting distant recurrence, as well as reduced breast cancer-specific survival. In patients with estrogen receptor (ER)-positive tumors, tumors with strong CXCL10 levels had improved effect of tamoxifen treatment in terms of local recurrence-free survival [risk ratio (RR) 0.46 (95 % CI 0.25–0.85, P = 0.01)] compared with patients with tumors expressing weak CXCL10 expression. Further, patients with ER-positive tumors with strong CXCR3 expression had an improved effect of tamoxifen in terms of breast cancer-specific survival [RR 0.34 (95 % CI 0.19–0.62, P < 0.001)] compared with the group with weak CXCR3 levels [RR 1.33 (95 % CI 0.38–4.79, P = 0.65)]. We show here for the first time that CXCL10 and CXCR3 expression are both predictors of favorable outcome in patients treated with tamoxifen.     

Pancreatic cancer–Pathology

IntroductionsPancreatic ductal adenocarcinoma (frequently simply being referred to as “pancreatic cancer”) represents the most frequent neoplasm of the pancreas, accounting for 85% to 90% of all pancreatic tumors [1, 2]. According to the definition of the World Health Organization [1], it “prob-ably arises from and is phenotypically similar to pancre