After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be ...implicated. The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment.
We studied how normal and mammary carcinoma cell growth and motility are affected by surgical wound fluids (WF), collected over 24 h following breast-conserving surgery in 45 patients, 20 of whom had received additional TARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed.
WF stimulated proliferation, migration, and invasion of breast cancer cell lines. The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients.
Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.
We evaluated the potential of PET/CT and (18)Ffluoromethylcholine (FCH) in the assessment of suspected recurrence of prostate cancer after treatment.
One hundred consecutive prostate cancer patients ...with a persistent increase in serum PSA (>0.1 ng/ml) after radical prostatectomy (58 cases), radiotherapy (21 cases) or hormonal therapy alone (21 cases) were investigated. After injection of 3.7-4.07 MBq/kg of FCH, both early (at <15 min) and delayed (at >60 min) PET/CT scans were performed in 43 patients, delayed PET/CT scans in 53 patients and early PET/CT scans in four patients.
Of the 100 patients, 54 (PSA 0.22-511.79 ng/ml) showed positive FCH PET/CT scans. Thirty-seven patients had bone and/or abdominal lymph node uptake, while 17 showed pelvic activity. Malignant disease was confirmed in all but one. Delayed SUV(max) of bone metastases was significantly higher (p<0.0001 by paired t test) than that measured at <15 min, whereas no differences were observed between early and delayed SUVs of malignant lymph nodes or pelvic disease. Forty-six patients (PSA 0.12-14.3 ng/ml) showed negative FCH PET/CT scans. Of the negative PET/CT scans, 89% were obtained in patients with serum PSA <4 ng/ml and 87% in patients with a Gleason score <8. In none of these cases could recurrent tumour be proven clinically during a follow-up of 6 months.
FCH PET/CT is not likely to have a significant impact on the care of prostate cancer patients with biochemical recurrence until PSA increases to above 4 ng/ml. However, in selected patients, FCH PET/CT helps to exclude distant metastases when salvage local treatment is intended.
To retrospectively assess toxicity and outcome of re-irradiation with stereotactic body radiation therapy (SBRT) in patients with recurrent or persistent non-small cell lung cancer (NSCLC), who were ...previously treated with radical radiation therapy (50-60 Gy). The secondary endpoint was to investigate whether there are dosimetric parameter predictors of severe radiation toxicity.
The analysis was conducted in 17 patients with "in-field" recurrent/persistent centrally located NSCLC, who underwent re-irradiation with SBRT. SBRT consisted of 30 Gy in 5 to 6 fractions; these prescriptions would be equivalent for the tumor to 37.5 to 40 Gy, bringing the total 2-Gy-per-fraction cumulative dose to 87 to 100 Gy, considering the primary radiation therapy treatment. Actuarial analyses and survival were calculated by the Kaplan-Meier method, and P values were estimated by the log-rank test, starting from the date of completion of SBRT. Dosimetric parameters from the subgroups with and without grade ≥3 pulmonary toxicity were compared using a 2-tailed Student t test.
The median follow-up was 18 months (range, 4-57 months). Only 2 patients had local failure, corresponding to a local control rate of 86% at 1 year. The Kaplan-Meier estimates of overall survival (OS) rates at 1 and 2 years were 59% and 29%, respectively; the median OS was 19 months. Four patients (23%) experienced grade 3 radiation pneumonitis, and 1 patient developed fatal pneumonitis. One patient died of fatal hemoptysis 2 months after the completion of SBRT. Unexpectedly, heart maximum dose, D5 (minimum dose to at least 5% of the heart volume), and D10 were correlated with risk of radiation pneumonitis (P<.05).
Re-irradiation with SBRT for recurrent/persistent centrally located NSCLC achieves excellent results in terms of local control. However, the high rate of severe toxicity reported in our study is of concern.
Abstract Purpose We have previously shown the feasibility of delivering high doses of radiotherapy in malignant pleural mesothelioma (MPM) patients who underwent radical pleurectomy/decortication ...(P/D) or surgical biopsy. In this report, we present the long-term results of MPM patients treated with radical P/D followed by high doses of radiotherapy. Methods and materials Twenty consecutive MPM patients were enrolled in this prospective study and underwent radical P/D followed by high dose radiotherapy. The clinical target volume was defined as the entire hemithorax excluding the intact lung. The dose prescribed was 50 Gy in 25 fractions. Any FDG-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. Nineteen patients received cisplatin/pemetrexed chemotherapy. Kaplan–Meier analysis was used to calculate rates of overall survival (OS), progression-free survival (PFS), and loco-regional control (LRC). Results The median follow-up was of 27 months. The median OS and PFS were 33 and 29 months, respectively. The median LRC was not reached. The Kaplan–Meier estimates of OS at 2 and 3 years were 70% and 49%, respectively. The estimates of PFS at 2 and 3 years were 65% and 46%, respectively. The estimates of LRC at 2 and 3 years were 68% and 59%, respectively. The predominant pattern of failure was distant: 7 patients developed distant metastases as the first site of relapse, whereas only 3 patients experienced an isolated loco-regional recurrence. No fatal toxicity was reported. Five Grades 2–3 pneumonitis were documented. Conclusions High dose radiation therapy following radical P/D led to excellent loco-regional control and survival results in MPM patients. A median OS of 33 months and a 3-year OS rate of 49% are among the best observed in recent studies, supporting the idea that this approach represents a concrete therapeutic option for malignant pleural mesothelioma.
Abstract Purpose To extend the application of current radiation therapy (RT) based normal tissue complication probability (NTCP) models of radiation-induced fibrosis (RIF) of the breast to include ...the effects of fractionation, inhomogeneous dose, incomplete recovery, and time after the end of radiotherapy in partial breast irradiation (PBI). Materials and methods An NTCP Lyman model with biologically effective uniform dose (BEUD) with and without a correction for the effect of incomplete repair was used. The time to occurrence of RIF was also taken into account. The radiobiological parameters were determined by fitting incidences of moderate/severe RIF in published randomized studies on RT of the breast. The NTCP model was used to calculate the risk of toxicity in 35 patients treated with intensity modulated, non-accelerated PBI and the result was compared with observed incidence of RIF. Results With α / β fixed at 3Gy the parameters of the model without correction for incomplete repair extracted from fitting were: 50% complication probability biologically effective dose BEUD50 = 107.2 Gy (95%CI = 95.9–118.6 Gy), volume parameter n = 0.06 (95%CI = 0–0.23), and slope of dose response m = 0.22, (95%CI = 0.20–0.23). After including the correction for incomplete repair with repair halftime for subcutaneous tissue of τ = 4.4 h we obtained BEUD50 = 105.8 Gy (95%CI = 96.9–114.6Gy), n = 0.15 (95%CI = 0–0.33), m = 0.22 (95%CI = 0.20–0.23). Average NTCP predicted by these models, 4.3% and 2.0% respectively, offered a good agreement with RIF incidence in our patients, 5.7%, after an average follow-up of 12 months. Conclusion The NTCP models of RIF, incorporating the effects of fractionation, volume effect, and latency of toxicity look promising to model PBI. Clinical validation from a prospective PBI treatment study is under development and will help test this preliminary result.
To assess the locoregional failure in patients with Stage I-II breast cancer treated with radical mastectomy and to evaluate whether a subset of these patients might be at sufficiently high risk of ...locoregional recurrence (LRR) to benefit from postmastectomy irradiation (PMRT).
Stage I-II breast cancer patients (n = 150) treated with radical mastectomy without adjuvant irradiation between 1999 and 2005 were analyzed. The pattern of LRR was reported. Kaplan-Meier analysis was used to calculate rates of LRR, and Cox proportional hazards methods were used to evaluate potential risk factors.
Median follow-up was 75 months. Mean patient age was 56 years. One-hundred forty-three (95%) patients received adjuvant systemic therapy: 85 (57%) hormonal therapy alone, 14 (9%) chemotherapy alone, and 44 (29%) both chemotherapy and hormonal therapy. Statistically significant factors associated with increased risk of LRR were premenopausal status (p = 0.004), estrogen receptor negative cancer (p = 0.02), pathologic grade 3 (p = 0.02), and lymphovascular invasion (p = 0.001). T and N stage were not associated with increased risk of regional recurrence. The 5-year LRR rate for patients with zero or one, two, three, and four risk factors was 1%, 10.3%, 24.2%, and 75%, respectively.
A subset of patients with early-stage breast cancer is at high risk of LRR, and therefore PMRT might be beneficial.
This study aimed to assess the safety of high doses of radiation delivered with tomotherapy to the intact lung after radical pleurectomy/decortication or biopsy for malignant pleural mesothelioma ...(MPM).
Twenty-eight patients were enrolled in this prospective study and underwent adjuvant or definitive tomotherapy after radical pleurectomy/decortication (n = 20) or pleural biopsy (n = 8) for MPM. The dose prescribed to the planning target volume, defined as the entire hemithorax, including chest-wall incisions and drain sites and excluding the intact lung, was 50 Gy delivered in 25 fractions. All patients underwent fluorodeoxyglucose-positron emission tomography for staging after surgery. Any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease were given a simultaneous boost of radiotherapy to 60 Gy. Specific lung dosimetric parameters were reported. Toxicity was graded using the modified Common Toxicity Criteria version 3.0.
The median follow-up was of 19 months (range, 6–29 months). Five patients (17.8%) experienced severe respiratory symptoms corresponding to grade 2 pneumonitis in three cases, and grade 3 pneumonitis in two cases. No fatal respiratory toxicity was reported. Controlateral lung V5 was strongly correlated with the risk of pneumonitis. Patients who developed grade 2 and 3 pneumonitis had a higher controlateral lung V5 (mean V5=32%) than those without pneumonitis (mean V5=17%) (p=0.002). Other two grade 3 toxicities were registered: one severe pain to the chest wall, and one severe thrombocytopenia.
Tomotherapy allows the safe delivery of high dose of radiation to the hemithorax of MPM patients with intact lung.
Radiotherapy (RT) has a remarkable success rate in the treatment of patients with glottic carcinoma. The objectives of the current study were to assess the results in a group of consecutive patients ...with comparable characteristics who were treated with RT (6-megavolt photon linear accelerator) and to determine the prognostic factors that may influence local control in patients with early-stage glottic carcinoma. The impact on local control of tobacco smoking and second primary malignancies also was investigated.
Four hundred ten patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 1986 and 2001 were analyzed retrospectively with regard to local control and overall survival. Potential prognostic factors for local control were evaluated with univariate and multivariate models. The impact of technologic advances also was evaluated.
The 5-year and 10-year overall survival rates were 83% and 63.5%, respectively. The overall 10-year local control rate for patients with T1-T2 glottic carcinoma was 89%. The median time to recurrence was 7 months. Univariate analysis showed that tumor category, tumor size, macroscopic appearance of the lesion, RT fraction size, persistent edema, year of RT treatment, unchanged dysphonia, and surgical option all had a significant influence on local control; whereas multivariate analysis showed that only persistent dysphonia and year of RT treatment were significantly associated with increased local control. A 22.2% rate of second primary malignancies was reported: second primary tumors were the major cause of death in the patients studied. Only 2 patients died of laryngeal carcinoma; 304 patients were alive with their disease in complete remission, 1 patient was alive with recurrent laryngeal carcinoma after undergoing salvage surgery, and 103 patients died of either intercurrent disease or a second primary tumor.
The use of a 6-megavolt photon linear accelerator achieved a high rate of local control in patients with T1-T2 glottic carcinoma. Dysphonia and the year of RT treatment were the most important prognostically significant factors for patient outcome. The occurrence of a second primary tumor was the most frequent cause of death, especially among patients who did not stop smoking after a diagnosis of glottic carcinoma.
The present prospective study seeks to evaluate overall and disease free survival, response and organ preservation rate, and toxicity of an intensive chemotherapy regimen (CT) followed by ...unconventional radiotherapy (RT) in patients with locally advanced operable head and neck cancer. Between January 1998 and December 2006 (June 2005), 115 patients with locally advanced, operable head and neck cancer were evaluated. A total of 333 cycles of neoadjuvant CT (cisplatin–5FU, days 1, 14, 28) followed by hyperfractionated/accelerated radiotherapy were given to 108 patients. A total of 108 patients were evaluable and received the planned CT–RT treatment. Two months after the end of RT, 97.2% of patients had a clinical complete remission of the primary and 67.5% of the neck node site. The overall survival was 55% and cause-specific survival was 73% at 5 years. Of the 33 relapsed patients, 12 recurred only at the primary site and 10 patients had distant metastases. The overall organ preservation rate was 73.5%. The chemotherapy regimen reported an overall cardiotoxicity from 5FU in 14% of patients, with severe toxicity in 3%. The radiotherapy schedule developed 84% of Grade 3–4 mucositis in the observed patients. The accelerated CT–RT regimen is able to achieve a high rate of larynx preservation, a good tolerability, and a satisfactory cause-specific overall survival.
The current standard local treatment for nonresectable pancreatic carcinoma is radiotherapy (RT) with concurrent 5-fluorouracil (5-FU); however, the optimal schedule for 5-FU administration has not ...been fully established. In this study, we report on our experience with the combination of RT and continuous infusion 5-FU in a group of patients with locally nonresectable pancreatic carcinoma.
Forty-two patients with adenocarcinoma of the pancreas were enrolled in a prospective clinical trial. RT was delivered using a four-field technique to a total dose of 59.4 Gy in 33 fractions. 5-FU was given through a central venous catheter at a dose of 300 mg/m(2)/day, 7 d/wk, throughout the entire course of RT.
All patients completed the RT as planned, and 33 (78%) completed the full regimen of chemotherapy. Ten patients (23%) had a partial response, and 32 (77%) had stable disease. Subjective response, defined as the disappearance of symptoms observed at diagnosis, was also evaluated. Two patients (6%) had a complete, and 24 (75%) a partial, remission of symptoms. The median time to progression was 6.2 months, and the median survival time was 9.1 months.
In terms of local control, the results of our study, with RT and protracted 5-FU infusion, compare well with those of other studies using RT and bolus 5-FU. The control of distant metastatic disease remains an open issue. However, the palliation of symptoms achieved by our treatment schedule in patients with a very poor prognosis and severe symptoms may be regarded as a positive result.
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