Khashayar Fakhrian

Multicenter, Phase III Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology: Follow-Up Analysis of the Survival Data 6 Years After Cessation of Randomization

Purpose. In 2010, we reported that selenium (Se) supplementation during radiation therapy (RT) is effective for increasing blood Se levels in Se-deficient cervical and uterine cancer patients, and reduced the number of episodes and severity of RT-induced diarrhea. In the current study, we examine whether of Se supplementation during adjuvant RT affects long-term survival of these patients. Patients and Methods. Former patients were identified and questioned with respect to their health and well-being. Results. A total of 81 patients were randomized in the initial supplementation study, 39 of whom received Se (selenium group, SeG) and 42 of whom served as controls (control group, CG). When former patients were reidentified after a median follow-up of 70 months (range = 0-136), the actuarial 10-year disease-free survival rate in the SeG was 80.1% compared to 83.2% in the CG (P = .65), and the actuarial 10-year overall survival rate of patients in the SeG was 55.3% compared to 42.7% in the CG (P = .09). Conclusions. Our extended follow-up analysis demonstrates that Se supplementation had no influence on the effectiveness of the anticancer irradiation therapy and did not negatively affect patients’ long-term survival. In view of its positive effects on RT-induced diarrhea, we consider Se supplementation to be a meaningful and beneficial adjuvant treatment in Se-deficient cervical and uterine cancer patients while undergoing pelvic radiation therapy.

Effect of Irradiation on Tissue Penetration Depth of Doxorubicin after Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a Novel Ex-Vivo Model.

Background: This study was performed to assess the impact of irradiation on the tissue penetration depth of doxorubicin delivered during Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC). Methods: Fresh post mortem swine peritoneum was cut into 10 proportional sections. Except for 2 control samples, all received irradiation with 1, 2, 7 and 14 Gy, respectively. Four samples received PIPAC 15 minutes after irradiation and 4 other after 24 hours. Doxorubicin was aerosolized in an ex-vivo PIPAC model at 12 mmHg/36°C. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. Results: Doxorubicin penetration after PIPAC (15 minutes after irradiation) was 476 ± 74 µm for the control sample, 450 ± 45µm after 1 Gy (p > 0.05), 438 ± 29 µm after 2 Gy (p > 0.05), 396 ± 32 µm after 7 Gy (p = 0.005) and 284 ± 57 after 14 Gy irradiation (p < 0.001). The doxorubicin penetration after PIPAC (24 hours after irradiation) was 428 ± 77 µm for the control sample, 393 ± 41 µm after 1 Gy (p > 0.05), 379 ± 56 µm after 2 Gy (p > 0.05), 352 ± 53 µm after 7 Gy (p = 0.008) and 345 ± 53 after 14 Gy irradiation (p = 0.001). Conclusions: Higher (fractional) radiation dose might reduce the tissue penetration depth of doxorubicin in our ex-vivo model. However, irradiation with lower (fractional) radiation dose does not affect the tissue penetration negatively. Further studies are warranted to investigate if irradiation can be used safely as chemopotenting agent for patients with peritoneal metastases treated with PIPAC.

Survival and symptom relief after palliative radiotherapy for esophageal cancer

Purpose: The aim of this study was to assess the 6-months dysphagia-free survival, improvement in swallowing function, complication rate, and overall survival in patients with incurable esophageal cancer treated with palliative radiotherapy. Methods: We retrospectively reviewed data from 139 patients (median age 72 years) with advanced/recurrent incurable esophageal cancer, who were referred to 3 German radiation oncology centers for palliative radiotherapy between 1994 and 2014. Radiotherapy consisted of external beam radiotherapy (EBRT) with 30 - 40.5 Gy/2.5 - 3 Gy per fraction, brachytherapy alone (BT) with 15 - 25 Gy/5 - 7Gy per fraction/weekly and EBRT + BT (30 - 40.5 Gy plus 10 - 14 Gy with BT) in 65, 46, and 28 patients, respectively. Dysphagia-free survival (Dy-PFS) was defined as the time to worsening of dysphagia for at least one point, a new loco-regional failure or death of any cause. Results: Median follow-up time was 6 months (range 1-6 months). Subjective symptom relief was achieved in 72 % of patients with median response duration of 5 months. The 1-year survival rate was 30%. The 6-months Dy-PFS time for the whole group was 73 ± 4%. The 6-months Dy-PFS was 90 ± 4% after EBRT, 92 ± 5% after EBRT + BT and 37 ± 7% after BT, respectively (p<0.001). Five patients lived for more than 2 years, all of them were treated with EBRT ± BT. Ulceration, fistula and stricture developed in 3, 6 and 7 patients, respectively. Conclusions: Radiotherapy leads to symptom improvement in the majority of patients with advanced incurable esophageal cancer. The present results favor EBRT ± BT over BT alone. Due to the retrospective nature of this study, imbalances in baseline characteristics might have contributed to this finding, and further trials appear necessary.

Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU

PurposeThe purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution.MethodsWe retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988–2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988–2006 with 39.6–40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003–2010 with 44–45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, < 10 % residual tumor), grade 2 (10–50 % residual tumor), and grade 3 (> 50 % residual tumor).ResultsMedian follow-up time from the start of N-RCT was 100 months (range 2–213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 ± 5 %. In the multivariate analysis, worse ECOG performance status (p < 0.001), weight loss > 10 % before the start of the N-RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p < 0.001) were significantly associated with a poor OS. PCR and pSTR rates for group 1 were 36 % and 18 % compared to 53 % and 22 % for group 2 (p = 0.011). There was a tendency for a better outcome in group 2 patients without statistical significance. The 5-year OS, disease-free survival and recurrent-free survival were 36 ± 7 %, 35 ± 6, and 36 ± 7 % for group 1 and 55 ± 7, 49 ± 7, and 53 ± 7 in group 2 (p = 0.117, p = 0.124, and p = 0.087). There was no significant difference between the two groups considering the postoperative morbidity and mortality.ConclusionHigher radiation doses and more use of simultaneous cisplatin lead to higher pathologic response rates to N-RCT and may be associated with better survival outcomes. Prospective controlled trials are needed to assess the true value of intensified N-RCT regimens.ZusammenfassungHintergrundWir stellen die Ergebnisse von Patienten mit Plattenepithelzellkarzinomen des Ösophagus (ESCC) vor, welche an unserem Institut mit neoadjuvanter Radiochemotherapie (N-RCT) mit Cisplatin und/oder 5-Fluorouracil (5-FU)  plusanschließender Operation behandelt worden sind.Patienten und MethodikWir haben retrospektiv die Daten jener Patienten analysiert, welche sich in unserer Abteilung zur N-RCT vorstellten. Von 1988 bis 2011 wurden 103 Patienten mit N-RCT behandelt. Gruppe 1: Von 1988 bis 2006 mit 39,6–40 Gy und 5-FU (n = 55), mit (n = 17) oder ohne Cisplatin (n = 38). Gruppe 2: Von 2003 bis 2010 mit 44–45 Gy und 5-FU mit (n = 40) oder ohne Cisplatin (n = 8). An allen Patienten wurden anschließend eine radikale Resektion des Ösophagus mit einer der Lokalisation entsprechenden Rekonstruktion und eine 2-Felder-Lymphdissektion vollzogen. Die histomorphologische Remission wurde wie folgt klassifiziert: Grad 1a (komplette Remission, 0 % Resttumor), Grad 1b (partielle/subtotale Remission, < 10 % Resttumor), Grad 2 (10–50 % Resttumor) und Grad 3 (> 50 % Resttumor).ErgebnisseDie mediane Nachbeobachtungszeit seit Beginn der N-RCT lag bei 100 Monaten (Intervall 2–213 Monate). Die mediane Gesamtüberlebenszeit (OS) für das gesamte Kollektiv betrug 42 Monate bei einer 5-Jahres-überlebensrate von 45 ± 5 %. In der multivarianten Analyse waren ein schlechterer ECOG-Performance-Status (p < 0,001), ein Gewichtsverlust über 10 % vor Beginn der N-RCT (p = 0,025), ein höherer pT-Status (p = 0,001) und eine pathologische Remission 2./3. Grades (p < 0,015) signifikant mit einem schlechteren OS assoziiert. Eine pathologisch komplette Remission (0 % Resttumor) bzw. subtotale Tumorregression (< 10 % Resttumor) konnten bei 36 % bzw. 18 % der Patienten in Gruppe 1 und bei 55 % bzw. 22 % der Patienten in Gruppe 2 erreicht werden (p = 0,011). Insgesamt gab es die Tendenz für ein besseres Ergebnis für Patienten der Gruppe 2, welche jedoch statistisch nicht signifikant war. Die 5-Jahres-Gesamtüberlebensraten, krankheitsfreies überleben und rezidivfreies überleben in Gruppe 1 waren 36 ± 7 %, 35 ± 6 und 36 ± 7 % bzw. 55 ± 7, 49 ± 7 und 53 ± 7 in Gruppe 2 (p = 0,117, p = 0,124 und p = 0,087). Bezüglich der postoperativen Morbidität und Mortalität gab es keinen signifikanten Unterschied zwischen den beiden Gruppen.SchlussfolgerungEine intensivere N-RCT führte zu einer höheren kompletten Remissionsrate. Kontrollierte randomisierte Studien sind nötig, um zu beurteilen, ob intensivierte N-RCT-Konzepte die Ergebnisse von Patienten mit ESCC verbessern können.

Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU: more than 20 years' experience at a single institution.

PurposeThe purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution.MethodsWe retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988–2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988–2006 with 39.6–40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003–2010 with 44–45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, < 10 % residual tumor), grade 2 (10–50 % residual tumor), and grade 3 (> 50 % residual tumor).ResultsMedian follow-up time from the start of N-RCT was 100 months (range 2–213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 ± 5 %. In the multivariate analysis, worse ECOG performance status (p < 0.001), weight loss > 10 % before the start of the N-RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p < 0.001) were significantly associated with a poor OS. PCR and pSTR rates for group 1 were 36 % and 18 % compared to 53 % and 22 % for group 2 (p = 0.011). There was a tendency for a better outcome in group 2 patients without statistical significance. The 5-year OS, disease-free survival and recurrent-free survival were 36 ± 7 %, 35 ± 6, and 36 ± 7 % for group 1 and 55 ± 7, 49 ± 7, and 53 ± 7 in group 2 (p = 0.117, p = 0.124, and p = 0.087). There was no significant difference between the two groups considering the postoperative morbidity and mortality.ConclusionHigher radiation doses and more use of simultaneous cisplatin lead to higher pathologic response rates to N-RCT and may be associated with better survival outcomes. Prospective controlled trials are needed to assess the true value of intensified N-RCT regimens.ZusammenfassungHintergrundWir stellen die Ergebnisse von Patienten mit Plattenepithelzellkarzinomen des Ösophagus (ESCC) vor, welche an unserem Institut mit neoadjuvanter Radiochemotherapie (N-RCT) mit Cisplatin und/oder 5-Fluorouracil (5-FU)  plusanschließender Operation behandelt worden sind.Patienten und MethodikWir haben retrospektiv die Daten jener Patienten analysiert, welche sich in unserer Abteilung zur N-RCT vorstellten. Von 1988 bis 2011 wurden 103 Patienten mit N-RCT behandelt. Gruppe 1: Von 1988 bis 2006 mit 39,6–40 Gy und 5-FU (n = 55), mit (n = 17) oder ohne Cisplatin (n = 38). Gruppe 2: Von 2003 bis 2010 mit 44–45 Gy und 5-FU mit (n = 40) oder ohne Cisplatin (n = 8). An allen Patienten wurden anschließend eine radikale Resektion des Ösophagus mit einer der Lokalisation entsprechenden Rekonstruktion und eine 2-Felder-Lymphdissektion vollzogen. Die histomorphologische Remission wurde wie folgt klassifiziert: Grad 1a (komplette Remission, 0 % Resttumor), Grad 1b (partielle/subtotale Remission, < 10 % Resttumor), Grad 2 (10–50 % Resttumor) und Grad 3 (> 50 % Resttumor).ErgebnisseDie mediane Nachbeobachtungszeit seit Beginn der N-RCT lag bei 100 Monaten (Intervall 2–213 Monate). Die mediane Gesamtüberlebenszeit (OS) für das gesamte Kollektiv betrug 42 Monate bei einer 5-Jahres-überlebensrate von 45 ± 5 %. In der multivarianten Analyse waren ein schlechterer ECOG-Performance-Status (p < 0,001), ein Gewichtsverlust über 10 % vor Beginn der N-RCT (p = 0,025), ein höherer pT-Status (p = 0,001) und eine pathologische Remission 2./3. Grades (p < 0,015) signifikant mit einem schlechteren OS assoziiert. Eine pathologisch komplette Remission (0 % Resttumor) bzw. subtotale Tumorregression (< 10 % Resttumor) konnten bei 36 % bzw. 18 % der Patienten in Gruppe 1 und bei 55 % bzw. 22 % der Patienten in Gruppe 2 erreicht werden (p = 0,011). Insgesamt gab es die Tendenz für ein besseres Ergebnis für Patienten der Gruppe 2, welche jedoch statistisch nicht signifikant war. Die 5-Jahres-Gesamtüberlebensraten, krankheitsfreies überleben und rezidivfreies überleben in Gruppe 1 waren 36 ± 7 %, 35 ± 6 und 36 ± 7 % bzw. 55 ± 7, 49 ± 7 und 53 ± 7 in Gruppe 2 (p = 0,117, p = 0,124 und p = 0,087). Bezüglich der postoperativen Morbidität und Mortalität gab es keinen signifikanten Unterschied zwischen den beiden Gruppen.SchlussfolgerungEine intensivere N-RCT führte zu einer höheren kompletten Remissionsrate. Kontrollierte randomisierte Studien sind nötig, um zu beurteilen, ob intensivierte N-RCT-Konzepte die Ergebnisse von Patienten mit ESCC verbessern können.

The prognostic value of irradiated lung volumes on the prediction of intra-/ post-operative mortality in patients after neoadjuvant radiochemotherapy for esophageal cancer. A retrospective multicenter study.

Purpose: To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S). Methods and Materials: Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection). Results: A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051). Conclusions: Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU@@@Langzeitergebnisse der trimodalen Therapie des Ösophagusplattenepithelkarzinoms mit Cisplatin und/oder 5-FU: More than 20 years’ experience at a single institution@@@Mehr als 20 Jahre Erfahrung an einem einzigen Institut

PurposeThe purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution.MethodsWe retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988–2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988–2006 with 39.6–40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003–2010 with 44–45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, < 10 % residual tumor), grade 2 (10–50 % residual tumor), and grade 3 (> 50 % residual tumor).ResultsMedian follow-up time from the start of N-RCT was 100 months (range 2–213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 ± 5 %. In the multivariate analysis, worse ECOG performance status (p < 0.001), weight loss > 10 % before the start of the N-RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p < 0.001) were significantly associated with a poor OS. PCR and pSTR rates for group 1 were 36 % and 18 % compared to 53 % and 22 % for group 2 (p = 0.011). There was a tendency for a better outcome in group 2 patients without statistical significance. The 5-year OS, disease-free survival and recurrent-free survival were 36 ± 7 %, 35 ± 6, and 36 ± 7 % for group 1 and 55 ± 7, 49 ± 7, and 53 ± 7 in group 2 (p = 0.117, p = 0.124, and p = 0.087). There was no significant difference between the two groups considering the postoperative morbidity and mortality.ConclusionHigher radiation doses and more use of simultaneous cisplatin lead to higher pathologic response rates to N-RCT and may be associated with better survival outcomes. Prospective controlled trials are needed to assess the true value of intensified N-RCT regimens.ZusammenfassungHintergrundWir stellen die Ergebnisse von Patienten mit Plattenepithelzellkarzinomen des Ösophagus (ESCC) vor, welche an unserem Institut mit neoadjuvanter Radiochemotherapie (N-RCT) mit Cisplatin und/oder 5-Fluorouracil (5-FU)  plusanschließender Operation behandelt worden sind.Patienten und MethodikWir haben retrospektiv die Daten jener Patienten analysiert, welche sich in unserer Abteilung zur N-RCT vorstellten. Von 1988 bis 2011 wurden 103 Patienten mit N-RCT behandelt. Gruppe 1: Von 1988 bis 2006 mit 39,6–40 Gy und 5-FU (n = 55), mit (n = 17) oder ohne Cisplatin (n = 38). Gruppe 2: Von 2003 bis 2010 mit 44–45 Gy und 5-FU mit (n = 40) oder ohne Cisplatin (n = 8). An allen Patienten wurden anschließend eine radikale Resektion des Ösophagus mit einer der Lokalisation entsprechenden Rekonstruktion und eine 2-Felder-Lymphdissektion vollzogen. Die histomorphologische Remission wurde wie folgt klassifiziert: Grad 1a (komplette Remission, 0 % Resttumor), Grad 1b (partielle/subtotale Remission, < 10 % Resttumor), Grad 2 (10–50 % Resttumor) und Grad 3 (> 50 % Resttumor).ErgebnisseDie mediane Nachbeobachtungszeit seit Beginn der N-RCT lag bei 100 Monaten (Intervall 2–213 Monate). Die mediane Gesamtüberlebenszeit (OS) für das gesamte Kollektiv betrug 42 Monate bei einer 5-Jahres-überlebensrate von 45 ± 5 %. In der multivarianten Analyse waren ein schlechterer ECOG-Performance-Status (p < 0,001), ein Gewichtsverlust über 10 % vor Beginn der N-RCT (p = 0,025), ein höherer pT-Status (p = 0,001) und eine pathologische Remission 2./3. Grades (p < 0,015) signifikant mit einem schlechteren OS assoziiert. Eine pathologisch komplette Remission (0 % Resttumor) bzw. subtotale Tumorregression (< 10 % Resttumor) konnten bei 36 % bzw. 18 % der Patienten in Gruppe 1 und bei 55 % bzw. 22 % der Patienten in Gruppe 2 erreicht werden (p = 0,011). Insgesamt gab es die Tendenz für ein besseres Ergebnis für Patienten der Gruppe 2, welche jedoch statistisch nicht signifikant war. Die 5-Jahres-Gesamtüberlebensraten, krankheitsfreies überleben und rezidivfreies überleben in Gruppe 1 waren 36 ± 7 %, 35 ± 6 und 36 ± 7 % bzw. 55 ± 7, 49 ± 7 und 53 ± 7 in Gruppe 2 (p = 0,117, p = 0,124 und p = 0,087). Bezüglich der postoperativen Morbidität und Mortalität gab es keinen signifikanten Unterschied zwischen den beiden Gruppen.SchlussfolgerungEine intensivere N-RCT führte zu einer höheren kompletten Remissionsrate. Kontrollierte randomisierte Studien sind nötig, um zu beurteilen, ob intensivierte N-RCT-Konzepte die Ergebnisse von Patienten mit ESCC verbessern können.