Alba Fiorentino

In Regard to Miralbell et al

To the Editor: In a recent analysis of 7 international institutional datasets, Miralbell et al (1) contributed to the wellknown debate on how low is the a/b value of prostate cancer (2-4). Based on the multiple primary datasets collected for analysis, the authors deduced the dose fractionation sensitivity of prostate cancer as a/b Z 1.4 Gy. Moreover, when the a/b ratio was allowed to vary among risk groups, the values of 0.6, 1.7, and 1.6 Gy for low-, intermediate-, and high-risk groups were obtained. However, in arriving at those results, the authors obtained extremely low values for a, and correspondingly the estimated number of prostate clonogens were inconsistent and difficult to be interpreted from the biological point of view. To investigate this aspect, we tried to use all of the Miralbell et al clinical data and results, with exception of the number of clonogens and intrinsic radiosensitivity a. Our final aim was to verify the compatibility of the results obtained by Miralbell et al about a/b, with a more realistic number of clonogenic cells. In particular, with regard to the number of clonogens, we used values as those reported by Wang et al (5) that have estimated this number for low-, intermediate-, and high-risk groups. Furthermore, to estimate the intrinsic radiosensitivitydconsidered as a free parameter in our analysisdthe following standard formula of tumor control probability (ie, biological relapse free survival [bRFS]) based on the linear quadratic model was used:

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma

BackgroundCombining Gliadel wafers and radiochemotherapy with TMZ may carry the risk of increased adverse events (AE). We analyzed the efficacy and safety in patients with glioblastoma who underwent multimodal treatment with implantation of Gliadel wafers.MethodsOne hundred sixty-five consecutive patients with newly diagnosed (77 patients) or recurrent (88 patients) glioblastoma were studied. Forty-seven patients underwent surgery + Gliadel. The impact of age (≥65 vs. <65), resection extent (gross total vs. partial), use of Gliadel and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on overall survival (OS, for patients with newly diagnosed glioblastoma) and on recurrence-survival (for patients with recurrent glioblastoma) was analyzed with Cox regression. The impact of age, history (newly diagnosed vs. recurrent glioblastoma), number of Gliadel wafers implanted (0 vs. <8 vs. 8), resection extent (gross-total vs. partial) and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on the occurrence of AE and on the occurrence of implantation site-related AE (ISAE) was analyzed with the logistic regression model. Significance was set at p < 0.05.ResultsMultivariate analysis showed the only factor associated with longer survival, both for newly diagnosed and for recurrent GBM, was resection extent. Both patients with a higher number of wafers implanted and patients with recurrent tumors were significantly at risk for AE and ISAE. Patients with eight Gliadel wafers implanted had a 3-fold increased risk of AE and a 5.6-fold increased risk of ISAE, and patients with recurrent tumor had a 2.8-fold increased risk of AE and a 9.3-fold increased risk of ISAE.ConclusionsAdding Gliadel to standard treatment did not significantly improve the outcome. The toxicity after Gliadel use was significantly higher, both for patients with newly diagnosed and patients with recurrent glioblastoma.

Single-Arm Phase II Study of Conformal Radiation Therapy and Temozolomide plus Fractionated Stereotactic Conformal Boost in High-Grade Gliomas

Purpose:To assess survival, local control and toxicity using fractionated stereotactic conformal radiotherapy (FSCRT) boost and temozolomide in high-grade gliomas (HGGs).Patients and Methods:Patients affected by HGG, with a CTV1(clinical target volume, representing tumor bed ± residual tumor + a margin of 5 mm) ≤ 8 cm were enrolled into this phase II study. Radiotherapy (RT, total dose 6,940 cGy) was administered using a combination of two different techniques: three-dimensional conformal radiotherapy (3D-CRT, to achieve a dose of 5,040 or 5,940 cGy) and FSCRT boost (19 or 10 Gy) tailored by CTV1diameter (≤ 6 cm and > 6 cm, respectively). Temozolomide (75 mg/m2) was administered during the first 2 or 4 weeks of RT. After the end of RT, temozolomide (150–200 mg/m2) was administered for at least six cycles. The sample size of 41 patients was assessed by the single proportion–powered analysis.Results:41 patients (36 with glioblastoma multiforme [GBM] and five with anaplastic astrocytoma [AA]) were enrolled; RTOG neurological toxicities G1–2 and G3 were 12% and 3%, respectively. Two cases of radionecrosis were observed. At a median follow-up of 44 months (range 6–56 months), global and GBM median overall survival (OS) were 30 and 28 months. The 2-year survival rate was significantly better compared to the standard treatment (63% vs. 26.5%; p < 0.00001). Median progression-free survival (PFS) was 11 months, in GBM patients 10 months.Conclusion:FSCRT boost plus temozolomide is well tolerated and seems to increase survival compared to the standard treatment in patients with HGG.ZusammenfassungZiel:Untersuchung von Uberleben, lokaler Tumorkontrolle und Toxizitat einer fraktionierten stereotaktischen konformalen Strahlentherapie (FSCRT) mit Boostbestrahlung in Kombination mit Temozolomid bei hochmalignen Gliomen (HMG).Patienten und Methodik:Patienten mit HMG und einem CTV1(klinisches Zielvolumen, d. h. Tumorbett ± Resttumor + einem Sicherheitsabstand von 5 mm) ≤ 8 cm wurden in diese Phase-II-Studie eingeschlossen. Die Strahlentherapie (Gesamtdosis 6 940 cGy) wurde als Kombination aus zwei unterschiedlichen Techniken appliziert: dreidimensionale konformale Strahlentherapie (3D-CRT, um eine Strahlendosis von 5 040 oder 5 940 cGy zu erreichen) und lokale Dosisaufsattigung mit FSCRT-Boost (19 oder 10 Gy), die auf den CTV1-Durchmesser (≤ 6 cm bzw. > 6 cm) zugeschnitten war. Temozolomid (75 mg/m2) wurde wahrend der ersten 2 oder 4 Wochen der Strahlentherapie verabreicht. Nach dem Ende der Strahlentherapie erhielten die Patienten Temozolomid (150–200 mg/m2) fur wenigstens sechs Zyklen. Die Fallzahl wurde mit Hilfe eines einfach-proportionalen Testverfahrens („single proportion-powered analysis“) bei 41 Patienten bestimmt.Ergebnisse:41 Patienten (36 mit Glioblastoma multiforme [GBM] und funf mit anaplastischem Astrozytom [AA]) wurden behandelt; Neurotoxizitat gemas RTOG-Skala G1–2 bzw. G3 wurde in 12% bzw. 3% der Patienten beobachtet. Zwei Falle von Radionekrose traten auf. Bei einer mittleren Beobachtungszeit von 44 Monaten (Range 6–56 Monate) lagen die mittlere Gesamt- und die GBM-spezifische Uberlebenszeit (OS) bei 30 und 28 Monaten. Die 2-Jahres-Uberlebensrate war signifikant besser im Vergleich zur Standardbehandlung (63% vs. 26,5%; p < 0.00001). Die mittlere progressionsfreie Uberlebenszeit (PFS) betrug 11 Monate, bei GBM-Patienten 10 Monate.Schlussfolgerung:FSCRT-Boostbestrahlung plus Temozolomid wird gut toleriert und scheint im Vergleich zur Standardbehandlung die Uberlebenszeit von Patienten mit HMG zu verbessern.

Dose–volume-related dysphagia after constrictor muscles definition in head and neck cancer intensity-modulated radiation treatment

OBJECTIVE Dysphagia remains a side effect influencing the quality of life of patients with head and neck cancer (HNC) after radiotherapy. We evaluated the relationship between planned dose involvement and acute and late dysphagia in patients with HNC treated with intensity-modulated radiation therapy (IMRT), after a recontouring of constrictor muscles (PCs) and the cricopharyngeal muscle (CM). METHODS Between December 2011 and December 2013, 56 patients with histologically proven HNC were treated with IMRT or volumetric-modulated arc therapy. The PCs and CM were recontoured. Correlations between acute and late toxicity and dosimetric parameters were evaluated. End points were analysed using univariate logistic regression. RESULTS An increasing risk to develop acute dysphagia was observed when constraints to the middle PCs were not respected [mean dose (Dmean) ≥50 Gy, maximum dose (Dmax) >60 Gy, V50 >70% with a p = 0.05]. The superior PC was not correlated with acute toxicity but only with late dysphagia. The inferior PC was not correlated with dysphagia; for the CM only, Dmax >60 Gy was correlated with acute dysphagia ≥ grade 2. CONCLUSION According to our analysis, the superior PC has a major role, being correlated with dysphagia at 3 and 6 months after treatments; the middle PC maintains this correlation only at 3 months from the beginning of radiotherapy, but it does not have influence on late dysphagia. The inferior PC and CM have a minimum impact on swallowing symptoms. ADVANCES IN KNOWLEDGE We used recent guidelines to define dose constraints of the PCs and CM. Two results emerge in the present analysis: the superior PC influences late dysphagia, while the middle PC influences acute dysphagia.

Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study

We explored the feasibility of concurrent palliative chemotherapy and low-dose fractionated radiotherapy (LD-FRT) in glioblastoma multiforme (GBM). Patients with recurrent/progressive GBM at least 3 months after the end of primary radiotherapy received 0.3 Gy twice daily with cisplatin and fotemustine if progressing on temozolomide, or 0.4 Gy twice daily with temozolomide if recurrent 4-6 months later (retreatment group). Newly diagnosed GBM with gross residual mass received 30 Gy with concomitant and adjuvant temozolomide and 0.4 Gy twice daily from the second adjuvant cycle (naive group) for 2-4 cycles. Twenty-six patients were enrolled. In the retreatment group (n = 17; median LD-FRT total dose 7.2 Gy [range 2.4-11.6]), grade 3 or 4 hematological toxicity was observed in 5.9% of patients. Median follow-up time was 20 months (range 4-35). Median progression-free survival (PFS) and overall survival (OS) from the time of recurrence or progression were 4 and 8 months, respectively (OS at 6 months, 69%; at 12 months, 16.7%). In the naive group (n = 9; median LD-FRT total dose 8 Gy [range 3.2-16]), grade 3 or 4 hematological toxicity was observed in 11.1% of patients. Median follow-up time was 17 months (range 8-20)-median PFS was 9 months, with PFS at 6 months and at 1 year of 66.7% and 26.7%, respectively; and median OS was 12 months, with OS at 6 months and at 1 year of 77.8% and 34.6%, respectively. LD-FRT with concurrent chemotherapy was well tolerated.

Correlation between egfr expression and accelerated proliferation during radiotherapy of head and neck squamous cell carcinoma

PurposeTo investigate the correlation between the expression of Epidermal Growth Factor receptor (EGFr) and the reduction of the effective doubling time (TD) during radiotherapy treatment and also to determine the dose per fraction to be taken into account when the overall treatment time (OTT) is reduced in accelerated radiotherapy of head and neck squamous cell carcinoma (HNSCC).MethodsA survey of the published papers comparing 3-years of local regional control rate (LCR) for a total of 2162 patients treated with conventional and accelerated radiotherapy and with a pretreatment assessment of EGFr expression, was made. Different values of TD were obtained by a model incorporating the overall time corrected biologically effective dose (BED) and a 3-year clinical LCR for high and low EGFr groups of patients (HEGFr and LEGFr), respectively. By obtaining the TD from the above analysis and the sub-sites’ potential doubling time (Tpot) from flow cytometry and immunohistochemical methods, we were able to estimate the average TD for each sub-site included in the analysis. Moreover, the dose that would be required to offset the modified proliferation occurring in one day (Dprolif), was estimated.ResultsThe averages of TD were 77 (27-90)95% days in LEGFr and 8.8 (7.3-11.0)95% days in HEGFr, if an onset of accelerated proliferation TK at day 21 was assumed. The correspondent HEGFr sub-sites’ TD were 5.9 (6.6), 5.9 (6.6), 4.6 (6.1), 14.3 (12.9) days, with respect to literature immunohistochemical (flow cytometry) data of Tpot for Oral-Cavity, Oro-pharynx, Hypo-pharynx, and Larynx respectively. The Dprolif for the HEGFr groups were 0.33 (0.29), 0.33 (0.29), 0.42 (0.31), 0.14 (0.15) Gy/day if α = 0.3 Gy-1 and α/β = 10 Gy were assumed.ConclusionsA higher expression of the EGFr leads to enhanced proliferation. This study allowed to quantify the extent of the effect which EGFr expression has in terms of reduced TD and Dprolif for each head and neck sub-site.

The impact of repeated surgery and adjuvant therapy on survival for patients with recurrent glioblastoma

OBJECTIVE Treatment of glioblastoma recurrence can have a palliative aim, after considering risks and potential benefits. The aim of this study is to verify the impact of surgery and of palliative adjuvant treatments on survival after recurrence. METHODS From January 2002 to June 2008, we treated 76 consecutive patients with recurrent glioblastoma. Treatment was: 1-surgery alone--17 patients; 2-adjuvant-therapy alone--24 patients; 3-surgery and adjuvant therapy--16 patients; no treatment--19 patients. The impact on median overall-survival (OS-time between recurrence and death/last follow-up) of age, Karnofsky performance scale (KPS), resection extent and adjuvant treatment scheme (Temozolomide alone vs low-dose fractionated radiotherapy vs others) was determined. Survival curves were obtained through the Kaplan-Meier method. Cox proportional-hazards was used for multivariate analyses. Significance was set at p<0.05. RESULTS Median OS was 7 months. At univariate analysis, patients with a KPS≥70 had a longer OS (9 months vs 5 months--p<0.0001). OS was 6 months for patients treated with surgery alone, 5 months for patients that received no treatment, 8 months for patients treated with chemotherapy alone, 14 months for patients treated with surgery and adjuvant therapy--p=0.01. Patients with a KPS<70 were significantly at risk for death - HR 2.8 - p=0.001. Subgroup analysis showed no significant differences between patients receiving gross total or partial tumor resection and among patients receiving different adjuvant therapy schemes. Major surgical morbidity at tumor recurrence occurred in 16 out of 33 patients (48%). CONCLUSION It is fundamental, before deciding to operate patients for recurrence, to carefully consider the impact of surgical morbidity on outcome.

Whole-brain radiotherapy combined with surgery or stereotactic radiotherapy in patients with brain oligometastases: Long-term analysis

Objective:To verify whether the treatment of brain oligometastases with whole-brain radiotherapy (WBRT) plus stereotactic radiotherapy (SRT) or surgical resection results in different outcomes.Methods:Files of patients affected by brain metastases submitted to surgical resection followed by WBRT (group A) or WBRT + SRT (group B) were retrospectively selected for this study. The two treatment groups were matched for the following potential prognostic factors: WBRT schedule, age, gender, performance status, tumor type, number of brain metastases, extra-cerebral metastases, and recursive partitioning analysis class (RPA). The outcomes of patients in both groups were evaluated in terms of toxicity, local control, and overall survival.Results:Total of 97 patients were selected (56 male; 42 female) who were respectively submitted to surgical resection followed by WBRT (group A, n = 50 patients) or WBRT + SRT (Group B, n = 47 patients). Median follow-up was 95 months (range, 8–171 months). The 1-year local control rates were 46.0% and 69.0% respectively. No significant difference in local tumor control was observed between group A and B (p = 0.10). Median overall survival was 15 and 19 months in group A and B, respectively. One-year survival was 56.0% and 62%, respectively. No difference was observed in the two groups (p = 0.40).Conclusion:Surgery remains the main therapeutic approach in symptomatic patients; nevertheless, our data support the use of WBRT plus SRT in one or two brain metastases smaller than 3 cm.Zielsetzung:Zu untersuchen, ob die Behandlung von Oligohirnmetastasen mit Ganzhirnbestrahlung (whole-brain radiotherapy, WBRT) plus stereotaktischer Radiotherapie (SRT) oder chirurgischer Resektion unterschiedliche Ergebnisse bringt.Methoden:Krankenakten von Patienten mit operativ entfernten Hirnmetastasen und anschließender WBRT (Gruppe A) oder WBRT + SRT (Gruppe B) wurden retrospektiv für diese Studie ausgewählt. Die zwei Beghandlungsarme wurden für folgende prognostische Parameter gematcht: WBRT-Schema. Alter, Geschlecht, Allgemeinzustand, Art des Primärtumors, Anzahl der Hirnmetastasen, extrazerebrale Metastasen, Recursive-Partioning-Analysis-(RPA-)Klasse. Das Behandlungsergebnis für beide Patientengruppen wurde im Hinblick auf Toxizität, lokale Tumorkontrolle und Gesamtüberleben bewertet.Ergebnisse:Insgesamt wurden 97 Patienten ausgewählt (56 m; 42 w), die entweder mit operativer Entfernung und anschließender WBRT (Gruppe A, n = 50 Pat.) oder mit WBRT + SRT (Gruppe B, n = 47 Pat.) behandelt wurden. Die mediane Beobachtungszeit betrug 95 Monate (Spanne 8–171). Die lokale Tumorkontrolle nach 1 Jahr betrug 46,0% (Gruppe A) und 69,0% (Gruppe B), ohne dass dieser Unterschied statistisch signifikant wäre (p = 0,10). Das mediane Gesamtüberleben betrug jeweils 15 und 19 Monate in Gruppe A and B. Die 1-Jahres-Überlebensrate betrug jeweils 56,0% and 62%. Es wurde kein Unterschied zwischen den beiden Gruppen gefunden (p = 0,40).Schlussfolgerung:Die chirurgische Entfernung bleibt die Behandlungsoption bei symptomatischen Patienten. Unsere Daten sprechen für eine Behandlung mit WBRT plus SRT bei Vorliegen von ein oder zwei Hirnmetastasen, die kleiner als 3 cm sind.

Postoperative infection may influence survival in patients with glioblastoma: simply a myth?

BACKGROUND:It is a prevalent myth that a postoperative infection may actually confer a survival advantage in patients with malignant glioma. This contention is based largely on anecdotal reports. Recently, a single-center study showed there was no survival advantage in those patients who had glioblastoma with postoperative infection. OBJECTIVE:To examine the impact of postoperative infections on outcome in patients with glioblastoma treated at our center. METHODS:This study included 197 patients with newly diagnosed primary glioblastoma treated from January 2001 to January 2008. Of the 197 patients, 10 (5.08%) had postoperative bacterial infection. The Kaplan-Meier method, log-rank test, and Breslow test were used in the univariate approach; Cox regression was used in the multivariable approach. RESULTS:The median survival was 16 months (95% confidence interval [CI], 14-18 mo). The infection group had a significant advantage in the median survival: 30 months (95% CI, 21-39) vs 15 months (95% CI, 13-17) for patients without postoperative infection. This advantage was also confirmed by Cox regression; in fact, patients not developing a postoperative infection showed an adjusted hazard ratio for death of 2.3 (95% CI, 1-5.3). CONCLUSION:The association between infection and prolonged survival is not definitive; we acknowledge the considerable difficulties in undertaking this type of study in a retrospective manner. Our results can instead stimulate further multicentric studies (to increase the number of patients) or experimental studies using genetically modified bacteria for treatment of glioblastoma.

Whole-Brain Radiotherapy Combined with Surgery or Stereotactic Radiotherapy in Patients with Brain Oligometastases

Objective:To verify whether the treatment of brain oligometastases with whole-brain radiotherapy (WBRT) plus stereotactic radiotherapy (SRT) or surgical resection results in different outcomes.Methods:Files of patients affected by brain metastases submitted to surgical resection followed by WBRT (group A) or WBRT + SRT (group B) were retrospectively selected for this study. The two treatment groups were matched for the following potential prognostic factors: WBRT schedule, age, gender, performance status, tumor type, number of brain metastases, extra-cerebral metastases, and recursive partitioning analysis class (RPA). The outcomes of patients in both groups were evaluated in terms of toxicity, local control, and overall survival.Results:Total of 97 patients were selected (56 male; 42 female) who were respectively submitted to surgical resection followed by WBRT (group A, n = 50 patients) or WBRT + SRT (Group B, n = 47 patients). Median follow-up was 95 months (range, 8–171 months). The 1-year local control rates were 46.0% and 69.0% respectively. No significant difference in local tumor control was observed between group A and B (p = 0.10). Median overall survival was 15 and 19 months in group A and B, respectively. One-year survival was 56.0% and 62%, respectively. No difference was observed in the two groups (p = 0.40).Conclusion:Surgery remains the main therapeutic approach in symptomatic patients; nevertheless, our data support the use of WBRT plus SRT in one or two brain metastases smaller than 3 cm.Zielsetzung:Zu untersuchen, ob die Behandlung von Oligohirnmetastasen mit Ganzhirnbestrahlung (whole-brain radiotherapy, WBRT) plus stereotaktischer Radiotherapie (SRT) oder chirurgischer Resektion unterschiedliche Ergebnisse bringt.Methoden:Krankenakten von Patienten mit operativ entfernten Hirnmetastasen und anschließender WBRT (Gruppe A) oder WBRT + SRT (Gruppe B) wurden retrospektiv für diese Studie ausgewählt. Die zwei Beghandlungsarme wurden für folgende prognostische Parameter gematcht: WBRT-Schema. Alter, Geschlecht, Allgemeinzustand, Art des Primärtumors, Anzahl der Hirnmetastasen, extrazerebrale Metastasen, Recursive-Partioning-Analysis-(RPA-)Klasse. Das Behandlungsergebnis für beide Patientengruppen wurde im Hinblick auf Toxizität, lokale Tumorkontrolle und Gesamtüberleben bewertet.Ergebnisse:Insgesamt wurden 97 Patienten ausgewählt (56 m; 42 w), die entweder mit operativer Entfernung und anschließender WBRT (Gruppe A, n = 50 Pat.) oder mit WBRT + SRT (Gruppe B, n = 47 Pat.) behandelt wurden. Die mediane Beobachtungszeit betrug 95 Monate (Spanne 8–171). Die lokale Tumorkontrolle nach 1 Jahr betrug 46,0% (Gruppe A) und 69,0% (Gruppe B), ohne dass dieser Unterschied statistisch signifikant wäre (p = 0,10). Das mediane Gesamtüberleben betrug jeweils 15 und 19 Monate in Gruppe A and B. Die 1-Jahres-Überlebensrate betrug jeweils 56,0% and 62%. Es wurde kein Unterschied zwischen den beiden Gruppen gefunden (p = 0,40).Schlussfolgerung:Die chirurgische Entfernung bleibt die Behandlungsoption bei symptomatischen Patienten. Unsere Daten sprechen für eine Behandlung mit WBRT plus SRT bei Vorliegen von ein oder zwei Hirnmetastasen, die kleiner als 3 cm sind.