E. Scardino

CORRELATION BETWEEN ACUTE AND LATE TOXICITY IN 973 PROSTATE CANCER PATIENTS TREATED WITH THREE-DIMENSIONAL CONFORMAL EXTERNAL BEAM RADIOTHERAPY

PURPOSE To analyze the correlation between acute and late injury in 973 prostate cancer patients treated with radiotherapy and to evaluate the effect of patient-, tumor-, and treatment-related variables on toxicity. METHODS AND MATERIALS Of the 973 patients, 542 and 431 received definitive or postprostatectomy radiotherapy, respectively. Three-dimensional conformal radiotherapy included a six-field technique and two-dynamic arc therapy. Toxicity was classified according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. The correlation between acute and late toxicity (incidence and severity) was assessed. RESULTS Multivariate analysis showed that age </=65 years (p = .06) and use of the three-dimensional, six-field technique (p <.0001) correlated significantly with greater acute rectal toxicity. The three-dimensional, six-field technique (p = .0002), dose >70 Gy (p = .014), and radiotherapy duration (p = .05) correlated with greater acute urinary toxicity. Acute rectal toxicity (p <.0001) was the only factor that correlated with late rectal injury on multivariate analysis. Late urinary toxicity correlated with acute urinary events (p <.0001) and was inversely related to the use of salvage radiotherapy (p = .018). A highly significant correlation was found between the incidence of acute and late events for both rectal (p <.001) and urinary (p <.001) reactions. The severity of acute toxicity (Grade 2 or greater) was predictive for the severity of late toxicity for both rectal and urinary events (p <.001). CONCLUSION The results of our study have shown that the risk of acute reactions depends on both patient-related (age) and treatment-related (dose, technique) factors. Acute toxicity was an independent significant predictor of late toxicity. These findings might help to predict and prevent late radiotherapy-induced complications.

Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone.

OBJECTIVE Experimental and preliminary clinical studies have suggested that the pineal hormone melatonin (MLT) may stimulate hormone receptor expression on both normal and cancer cells. Moreover, MLT has appeared to inhibit the growth of some cancer cell lines, including prostate cancer, either by exerting a direct cytostatic action, or by decreasing the endogenous production of some tumor growth factors, such as prolactin (PRL) and insulin-like growth factor-1 (IGF-1). On this basis, a study was carried out to evaluate the clinical efficacy of a neuroendocrine combination consisting of the LHRH analogue triptorelin plus MLT in metastatic prostate cancer progressing on triptorelin alone. MATERIAL AND METHODS The study including 14 consecutive metastatic prostate cancer patients with poor clinical conditions (median age: 70.5 years; median PS: 50%), refractory or resistant to a previous therapy with the LHRH analogue triptorelin alone. Triptorelin was injected i.m. at 3.75 mg every 28 days, and MLT was given orally at 20 mg/day in the evening every day until progression, starting 7 days prior to triptorelin. RESULTS AND CONCLUSIONS A decrease in PSA serum levels greater than 50% was obtained in 8/14 (57%) patients. Moreover, PSA mean concentrations significantly decreased on therapy of triptorelin plus MLT. In addition, a normalization of platelet number was obtained in 3/5 patients with persistent thrombocytopenia prior to study. Mean serum levels of both PRL and IGF-1 significantly decreased on therapy. Finally, a survival longer than 1 year was achieved in 9/14 (64%) patients. This preliminary study would suggest that the concomitant administration of the pineal hormone MLT may overcome the clinical resistance to LHRH analogues and improve the clinical conditions in metastatic prostatic cancer patients.

Local staging of penile cancer using magnetic resonance imaging with pharmacologically induced penile erection.

PurposeThis study was undertaken to compare the local staging of penile cancer by magnetic resonance imaging (MRI) combined with pharmacologically induced penile erection (PIPE), with clinical examination and pathology, and to verify whether MRI-PIPE led to changes in treatment planning in our cohort.Materials and methodsThirteen patients with untreated penile cancer underwent local staging by clinical examination and MRI-PIPE obtained by intracavernosal injection of 10 μg prostaglandin E1. Transverse, sagittal and coronal T2-weighted and T1-weighted (before and after intravenous gadolinium injection) images were obtained with a four-channel phased-array coil. Tumours were treated according to stage, as defined by MRI-PIPE and clinical examination. Stage T1 tumours underwent laser ablation and stage T2 or T3 tumours partial or total penectomy.ResultsTwelve penile cancers were squamous cell carcinomas and one was a sarcoma. MRI-PIPE correctly staged 12 out of 13 patients, failing to detect one in situ carcinoma. Clinical examination correctly staged eight out of 13 patients, overstaging two patients (one Tis was overstaged as T1 and one T1 as T2) and understaging three patients (two T2 as T1 and one T3 as T2).ConclusionMRI-PIPE performed better than the clinical examination and changed treatment planning in three patients.RiassuntoObiettiviConfrontare la stadiazione locale del tumore del pene definita con la risonanza magnetica abbinata all’erezione farmacologicamente indotta con iniezione intracavernosa di prostaglandine (RM con test di farmacoinfusione intracavernosa, RM-TFI) con l’esame clinico e con l’anatomia patologica. Verificare se la RM-TFI abbia determinato cambiamenti nella strategia terapeutica.Materiali e metodiTredici pazienti con tumore del pene mai trattato sono stati esaminati con RM-TFI (ottenuta con iniezione intracavernosa di 10 μg di prostaglandine E1). Sono state acquisite immagini assiali, coronali e sagittali pesate in T2 e T1 (prima e dopo iniezione endovenosa di gadolinio), utilizzando una bobina phased-array a quattro canali. In accordo con la stadiazione della RM-TFI e dell’esame clinico, i tumori in stadio T1 sono stati sottoposti ad ablazione laser, mentre i tumori T2 e T3 a penectomia parziale o totale.RisultatiDodici tumori del pene sono risultati squamocellulari e uno sarcoma. La RM-TFI ha stadiato correttamente dodici pazienti su tredici, non riconoscendo la presenza di un carcinoma in situ, e l’esame clinico otto pazienti su tredici, sovrastadiando due pazienti (un carcinoma in situ come T1 ed uno stadio T1 come T2) e sottostadiando tre pazienti (due stadi T2 come T1 ed uno stadio T3 come T2).ConclusioniLa RM-TFI si è dimostrata superiore all’esame clinico e ha modificato la strategia terapeutica in tre pazienti.

Localization of Avidin in Superficial Bladder Cancer: A Potentially New Approach for Radionuclide Therapy

OBJECTIVE To verify whether native avidin, made radioactive through the binding with technetium-99m labeled biotin (99mTc-biotin), selectively accumulated in superficial tumor tissues following intravesical administration. METHODOLOGY A total of fifteen patients with transitional cell bladder cancer were instilled intravesically with radiolabeled avidin. Cold biopsies were obtained from macroscopically normal and tumor tissues before transurethral resection (TUR) and the radioactivity in the samples was measured. RESULTS Increased accumulation of radiolabeled avidin was observed in tumor tissue compared to normal bladder tissue and in some cases, remarkably high quotients of uptake (q) in tumor versus normal tissues were determined (86 and 44). The three patients instilled with a deglycosylated avidin at neutral pI, who served as a control, showed no significant uptake in either tumor or normal urothelium and no difference in relative uptake (q=1.0). CONCLUSION This pilot study indicated that intravesical administration of radiolabeled avidin resulted in a preferential accumulation in tumor tissue compared to normal urothelium. The instillation of radiolabeled avidin warrant further investigations in order to explore the possibility to treat superficial bladder neoplasms locally by replacing 99mTc with high energy beta emitting radionuclides associated with biotin.

Phase II trial of estramustine phosphate and oral etoposide in patients with hormone-refractory prostate cancer

BACKGROUND There is a need for active agents with a better safety profile than docetaxel, yet good activity, for patients with hormone-refractory prostate cancer (HRPC). We carried out a phase II trial to determine the activity and safety of estramustine plus oral etoposide in HRPC. PATIENTS AND METHODS Patients were given estramustine (280 mg twice daily) and etoposide (100 mg/day, days 1-21) in 28-day cycles until disease progression or unacceptable toxicity. Primary end points were overall response rate and safety, as determined by prostate-specific antigen (PSA) levels and lesion assessment. RESULTS From November 2001 to February 2007, 75 patients were enrolled. All patients were assessable for safety; 17 (22.6%) had grade 3/4 toxicity. PSA response was assessable in 69, 14 of whom had a >50% reduction in PSA. Of 10 patients with one or more measurable lesions, two (20%) had partial response and two (20%) disease stabilization. Overall, median time to progression was 4.4 months (range 1 week-43 months); median survival was 23 months (range 3 weeks-64+ months). CONCLUSIONS Estramustine plus etoposide is active and has a manageable safety profile in patients with HRPC. In asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments.

Gefitinib combined with endocrine manipulation in patients with hormone-refractory prostate cancer: quality of life and surrogate markers of activity.

We investigated efficacy of gefitinib in hormone-refractory prostate cancer. Between March 2003 and December 2004, 23 patients with hormone-refractory prostate cancer were assigned to receive 250 mg oral gefitinib daily in addition to antiandrogen and luteinizing hormone-releasing hormone analogue for at least 2 months or until disease progression. Patients with progression stopped antiandrogen therapy, and received gefitinib and the luteinizing hormone-releasing hormone analogue. Serum HER2 and epidermal growth factor receptor extracellular domain were evaluated every 2 months. Gefitinib treatment did not result in any objective measurable response or responses in prostate-specific antigen. Median time to progression was 70 days (33–336). Median overall survival was 293 days (25–75 percentile: 235–349). HER2 extracellular domain mean value was 9.6 ng/ml (range 6.9–13.3) at basal time and was 10.1 (range 6.0–14.1) after 2 months. Epidermal growth factor receptor mean basal value was 51.0 ng/ml (range 41.4–75.3). After 2 months of treatment the mean value was 51.1 ng/ml (range 41.5–61.4). One patient had reduction in the pain score from baseline without an increase in the analgesic score. Four patients (17%) out of 23 had pain progression with an increase from baseline of at least 25% in the analgesic score. The study was discontinued before target accrual was reached owing to lack of efficacy of the drug. Our results do not support the efficacy of gefitinib in combination with endocrine treatment for hormone-refractory prostate cancer.

Paradoxical Stimulation of Prolactin Secretion by L–Dopa in Metastatic Prostate Cancer and Its Possible Role in Prostate–Cancer–Related Hyperprolactinemia

Objective: In addition to sex steroids, prolactin (PRL) may also stimulate prostate cancer growth. Abnormally high blood levels of PRL have been noted in metastatic prostate cancer patients. However, most studies have been limited to the evaluation of basal levels of PRL rather than to investigate its secretion in response to classical endocrine dynamic tests. This study was carried out to analyze PRL secretion in metastatic prostate cancer patients both at basal conditions and in response to L–Dopa and metoclopramide, which represents the most classical inhibitory and stimulatory tests for PRL secretion, respectively.Methods: The study included 12 patients with metastatic prostate cancer. On separate occasions, PRL secretion was evaluated in response to L–Dopa (500 mg orally) and to metoclopramide (10 mg i.v. as a bolus). Serum levels of PRL were measured by RIA.Results: Mean PRL concentrations significantly increased after metoclopramide administration, even though no PRL response occurred in 6 of 12 patients. L–Dopa was unable to reduce PRL levels, which, in contrast, paradoxically significantly increased in response to L–Dopa, with mean values comparable to those achieved after metoclopramide injection.Conclusion: By showing a paradoxical stimulatory effect of L–Dopa on PRL secretion and a lack of response to metoclopramide in some patients, this study would suggest the existence of evident alterations in the neuroendocrine regulation of PRL release in advanced prostate cancer.

Health-related quality of life in patients with hormone refractory prostate cancer receiving gefitinib

Objectives: Improvements in quality of life (QoL) and disease-related symptoms are key goals in the treatment of hormone refractory prostate cancer (HRPC). Our aim was to evaluate the impact of gefitinib on QoL of patients with HRPC. Methods: Patients with HRPC received gefitinib 250 mg daily in addition to antiandrogen plus luteinizing hormone-releasing hormone (LHRH) analogue for at least 2 months or until disease progression. QoL was evaluated monthly by the European Organisation for Research on the Treatment of Cancer (EORTC) QLQ-C30 questionnaire. Pain was assessed daily by patients and scored by visual analogue scale and analgesic consumption in a diary. Monthly pain intensity was estimated using the McGill-Melzack questionnaire. Results: Analysis of global health status according to EORTC QLQ-C30 showed an improvement of the status in only 6 patients (26%). The greatest benefit in the patients was in the subscale representing prostate-specific concerns (including appetite, pain, physical comfort, and genitourinary function). Improvement of symptoms was correlated with antiandrogen withdrawal. Global health status and QoL decreased during treatment according to tumor progression. Conclusions: Among HRPC patients treated with gefitinib, improvement of symptoms preceded evidence of biochemical response of prostate-specific antigen following antiandrogen withdrawal. These findings suggest no beneficial effect of gefitinib in QoL improvement.

INTRAOPERATIVE RADIOTHERAPY FOR LOCALLY ADVANCED PROSTATE CANCER: THE EXPERIENCE OF THE EUROPEAN INSTITUTE OF ONCOLOGY

521 INTRAOPERATIVE RADIOTHERAPY FOR LOCALLY ADVANCED PROSTATE CANCER: THE EXPERIENCE OF THE EUROPEAN INSTITUTE OF ONCOLOGY Andrea Vavassori*, Mario Ciocca, Barbara Jereczek, Dario Zerini, Giovanni Ivaldi, Cristiana Fodor, Roberta Lazzari, Federica Cattani, Elena Rondi, Cristina Garibaldi, Raffaella Cambria, Victor Matei, Epifanio Scardino, Fabrizio Verweij, Gennaro Musi, Bernardo Rocco, Ottavio De Cobelli, Roberto Orecchia. Milan, Italy. INTRODUCTION AND OBJECTIVE: To present the technique adopted for intraoperative radiotherapy (IORT) for locally advanced prostate cancer. METHODS: Between June 2005 and February 2007, 24 patients (pts) with non-metastatic prostate cancer were treated with IORT before prostatectomy as part of their surgical procedure. Median

Stadiazione locale del tumore del pene con risonanza magnetica abbinata a test di farmacoinfusione intracavernosa (RM-TFI)

PurposeThis study was undertaken to compare the local staging of penile cancer by magnetic resonance imaging (MRI) combined with pharmacologically induced penile erection (PIPE), with clinical examination and pathology, and to verify whether MRI-PIPE led to changes in treatment planning in our cohort.Materials and methodsThirteen patients with untreated penile cancer underwent local staging by clinical examination and MRI-PIPE obtained by intracavernosal injection of 10 μg prostaglandin E1. Transverse, sagittal and coronal T2-weighted and T1-weighted (before and after intravenous gadolinium injection) images were obtained with a four-channel phased-array coil. Tumours were treated according to stage, as defined by MRI-PIPE and clinical examination. Stage T1 tumours underwent laser ablation and stage T2 or T3 tumours partial or total penectomy.ResultsTwelve penile cancers were squamous cell carcinomas and one was a sarcoma. MRI-PIPE correctly staged 12 out of 13 patients, failing to detect one in situ carcinoma. Clinical examination correctly staged eight out of 13 patients, overstaging two patients (one Tis was overstaged as T1 and one T1 as T2) and understaging three patients (two T2 as T1 and one T3 as T2).ConclusionMRI-PIPE performed better than the clinical examination and changed treatment planning in three patients.RiassuntoObiettiviConfrontare la stadiazione locale del tumore del pene definita con la risonanza magnetica abbinata all’erezione farmacologicamente indotta con iniezione intracavernosa di prostaglandine (RM con test di farmacoinfusione intracavernosa, RM-TFI) con l’esame clinico e con l’anatomia patologica. Verificare se la RM-TFI abbia determinato cambiamenti nella strategia terapeutica.Materiali e metodiTredici pazienti con tumore del pene mai trattato sono stati esaminati con RM-TFI (ottenuta con iniezione intracavernosa di 10 μg di prostaglandine E1). Sono state acquisite immagini assiali, coronali e sagittali pesate in T2 e T1 (prima e dopo iniezione endovenosa di gadolinio), utilizzando una bobina phased-array a quattro canali. In accordo con la stadiazione della RM-TFI e dell’esame clinico, i tumori in stadio T1 sono stati sottoposti ad ablazione laser, mentre i tumori T2 e T3 a penectomia parziale o totale.RisultatiDodici tumori del pene sono risultati squamocellulari e uno sarcoma. La RM-TFI ha stadiato correttamente dodici pazienti su tredici, non riconoscendo la presenza di un carcinoma in situ, e l’esame clinico otto pazienti su tredici, sovrastadiando due pazienti (un carcinoma in situ come T1 ed uno stadio T1 come T2) e sottostadiando tre pazienti (due stadi T2 come T1 ed uno stadio T3 come T2).ConclusioniLa RM-TFI si è dimostrata superiore all’esame clinico e ha modificato la strategia terapeutica in tre pazienti.