A. Galardi

No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT).

BACKGROUND AND PURPOSE To evaluate the effect of adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation (NACT-RT). The study was funded by the Italian National Research Council (CNR). METHODS From September 1992 to January 2001, 655 patients with LARC (clinically T3-4, any N) treated with NACT-RT and surgery, were randomized in two arms: follow-up (Arm A) or 6 cycles of ACT with 5 fluorouracil (5FU)-Folinic Acid (Arm B). NACT-RT consisted of 45Gy/28/ff concurrent with 5FU (350mg/sqm) and Folinic Acid (20mg/sqm) on days 1-5 and 29-33; surgery was performed after 4-6weeks. Median follow up was 63·7months. Primary end point was overall survival (OS). RESULTS 634/655 patients were evaluable (Arm A 310, Arm B 324); 92·5% of Arm A and 91% of Arm B patients received the preoperative treatment as in the protocol; 294 patients of Arm A (94·8%) and 296 of Arm B (91·3%) underwent a radical resection; complete pathologic response and overall downstaging rates did not show any significant difference in the two arms. 83/297 (28%) patients in Arm B, never started ACT. Five year OS and DFS did not show any significant difference in the two treatment arms. Distant metastases occurred in 62 patients (21%) in Arm A and in 58 (19·6%) in Arm B. CONCLUSIONS In patients with LARC treated with NACT-RT, the addition of ACT did not improve 5year OS and DFS and had no impact on the distant metastasis rate.

UTERINE SARCOMA: TWENTY-SEVEN YEARS OF EXPERIENCE

PURPOSE A correlation of treatment for uterine sarcoma with outcome, prognostic importance of pathology, and clinical parameters. PATIENTS AND METHODS One hundred forty-one patients (median age: 56 years, range: 19-85 years) with a histologically verified uterine sarcoma were identified from a database compiled at the Royal Marsden Hospital and the University of Florence between 1974 and 2001. Seventy-two patients had leiomyosarcoma, 42 had mixed müllerian tumors, 22 had endometrial stromal sarcoma, 1 hemangiopericytoma, 1 rhabdomyosarcoma, and 3 patients had unspecified sarcoma. According to FIGO classification, Stage I, II, III, and IV tumors were identified in 71, 13, 31, and 26 patients, respectively. RESULTS At the time of analysis, 73.7% of patients were dead, and 26.3% were alive with a median survival of 2 years from initial diagnosis. Univariate analysis for cause-specific survival demonstrated statistical significance for histology (p = 0.02), grade (p = 0.003), stage (p = 0.007), and age (p = 0.02). Multivariate analysis demonstrated significant prognostic values for stage (p = 0.02) and histology (p = 0.05) only. Postoperative radiotherapy with a total dose higher than 50 Gy seems to be significant (p = 0.001) in reducing local recurrence. CONCLUSIONS Our data favor treatment for Stages I, II, and III of uterine sarcoma with radical surgery plus radical dose irradiation comprising both external beam radiotherapy and brachytherapy.

Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer: a retrospective analysis

Aims and background Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer. Unfortunately, the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure. In order to limit anthracycline-related cardiotoxicity, liposomal formulations of doxorubicin have been developed. This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer. Methods Patients received non-pegylated liposomal doxorubicin in combination with either cyclophosphamide (n = 14) or docetaxel (n = 20) for up to eight cycles, and efficacy and safety were assessed according to standard criteria. Results The overall response rate was 71%. The median progression-free survival was 8 months in patients receiving non-pegylated liposomal doxorubicin plus cyclophosphamide and 13.8 months in those receiving non-pegylated liposomal doxorubicin plus docetaxel (P = 0.2). The most commonly observed toxicities were grade 1–2 leucopenia, alopecia, nausea and vomiting; no grade 3–4 toxicities were observed. Overall, three patients (9%) experienced grade 1 cardiac toxicity. Conclusions Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer.

Time to surgery and pathologic complete response after neoadjuvant chemoradiation in rectal cancer: A population study on 2094 patients

Highlights • A large population based analysis to evaluate pathologic response according to time of surgery.• LARC patients were treated with modern techniques of radiotherapy and surgery.• The rate of pCR increased according to time interval from 12.6% to 31.1%.• The pCR increasing was 1.5% (about 0.2%/die) per each week of waiting.• Lengthening the interval (>13 weeks) significantly improved the pathological response.

Pegylated Liposomal Doxorubicin (Caelyx®) and Oral Vinorelbine in First-Line Metastatic Breast Cancer Patients Previously Treated with Anthracyclines

Abstract Doxorubicin is highly effective and widely used in breast cancer; however, its use is limited by cardiotoxicity related to its cumulative dose. In previous studies, pegylated liposomal doxorubicin (PLD) has shown an acceptable toxicity profile with minimal cardiotoxicity. Between June 2006 and October 2009, 27 metastatic breast cancer patients were treated with first-line PLD and vinorelbine at the University of Florence, Radiotherapy Unit. PLD (30 mg/m2) was administered on day 1, and oral vinorelbine (60 mg/m2) was administered on days 1 and 8 of a 4-week cycle. All patients were previously treated with anthracycline-based adjuvant chemotherapy. Median age was 52 years (range 38–69) and median time to metastasis was 78.5 months. There were no treatment interruptions or discontinuation for cardiac toxicity and no treatment-related deaths. Grade 3 hematological toxicity was observed in 18.6% of patients, and 3.7% had grade 3 non-hematological adverse events. With a median follow-up of 13.2 months (range 3–33), median response duration was 6.1 months, and median PFS was 5.3 months. The overall clinical benefit rate was 55.5%. Our experience adds to evidence supporting the activity and cardiac safety of PLD and vinorelbine in metastatic breast cancer patients previously treated with anthracycline-based adjuvant chemotherapy.

Oral Ibandronate in Metastatic Bone Breast Cancer: The Florence University Experience and a Review of the Literature

Abstract Ibandronate is an amino-bisphosphonate approved in metastatic breast cancer to reduce skeletal complications and to alleviate bone pain. We report our experience about the safety of oral ibandronate and review the literature. We treated 44 patients and administered 524 cycles of oral ibandronate (a single cycle was defined as a 50 mg capsule once daily for 28 days) with a median of 12 cycles (range 6-24). At a median follow-up of 18.5 months (range 6-28) the mean pain score decreased from 1.59 (SD±0.97) at baseline to 0.41 (SD±0.72) after 48 weeks of treatment. The mean analgesic score was 1.89 (SD±1.37) at baseline and 1.46 (SD±1.62) after 48 weeks of treatment. Ibandronate was generally well-tolerated; we had no Grade 3-4 adverse events. No patients had deterioration of renal function. No patients developed bisphosphonate-associated osteonecrosis of the jaw. Our experience confirmed that ibandronate may be a useful and safe co-analgesic to conventional treatments for bone pain in selected metastatic breast cancer patients.

Neoadjuvant oxaliplatin and 5-fluorouracil with concurrent radiotherapy in patients with locally advanced rectal cancer: a singleinstitution experience

PurposeThe aim of this study was to evaluate the rate of pathological response (PR), disease control and safety of neoadjuvant chemotherapy using oxaliplatin (OX) and 5-fluorouracil (5-FU) with concurrent radiotherapy for treating locally advanced rectal cancer.Materials and methodsBetween November 2002 and December 2010, 90 patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (CRT) were retrospectively analysed. All patients underwent preoperative radiotherapy (45 Gy in 1.8-Gy fractions) with concurrent OX (80 mg/m2 i.v., day 1) and a 120-h continuous infusion of 5-FU (1,000 mg/m2 per day). Surgery was performed within 6 weeks after completion of CRT treatment.ResultsComplete pathological response was obtained in six patients (6.7%), and 39 (43.3%) had their disease downstaged. The median follow-up period was 4.7 years (6 months to 9 years). Local recurrence occurred in two patients (2.2%), one of whom developed also liver metastases. Distant metastases not associated with local relapse occurred in 23 (25.6%) patients. Overall (OS) and disease-free (DFS) survival were 62.9% and 52.8%, respectively. CRT was well tolerated, with only one grade 3 (1.2%) haematological toxicity (neutropaenia).ConclusionsNeoadjuvant systemic chemotherapy based on OX and 5-UC associated with radiotherapy is well tolerated, with good results in terms of pathological response, disease control and survival, in rectal cancer patients.RiassuntoObiettivoLo scopo di questo studio è quello di valutare la risposta patologica (PR), il controllo di malattia e la sicurezza del trattamento chemioterapico basato sull’uso di oxaliplatino e 5-fluorouracile in associazione alla radioterapia nel trattamento del tumore del retto localmente avanzato.Materiali e metodiSono stati analizzati retrospettivamente, nel periodo compreso tra novembre 2002 e dicembre 2010, 90 pazienti affetti da tumore del retto localmente avanzato sottoposti a radio-chemioterapia (CRT) pre-operatoria. Tutti i pazienti hanno ricevuto una radioterapia pre-operatoria (45 Gy in 1,8 Gy per frazione) associata ad oxaliplatino (80 mg/m2 endovena, giorno 1) ed un’infusione continua di 120 ore di 5-fluorouracile (1000 mg/m2 al giorno). La chirurgia è stata eseguita entro 6 settimane dal completamento del trattamento CRT.RisultatiIn 6 pazienti è stata ottenuta una risposta patologica completa (6,7%), in 39 pazienti (43,3%) è stata evidenziata una riduzione dello stadio iniziale di malattia. Il follow-up mediano è stato di 4,7 anni (da 6 mesi a 9 anni). Due pazienti hanno sviluppato una ricaduta locale (2,2%), uno ha sviluppato anche metastasi epatiche. Ventitre pazienti (25,6%) hanno presentato metastasi a distanza non associate a recidiva locale. La sopravvivenza globale (OS) e la sopravvivenza libera da malattia (DFS) sono state rispettivamente del 62,9% e 52,8%. La CRT è stata ben tollerata infatti un solo paziente (1,2%) ha sviluppato una tossicità ematologica (neutropenia) di grado 3.ConclusioniNei pazienti affetti da tumore del retto, la chemioterapia pre-operatoria, basata sull’uso dell’oxaliplatino ed il 5-fluoruracile ed associata alla radioterapia, è ben tollerata con buoni risultati in termini di risposta patologica, controllo di malattia e sopravvivenza.

Adjuvant Trastuzumab in Breast Cancer: Experience from the University of Florence

Abstract The objective of this study was to evaluate the efficacy and tolerability profile of sequential trastuzumab in the adjuvant treatment of non-metastatic breast cancer. We analyzed 94 patients with non-metastatic breast cancer who under went postoperative treatment between November2003 and December 2008 at the University of florence. All patients received one year of sequential trastuzumab after adjuvant chemotherapy. Cardiac monitoring in our study consisted of assessment of left ventricular ejection fraction (LVEF) by echocardiography at baseline, after the completion of chemotherapy, then every 3 months during trastuzumab treatment and every 6 months thereafter. 91.6% of patients were alive without evidence of distant or local relapse, while 8.4% developed disease recurrence. The cumulative incidence of cardiotoxicity was 14.5%. In our experience trastuzumab given postoperatively with adjuvant chemotherapy was well tolerated and produced optimal clinical results in terms of disease-free survival.

COMPARISON OF DIFFERENT EXTERNAL BEAM TREATMENT TECHNIQUES TO DELIVER HIGH-DOSE IRRADIATION TO LOCAL RECURRENT RECTAL CARCINOMA

Aims and background Treatment of local-regional recurrent rectal carcinoma is a challenging problem, and local control may be dose dependent; doses should probably exceed 60 Gy. Our aim was to verify the possibility to deliver 66 Gy to the target, but less than 35 Gy to the small bowel, comparing different 3D irradiation techniques, in a selected group of patients. Methods Five patients with local recurrent rectal carcinoma were selected as representative of different presentations of the disease. Gross tumor volume and clinical target volume were defined [by RS]. Tumors ranged between 182 and 540 cc, and small bowel volumes between 748 and 1050 cc. A three-field technique, coplanar multiple fields, noncoplanar fields and a proton beam were compared using dose volume histograms. A positive result was scored when ≥90% of the target received the prescribed dose with no more than 5% of the small bowel receiving more than 35 Gy. Doses were escalated in steps of 2 Gy from 60 to 66 Gy. Results The number of plans fitting the constraints were 7/19, 11/19, 18/19 for doses of 66 Gy, 64 Gy and 62 Gy, respectively. The stage of the tumor did not seem to correlate with the possibility to homogeneously cover the target with the prescribed dose. Conclusions Simple coplanar and complex coplanar techniques (up to six fields), positioning the patient in a prone position with dislocation of the bowel, seem to be the best solutions to treat almost all of the patients with doses of 64 Gy. Where higher doses are concerned, it is not possible to suggest a “standard” solution. More personalized techniques have to be tested to define the best option.

Radioterapia neoadiuvante associata ad oxaliplatino e 5-fluorouracile in pazienti affetti da tumore rettale localmente avanzato: l'esperienza di un singolo centro

PurposeThe aim of this study was to evaluate the rate of pathological response (PR), disease control and safety of neoadjuvant chemotherapy using oxaliplatin (OX) and 5-fluorouracil (5-FU) with concurrent radiotherapy for treating locally advanced rectal cancer.Materials and methodsBetween November 2002 and December 2010, 90 patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (CRT) were retrospectively analysed. All patients underwent preoperative radiotherapy (45 Gy in 1.8-Gy fractions) with concurrent OX (80 mg/m2 i.v., day 1) and a 120-h continuous infusion of 5-FU (1,000 mg/m2 per day). Surgery was performed within 6 weeks after completion of CRT treatment.ResultsComplete pathological response was obtained in six patients (6.7%), and 39 (43.3%) had their disease downstaged. The median follow-up period was 4.7 years (6 months to 9 years). Local recurrence occurred in two patients (2.2%), one of whom developed also liver metastases. Distant metastases not associated with local relapse occurred in 23 (25.6%) patients. Overall (OS) and disease-free (DFS) survival were 62.9% and 52.8%, respectively. CRT was well tolerated, with only one grade 3 (1.2%) haematological toxicity (neutropaenia).ConclusionsNeoadjuvant systemic chemotherapy based on OX and 5-UC associated with radiotherapy is well tolerated, with good results in terms of pathological response, disease control and survival, in rectal cancer patients.RiassuntoObiettivoLo scopo di questo studio è quello di valutare la risposta patologica (PR), il controllo di malattia e la sicurezza del trattamento chemioterapico basato sull’uso di oxaliplatino e 5-fluorouracile in associazione alla radioterapia nel trattamento del tumore del retto localmente avanzato.Materiali e metodiSono stati analizzati retrospettivamente, nel periodo compreso tra novembre 2002 e dicembre 2010, 90 pazienti affetti da tumore del retto localmente avanzato sottoposti a radio-chemioterapia (CRT) pre-operatoria. Tutti i pazienti hanno ricevuto una radioterapia pre-operatoria (45 Gy in 1,8 Gy per frazione) associata ad oxaliplatino (80 mg/m2 endovena, giorno 1) ed un’infusione continua di 120 ore di 5-fluorouracile (1000 mg/m2 al giorno). La chirurgia è stata eseguita entro 6 settimane dal completamento del trattamento CRT.RisultatiIn 6 pazienti è stata ottenuta una risposta patologica completa (6,7%), in 39 pazienti (43,3%) è stata evidenziata una riduzione dello stadio iniziale di malattia. Il follow-up mediano è stato di 4,7 anni (da 6 mesi a 9 anni). Due pazienti hanno sviluppato una ricaduta locale (2,2%), uno ha sviluppato anche metastasi epatiche. Ventitre pazienti (25,6%) hanno presentato metastasi a distanza non associate a recidiva locale. La sopravvivenza globale (OS) e la sopravvivenza libera da malattia (DFS) sono state rispettivamente del 62,9% e 52,8%. La CRT è stata ben tollerata infatti un solo paziente (1,2%) ha sviluppato una tossicità ematologica (neutropenia) di grado 3.ConclusioniNei pazienti affetti da tumore del retto, la chemioterapia pre-operatoria, basata sull’uso dell’oxaliplatino ed il 5-fluoruracile ed associata alla radioterapia, è ben tollerata con buoni risultati in termini di risposta patologica, controllo di malattia e sopravvivenza.