Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.

BACKGROUND: To report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS). METHODS: Patients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model. RESULTS: Between January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103-135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively. CONCLUSIONS: At a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176).

A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study.

BACKGROUND: The management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC. PATIENTS AND METHODS: Patients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P). Vandetanib (300 mg or 100 mg) or placebo was given in single oral daily doses. Gemcitabine 1000 mg/m(2) was i.v. infused on day 1 and day 8 of each 21-day cycle. The primary end point was progression-free survival (PFS). Secondary end points were: objective response rate (ORR), disease control rate, overall survival, duration of response, performance status and safety outcomes. RESULTS: A total of 173 patients (mean age 63.6 years) were recruited at 19 centers across Italy. Median (95% confidence intervals) PFS (days) were 105 (72-155), 114 (91-193) and 148 (71-225), respectively, for the V, V/G and G/P treatment groups, with no statistical difference among them (P = 0.18). No statistical difference between treatments was observed for secondary end points, except ORR, which slightly favored the V/G combination over other treatments. The proportion of patients reporting adverse events (AEs) was similar for the three groups (96.6% in V arm, 91.4% in the V/G arm and 89.3% in the G/P arm). CONCLUSIONS: Vandetanib treatment did not improve PFS in patients with advanced BTC. The safety profile of vandetanib did not show any additional AEs or worsening of already known AEs. CLINICAL TRIAL NUMBER: NCT00753675.

Phase II prospective study with sorafenib in advanced soft tissue sarcomas after anthracycline-based therapy.

INTRODUCTION: We investigated the activity and safety of sorafenib, a multitargeted tyrosine-kinase inhibitor, in patients with advanced soft tissue sarcomas (STS). PATIENTS AND METHODS: An open-label nonrandomised multicentre phase II study was conducted in advanced STS patients pre-treated with anthracycline-based chemotherapy. Patients received sorafenib 400 mg twice daily for 28 days. The primary end point was the progression-free survival (PFS) rate at 6 months. Toxicity was assessed. Clinical outcomes were evaluated in all histologies and in leiomyosarcoma (L) and angiovascular sarcomas (A). RESULTS: Between November 2006 and January 2010, 101 patients (36 L, 19 A, and 46 others) were enrolled; 76 patients per-protocol (PP) and 100 per intention-to-treat (ITT) were assessable for the primary end point. In the PP analysis, 11 (14.5%) achieved partial response and 25 (32.9%) stable disease; 6-month PFS rates were all histologies, 34.5%; L, 38.4%; and A, 56.3%. In the ITT analysis, 6-month PFS results were 27.1, 35, and 35.5% in all histologies, L, and A, respectively. When stratified by histology, we observed a better PFS favouring leiomyosarcoma versus other histologies (P = 0.033). Treatment was well tolerated. CONCLUSIONS: Sorafenib appears to be a promising option in leiomyosarcoma patients. This finding warrants further evaluation in histology-driven trials.

Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall.

BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.

A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer.

BACKGROUND: Gefitinib inhibits the epidermal growth factor receptor tyrosine kinase and preclinical studies indicate that it may enhance CPT-11 cytotoxicity. This randomized phase II trial investigates the feasibility and efficacy of gefitinib and 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients were randomized to FOLFIRI +/- gefitinib 250 mg daily p.o. Patients randomized to FOLFIRI + gefitinib without disease progression after 6 months continued to receive gefitinib alone until disease progression. RESULTS: From October 2002 to September 2004, 100 patients were enrolled. Twenty-three patients (47.9%) in the FOLFIRI arm and 23 (45.1%) in the FOLFIRI + gefitinib arm experienced an objective response. The median progression-free survival and overall survival were 8.3 and 18.6 months in the FOLFIRI arm, and 8.3 and 17.1 months in the FOLFIRI + gefitinib arm, respectively. In the combination arm, grades 3-4 adverse events were experienced by 35 (67.3%) patients versus 25 patients (52.1%) in the FOLFIRI arm; 12 patients (23.1%) withdrew for an adverse event in the FOLFIRI + gefitinib arm and 5 (10.4%) in the FOLFIRI arm. CONCLUSIONS: These data show that adding gefitinib to FOLFIRI does not improve the efficacy of FOLFIRI regimen. These disappointing results could be related to the high toxicity observed that led to significant dose reductions and delays.

Solitary pancreatic head metastasis from tibial adamantinoma: a rare indication to pancreaticoduodenectomy.

Pancreatic metastases are rare, <2% of all pancreatic neoplasia. This is the first case of pancreatic metastasis from adamantinoma, a rare, low grade and slow growing tumor which is frequently localized in long bones. We describe a case of a 45-year-old woman presenting with increased bilirubin level. Computed tomography and ecoendoscopic ultra sonography revealed a pancreatic head mass. Fine-needle aspiration biopsy was consistent with metastatic adamantinoma. The patient was submitted to a standard pancreaticoduodenectomy. As in the case presented, standard pancreatic resections are safe and feasible options to treat non-pancreatic primary tumor improving patient's survival and quality of life.

New advances in biology and treatment of gastrointestinal stromal tumours (GISTs).

Gastrointestinal stromal tumours (GISTs) are a precise oncogenetic entity that has started the new era of targeted therapies in solid tumours. GISTs are now a model to understand the role of oncogenic kinase mutation in tumourigenesis, duplication, cell regulation, apoptosis and drug resistance. Ninety-five percent of GISTs have some activacting mutation of c-KIT or PDGFRA tyrosine kinase. The studies of the last two years have found concrete correlations between mutations and anatomical locations of GISTs, prognosis, response to therapy and resistance to therapy. Genotyping has increased of importance in the last years as a new field for translational researches. The important advances made in molecular studies are now a practical tool in diagnosis and therapy of GISTs.

[Clinical guidelines for the management of gastrointestinal stromal tumors]. / Raccomandazioni cliniche per la diagnosi, la terapia ed il follow-up dei tumori stromali gastrointestinali.

Treatment of gastrointestinal stromal tumors (GIST) has been revolutioned by the recently discovered molecular mechanism responsible for the oncogenesis of this disease. In addition, due to the rapid progress at molecular and clinical level observed in the last few years, there is a need to review the current state of the art in order to delineate appropriate guidelines for the optimal management of these tumors. A panel of experts from several specialities, including medical oncology, surgery, pathology, molecular biology and imaging, were invited to participate in a meeting to present and discuss a number of pre-selected questions, and to achieve a consensus according to the categories of the National Comprehensive Cancer Network (NCCN) and the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers. Generally, consensus points were from categories 2A of the NCCN and B2 of the SOR. Conventional histologic examination with immunohistochemistry for CD117, CD34, SMA, S-100 and desmin is considered standard. Molecular analysis for the identification of KIT and PDGFRA mutation may be indicated in CD117-negative GIST. Complete tumor resection with negative margins is the optimal surgical treatment. Adjuvant imatinib should be considered an experimental approach. Neoadjuvant imatinib is also experimental, although its use may be justified in unresectable or marginally resectable GIST. Imatinib should be started in metastatic or recurrent disease, and should be continued until progressive disease or drug intolerance. In these cases, sunitinib can be used. The optimal criteria for the assessment and monitoring of GIST undergoing imatinib therapy are not well known, but they should include reduction in tumor size and disease stabilization, as well as reduction of tumor density on CT scan and metabolic activity on PET scan.

Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin.

PURPOSE: In osteosarcoma of the extremity, a strong correlation between chemotherapy-induced necrosis and prognosis has been reported. The aim of this study was to investigate the possible factors that influence histologic response to primary chemotherapy. PATIENTS AND METHODS: In 272 patients with high-grade osteosarcoma of the extremity preoperatively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), and doxorubicin (ADM), the histologic response to chemotherapy was evaluated and graded as complete (no viable tumor cells) or incomplete (persistence of viable tumor cells). Several factors, such as metastatic disease to the lung at diagnosis, sex, age, site and tumor volume, histologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH), and methotrexate (MTX) pharmacokinetics were investigated to test their predictive significance on histologic response. RESULTS: Fifty-one patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic response (P = .006). After multivariate analysis, performed on patients with localized disease only, MTX serum peak (> or = 700 micromol/L) and histologic subtype were proven to be significant predictive factors of histologic response. A complete response was seen in 28.8% of patients with 700 micromol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblastic subtype was less responsive (6.1% of complete response), compared with the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%). CONCLUSION: Patients with metastatic osteosarcoma and localized chondroblastic osteosarcoma have a reduced chemosensitivity to primary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 micromol/L or greater when MTX is infused in 6 hours.

Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.

PURPOSE: Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents. PATIENTS AND METHODS: Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter > or = 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4'-epidoxorubicin 60 mg/m(2) days 1 and 2 and ifosfamide 1.8 g/m(2) days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor). RESULTS: After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P =.04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P =.03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P =.04). CONCLUSION: Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.

Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.

PURPOSE: This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma. PATIENTS AND METHODS: The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS: A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION: The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.

Biology, diagnosis and therapeutic options in gastrointestinal stromal tumours.

Gastrointestinal stromal tumours (GIST) are the most common form of mesenchymal tumour of the intestinal tract. The incidence in Italy is approximately 800-1,400 new cases/year; the most common localization is the stomach (50-60%), small bowel (20-30%), rectum (10%) and esophagus (5%). Extra-abdominal localizations are very rare. GIST characteristically express the Kit protein, a transmembrane tyrosine kinase receptor for the specific ligand. Most GIST have a mutation in kit receptor which becomes constitutive for the neoplasm. Kit mutation is a early tumorogenesis event. The disease clinically can present as an occasionally finding or can be diagnosed after hemorrhage, perforation or obstruction of the gastrointestinal tract. Surgery is the mainstay of the therapy mainly in primary tumour. More debated is its role in metastatic disease. In this situation imatinib mesilate, a tyrosine kinase inhibitor, is the drug of choice which has changed the natural history of the disease. Metastatic GIST before imatinib mesilate discovery had 6 months survival, now in the 3 published studies after 3 years of follow-up, median survival has not already reached. New drugs are now under evaluation in order to prolong the pharmacological activity of tyrosine kinase inhibition after progression of the disease.

Ifosfamide in the elderly: clinical considerations for a better drug management.

The therapeutic strategy used for elderly affected by malignant neoplasms should take into account the common variables present in oncological patients, and the specific alteration of the elderly metabolism and their possible morbidity. Ifosfamide is an active drug for various tumors with elevated incidence in the elderly. We analyze the principle criteria in the selection of these patients and the alterations of metabolism which correlates to aging with their consequences on the pharmacokinetics of ifosfamide. Finally, we propose clinical guidelines to optimize the use of ifosfamide in elderly patients affected by malignant tumors.

Cea and ca-19.9 as markers of colorectal neoplasms during chemotherapeutic treatment.

Carcinoembryonic antigen and CA 19.9 are markers of colorectal neoplasms, often related to tumor burden. Elevated pre-operative levels parallel disease extent and may foresee adverse prognosis. CEA and CA 19.9 may increase post-operatively, indicating tumor recurrence. Only limited data are available on the influence of chemotherapeutic treatments on these two markers, to detect chemotherapy-induced cytolysis. We measured CEA and CA 19.9 before and after a chemotherapy regimen of five days consisting of folinic acid and 5-fluorouracil in forty patients with colorectal cancer. No consistent fluctuation was detected, the examined tumor markers being related in a given patient only to tumor burden.

Reversal of multidrug-resistance using Valspodar (PSC 833) and doxorubicin in osteosarcoma.

High-grade osteosarcoma is an extremely aggressive neoplasm, where over 80% of patients present with life-threatening micrometastases at diagnosis. Systemic control of the disease is therefore critical for the treatment of these patients and neoadjuvant chemotherapy using various drugs, including doxorubicin (DXR), which has been demonstrated to be the most effective regimen. Multidrug resistance (MDR) to some anticancer agents, including DXR, mediated by the MDR1 gene product P-glycoprotein (Pgp), has been shown to be a major cause of chemotherapy failure in osteosarcoma. We analyzed the effect of a cyclosporine A derivate Valspodar (PSC 833) on MDR human osteosarcoma cells. We also evaluated Pgp expression in sporadic appendicular canine osteosarcoma. Moreover, dogs were treated with combined administration of DXR and PSC 833. Several blood samples were collected for the determination of DXR and PSC 833 levels. PSC 833 induced a complete reversal of the resistant phenotype at concentrations compatible with the clinical use. Pgp was present in 12/18 (66.6%) of the cases. At the time of DXR administration, adequate blood concentrations of PSC 833, to provide a complete MDR reversal, were obtained without clinical or laboratory findings of toxicity. Combination therapy with DXR and PSC 833 allowed a 30% decrease in DXR dose infusion with equivalent therapeutic exposure. The high incidence of Pgp expression in osteosarcoma confers to the study a rationale for an effective regimen based on down-modulation of MDR.

Neoadjuvant chemotherapy for osteosarcoma of the extremity in patients in the fourth and fifth decade of life.

From January 1986 to March 1993, 29 patients aged between 40 and 60 years with primary high grade osteosarcoma of the extremity were treated at Rizzoli Institute with neoadjuvant chemotherapy. Before surgery patients received cisplatin and adriamycin. Postoperatively, patients with a good histologic response received the same two drugs preoperatively used, while in case of poor response ifosfamide and etoposide were added to cisplatin and adriamycin. Twenty-five patients (86%) were surgically treated with a limb salvage, whereas 4 patients (14%) were amputated. With a median follow-up of 8 years (5-12), the 8-year event-free survival was 57% and the 8-year overall survival was 62%. No chemotherapy-related deaths were recorded and toxicity was manageable. These results are significantly better than those achieved in 24 patients of the same age, treated at Rizzoli Institute between 1975 and 1985 only with surgery (87% of amputation and 17% of 8-year event-free and overall survival) and indicate an advantage for the use of neo-adjuvant chemotherapy also in patients with high grade osteosarcoma of the extremity older than 40 years.

Low dose adriamycin and ifosfamide in the treatment of advanced adult soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are infrequent tumors (up to 1% of all neoplasms) in adult patients. Treatment of advanced disease is largely unsatisfactory. Only a few drugs are active agents and combination regimens offer limited and short-lived activity. High dose chemotherapy may be administered only to limited groups of patients. PATIENTS AND METHODS: We evaluated, in a phase II study, the adriamycin and ifosfamide combination regimen. The drugs were administered at 60 mg/sqm and 6 g/sqm dosage, respectively. The total number of treated patients was 42 of which 40 were evaluable. RESULTS: We observed 6 complete responses (14% response rate) and 6 partial responses (14%). The mean survival was 6 months (median 7.6 months). Toxicity was limited and reversible. CONCLUSION: While high dose chemotherapy may be reserved for selected groups of patients, an adriamycin and ifosfamide combination regimen at conventional doses can be administered to the great majority of patients with suboptimal performance status or with advanced age.

Non small cell lung cancer treatment with vinorelbine monochemotherapy: a phase II study.

Non small cell lung cancer is one of the leading causes of death in the industrial countries and some 70% of patients have non surgically eradicable disease. Platinum based combined regimens can achieve 35-40% objective responses, but advanced age, low performance status and concurrent diseases can exclude up to 60% of patients from an adequate poliychemotherapy treatment.

Palmar-plantar erythrodysestasia syndrome associated with 5-fluorouracil treatment.

Palmar-Plantar Erythrodysestasia Syndrome (PPES) or Hand-Foot Syndrome (H&F S) is an underestimated adverse reaction to chemotherapeutic agents, mainly related to 5-Fluorouracil. From March 1991 to February 1992, at the San Giovanni Oncologic Hospital of Torino, we observed 12 out of 163 patients (7.3%) displaying PPES while being treated with 5-FU containing regimens. No correlation with type of neoplastic disease, sex, age and total dose of administered 5FU was observed. Dose reductions or drug suspension achieved PPES reversal. The etiopathogenesis remains unclear. Both an idiosyncratic pattern and cutaneous drug accumulation are suggested.

Radiation therapy and chemotherapy in the conservative treatment of carcinoma of the anal canal: survival and late morbidity in a series of 25 patients.

Combined radiation therapy and chemotherapy have been reported to produce a high incidence of complete regression of epithelial cancer of the anal canal. Our group has treated 25 patients since June 1986. Treatment included chemotherapy (first period: Mitomycin C + 5-Fluorouracil; second period: Carboplatin + 5-Fluorouracil) and simultaneous whole-pelvis irradiation (50.40 Gy). Our results confirm that radiochemotherapy can achieve good local control: all patients were in complete clinical remission three months after the completion of combined therapy. Seven, patients developed recurrences; the actuarial survival rate was 78.5% and the disease free survival rate 67%. Acute toxicity was tolerable, but a relatively high number of patients exhibited chronic treatment-related symptoms. In order to reduce late side effects, other studies are necessary to explore if, in patients with small tumors, less extensive locoregional treatment can be effective without reducing the survival rate.