V. Quagliuolo

Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: A randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group

PURPOSE A previous randomized clinical trial by the Italian Sarcoma Group (ISG) had shown a survival benefit of adjuvant chemotherapy (CT) in high-risk extremity soft tissue sarcoma (STS). However, the dose-intensity of the last two cycles was suboptimal. We then undertook a multicentric international phase III study to compare three and five cycles of the same CT. PATIENTS AND METHODS Patients were randomly assigned either to receive three cycles of preoperative CT with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and granulocyte colony-stimulating factor (arm A) or to receive the same three cycles of preoperative CT followed by two further cycles of postoperative CT (arm B). Noninferiority of the primary end point, overall survival (OS), was assessed by the CI of the hazard ratio (HR; arm A/arm B) obtained from the Cox model. RESULTS Between January 2002 and April 2007, 328 patients were recruited (164 patients in each arm). At a median follow-up of 63 months (interquartile range, 49 to 77 months), 100 deaths were recorded, 49 in arm A and 51 in arm B. Five-year OS probability was 0.70 for the entire group of patients (0.68 in arm A and 0.71 in arm B). The HR of arm A versus arm B was 1.00 (90% CI, 0.72 to 1.39). CONCLUSION In this population of patients with high-risk localized STS, three cycles of full-dose preoperative CT were not inferior to five cycles. The outcome compares favorably with the expected survival of patients with high-risk STS and was superimposable on the CT arm of the previous ISG trial.

High-Dose Chemotherapy in Poor-Prognosis Adult Small Round-Cell Tumors: Clinical and Molecular Results From a Prospective Study

PURPOSE The prognosis of metastatic/high-risk localized small round-cell tumors (SRCTs) treated conventionally is dismal. In this phase II study, we explored a high-dose chemotherapy (HD-CT) approach and analyzed the clinical significance of fusion transcripts detection. PATIENTS AND METHODS From June 1997 to November 1999, 28 SRCT patients (median age, 26 years; 14 peripheral primitive neuroectodermal tumors [pPNETs], seven rhabdomyosarcomas [RMSs], and seven desmoplastic small round-cell tumors [DSRCTs]) received induction chemotherapy with ifosfamide, epirubicin, and vincristine followed by HD-CT. Local treatment (radiotherapy and/or surgery) was performed when possible. Molecular analysis was performed on peripheral-blood and leukapheresis products by reverse-transcriptase polymerase chain reaction. RESULTS Overall response (OR) was 65% (18 of 28), with 40% complete response and 25% partial response. According to histology, the OR rate was 86% in pPNET and 43% in both RMS DSRCT. With a median follow-up of 35 months, median overall survival was 16 months and median progression-free survival (PFS) was 10 months. PFS was statistically better in pPNET than other histologic types (P =.0045). No correlation was found between the fusion transcript and clinical outcome during follow-up. Furthermore, transcript detection in leukapheretic products was not of prognostic significance. CONCLUSION Intensive HD-CT seems to enhance the response rate and survival when compared with conventional treatment in poor-prognosis pPNET. The poor results of this treatment in RMS and DSRCT do not support the inclusion of such an approach in these patient subsets. No definitive conclusions can currently be drawn concerning the clinical implications of the detection of fusion transcripts during treatment or follow-up.

Tumor response assessment by modified Choi criteria in localized high-risk soft tissue sarcoma treated with chemotherapy.

The objective of this study was to compare the prognostic relevance of Response Evaluation Criteria in Solid Tumors (RECIST) versus Choi criteria for the assessment of response in patients with high‐risk soft tissue sarcoma of the extremities or trunk wall who received preoperative chemotherapy with or without radiotherapy in a phase 3 trial.

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.

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).

Prospective study of high-dose chemotherapy and autologous peripheral stem cell transplantation in adult patients with advanced desmoplastic small round-cell tumour.

A total of 10 desmoplastic small round-cell tumour patients were treated by high-dose chemotherapy with stem cell support. After high-dose chemotherapy, no complete response conversion was obtained and EWS-WT1 fusion transcript detection was positive in the peripheral blood during follow-up in all patients. High-dose chemotherapy did not seem to change the results in desmoplastic small round-cell tumour.

Peritonectomy and hyperthermic intraperitoneal chemotherapy: Cost analysis and sustainability

BACKGROUND Malignancies of the peritoneum remain a challenge in any hospital that accepts to manage them, due not only to difficulties associated with the complexity of the procedures involved but also the costs, which - in Italy and other countries that use a diagnosis-related group (DRG) system - are not adequately reimbursed. MATERIAL AND METHODS We analyzed data relative to 24 patients operated on between September 2010 and May 2013 with special regard to operating room expenditure, ICU stay, duration of hospitalization, and DRG reimbursement. The total costs per patient included clinical, operating room, procedure, pathology, imaging, ward care, allied healthcare, pharmaceutical, and ICU costs. RESULTS Postoperative hospital stay, drugs and materials, and operating room occupancy were the main factors affecting the expenditure for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. We had a median hospitalization of 14 days, median ICU stay of 2.4 days, and median operating room occupancy of 585 min. The median expenditure for each case was € 21,744; the median reimbursement by the national health system € 8,375. CONCLUSIONS In a DRG reimbursement system, the economic effort in the management of patients undergoing peritonectomy procedures may not be counterbalanced by adequate reimbursement. Joint efforts between medical and administration parties are mandatory to develop appropriate treatment protocols and keep down the costs.

The "old drug" DTIC as a second/third line chemotherapy in advanced soft tissue sarcomas (STS)

9032 Background: There is not a standard second line chemotherapy in advanced STS. DTIC is one of the most active drugs in the treatment of STS with a response rate (RR) of 17%. As a second line chemotherapy the data available confirm these interesting results. Therefore we conducted a retrospective analysis about 44 patients (pts) treated in our Institute with DTIC as second/third line therapy between May 1997 and October 2003. The aim of our analysis was to evaluate the RR, the progression free survival (PFS) and the median duration of response. METHODS About 44 pts anlysed, 36 were evaluable; 8 pts, after first cycle, were treated elsewhere. The median age was 55,5 (range 24-75). The 75% of pts (27/36) were metastatic and the 72% (26/36) had a disease grading 2-3. DTIC was done as second line chemotherapy in 70% of pts(25/36). The 75% of pts (27/36) and the 25% (9/36) had respectively progressive and relapsed disease before to start the treatment. DTIC was given every 21 days with three different schedules: DTIC 800 mg/sqm day 1 (20 pts); DTIC 400 mg/sqm days 1 and 2 (6 pts); DTIC 300 mg/sqm days 1, 2 and 3 (10 pts). RESULTS Among 36 evaluable pts, 3 (8%) achieved partial response (PR) and 7 (19%) stable disease (SD), with an overall disease control of 28%. No complete response was observed. As second line therapy DTIC achieved 2/25 PR and 5/25 SD. The median PFS and the median duration of response were respectively 2 and 8 months. The progression free rate at 3 and 6 months was respectively 33% (SE 7.86%) and 25% (SE 7.2%). No grade 3-4 hematologic and non-hematologic toxicity according to W.H.O. was observed. CONCLUSIONS Our results suggest that DTIC as a second/third line therapy yields a satisfactory disease control in progressive STS; its activity seems to be comparable to other treatments, such as the high dose of ifosfamide or ET-743, but with a lower toxicity profile. The increse of dose-intensity to obtain a better RR is questionable considering cost-benefit ratio in terms of toxicities and overall survival. No significant financial relationships to disclose.