Abstract Aim To explore the effect of preoperative imatinib mesylate (IM) in patients with unresectable or locally advanced primary gastrointestinal stromal tumor (GIST). Methods From January 2003 to ...January 2008, all patients affected by bulky localized GIST who presented at our institution were considered for preoperative IM with cytoreductive intent. Clinical, pathological and molecular characteristics were assessed and the rate of response recorded. Progression-free survival (PFS) was calculated according to Kaplan–Meier analysis. Results Fifteen patients (1 esophageal, 7 gastric, 3 duodenal, 4 rectal GISTs) received preoperative IM for a median of 9 months. All patients had tumor shrinkage, with a median size reduction of 34%. One patient had radiological complete response. In all cases an improvement of the originally planned surgical procedure was obtained: 3 patients initially considered unresectable underwent complete surgery; 7 patients with initial indication for extensive surgery were more conservatively operated on; 4 patients initially deemed at high perioperative risk underwent safe surgery. Due to the small sample size, no association between tumor shrinkage and tumor site, size, IM duration, mutational status and pathological response could be formally explored. PFS at 3 years from IM onset was 77%. Conclusions In unresectable or locally advanced GISTs, preoperative IM is a useful tool both to improve resectability and reduce surgical morbidity. It should be therefore always be considered before embarking on a major surgical procedure. The long-term impact of IM on PFS and survival is presently under investigation in multicenter prospective randomized trials.
Summary EGFR overexpression in salivary gland carcinomas provides the rational for the investigation of anti-EGFR treatments in recurrent and/or metastatic salivary gland cancers (RMSGCs). The ...activity of cetuximab in terms of clinical benefit rate (CBR) defined as the occurrence of objective response (CR or PR) or stable disease (SD) for ⩾6 months was investigated. From April to December 2005, 30 patients 23 adenoid cystic carcinoma (ACC) and 7 non-ACC were treated with cetuximab at 400 mg/m2 /week followed by 250 mg/m2 /week until progression, major toxicity or voluntary discontinuation. EGFR expression and gene status were retrospectively analyzed by immunocytochemistry and fluorescence in situ hybridization, respectively. A median of 14 courses of cetuximab (range 5–54) were infused. Skin toxicity was the main adverse event. Cetuximab provides a CBR in 50% (95% CL, 31 to 69%) of cases. None tumor sample showed EGFR gene amplification and an increased EGFR copy number was observed in 12% of samples, all ACC. Skin rash ⩾G2, EGFR overexpression and EGFR copy number were not statistically correlated to CB. In RMSGCs further evaluations of EGFR targeting agents are advisable and should take place by appropriate tumor biological selection, differentiating ACC from non-ACC.
Abstract Background Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas ...(RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 VEGFR2, platelet-derived growth factor receptor α PDGFRα and β, RET, KIT). Patients and methods Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). Results Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval CI: 6–32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31–69%); DCR was 76% (95% CI: 59–88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRβ in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRβ, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer SDC, one high-grade mucoepidermoid HG-MEC and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRβ immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). Conclusions Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRβ-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.
Trabectedin has been approved in Europe as second-line therapy for advanced soft tissue sarcomas. A previous analysis showed that myxoid liposarcomas (MLS) are particularly sensitive to the drug. We ...report on the long-term efficacy of trabectedin in a subgroup of that series.
Since September 2002, 32 advanced pretreated MLS patients received trabectedin at our center. Data were reviewed focusing on their long-term outcome.
Trabectedin was given as a 24-h continuous infusion every 21 days. A total of 376 and a median of 12 courses per patient (range 2–26; interquartiles range (IQR) 8–15) were delivered. Response rate per RECIST was 50% 95% confidence interval (CI) 32% to 68%, median progression-free survival (PFS) was 17 months (95% CI 13.5–30.1) and median overall survival is still not reached. In 10 patients, therapy was stopped in the absence of any evident disease, mostly after complete surgery of residual lesions. In these 10 patients, at a median follow-up of 25 months, PFS was 28.1 months (95% CI 25.6–36.4) from treatment start.
These data indicate that the high response rate of MLS to trabectedin translates into prolonged PFS. Surgery of residual metastatic disease is already used quite extensively in metastatic MLS. Trabectedin may give further significance to this kind of surgery.
Background: Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, ...sirolimus, to IM in IM-resistant advanced chordoma. Patients and methods: Since July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis. Results: The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (≥10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit RECIST complete response + PR + SD ≥6 months was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off. Conclusion: In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.
To evaluate neoadjuvant trabectedin (1.5 mg/m2 24-h i.v. infusion every 3 weeks; three to six cycles) in patients with locally advanced myoxid liposarcoma (ML) previously untreated with chemotherapy ...or radiation.
Primary efficacy end point was pathological complete response (pCR) or tumoral regression rate. Objective response according to RECIST (v.1.0) was a secondary end point.
Three of 23 assessable patients had pCR 13%; 95% confidence interval (CI), 3% to 34%. Furthermore, very good and moderate histological responses were observed in another 2 and 10 patients, respectively. Histological decrement in the cellular and vascular tumor component and maturation of tumor cells to lipoblasts were observed in both myoxid and myoxid/round cell variants. Seven patients had partial response according to RECIST (objective response rate of 24%; 95% CI, 10% to 44%). No disease progression was reported. Neoadjuvant trabectedin was usually well tolerated, with a safety profile similar to that described in patients with soft tissue sarcoma or other tumor types.
Trabectedin 1.5 mg/m2 given as a 24-h i.v. infusion every 3 weeks is a therapeutic option in the neoadjuvant setting of ML.
Angiosarcoma is a highly aggressive soft tissue sarcoma. Responses to anthracyclines plus/minus ifosfamide, and taxanes alone or in combination with gemcitabine are well documented. Very few data are ...available on gemcitabine as a single agent.
We retrospectively reviewed all cases of advanced progressive angiosarcoma treated with gemcitabine as a single agent (1000 mg/m2 i.v. every week for 3 weeks every 4 weeks), at Istituto Nazionale Tumori and within the Italian Rare Cancers Network from January 2008 to November 2010.
Twenty-five patients mean age: 52 years; radiation therapy (RT)-related: 8 received gemcitabine. Best tumor response by RECIST was as follows: complete response = 2, partial response = 14, stable disease = 2, progressive disease = 7 cases, for an overall response rate (PR + CR) of 68%. Six of eight post-RT angiosarcomas responded to treatment. Median overall survival (OS) was 17 months. Median progression-free survival (PFS) was 7 months (range 1–40 months). One patient with a locally advanced thyroid angiosarcoma became resectable after 5 months of gemcitabine, with <10% residual viable tumor cells seen on surgical specimen. Overall, gemcitabine was well tolerated.
Gemcitabine is active in both RT- and non-RT-related angiosarcoma, with dimensional and possibly long-lasting responses. A formal phase II study on gemcitabine as a single agent is warranted.
Abstract Because plasma DNA may be a useful tool for cancer detection, we screened primary tumors and related multiple plasma samples at the time of surgery and during the follow-up period for plasma ...DNA level as well as for K-Ras mutations and p16 INK4a promoter hypermethylation in colorectal cancer patients. At the time of surgery, DNA levels were higher in tumor patients than in healthy donors, and K-Ras and p16 INK4a alterations were detected in 7 and 11 cancers respectively, and in all related plasma samples. During the follow-up, plasma DNA levels decrease progressively but rapidly increased when a relapse occurred, whereas K-Ras and p16 INK4a alterations were detected only in relapsed patients. Therefore, combined quantitative and qualitative analyses of plasma DNA confirm the presence of colorectal cancer, define disease-free status and indicate the presence of relapse.
Abstract Background To report on anthracycline-based chemotherapy in a retrospective case-series analysis of solitary fibrous tumour (SFT) patients treated within the Italian Rare Cancer Network. ...Patients and methods We reviewed a set of SFT treated with chemotherapy since 2002, focusing on anthracycline, administered alone or in combination with ifosfamide. Responses to ifosfamide as a single agent were also evaluated. Pathologic diagnosis was centrally reviewed, distinguishing typical, malignant (MSFT) and dedifferentiated (DSFT) subtypes. Results Among 42 SFT patients treated with chemotherapy, we selected 31 cases (mean age: 62 years; locally advanced/metastatic: 13/18; front-line/further line: 25/6; typical/MSFT/DSFT/not assessable: 1/17/12/1) who received anthracycline-based chemotherapy (anthracycline monotherapy: eight; anthracycline + ifosfamide: 23). 30 patients are evaluable for response. Best response by Response Evaluation Criteria in Solid Tumours (RECIST) was: partial response (PR): 6 (20%), stable disease (SD): eight (27%), progressive disease (PD): 16 (53%) cases. Responses were confirmed after 3 months. Median progression-free survival (PFS) was 4 (range 2–15) months, with 20% of patients being progression-free at 6 months. PR was found in 2/18 (11%) MSFT and 4/12 (30%) DSFT, with a median PFS of 3.5 and 5 months in MSFT and DSFT, respectively. 19 patients received high-dose prolonged-infusion ifosfamide (front-line/further line: 11/8; typical/MSFT/DSFT: 0/15/4) with two (10%) PR, five (26%) SD, 12 (63%) PD. Conclusions This retrospective series suggests that in SFT anthracyclines have a degree of antitumour activity in the range of soft tissue sarcoma chemotherapy. Ifosfamide monotherapy seemed to have lower activity. A higher response rate was observed in DSFT in comparison to MSFT. Studies on targeted therapies are ongoing.
Abstract Background To explore the activity of pazopanib in solitary fibrous tumour (SFT). Patients and methods In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, ...regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm3 . Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure. Results In the xenograft model, pazopanib showed the lowest antitumour activity (21%TVI), while regorafenib was the most active (95%TVI). Sorafenib, bevacizumab, sunitinib were markedly active (78/70/65%TVI). Axitinib was marginally active (51%TVI). In the retrospective case-series, three patients carried malignant-SFT (MSFT), three DSFT. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: three stable disease (SD), all MSFT, three progressive disease (PD), all DSFT, corresponding to one partial response (PR), two SD, three PD by Choi criteria. Median-progression-free survival was 3 months (range 1–15). In one patient, sunitinib was started after pazopanib failure, with a response. Conclusions In dedifferentiated-SFT xenograft pazopanib induced a marginal antitumour activity, while regorafenib appeared the most active and promising agent. When administered in patients, pazopanib showed a modest activity in terms of tumour growth stabilisation, observed only in non-dedifferentiated cases.
PDF
