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A combination of docetaxel (D), oxaliplatin (O), and capecitabine (C) (DOC) was studied in this dose-escalation phase Ib trial in patients with untreated advanced gastric cancer. Dose-limiting toxicity (DLT) included any grade 4 hematological or any grade 3 non-hematological toxicity, besides alopecia and nausea or vomiting. Cohorts of three patients, expanded to six if one DLT occurred, were studied. Two DLTs out of three patients, or ≥3 out of six patients defined the toxic level. The preceding level, maximum tolerated dose (MTD), was further expanded to nine patients. The primary objective was to establish the MTD of the DOC regimen. Twenty-one patients entered four dose levels. Levels I, II, and IIb were considered safe and included 3, 6, and 6 patients, respectively. Level III defined our toxic level with three analyzed patients. Therefore, level IIB was expanded to 9 patients. No other DLTs were recorded. Fractionation of doses and the use of less toxic and more convenient derivatives are the rationales for this new combination. The MTD (mg/m2) was: D, 30 and O, 70, both on days 1 and 8, i.v.; C 1000 per day, days 2–15, p.o.; all given every 3 weeks. A cooperative phase II study has been opened.

Elderly patients constitute a subpopulation with special characteristics that differ from those of the general population and have been under-represented in clinical trials. We, prospectively, analyzed the toxicity and efficacy of the original FOLFOX4-regimen in the treatment of elderly patients affected by metastatic (m) colorectal cancer (CRC). Thirty-six consecutive patients aged 67–82 years (median age 72 years), 22 males and 14 females, with mCRC and measurable disease, were enrolled in the study. The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. A total of 36 patients, aged 67–82 years were included. Twenty-two and 14 patients were male and female, respectively. The median age was 72 years (range 67–82). The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The overall response rate (ORR) was 44.4% and similar to original study. Median progression-free survival (PFS) was 7.5 months and median overall survival (OS) was 16 months. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. Tolerability, however, was manageable and no toxic death occurred. FOLFOX4-regimen maintains its efficacy, and safety ratio in elderly patients with mCRC and good performance status. It would be considered the treatment of choice in the treatment of this particular setting of patients.

BACKGROUND. Chondrosarcoma (CS) is a rare and heterogeneous sarcoma in which, after failure of surgery and radiotherapy, chemotherapy plays only a marginal role. Different molecular pathways have been shown to be activated in CS; in particular, both isoforms of platelet-derived growth factor receptor (PDGFR) are expressed and phosphorylated. These observations prompted investigation of the activity of imatinib mesylate (IM) in patients with advanced CS in a phase 2 trial. METHODS. Between January 2007 and June 2009, patients with metastatic, nonresectable CS were treated with 400 mg of IM administered twice daily until disease progression or unacceptable toxicity. Two criteria determined patient trial eligibility: ≥1 prior line of chemotherapy and immunohistochemical expression of either PDGFR-α or PDGFR-β. The primary objective of the trial was objective response. As secondary objectives, the authors selected progression-free survival (PFS) at 4 months, overall survival, and clinical benefit (EUDRACT number 2006-006446-33). RESULTS. Twenty-six patients were enrolled and all demonstrated PDGFR positivity and phosphorylation. No objective response was demonstrated. The 4-month PFS rate was 31% (95% confidence interval [95% CI], 16%-53%). The median overall survival was 11 months (95% CI, 6 months-15 months). Neither long-lasting freedom from disease progression nor clinical benefit was observed. The IM dose was temporarily reduced in 60%15 of the patients because of toxicity. CONCLUSIONS. IM was found to be relatively well-tolerated, but failed to demonstrate meaningful clinical activity in terms of both objective response and freedom from disease progression. Advanced CS remains an incurable disease, and effective targeted therapies are still awaited. Cancer 2011. © 2010 American Cancer Society.

PurposeUGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.Patients and MethodsIn a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy.ResultsUGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7when compared with TA6/TA6patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)×(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7genotype and a higher response rate, indicating that the polymorphism is functionally relevant.ConclusionThe results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.

Oxaliplatin is a new, third-generation platinum complex. It has a good safety profile characterized by low hematological-gastrointestinal toxicity. No significant nephro-ototoxicity has been observed. Acute peripheral neuropathy is a common event affecting, as grade 1 or 2, 85-95% of patients. Recently, data on dysphonia toxicity, after the administration of oxaliplatin, has been reported in literature. This toxicity with acute onset can be misunderstood if not carefully looked for. However, it is self-limiting and a non-permanent (grade 1-2) neurotoxic phenomenon, which impairs transiently the quality of life of a percentage of oxaliplatin-treated patients. We report our experience in consecutive patients affected by advanced colorectal cancer treated with oxaliplatin-based chemotherapy. Overall, we observed 13 (16%) cases of dysphonia out of 81 consecutive patients treated with oxaliplatin-based chemotherapy. This toxic effect was self-limiting and all patients recovered rapidly. Nonetheless, a deeper understanding of this phenomenon is essential to give correct information to the patients.

Ifosfamide and anthracyclines are the only active agents in advanced soft tissue sarcomas. Doxorubicin was always used in sarcomas, whereas ifosfamide was reintroduced in the clinic after the discovery of mesna which prevents its typical dose-limiting toxicity: hemorrhagic cystitis. In the adjuvant setting, doxorubicin was used alone or in combination in the first-generation trials, whereas its parent compounds epirubicin and ifosfamide were employed in the second-generation adjuvant trials, which started in the early 90s. Other relevant aspects of the second-generation trials are the use of the hematopoietic growth factors and the increase of the dose intensity, the introduction of more restrictive selection criteria and the use of the two most active agents, ifosfamide and anthracyclines. Only the Italian cooperative trial has been concluded, and the results reported and updated. After a median follow-up of 89.6 months (range 56–119), the intention-to-treat analysis still reveals a difference in overall survival which, however, is not statistically significant. However, the 5-year overall survival estimate, which is a reasonable end point for the survival analysis of adjuvant treatment in soft tissue sarcomas, was 66.0 and 46.1% for the treatment and the control groups, respectively (p = 0.04).

Summary Background: The combination of paclitaxel (P) and carboplatin (C) is an effective treatment for advanced NSCLC. Gemcitabine (G) is an active new drug. We planned a phase I study to find the maximum tolerated dose (MTD) of the PCG combination. A phase II study was subsequently conducted to evaluate the activity and toxicity of PCG. Patients and methods: Forty-five patients entered the study. Twenty-eight had stage IIIA-B disease, 17 stage IV. In the phase I study, with a fixed dose of C at AUC = 6 on day 1, P was escalated using increments of 25 mg/m 2 starting from 175 mg/m 2 on day 1 and G with increments of 200 mg/m 2 starting from 800 mg/m 2 on day 1 and 8. Results: Fourteen patients entered the phase I study. The MTD was reached at P 200 mg/m 2 , C AUC = 6 and G 1000 mg/m 2 . Neutropenic fever and grade 3 diarrhea were the dose limiting toxicities. Thirty-one patients were treated in the phase II study with P 175 mg/m 2 , C AUC = 6 and G 1000 mg/m 2 . Response rate was 57% (68% in stage III and 47% in stage IV). Myelosuppression was the main toxicity, with grade 3-4 leukopenia occurring in 35% of cases. Grade 3 anemia was observed in 24% of cases and grade 3-4 thrombocytopenia occurred in 34% of patients. Non-hematological toxicity was mild. Median survival and one-year actuarial survival were 20.5 months and 74% for stage III and 11.5 months and 47% for stage IV. Conclusions: PCG is a promising regimen for treating advanced NSCLC. A phase III study comparing PCG to paclitaxel plus carboplatin in advanced NSCLC is ongoing. On the other hand, we are planning to introduce the PCG regimen in the treatment of stage II—III patients in the setting of a multimodality treatment.

Purpose. The prognosis of advanced soft tissue sarcoma is poor, only a few drugs showing some activity with response rates around 15– 25%. Consequently drug development seems mandatory to improve treatment outcome. Following previous favourable EORTC experience, the Italian Group on Rare Tumors started a phase II study with docetaxel to confirm the activity of this drug in soft tissue sarcoma. Patients and methods. Thirty-seven patients with soft tissue sarcoma resistant to at least one anthracyclinecontaining regimen were enrolled in a phase II multicenter study evaluating docetaxel 100 mg/m2 in a 1-h i.v. infusion q3 weeks. Results.Thirty-seven patients were enrolled onto this phase II study and 36 were evaluable for response. Only one partial remission was observed [2.8% with 95% confidence interval (CI) 0.1– 16.2%]. Median progression-free and overall survival were 42 and 350 days, respectively. Neutropenia and leukopenia as well as cutaneous manifestations were the most common toxicities. Discussion. The results of this phase II study do not confirm a previous EORTC repor t on the activity of docetaxel in soft tissue sarcoma, but are consistent with other more recent phase II studies. The accumulated evidence does not justify the use of this drug in the management of patients suffering from this disease, resistant to anthracyclinecontaining regimens.

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/m2 and ifosfamide 9 g/m2 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.

BACKGROUND. 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. METHODS. Patients received 3 cycles of preoperative epirubicin þ ifosfamide with or without radiotherapy. The diagnostic concordance between RECIST and Choi criteria and their correlation with overall survival (OS) and freedom from progression (FFP) were evaluated in a univariate Cox regression model. RESULTS. In 243 of 321 eligible patients, RECIST, Choi criteria, and histology were predictive for OS and FFP. In the subgroup of 69 patients who received chemotherapy alone and were evaluable by both RECIST and Choi criteria, Choi criteria were associated significantly with OS and FFP, whereas RECIST predicted only FFP, and the pattern of agreement observed between the 2 criteria was unsatisfactory. On a dichotomous scale, comparing objective response (complete and partial responses) and lack of response (stable and progressive disease) to preoperative chemotherapy according to RECIST and Choi criteria, only Choi criteria were predictive of OS and FFP, and fair agreement between RECIST and Choi criteria was observed. When lack of progression and progression were compared (complete and partial responses þ stable disease vs progressive disease), both assessment criteria were significantly predictive of OS and FFP, and there was substantial agreement between the 2 criteria. CONCLUSIONS. Response to chemotherapy with or without radiotherapy was associated with a better outcome in patients with high-risk soft tissue sarcoma. Choi criteria were better predictors than RECIST in patients who received preoperative chemotherapy alone. Cancer 2012;118:5857-66. V C 2012 American Cancer Society.

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/m2 and ifosfamide 9 g/m2 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.

BACKGROUND The tumor suppressor protein p53 is overexpressed in a large fraction of human tumors. It has been supposed that p53 abnormalities may be an early event that contributes to the neoplastic transformation; alternatively, p53 overexpression might be related to progression toward more aggressive tumor phenotypes. The aim of the present work was to better clarify the role of p53 overexpression in human soft tissue sarcomas (IISTS). DESIGN p53 immunohistochemistry analysis using the Pab 1801 was performed in frozen samples of HSTS obtained from 61 patients. Tumors were classified according to the WHO criteria, histologic grading was based on the criteria of Enzinger and Weiss, and DNA ploidy and S-phase determination was performed by flow cytometrical analysis. RESULTS Of all the HSTS we analyzed, p53 protein over-expression occurred more frequently in G3 grade tumors (p < 0.01), HSTS of III A-B stage (p = 0.02) and in aneuploid tumors (p < 0.01). CONCLUSIONS The association of p53 overexpression with parameters of biological aggressiveness suggests an involvement of p53 in the neoplastic progression of HSTS. This assumption is supported by the findings that in tumors with a mixed diploid/aneuploid neoplastic cell population p53 protein expression was significantly (p < 0.01) higher in the aneuploid cell subpopulation. In conclusion, our study suggests that overexpression of p53 is present mainly in the most biologically aggressive forms of HSTS and may therefore represent a neoplastic progression index possibly useful for prognostic purposes.

Elderly patients constitute a subpopulation with special clinical features that differ from those of the general population and are under-represented in clinical trials. We retrospectively analyzed the toxicity and efficacy of oxaliplatin-based chemotherapy in the treatment of elderly patients affected by metastatic (m) CRC. Seventy-five consecutive patients aged 65-75 years (median age 71 years), 51 males and 24 females, with mCRC and measurable disease, were analyzed. The primary site of metastases was the liver (38.6% of patients). The majority of patients had a performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) PS before treatment of 0-1 (96%). The overall response rate was 57.3%, median progression-free survival was 7 months and median overall survival was 27 months. The main hematological and extra-hematological toxicities (grade 3 or 4) were neutropenia (20.0%), and neurological toxicity or diarrhea (6.7%), respectively. No toxic death occurred. Oxaliplatin-based chemotherapy maintains its efficacy, and safety in elderly patients with mCRC and good PS. This regimen should be considered in the treatment of this particular setting of patients.

Background: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. Patients and Methods: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m2/12 days as continuous infusion) and doxorubicin (75 mg/m2 on day 8) every 28 days with granulocyte colony-stimulating factor. Results: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. Conclusions: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

Angiosarcomas are rare soft tissue malignancies. Typically they originate from the skin of the scalp or face, whereas visceral sarcomas are very rare. We report the case of a 67-year-old man affected by a large angiosarcoma of the kidney. After surgical removal, a rapid peritoneal, visceral and cutaneous diffusion developed. Palliative chemotherapy, based on anthracycline and ifosfamide, which are normally used to treat all other high-grade spindle cell sarcomas, was totally inactive. On the basis of these results and of the biological characteristics of these rare neoplasms it is mandatory to develop other therapeutic approaches. Antiangiogenetic agents are of interest for this disease due to the peculiar origin of the cells of these sarcomas.

The aim of the study was to evaluate tolerance and efficacy of preoperative treatment with capecitabine in combination with radiation therapy (RT) in patients with locally advanced, resectable, rectal cancer.Fifty-three patients with potentially resectable T3, N0-2 (87%) and T4, N0-2 (13%) rectal cancer were treated with capecitabine (825 mg/m2, twice daily for 7 days/week) and concomitant RT (50.4 Gy/28 fractions). Patients underwent surgery after 6-8 weeks followed, upon physician's indications, by 4-months adjuvant capecitabine. The primary end point was to determine the rate of pathologic complete response. Secondary end points were to assess the rate of clinical response and the safety profile.All patients but two completed the RT programme and 47 (89%) received 81%-100% of the capecitabine dose (100% of dose in 72% patients, 81%-95% in 17% patients and 48%-74% in 11% of patients). No patient had grade 4 toxicity. Grade 3 toxicity occurred in six patients (11%) and consisted mainly of leucopenia (4%) and hand-foot syndrome (4%). Mild or moderate toxicity was common and included leucopenia (72%), diarrhea (40%), proctitis (34%) and skin toxicity (20%). The overall clinical response rate was 58% and the downstaging rate was 57%, with a pathologic complete response rate of 24%. Among 34 patients with low-lying tumors (or=5 cm from anal verge), 20 (59%) had a sphincter-saving operation.Preoperative chemoradiation with capecitabine and RT appeared to be effective in locally advanced resectable, rectal cancer. The favorable safety profile of the combination might warrant the use of capecitabine and RT with other effective new drugs.

Purpose: Irinotecan (CPT11) is a prodrug activated in humans mainly by carboxylesterase 2 (CES2) generating the SN38 metabolite responsible for the drug efficacy and toxicity. The interpatients variability in CPT11 activation step could cause unpredictable toxicity. To identify a predictive molecular marker for CPT11 activation in cancer patients, we investigated the CES2 mRNA expression in peripheral blood mononuclear cells (PBMC) and correlated it to CPT11 activation rate, toxic effects, and response.Experimental Design: Forty-five colorectal cancer patients were treated with a CPT11-including regimen (FOLFIRI). CES2 mRNA expression in PBMC was quantified by reverse transcription-PCR in real time. Plasma concentrations of CPT11, SN38, and SN38-glucuronide were determined by high-performance liquid chromatography and the pharmacokinetic variables calculated adopting the noncompartmental model. Toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria scale and response by the WHO criteria.Results: A high interindividual variability in CES2 mRNA relative expression was observed (median, 1.45; range, 0.01-28.21). CES2 mRNA expression level was significantly associated with CPT11 activation ratio [(AUCSN38 + AUCSN38G)/AUCCPT11]. Patients with CES2 mRNA expression above the median cutoff value presented an activation ratio higher (median, 0.25; range, 0.15-0.42) than those with CES2 mRNA below the median (median, 0.20; range, 0.10-0.40; P = 0.013). This was associated with a nonsignificant trend of 1.34-fold increase of SN38 AUC in the group of patients with high CES2 mRNA expression (mean, 1.03 ± 0.62 versus 0.77 ± 0.32 μmol/L hour). Eight of 23 high CES2 mRNA–expressing patients (34.8%) developed grade 3 to 4 neutropenia or diarrhea compared with 2 of 22 (9.1%) in the low CES2-expressing group (P = 0.071).Conclusion: Our data support a predictive power of CES2 mRNA expression in PBMC for the activation rate of CPT11.

During the past two decades, significant advances have been made in the management of patients with rectal cancer. A number of clinical studies have demonstrated the efficacy of preoperative chemoradiation therapy with 5-fluorouracil (5-FU)-based regimens in decreasing local recurrences and improving survival and the likelihood of sphincter preservation. Although 5-FU has been the standard drug used in combination with radiation therapy for many years, new effective drugs including capecitabine, raltitrexed, irinotecan and oxaliplatin have been recently investigated in combination with radiation therapy in the preoperative setting. In addition, novel targeted biological agents including epidermal growth factor receptor inhibitors and vascular endothelial growth factor inhibitors have been shown to enhance the antitumor effect of both radiation and chemotherapy and are currently being explored in initial clinical trials. In the present review we summarize the results of adjuvant therapy. In addition, we will discuss the recently reported phase I-II trials with new drug plus radiation combinations in the preoperative treatment of patients with rectal cancer.

Gastric cancer is one of the most frequent human tumors. Most patients are diagnosed at advanced stages, and fatal outcome is expected. Seven-hundred and seven patient charts were retrospectively reviewed. Univariate and multivariate analyses were performed to evaluate the impact of clinicopathologic and treatment variables on survival. Most patients (50%) were at advanced stages, harboring poorly differentiated tumors. Surgery, mostly palliative, was performed in 85% of patients. Chemotherapy was administered to 52% of patients. On univariate analysis, significant prognostic factors were age, TNM stage, chemotherapy, radiotherapy, tumor grade, curative surgery attempt, performance status and tumor site. On multivariate analysis, independent prognostic factors were TNM stage, tumor site, postsurgical residual disease and chemotherapy. Median survival was 16.5 months. In our study, the use of chemotherapy has been shown to be an independent factor with a favorable impact on survival, also related to the regimen used. However, phase III prospective randomized trials are awaited.

The positive results recently reported by the Intergroup 0116 Study with adjuvant chemoradiation have stimulated an increasing interest in the combined modality treatment of gastric cancer. The significant improvement in disease-free and overall survival reported in this study was related mainly to an improvement in local control rather than to a decrease in the incidence of metastatic disease. Therefore, new and potentially more effective chemotherapy regimens could be considered and the feasibility of their integration with radiation therapy needs to be explored to further improve the treatment in gastric cancer. Our experience with combined radiation therapy and 5-FU-with or without 5-FU based chemotherapy--in unresectable and in partially or radically resected gastric cancer is retrospectively reviewed. In addition, an initial prospective evaluation of the feasibility and toxicity of radiation and 5-FU following adjuvant chemotherapy with modern platinum containing regimens is reported. Our data and the current available experiences with investigational approaches in gastric cancer involving preoperative chemotherapy and intraoperative radiotherapy will be considered in exploring a new combined modality treatment program.

Aims: The aim of this study was to report prognostic factors, end-points of local recurrence, distant recurrence, post-metastasis survival, and overall survival in a cohort of patients with soft tissue sarcomas. Methods:We analysed a database of 395 patients affected by primary soft tissue sarcomas of various primary sites, treated and followed up at the Centro di Riferimento Oncologico, Aviano, Italy from January 1985 to January 1997. Results: Grade, size, stage, surgical margins, distant metastasis, age, sex, performance status, and haemoglobin value were significant for overall survival. Histology, grade, stage, and surgical margins were significant for local recurrence. Grade, size, and stage, were significant for distant recurrence; and surgical margin was significant variable for post-metastasis survival. Conclusions: Grade, size, and TNM stage (UICC/AJCC) have stronger prognostic significance for overall survival and distant recurrence than for local relapse. Positive surgical margins are the main predictors for local relapse. Age was the most consistent adverse independent prognostic factor for survival.

562 Background: Dosing based on UGT1A1*28 genotyping has been demonstrated to reduce irinotecan-related adverse events. Previous data (Toffoli et al. JCO, 2010) showed that mCRC pts treated with first-line FOLFIRI tolerated higher doses (310 mg/m2 for *1/*28; 370 mg/m2 for *1/*1) of irinotecan than the standard 180 mg/m2. The aims of this study (NCT01183494; supported by Eudract 2009-012227-28) were to define the maximally-tolerated dose (MTD) of irinotecan in FOLFIRI plus BEV as first-line therapy in mCRC pts and to determine whether BEV alters irinotecan pharmacokinetics (PK). Methods: Pts were accrued at 3 sites: Chicago (USA), Aviano (Italy), Rome (Italy). In *1/*28 and *1/*1 pts (*28/*28 pts were excluded), irinotecan was administered at an initial dose of 260 mg/m2 IV every 2 weeks. The dose was escalated to 310 and 370 mg/m2 if 0/3, 2 IV bolus followed by 2400 mg/m2 IV over 46 hours, plus 200 mg/m2leucovorin. BEV was administered at 5 mg/kg IV on day 3 (2 days after irinotecan) and on day 15 (before irinotecan), then every 2 weeks. Irinotecan PK were collected on days 1-3 (in absence of BEV) and on days 15-17 (in presence of BEV). Results: 44 pts (23 *1/*28; 21 *1/*1) were enrolled and 43 were evaluable for DLTs during cycle 1 (Table). Neutropenia and diarrhea were the most common DLTs and were each observed in 5 of 11 (45%) pts with DLTs. The MTD is 260 mg/m2 in the *1/*28 cohort and at least 310 mg/m2in the *1/*1 cohort. In a preliminary analysis of 22 pts, BEV decreased the AUC of SN-38, the active metabolite of irinotecan (p = 0.026 by Wilcoxon matched pairs signed rank test). Conclusions: In first-line therapy of mCRC with FOLFIRI plus BEV, irinotecan doses higher than the standard dose can be safely administered based on UGT1A1 genotype. The impact of this genotype-guided dosing approach on survival will be established in future trials. Clinical trial information: NCT01183494. [Table: see text]

We report a case of a 28-year-old man with angiosarcoma of the spleen and liver metastases. The aim of this paper is to underline the importance of planned splenectomy in these patients even if they have metastatic disease, and to propose an intensive chemotherapy regimen consisting of anthracyclines, ifosfamide and mesna with G-CSF support.

PurposeTo evaluate the maximum tolerated doses (MTD) of ifosfamide when given as a continuous infusion and in combination with fixed doses of bolus 4′-epidoxorubicin in advanced previously untreated adult soft tissue sarcoma patients.MethodsTreatment consisted of epidoxorubicin, 60 mg/m2days one and two, and ifosfamide, 1.5 g/m2every 12 hrs as a 72-hr infusion, at the first level. Further levels of ifosfamide were defined as increments of 12 hrs of the same infusion program. G-CSF 300 μg/die was administered from days +7 to +14. Dose-limiting toxicity (DLT) was defined as: G4 leukopenia or thrombocytopenia of ≥5 days; any G3 neuro or nephrotoxicity; G4 toxicity of any kind. Patients had to complete at least 2 consecutive cycles, and MTD was defined as the level in which 20% of patients developed a DLT; 10-15 patients were entered in each level.ResultsFirst level: overall, 13 patients entered, 3 were not assessable for MTD, and only one developed a DLT. Second level: 18 patients entered, 3 were not assessable for MTD. Hematologic DLT was observed in 3/15 assessable patients. Therefore, the MTD was found at the ifosfamide level of 10.5 g/m2given in 84 hrs. Eight patients of 29 assessable for response achieved an objective response: 1 complete and 7 partial. The overall response rate was 28% (95% CI: 13-47%).ConclusionsIf we accept 4-day G4 leukopenia as a reliable cutoff for safety, ifosfamide intensification cannot be substantially exploited over already available schedules with the combination of ifosfamide and anthracyclines.

Carcinoma of the nasal vestibule has an individual clinical character; in this retrospective analysis the data of 12 consecutive patients are reported. Small lesions were treated by surgical resection and larger tumours by intra-arterial chemotherapy (IAC) followed by external beam radiotherapy. One patient had a recurrence which was successfully treated surgically; six had previous or subsequent malignancies. The results of the most recent series reported in the literature are reviewed and the rationale of the IAC approach is discussed. The reported treatment policy seems effective in achieving the highest cure rate with the best functional results.

10019 Background: We showed that non-dimensional criteria (i.e. contrast enhancement and tumor density) correlate with pathologic responses better than RECIST in a group of 38 high-risk STS treated...

10003 Background: A previous Italian randomized study showed a survival benefit of adjuvant chemotherapy (CT) in high-risk adult STS patients, and a recent meta-analysis was supportive as well. How...

1145 Background: Therapies targeting HER2 are very effective in metastatic breast cancer (MBC) combined with chemotherapeutic agents (CAs). Lapatinib (L) demonstrated activity and improved time to disease progression in pts who had progressed on trastuzumab (T) (Cameronet al 2008). Since April 2007, L in combination with capecitabine (X) was available in Italy within an expanded access program and thereafter as commercial drug. Methods: From April 2007 to March 2009, 58 HER2-positive MBC pts who had developed progression after antracycline-, taxane-, and T-based regimens, were treated with L plus X in our Institution. Results: Fifty-seven pts were evaluable for response. The median number of previous treatment lines, including the adjuvant setting, was 3 (ranging from 1 to 7). The median duration of previous T treatment (given alone or with chemotherapy) was 19 months (range 2.5-57 months). The median time to progression (MTTP) after first line T plus a cytotoxic agent (CA) was 11 months. At progression, ...

10060 Background: CS is a rare and heterogeneous disease in which, after failure of surgery and radiotherapy, chemotherapy has a marginal role, if any. Different molecular pathways were shown to be...

9620 Background: We have recently shown non-inferiority in preventing acute and delayed nausea and vomiting associated with MEC between the PALO plus 1-day DEX and PALO plus 3-day DEX regimens. Planned analysis stratified by type of chemotherapy (anthracycline + cyclophosphamide [AC] group or patients receiving at least one moderately emetogenic agent according to modified Hesketh classification) has been performed. Methods: A total of 332 chemo-naïve patients with solid tumors were randomized to receive a single IV dose of PALO 0.25 mg plus DEX 8 mg IV on day 1 of chemotherapy (arm A; n=166) or the same regimen followed by DEX 8 mg orally on days 2 and 3 (arm B; n=166). Endpoints included complete response rates (CR: no emetic episodes [EE], no rescue antiemetics; primary endpoint) and proportion of patients with no EE throughout the 5 days after the first cycle of chemotherapy. Subgroups were analyzed by two-sided chi-square test. Results: Per-protocol population included 324 patients (65% women; median age 57.5 years); 35% received AC regimens, and 65% other MEC regimens. There were no significant differences between arms in CR rates according to the type of chemotherapy: 1) CR rates on AC regimens (arm A, 55.8% versus arm B, 60.7%; p=0.599); and 2) CR rates on other MEC regimens (arm A, 68.5% versus arm B, 72%; p=0.576). No significant differences between arms were also observed in the rates of patients with no EE: 1) emesis-free patients on AC regimens (arm A, 78.8% versus arm B, 73.8%; p=0.528); 2) emesis-free patients on other MEC regimens (arm A, 83.8% versus arm B, 90%; p=0.184); 3) nausea-free patients on AC regimens (arm A, 38.5% versus arm B, 44.3%; p=0.533); and 4) nausea-free patients on other MEC regimens (arm A, 58.6% versus arm B, 64%; p=0.418). Conclusions: The single-day regimen of PALO and DEX can provide effective protection against acute and delayed emesis from AC- and MEC-based regimens while avoiding to unnecessarily prolong treatment with DEX. No significant financial relationships to disclose.

The toxicity profile and the pharmacokinetics of aphidicolin glycinate, a water-soluble analogue of aphidicolin, have been evaluated in two consecutive phase I clinical studies. In the first study, aphidicolin glycinate was given by 1-hour infusion for 5 consecutive days, every 3 weeks (daily x 5 study); in the second study, which was planned on the basis of the pharmacokinetic information obtained in the previous study, the drug was given by 24-hour continuous infusion. Treatment was repeated every 3 weeks. In the daily x 5 study, the daily dose was escalated from 12 mg/m2 to the maximum tolerated dose of 2250 mg/m2. Local toxicity was dose limiting. Elimination half-life was 2 +/- 0.2 hours (mean +/- SE) with aphidicolin being undetectable 6-8 hours after the end of the infusion. In the 24-hour continuous-infusion study, the dose was escalated from 435 mg/m2 to the maximum tolerated dose of 4500 mg/m2. Local toxicity was dose limiting, while other toxic effects were absent. The experimentally determined concentrations at the steady state were in agreement with those predicted on the basis of the available pharmacokinetic data. The targeted concentration at the steady state of 3 micrograms/mL was achieved at doses greater than or equal to 3000 mg/m2. Twenty-four-hour continuous infusion is the recommended schedule for clinical evaluations of aphidicolin glycinate as the synchronizing agent or in combination with cisplatin.

Fifty-two consecutive patients, affected by large T2 (greater than 3 cm), T3, T4, N0, or N1 previously untreated squamous cell carcinoma of the head and neck, entered this phase I-II study. Treatment consisted of a continuous 8-day infusion on the following daily schedule: cisplatin 25 mg and bleomycin 15 mg administered for 4 and 20 hours, respectively. Technical-related toxicities were 1 case each of coagulation and displacement of the catheter and 1 case of reversible monoparesis of the contralateral arm. Drug-related relevant toxicities accounted for 4 cass of grade 3 or 4 leukopenia and 2 cases of peripheral palsy of the 7th and 12th cranial nerve, respectively. Forty-five of 50 evaluable patients obtained an objective response. In particular, 13 patients obtained a complete response, 22 a partial response greater than or equal to 75%, and 10 a partial response greater than or equal to 50%. Furthermore, 5 of 31 patients showed a complete pathologic disappearance of the tumor, whereas in 12 of 31 only a microscopic residue was found.

The role of socioeconomic and anthropometric indicators, tobacco, alcohol consumption, dietary habits, and medical history in the etiology of soft-tissue sarcoma (STS) was examined in a hospital-based case-control study, conducted in the Friuli-Venezia Giulia region of northeast Italy, between 1985 and 1990. A total of 88 STS cases (53 males and 35 females; median age: 52 years) and of 610 controls (306 males and 304 females; median age: 54 years) were interviewed. There were significant excess risks associated with a history of herpes zoster infection (odds ratio [OR] = 2.4, 95 percent confidence interval [CI] = 1.1-5.3), chicken pox (OR = 2.2, CI = 1.2-4.3) and mumps in childhood (OR = 2.0, CI = 1.1-3.9). History of diabetes was also linked to a nonsignificant increase in STS risk (OR = 1.8, CI = 0.6-5.4), whereas exposure to radiation for diagnostic or therapeutic purposes was not related to the probability of developing STS. None of the investigated socioeconomic and anthropometric indicators seemed to affect STS risk; neither did tobacco smoking, nor consumption of alcohol, coffee, and tea beverages. Conversely, among the dietary habits investigated, a significant positive association emerged with an increasing frequency of consumption of dairy products (chi 2 for trend = 6.8, P less than 0.01) and oil (chi 2 for trend = 4.3, P less than 0.05), while a negative association was seen for intake of whole grain bread and pasta (OR for highest cf lowest tertile = 0.4, CI = 0.2-0.9).

The prognosis of patients traditionally treated by surgery and radiotherapy for advanced tumors of the head and neck may be improved with the introduction of chemotherapy [3]. Chemotherapy as primary treatment can be more effective because the tumor has an intact vascular supply and the cellular kinetics are favorable; besides, previously untreated patients have a better performance status (PS) and better tolerance of drug.

9028 Background: As from the first patients treated in 2000–2001, Imatinib mesylate was shown to be highly effective in advanced GIST, but patterns of tumor response were seen to be peculiar. Methods: From March to December 2002, 135 Italian patients with metastatic and/or locally advanced, inoperable, KIT-positive GIST entered a prospective clinical study on the best clinical use of Imatinib mesylate, organized by Novartis Pharma in cooperation with the Italian Sarcoma Group. A total of 129 patients were evaluable for tumor response at 9 months. Median age is 65 yrs; M:F ratio is 70:59; ECOG PS was 0–1 in 88% of patients, and 2–3 in 12%. Results: At 9 months, PR+CRs according to RECIST criteria were 44% in the whole group of 129 evaluable patients. At the same interval, the progression-free rate was substantially higher, i.e. >70%. In a single-institution subset of patients, the patterns of tumor response were reviewed and could be temptatively codified as one of the following: 1a) Pathologic complete re...

3540 Background: Preoperative RT with c.i. 5-fluorouracil (5-FU) improves local tumor control, sphincter preservation, and yields pathologic complete remissions (pCR) in 10–30% of patients (pts) wi...

Reports on FAMTX (5-FU, high-dose methotrexate and doxorubicin), EAP (etoposide, doxorubicin, cisplatin) and PELF (cisplatin, epirubicin, leucovorin and 5-FU) showed that survival rates remain very poor (median 7.3 months for FAMTX, 6.1 for EAP and 8.1 for PELF), and toxic deaths and heavy toxicity are of concern in planning these therapies. Moreover, for the FAMTX regimen, the method of methotrexate administration requires hospitalization for all pts and the control of MTX plasma levels for the adjustment of the leucovorin dosage. EAP regimen is delivered in an 8-day period and is also very difficult to administer on an outpatient basis. The original PELF regimen with epirubicin on day 1 and 5 is hampered by 9% of severe hematological and gastrointestinal toxicity. In a time of increasing financial constraints, and due to the still lacking evidence of a significant impact of combination chemotherapy on survival, in November ‘92 we started a study with a regimen feasible on an outpatient basis. Only chemo-nalve pts with histologically proven advanced gastric cancer and measurable disease (CT scan, ultrasound) were enrolled. A PELF-like regimen carried out on an outpatient basis was conducted as follows: cisplatin 30 mg/m2 day 1, 2, 3; 5-FU 500 mg/m2 d 1, 2, 3 i.v. bolus; l-leucovorin 100 mg/m2 d 1,2, 3 i.v. bolus preceding 5-FU, and epiadriamycin 50 mg/m2 d 1 only; granisetron antiemetic 3 mg i.v. for 3 days. The cycle was repeated every 3 weeks, or to bone marrow recovery, without the use of hematological growth factors. To date, 35 pts have entered the study, and 29 are evaluable for response. Median age is 59 years (range 32–71). Median PS at entry was 60 (range 50-90). Median number of administered cycles was 5 (range 1–10), for a total of 167 cycles. Five complete responses and 12 partial remissions were achieved, for an overall response rate of 55% (95% CL ± 18%); 7stable disease and 5 progressions were also noted. The median duration of response was 7 months (range 3-22+), Taxicity was mainly hematological, with leucopenia grade 3 in 11 pts and grade 4 in 4 pts, thrombocytopenia grade 1 in 1pt, and grade 2 and 3 in 2 pts, respectively. In conclusion, this regimen seems feasible on an outpatient basis, allowing the reduction of the cost of the treatment. The response rate is sufficiently high to merit further study.

Ifosfamide, an oxazophosphorin compound, active in mesenchimal tumours has recently been used at high doses (14–18 g/sqm) in order to increase the number of responses. Continuous infusion (C.L) of Ifosfamide probably decreases toxicity and increases the therapeutic window of the drug. Bone marrow and renal toxicities seem to be modified greatly by C.L.. Aim of our study has been to characterize the pharmacokinetic drug profile during C.L high dose-fosfamide (HD-IFO). From April to December 1994, 9 patients (pts) with advanced soft tissue sarcomas, 5 pts with osteosarcomas and I pts with Ewing's sarcoma with normal liver and renal function, treated with C.I. HD-IFO (14 g/sqm. over 4 days) and Mesna contemporary infusion, entered into the study. 33 chemotherapy courses were administered (range 1–4, mean 2.2). Pts were submitted to blood sampling previous starting of infusion, and 12, 24,48,72,96, 100, 104, 114, and 120 hours after treatment beginning. Plasma samples were stored at 0°C. Chemical analysis was perfonned using HPLC. Maximum concentration of the drug was observed at 24th hour ( C 24 : 61.5 ± 21.9/μg/ml) while decreased pseudo-steady rate levels were reached after 70–80 hours ( C ss: 28.3 ± 11.5 μg/ml). Tenninal half life was 3.2 ± 0.4 hours; AVC (following trapezoidal rule) was 3654 ± 1222 mg/l. × hour. Median Clearances (total dose/AVC) was 7.14 ± 3.31/h. At the second or following cycles a relevant reduction of Tl/2 and AVC (–20% and –25%) due to enzymatic auto induction was observed. In confront with Ifosfamide administration at the same doses but in 1 hour infusion we observed that C.I. leads to a higher AUC (3650 vs. 1230) to a shorter Tl/2 (3.2 h. vs. 5.9 h.) and to a relevant increase of total clearance (7.14 vs. 3.9). This significant difference in pharmacokinetic profile can explain the different spectrum of activity between the two manners of administration.

Adjuvant chemotherapy for STS still remains a matter of debate, since just few randomized studies have indicated a small advantage in terms of disease free interval or overall survival at preliminary reports. However, the majority of those trials have not included adequate doses of anthracyclines nor the today most active agent Ifosfamide (IFO). To re-evaluate the role of adjuvant chemotherapy in extremity STS, we started in June ‘92, a co-operative randomized prospective adjuvant study comparing a control arm to an intensified chemotherapy arm. Treatment consisted of Epirubicin 60 mg/m2, day 1&2, Ifosfamide 1.8 g/m2 × 5days as 1 hr infusion, MESNA 60% of the daily IFO dose fractionated in 3 separated doses, fluids 1.5–2.0 litres/day and G–CSF 300 μg/day from + 8 to + 15; treatment was scheduled every 3 weeks for a total of 5 cycles. Of the 37 up to now randomized pts to the chemotherapy arm, 25 are evaluable (5 cycles completed + two months follow-up) for the toxicity and dose intensity evaluation purpose (12 pts not yet evaluable). The median nadir of WBC and PLTS was 1300/μ1 (range: 200–8000/μ1); and, 120000/μ1 (range: 10000–250000/μ1), respectively. Overall, a G4 leukopenia and thrombocytopenia was noted in 30% and 5% of cycles respectively. Anemia progressively worsened and the median HB fall from basal values to the nadir of the 5th cycle was of 4 g/dl (range 0–9.8 g/dl); in 12 of 25 pts (48%) PRBC transfusions were given to prevent symptoms from anemia. Nevertheless, an optimal recovery to pre-treatment values was obtained after 2 months from end of treatment (median HB 13.5; range: 12.7–14.8). Neutropenic fever was observed in 15% of the cycles, prophylactic antibiotics were administered in further 3% of cycles. No pts received pits support. The median average received dose intensity (ARDI) was of 91% (range: 67–100%) and 19/25 pts (76%) received an ARDI > 80%. Causes of reduction in dose intensity were delay in retreatment in 24 cycles and reduction of the dose in 40 cycles. Even through the toxicity was substantial (anemia and leukopenia) it was possible to give an adequate dose intensity to the majority of pts. All but one pt (3 cycles received) completed the forseen 5 cycles employing the predefined dose reduction schema.

The authors report the final analysis of a prospective phase I-II study in 53 previously untreated patients with squamous cell carcinoma (48 patients) and other histologic classifications (5 patients) of the head and neck region. Treatment consisted of cisplatin 10 mg infused intra-arterially in a 12-hour period, twice a day for 5 to 10 days via an external infusion pump. After a rest period of 5 to 7 days treatment could be restarted, with the same schedule, until a maximal total dose of 400 mg or toxicity. Patients who received at least 200 mg of cisplatin were considered evaluable for response. In 3 patients catheterization was not performed because of technical difficulties, in 9 treatment was stopped before reaching the total dose of 200 mg, (because of catheter-related toxicity in 7 patients, drug toxicity in 1, and both toxicities in 1); therefore, the patients evaluable for response, drug toxicity and catheter toxicity were 41, 43, and 49 respectively. Overall, 8 patients (19.5%) obtained a complete response (CR) and 20 (48.8%) a partial response (PR) with an objective response rate (RR) of 68.3%. Eleven patients obtained a minor response (MR), whereas only 2 (4.8%) developed a progressive disease (PD). The figures, limited only to squamous cell carcinoma of oral cavity and oropharinx (33 patients), are as follows: CR 8 (24.2%), PR 17 (51.5%), MR 7 (21.2%), and PD 1 (3.0%) for an objective RR of 75.7%. No grade IV and only 5 grade III toxicity were observed; whereas the most frequent grade I and II drug-related toxicities were anemia, transient renal impairment, and thrombocytopenia. Catheter-related toxicity accounted for five central nervous system complications (three transient motor weaknesses, one hemiparesis, one embolism) and six local problems (one coagulation of the catheter, one displacement, and four local extravasations). Intra-arterial cisplatin is, in our experience, an effective treatment and further trials employing cisplatin combination chemotherapy are needed in order to establish the exact role of the intra-arterial approach before definitive local treatments.

Forty-six evaluable postmenopausal patients with locally advanced, inoperable T3-T4 breast carcinoma were treated with tamoxifen 10-20 mg twice daily for a period at least 6 weeks. Eight patients (17 %) had an objective response at the primary tumor site after 6 weeks of treatment. Improvement of response with a further single tamoxifen therapy was observed in 7 patients, resulting in an overall objective response in 14 of 46 (30 %). Median duration of response was 8 months (range 2-24). No response was obtained in the 5 patients with inflammatory signs. Toxicity of treatment was minimal. Median survival was 10 months (responders 17.5, non-responders 9). Tamoxifen seems to be a safe and effective treatment for locally advanced breast cancer without inflammatory signs in postmenopausal women.

Five patients with mycosis fungoides, hospitalized in the Division of Radiotherapy and Medical Oncology of the Ospedale Civile, Pordenone, from January 1975 to December 1978, were studied and treated as non-Hodgkin lymphomas. All patients had evidence of disseminated disease: 3 with bone marrow infiltration, 1 with splenic involvement and 1 with lymph node involvement. Three patients were treated with CVP, resulting in 2 complete remissions that lasted 18 months and 1 PR > 50% maintained for 7 months. One patient was treated with ABVD with a PR > 50% maintained for 10 months. The last patient was treated with prednisone and then with CV, but expired from pulmonary embolism after 1 cycle. Lymphocyte function, using E and EAC rosette and PHA, was evaluated before therapy in all patients: in the 2 patients who obtained a CR, an improvement in T-lymphocyte function was noted after therapy. The chromosome pattern of peripheral blood lymphocytes was altered before therapy in only one patient. Even if the follow-up period is still relatively brief, the duration of the 2 complete remissions must be stressed. In addition, a strict correlation between T-lymphocyte function and response to therapy was revealed in our study.