Eugenio Villa

Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial

BACKGROUND Patients with advanced pancreatic adenocarcinoma have a poor response, progression-free survival, and overall survival with standard treatment. We aimed to assess whether a four-drug regimen could improve 4 month progression-free survival compared with gemcitabine alone. METHODS In a randomised multicentre phase III trial, 52 patients were randomly assigned to 40 mg/m2 cisplatin and 40 mg/m2 epirubicin both given on day 1, 600 mg/m2 gemcitabine given intravenously over 1 h on days 1 and 8, and 200 mg/m2 fluorouracil a day given by continuous infusion on days 1-28 of a 4-week cycle (PEFG regimen), and 47 were assigned to 1000 mg/m2 gemcitabine given intravenously over 30 min once a week for 7 of 8 consecutive weeks in cycle 1 and for 3 of 4 weeks thereafter. The primary endpoint was 4-month progression-free survival. Secondary endpoints were overall survival, objective response, safety, and quality of life. Analyses were by intention to treat. FINDINGS 51 patients assigned PEFG and 46 assigned gemcitabine alone had disease progression. 49 patients in the PEFG group and 46 in the gemcitabine group died from progressive disease. More patients allocated PEFG than gemcitabine alone were alive without progressive disease at 4 months (60% [95% CI 46-72] vs 28% [17-42]; hazard ratio [HR] 0.46 [0.26-0.79]). 1-year overall survival in the PEFG group was 38.5% (25.3-51.7) and in the gemcitabine group was 21.3% (9.6-33.0; HR 0.68 [0.42-1.09]). More patients assigned PEFG showed disease response than did those assigned gemcitabine (38.5% [25.3-51.7] vs 8.5% [0.5-16.5]; odds ratio 6.60 [2.11-20.60], p=0.0008). More patients in the PEFG group had grade 3-4 neutropenia and thrombocytopenia than in the gemcitabine group (p<0.0001). INTERPRETATION The PEFG regimen could be considered for treatment of advanced pancreatic adenocarcinoma.

Gefitinib in Pretreated Non–Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC

PURPOSE To evaluate the correlation between HER2 expression and gefitinib (ZD 1839, Iressa; AstraZeneca, London, United Kingdom) efficacy in terms of response rate, time to progression (TTP), and overall survival (OS) time. PATIENTS AND METHODS Patients with pretreated advanced non-small-cell lung cancer (NSCLC) received gefitinib at a daily dose of 250 mg until disease progression. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine HER2/epidermal growth factor receptor (EGFR) status by immunohistochemistry. RESULTS From February 2001 to June 2002, 63 consecutive patients were enrolled onto the study. The overall disease control rate was 58.7% (partial response [PR], 15.9%; stable disease [SD], 42.8%), median TTP was 3.3 months, and median OS was 4.1 months. Among the 43 patients in whom EGFR/HER2 status was determined, we observed six PRs (14%) and 18 SDs (42%). Disease control, including PR and SD, was 40% in the 15 patients overexpressing HER2 and 64.3% in the 28 patients not overexpressing HER2 (P =.126). No difference was found between the two groups in terms of TTP (3.5 v 3.7 months, respectively) and OS (5.7 v 6.8 months, respectively). In addition, we did not find any difference in TTP, OS, toxicity, and symptom outcome in the group of patients overexpressing both HER2 and EGFR compared with patients who had no overexpression of HER2 CONCLUSION According to these data, efficacy, toxicity, and symptom outcome in patients with NSCLC treated with gefitinib do not seem to be related to HER2 expression.

Regression of Ocular Adnexal Lymphoma After Chlamydia Psittaci–Eradicating Antibiotic Therapy

PURPOSE Some infectious agents contributing to lymphomagenesis have been considered targets for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of ocular adnexal lymphomas. The present pilot study was carried out to assess whether C psittaci-eradicating antibiotic therapy is associated with tumor regression in ocular adnexal lymphomas. PATIENTS AND METHODS Nine patients with C psittaci-positive marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up. RESULTS All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four positive patients. Objective response was complete in two patients, partial response (> 50%) was observed in two patients, and minimal response (< 50%) was observed in three patients. Duration of response in the seven responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively. CONCLUSION C psittaci-eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas.

Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: Results of a critical review of the literature

BACKGROUND The optimal treatment for primary central nervous system lymphomas (PCNSL) has not been defined. PATIENTS AND METHODS Therapeutic results of 1180 immunocompetent patients (pts) with PCNSL reported in 50 series published in English between 1980 and 1995 were analysed. The impact on survival of age, treatment strategy, radiation field and doses, systemic and intrathecal chemotherapy (CHT) and treatment sequence was evaluated. RESULTS Univariate analyses showed a longer survival in pts of < or = 60 years (P < 0.00001): pts treated with > 40 Gy to whole brain (WB) (P = 0.02): pts receiving > 50 Gy to the tumor bed after a WB dose > 40 Gy (P = 0.02): pts submitted to a combined treatment as opposed to CHT alone (P = 0.007) or radiotherapy alone (P < 0.00001): pts receiving CHT followed by radiotherapy rather than in the reverse sequence (P = 0.05); pts treated with high-dose methotrexate (HDMTX) (P = 0.04) and pts receiving intrathecal CHT (P = 0.03). Multivariate analysis confirmed the independent prognostic value of age, WB dose, HD-MTX and intrathecal CHT. CONCLUSIONS Current data confirm the prognostic value of age and appear to support the use of systemic CHT consisting of HD-MTX and intrathecal drug administration followed by 41-50 Gy to WB and > 50 Gy to the tumor bed in the treatment of PCNSL in immunocompetent pts.

Significant correlation between rectal DVH and late bleeding in patients treated after radical prostatectomy with conformal or conventional radiotherapy (66.6 –70.2 Gy

PURPOSE Investigating the correlation between dosimetric/clinical parameters and late rectal bleeding in patients treated with adjuvant or salvage radiotherapy after radical prostatectomy. METHODS AND MATERIALS Data of 154 consecutive patients, including three-dimensional treatment planning and dose-volume histograms (DVHs) of the rectum (including filling), were retrospectively analyzed. Twenty-six of 154 patients presenting a (full) rectal volume >100 cc were excluded from the analysis. All patients considered for the analysis (n = 128) were treated at a nominal dose equal to 66.6-70.2 Gy (ICRU dose 68-72.5 Gy; median 70 Gy) with conformal (n = 76) or conventional (n = 52) four-field technique (1.8 Gy/fr). Clinical parameters such as diabetes mellitus, acute rectal bleeding, hypertension, age, and hormonal therapy were considered. Late rectal bleeding was scored using a modified Radiation Therapy Oncology Group scale, and patients experiencing >or=Grade 2 were considered bleeders. Median follow-up was 36 months (range 12-72). Mean and median rectal dose were considered, together with rectal volume and the % fraction of rectum receiving more than 50, 55, 60, and 65 Gy (V50, V55, V60, V65, respectively). Median and quartile values of all parameters were taken as cutoff for statistical analysis. Univariate (log-rank) and multivariate (Cox hazard model) analyses were performed. RESULTS Fourteen of 128 patients experienced >or=Grade 2 late bleeding (3-year actuarial incidence 10.5%). A significant correlation between a number of cutoff values and late rectal bleeding was found. In particular, a mean dose >or=54 Gy, V50 >or=63%, V55 >or=57%, and V60 >or=50% was highly predictive of late bleeding (p <or= 0.01). A rectal volume <60 cc and type of treatment (conventional vs. conformal) were also significantly predictive of late bleeding (p = 0.05). Concerning clinical variables, acute bleeding (p < 0.001) was significantly related to late bleeding, and a trend was found for hypertension (p = 0.11). After patients were grouped into those with V50 >or=63% and those with V50 <63% (DVH grouping), data were fitted with a Cox regression hazard model using DVH grouping, rectal volume, and the main clinical parameters as independent variables. Results of the analysis showed that DVH grouping (relative risk 3.3; p = 0.04) and acute bleeding (relative risk 7.1; p = 0.001) are independently predictive of late bleeding. CONCLUSIONS DVHs of the rectum are significantly correlated with late bleeding for patients irradiated at 66.6-70.2 Gy after radical prostatectomy.

Therapeutic management of primary central nervous system lymphoma: Lessons from prospective trials

Primary central nervous system lymphomas (PCNSL) are aggressive malignancies, exhibiting one of the worst prognoses among lymphomas. The best treatment modality for PCNSL has not yet been identified. Several therapeutic questions still remain unanswered, and some methodological pitfalls in clinical trials prevent definitive conclusions from being drawn. In this review, certain aspects of trial design as well as emerging therapeutic guidelines are analyzed, and future perspectives are discussed. In the vast majority of prospective trials, general criteria for treatment of aggressive lymphomas were adopted, choosing primary chemotherapy (CHT) followed by radiotherapy (RT) as therapeutic modality. This strategy produced a five-year survival of 22%- 40% in comparison to the 3%-26% reported with RT alone. Systemic high-dose methotrexate (HD-MTX) seems to be the most effective drug, producing a response rate of 80%-90% and a two-year survival of 60%-65%. To date, the addition of other drugs at conventional doses have not consistently improved outcome. With a few exceptions, any regimen without HD-MTX comprehensively performed no better than RT alone. In combined treatment. RT doses should be decided on the bases of response to primary CHT and the number of lesions, and, until definitive conclusions from well-designed trials are available, RT parameters should follow the widely accepted principles used for other aggressive lymphomas. CHT as exclusive treatment, keeping RT for relapses or persistent disease, appears to be an attractive strategy. However, the worldwide experience with this modality is still limited, and corroborating data are needed. Intrathecal CHT still has not found a defined role in PCNSL management. Preliminary data seem to indicate that adequate meningeal treatment with HD-MTX, but without intrathecal CHT, could also be suitable in positive-cerebrospinal fluid patients. Future efforts should be addressed to identify new active drugs and more efficient CHT combinations, to evaluate the efficacy of high-dose CHT supported by autologous peripheral blood stem cells transplantation, and to clarify the impact of RT delay in complete responders, the usefulness of intrathecal CHT, and the best management for elderly patients. The assessment of impact of treatment on neuropsychological functions and quality of life is a mandatory endpoint in clinical trials.

Definitive Results of a Phase II Trial of Cisplatin, Epirubicin, Continuous-Infusion Fluorouracil, and Gemcitabine in Stage IV Pancreatic Adenocarcinoma

PURPOSE To evaluate the efficacy and toxicity of a cisplatin, epirubicin, gemcitabine, and fluorouracil (PEF-G) schedule on stage IV pancreatic adenocarcinoma. PATIENTS AND METHODS Patients < or = 70 years, with no prior chemotherapy and with bidimensionally measurable stage IV pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or Karnofsky performance status between 50 and 70. Treatment consisted of 40 mg/m2 each of cisplatin and epirubicin day 1, gemcitabine 600 mg/m2 on days 1 and 8 every 4 weeks, and fluorouracil 200 mg/m2/d as a protracted venous infusion. RESULTS Between April 1997 and April 1999, 49 patients from a single institution were eligible for the study. Altogether, 203 cycles (median, four cycles) of PEF-G were delivered. The objective response rate was 58% in 43 assessable patients and 51% in the intent-to-treat population. Fourteen patients had stable disease. Grade 3 or 4 World Health Organization neutropenia occurred in 51% of cycles, thrombocytopenia in 28%, anemia in 7%, stomatitis in 5%, and diarrhea, and nausea, and vomiting in 2%. The median duration of response was 8.5 months. The median time to tumor progression was 7.5 months. The median survival was 11 months in the assessable population and 10 months in the intent-to-treat population. Clinical benefit was achieved in 22 (78%) of 28 assessable patients. CONCLUSION PEF-G is a well-tolerated and safe regimen; it obtained a very high rate of durable responses and deserves further evaluation in a phase III trial.

Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients

BACKGROUND Despite the consistent clinical results demonstrated by studies on anti-angiogenic drugs targeted against the vascular endothelial growth factor in metastatic colorectal cancer (mCRC) patients, no specific direct/indirect biomarker of their efficacy has been validated. In this field, circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs) have recently been proposed as noninvasive biomarkers. PATIENTS AND METHODS The absolute numbers of CEPs, total CECs (tCECs) and their resting (rCECs) and activated subsets were evaluated by multiparameter flow cytometry in 40 mCRC patients at baseline and before the administration of the third and sixth course of a bevacizumab-based first-line treatment. Fifty healthy subjects were utilized as control. RESULTS The overall response rate was 80%, overall clinical benefit was 90% and median progression-free survival (PFS) was 13.8 months. In our patients, tCECs and rCECs were significantly increased compared with healthy subjects. The patients who achieved a radiological response showed, at baseline, a significant decrease of rCECs and a trend in decrease of tCECs in comparison with patients not achieving response. Finally, a baseline absolute number of tCEC and rCEC <40 cells/ml was evidenced in patients with a longer PFS. No correlation was found regarding CEP. CONCLUSIONS Our study suggests significant correlations between both tCEC and rCEC baseline levels and the antitumor efficacy of a bevacizumab-based combination therapy in mCRC patients, thus confirming that these biomarkers could be used in the clinical setting as an early predictor of tumor response.

Sequential Tamoxifen and Aminoglutethimide Versus Tamoxifen Alone in the Adjuvant Treatment of Postmenopausal Breast Cancer Patients: Results of an Italian Cooperative Study

PURPOSE To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued. PATIENTS AND METHODS Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years. RESULTS At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P =.02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P =.0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm. CONCLUSION Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

LETHAL PULMONARY COMPLICATIONS SIGNIFICANTLY CORRELATE WITH INDIVIDUALLY ASSESSED MEAN LUNG DOSE IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES TREATED WITH TOTAL BODY IRRADIATION

PURPOSE To assess the impact of lung dose on lethal pulmonary complications (LPCs) in a single-center group of patients with hematologic malignancies treated with total body irradiation (TBI) in the conditioning regimen for bone marrow transplantation (BMT). METHODS The mean lung dose of 101 TBI-conditioned patients was assessed by a thorough (1 SD around 2%) in vivo transit dosimetry technique. Fractionated TBI (10 Gy, 3.33 Gy/fraction, 1 fraction/d, 0.055 Gy/min) was delivered using a lateral-opposed beam technique with shielding of the lung by the arms. The median lung dose was 9.4 Gy (1 SD 0.8 Gy, range 7.8--11.4). The LPCs included idiopathic interstitial pneumonia (IIP) and non-idiopathic IP (non-IIP). RESULTS Nine LPCs were observed. LPCs were observed in 2 (3.8%) of 52 patients in the group with a lung dose < or = 9.4 Gy and in 7 (14.3%) of 49 patients in the >9.4 Gy group. The 6-month LPC risk was 3.8% and 19.2% (p = 0.05), respectively. A multivariate analysis adjusted by the following variables: type of malignancy (acute leukemia, chronic leukemia, lymphoma, myeloma), type of BMT (allogeneic, autologous), cytomegalovirus infection, graft vs. host disease, and previously administered drugs (bleomycin, cytarabine, cyclophosphamide, nitrosoureas), revealed a significant and independent association between lung dose and LPC risk (p = 0.02; relative risk = 6.7). Of the variables analyzed, BMT type (p = 0.04; relative risk = 6.6) had a risk predictive role. CONCLUSION The mean lung dose is an independent predictor of LPC risk in patients treated with the 3 x 3.33-Gy low-dose-rate TBI technique. Allogeneic BMT is associated with a higher risk of LPCs.