Luigi Cavanna

Preoperative Chemotherapy Plus Trastuzumab, Lapatinib, or Both in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer: Results of the Randomized Phase II CHER-LOB Study

PURPOSE This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). PATIENTS AND METHODS In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. RESULTS A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019). CONCLUSION The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.

Randomized Phase III Trial of Gemcitabine Plus Cisplatin Compared With Single-Agent Gemcitabine As First-Line Treatment of Patients With Advanced Pancreatic Cancer: The GIP-1 Study

PURPOSE Single-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696). PATIENTS AND METHODS Patients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) > or = 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m(2) weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m(2) added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral alpha .05, 355 events were needed and 400 patients planned. RESULTS Four hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS > or = 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity. CONCLUSION The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer.

Role of Anti-Hepatitis C Virus (HCV) Treatment in HCV-Related, Low-Grade, B-Cell, Non-Hodgkin's Lymphoma: A Multicenter Italian Experience

PURPOSE Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkins lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. PATIENTS AND METHODS Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. RESULTS Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. CONCLUSION This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

ABVD Versus Modified Stanford V Versus MOPPEBVCAD With Optional and Limited Radiotherapy in Intermediate- and Advanced-Stage Hodgkin's Lymphoma: Final Results of a Multicenter Randomized Trial by the Intergruppo Italiano Linfomi

PURPOSE In this multicenter, prospective, randomized clinical trial on advanced Hodgkins lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to < or = two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). PATIENTS AND METHODS Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. RESULTS The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. CONCLUSION When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.

Complications of ultrasonically guided fine-needle abdominal biopsy: results of a multicenter Italian study and review of the literature

This report describes the complications following 10,766 ultrasonically guided fine-needle biopsies performed from 1979 to 1987 in 33 Italian echographic units. The mortality was 0.018%: the two reported deaths were due to hemoperitoneum and occurred in patients with hepatocellular carcinoma arising in a cirrhotic liver. Twenty patients (0.18%) had major complications. This series confirms that abdominal biopsy with fine needles is safe, even though our death rate was higher than in previous reports. Among the other nine fatalities following fine-needle abdominal biopsy reported in the literature, seven were secondary to hemorrhage. The biopsy of pancreatic carcinoma was more dangerous for needle-tract seeding (five of eight reported cases, including one in our series).

Clinico-pathological characterization of hepatitis C virus-related B-cell non-Hodgkin's lymphomas without symptomatic cryoglobulinemia

BACKGROUND Epidemiological evidence has suggested an association between hepatitis C virus (HCV) infection and B-cell lymphoproliferation. We studied the prevalence of HCV infection in a series of de novo B-cell non-Hodgkins lymphoma (B-NHL) cases and correlated virological findings with clinico-histological features. PATIENTS AND METHODS One hundred fifty-seven patients with de novo B-NHL were included in the study. Their serum was examined by ELISA and RIBA for the presence of anti-HCV antibodies, and either the peripheral blood mononuclear cells or the pathology tissues of all of the patients were examined by reverse transcriptase polymerase chain reaction for the presence of HCV RNA sequences. RESULTS HCV infection occurred in 22.3% of B-NHL patients and was documented before the diagnosis in about half of the positive cases. Of interest, HCV infection was more frequently found in follicular center, marginal zone and diffuse large-cell lymphoma types, but was not associated with symptomatic cryoglobulinemia. The median survival time was 48 months in HCV-positive and 52 months in HCV-negative B-NHL patients. CONCLUSIONS Our findings strengthen the pathogenetic link between HCV and B-NHL and show that HCV infection may be associated with the malignant proliferation of defined B-cell subsets other than the immunoglobulin Mk B-cell subset involved in the pathogenesis of mixed cryoglobulinemia type II and associated lymphoplasmacytoid lymphoma type. HCV-related liver disease did not affect the survival of our B-NHL patients.

Association between hepatitis C virus and non-hodgkin’s lymphoma, and effects of viral infection on histologic subtype and clinical course

PURPOSE Because an etiologic role for hepatitis C virus in non-Hodgkins B-cell lymphoma has been suggested by several reports, we assessed the prevalence of hepatitis C virus infection in patients with non-Hodgkins B lymphoma and in controls, and evaluated the influence of viral infection on histologic and clinical features of the lymphoma patients. PATIENTS AND METHODS We prospectively investigated 175 consecutive patients with non-Hodgkins lymphoma and 350 controls for serologic and molecular markers of hepatitis C virus infection. Controls were selected from inpatients (n = 175) and outpatients (n = 175) cared for at our hospital. Patients with lymphoma who had hepatitis C virus infection were tested for mixed cryoglobulinemia. Aminotransferase levels were measured in all lymphoma patients at baseline and during and after chemotherapy. RESULTS Hepatitis C virus prevalence in patients with non-Hodgkins lymphoma was significantly greater than in control subjects (37% vs 9%, P = 0.0001). Among patients with lymphoma, viral infection was associated with older mean (+/-standard deviation) age (67 +/- 14 vs 61 +/- 8 years, P = 0.001), and women (41 of 87, 47%) were more likely than men (24 of 88, 27%) to have evidence of hepatitis C infection (P = 0.006). Thirteen of the 20 cases of immunocytoma were associated with hepatitis C virus infection, which was also more common in patients with orbital and conjunctival localization of lymphoma. Patients with mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach were less likely to have evidence of hepatitis C infection. Mixed cryoglobulinemia was much more common in patients with hepatitis C virus infection (14 of 65 vs 1 of 110, P = 0.0001); it was not associated with the histologic type of lymphoma. Patients with and without hepatitis C virus infection underwent similar chemotherapy regimens and had no differences in response to chemotherapy or in overall and disease-free survival. Hepatic toxicity from chemotherapy was seen only in patients with hepatitis C virus infection, although all but one of these patients were able to complete their planned treatment. CONCLUSION These findings suggest that the hepatitis C virus may have a role as an etiologic agent in non-Hodgkins B-cell lymphoma. Some clinical and pathologic features of the disease are associated with hepatitis C virus infection, but the virus does not seem to affect prognosis.

Ultrasound-guided central venous catheterization in cancer patients improves the success rate of cannulation and reduces mechanical complications: A prospective observational study of 1,978 consecutive catheterizations

BackgroundA central venous catheter (CVC) currently represents the most frequently adopted intravenous line for patients undergoing infusional chemotherapy and/or high-dose chemotherapy with hematopoietic stem-cell transplantation and parenteral nutrition.CVC insertion represents a risk for pneumothorax, nerve or arterial punctures. The aim of this prospective observational study was to explore the safety and efficacy of CVC insertion under ultrasound (US) guidance and to confirm its utility in clinical practice in cancer patients.MethodsConsecutive adult patients attending the oncology-hematology department were eligible if they had solid or hematologic malignancies and required CVC insertion. Four types of possible complication were defined a priore: mechanical, thrombotic, infection and malfunctioning.The patient was placed in Trendelenburgs position, a 7.5 MHZ puncturing US probe was placed in the supraclavicular site and a 16-gauge needle was advanced under real-time US guidance into the last portion of internal jugular vein. The Seldinger technique was used to place the catheter, which was advanced into the superior vena cava until insertion into right atrium. Within two hours after each procedure, an upright chest X-ray and ultrasound scanning were carried out to confirm the CVC position and to rule out a pneumotorax. CVC-related infections, symptomatic vein thrombosis and malfunctioning were recorded.ResultsFrom December 2000 to January 2009, 1,978 CVC insertional procedures were applied to 1,660 consecutive patients. The procedure was performed 580 times in patients with hematologic malignancies and 1,398 times those with solid tumors. A single-needle puncture of the vein was performed on 1,948 of 1,978 procedures (98.48%); only eighteen attempts among 1,978 failed (0.9%).No pneumotorax, no major bleeding, and no nerve puncture were reported; four cases (0.2%) showed self-limiting hematomas. The mean lifespan of CVC was 189.7 +/- 18.6 days (range 7-701). Symptomatic deep-vein thrombosis of the upper limbs developed in 48 patients (2.42%). Catheter-related infections occurred in 197 (9.96%) of the catheters inserted. They were successfully treated with antibiotics and only in 48 (2.9%) patients definitive CVC removal was required for infection and/or thrombosis or malfunctioning.ConclusionsThis study represents the largest published series of consecutive patients with cancer undergoing CVC insertion under US guidance; this procedure allowed the completion of the therapeutic program for 1,930/1,978 (97.6%) of the catheters inserted. The absence of pneumotorax and other major complications indicates that US guidance should be mandatory for CVC insertion in patients with cancer.

Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir.

Primary effusion lymphoma (PEL) is a B-cell non-Hodgkin lymphoma, involving the serous cavities, which is invariably associated with Kaposi sarcoma-associated herpesvirus (KSHV)/ human herpesvirus-8 (HHV-8) and often with Epstein–Barr virus (EBV) infections. The disease accounts for less than 3% of AIDS-associated lymphomas, as recognized by the WHO, but a few cases have also been reported in transplant patients as well as in elderly human immunodeficiency virus (HIV)-negative men originating from areas endemic for HHV-8 infection, and at high risk for classic Kaposi sarcoma (KS). PEL has a poor prognosis, with a median survival of few months, in the majority of affected patients. In AIDS patients, combined chemotherapy, including high-dose methotrexate, may be attempted with the possibility to achieve complete remission, at least in some cases. On the contrary, in elderly and transplant patients, the use of chemotherapeutic regimens has been generally hampered by severe toxicity, and has revealed unsuccessful in the vast majority of the treated patients, raising the need for alternative treatment approaches. Cidofovir is an antiviral with a broad spectrum of activity against DNA viruses, and has been reported to be one of the most effective agents to inhibit HHV-8 replication in vitro. In addition to its antiviral activity, a potent antitumor activity has been recently attributed to cidofovir. Topical application of cidofovir resulted effective to treat both neoplastic genital lesions and recurrent laryngeal papillomatous lesions caused by human papillomavirus (HPV). In animal models, cidofovir has been found to be effective on virus-associated tumors, such as in nude mice with EBV-associated nasopharyngeal carcinoma, in which intratumoral injection of cidofovir induced in vivo regression of the tumors. The antitumor activity of cidofovir is not specifically related to the antiviral action of the compound. Consistent with this, cidofovir has also been shown to inhibit the growth of tumors, such as hemangiosarcomas, which are not associated with oncogenic viruses. In the current study, we tested whether cidofovir exerts an antitumor effect against two PEL cell lines in vitro, namely the HHV-8-positive BCBL-1 and the HHV-8-positive and EBVpositive HBL-6 cell lines. The EBV-negative and HHV-8negative RAMOS cell line was tested as control. Then, we investigated the effect of intracavity injections of cidofovir for the treatment of three elderly, HIV negative, patients with PEL. The BCBL-1, HBL-6 and the RAMOS cell lines were cultured in RPMI 1640 medium, supplemented with 15% of heat inactivated fetal calf serum (FBS), glutamine 1 mM and antibiotics, at 371C in a 5% CO2 humidified incubator. Cells were treated with cidofovir at 0.01, 0.1, 0.5, and 1 mM, for 3 and 6 days. At the end of the incubation period, cell count and viability were evaluated in triplicate, with Trypan blue dye exclusion assay. Apoptosis was studied by a combination of methods, including, morphology, propidium iodide staining (50 mg/ml) and analysis by flow cytometry (Becton and Dickinson Italia, Milano, Italy), the DNA fragmentation assay, and the in situ cell death detection kit (Boheringer Mannheim, Mannheim, Germany), which relies on the use of terminal deoxynucleotidyl transferase (TdT) that catalyses the polymerization of fluorescein-labeled nucleotides to free 30-hydroxyl residues of DNA fragments generated by endonucleases during apoptosis (TUNEL). Cidofovir caused a dose-dependent inhibition of BCBL-1 and HBL-6 cell proliferation and viability (Figure 1a–d), while in RAMOS cells, cidofovir inhibited proliferation but had no effect on viability (Figure 1e and f). Cidofovir induced a dose-dependent apoptosis in both the BCBL-1 and HBL-6 cell lines, after 3 and 6 days, as detected by flow cytometry analysis (Figure 2a). Apoptosis induced by cidofovir was confirmed by the observation of typical apoptotic features of cell morphology, by the characteristic ladder of fragmented genomic DNA on the DNA fragmentation assay, as well by the detection of fluorescein-labeled DNA strand breaks in apoptotic cells, by TUNEL assay (Figure 2b–d in supplementary information). On the contrary, RAMOS cells did not show any significant apoptosis up to 6-day treatment with cidofovir (Figure 2a and analysis of cell cycle distribution of RAMOS cells in supplementary information). In three patients, (pt. 1, pt. 2 and pt. 3) a diagnosis of HHV-8positive PEL, in Ann Arbor stage IV, was made, on the basis of morphologic, immunophenotypic and molecular analysis, as described. EBV coinfection was documented in pt. 1, while serology for HIV, hepatitis B and C viruses was negative in all three patients. In detail, pt. 1, a 96-year-old Italian man, was hospitalized for bilateral pleural effusion. No clinical evidence of KS was found. The patient was subjected to pleural drainage every 2 weeks for 4 months, without receiving any chemotherapy. Then, he was treated with two doses of intrapleura cidofovir, at 2.5 mg/kg, every 1 week. No recurrence of pleural effusion was observed after the second injection. PEL relapsed at the same site, as documented on standard radiographic examination, 10 months later. The patient refused cidofovir therapy and was subjected to pleural drainage. The patient died for heart failure. Pt. 2, a 70-year-old Italian man, was hospitalized for recurrent peritoneal effusions. The patient had a history of KS, for which he had received chemotherapy and radiotherapy 10 years before, with complete tumor regression. The patient was subjected to peritoneal drainages every 10 days for 2 months. Then, the patient received three doses of intraperitoneal cidofovir, at 5 mg/kg, every 1 week. No recurrence of peritoneal effusion was observed after the last cidofovir injection. PEL relapse was documented in the pleura 5 months later. The patient died for a cerebrovascular accident, with no peritoneal relapse. Pt. 3, a 77-year-old Italian man, was hospitalized for a 5-month history of bilateral pleural effusion requiring repeated pleural drainages. Chemotherapy was avoided because the patient had been suffering from heart failure. He was treated with three doses of intrapleura cidofovir, Received 31 May 2004; accepted 19 November 2004; Published online 20 January 2005 Correspondence: Dr M Luppi, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Policlinico, Via del Pozzo 71, 41100 Modena, Italy; Fax: þ 39 059 4224549; E-mail: mluppi@unimore.it

Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC).

Objective:Treatment options for advanced or metastatic gastric cancer (A/MGC) are limited and inclusion of novel substances is necessary. Few studies have confirmed the activity and tolerability of the combination of oxaliplatin (OXA) and 5-fluorouracil (5-FU) modulated with leucovorin (LV) administrated to patients with A/MGC. The goal of current study was to evaluate the efficacy and toxicity of Folfox-4 regimen in patients with A/MGC. Patients and Methods:Fifty-six patients were treated with Folfox-4 regimen. Treatment was continued until disease progression, unacceptable toxicity or until a patient chose to discontinue treatment. Responses to treatment and toxicity were recorded according to the WHO criteria and NCI toxicity criteria. Results:All patients were assessable for toxicity and response. Patients (71.4% male, 28.6% female) had a median age of 65 years (range, 28–78). All patients had histologically confirmed metastatic (89.3%) or advanced (10.7%) gastric cancer. Response was evaluated every 6 weeks; 1 complete (1.8%) and 23 (41.1%) partial remission were observed (overall response rate 42.9%). Twenty patients (35.7%) showed stable disease and 12 (21.4%) had a progressive disease. Median overall survival, time to progression and follow up were 10 months, 6 months, and 11.5 months, respectively. WHO grade 3 or 4 hematologic toxicities included leucopenia, neutropenia, thrombocytopenia, and anemia. No patient experienced neutropenic fever. Other grade 3/4 toxicities included nausea, vomiting, diarrhea, stomatitis, and anorexia. Three patients (5.3%) experienced grade 3 peripheral neuropathy. No treatment-related deaths were recorded. Conclusions:Folfox-4 regimen is active and well tolerated in patients with advanced/metastatic gastric cancer.