Diana Giannarelli

Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer: Results From the Italian Multicenter Randomized Study

PURPOSE Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity. PATIENTS AND METHODS Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B). RESULTS Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P =.007 and P =.02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P =.005 andP =.02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P =.36 and P =.29), respectively. Treatment had a significant impact on OS and PFS. CONCLUSION Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT.

Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study.

PURPOSE To compare the effectiveness of chemotherapy (CHT) with extended-field radiotherapy (RT) in the treatment of early-stage Hodgkins disease (ESHD), we report an 8-year updated analysis of a study in which treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) CHT was randomly compared with extended-field RT. PATIENTS AND METHODS From August 1979 to December 1982, 89 adult patients with pathologic stage I-IIA Hodgkins disease (HD) were randomly allocated to receive either RT with mantle field followed by periaortic irradiation (n = 45) or six monthly courses of MOPP CHT (n = 44). RESULTS All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission. Twelve relapses occurred in each group. Eight patients treated with MOPP and two of the RT arm died of HD. Three other patients of the CHT group died because of a second cancer. With a median follow-up greater than 8 years, the overall survival rate is significantly higher in the RT than in the CHT group (93% v 56%; P less than .001), whereas the rates of freedom from progression and relapse-free survival (RFS) were similar in the two groups (76% v 64% and 70% v 71%, respectively). Of the 12 patients relapsing after RT, 11 (92%) achieved a second CR, compared with only six of the 12 (50%) in the MOPP group. Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR, whereas in the RT group, a second CR was obtained regardless of the characteristics of the relapses. At 80 months, the probability of survival of relapsing patients calculated from time of relapse was 85% and 15% in the RT and CHT groups, respectively (P = .02). CONCLUSION We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors.

Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients

Background: To evaluate the modifications of circulating angiogenic factors, metalloproteinases and acute-phase cytokines after the first single zoledronic acid (ZA) intravenous infusion. Experimental Design:Eighteen consecutive breast cancer patients with bone metastases were evaluated for circulating levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), metalloproteinase 1 (MMP-1), metalloproteinase 2 (MMP-2), interleukins 1β, 6 and 8 (IL-1β, IL-6, IL-8), interferon γ, tumor necrosis factor α (TNF-α) and transforming growth factor β1 just before and 2 and 7 days after ZA infusion. Results: The MMP-2 basal value showed a statisticallysignificant decrease 48 h after ZA (p = 0.01), being at 7 days higher than the day 2 value (p = 0.03). The VEGF basal value showed a statisticallysignificant decrease 48 h after ZA infusion (p = 0.03), increasing above the basal level at 7 days (p = 0.07). The bFGF basal level almost significantly decreased 2 days after infusion (p = 0.06), being at 7 days higher than the basal value (p = 0.09). Comparing the day 2 values with basal ones, the linear regression model showed a significantpositive correlation between IL-8 and bFGF (p = 0.02), IL-8 and TNF-α (p < 0.0001), bFGF and TNF-α (p = 0.01), MMP-1 and TNF-α (p = 0.02). Conclusions: ZA could exert an antiangiogenic activity and inhibition of tumor cell bone invasiveness by a transient reduction of VEGF, bFGF and MMP-2 circulating levels after infusion.

Prognostic relevance of altered Fas (CD95)‐system in human breast cancer

The Fas ligand (FasL) and its receptor Fas (APO‐1 or CD95) are members, respectively, of the tumor necrosis factor family that, upon interaction with each other, play a key role in the initiation of one apoptotic pathway. Faulty regulation of the Fas system has been described in a variety of human tumors with different histogenetic origin. Here, we describe the expression and distribution of Fas receptor and ligand pair antigens in surgical samples collected from a cohort of 186 patients bearing breast neoplasms (45 benign and 141 malignant lesions). Immunoperoxidase staining of formalin‐fixed tissues showed that 91.1% of benign lesions expressed Fas, which was present in only 56.7% of malignant tumors. On the other hand, FasL was found positive in 22.2% of benign neoplasms and up‐regulated in in situ as well as invasive carcinomas (53.9%). Moreover, in malignant tumors, the expression of receptor and ligand antigens appeared to be inversely related. When these findings were correlated with pathological parameters of prognostic relevance, a significant association was observed between FasL and the presence of metastatic lymph nodes and larger tumor size while Fas expression correlated to node‐negative status and smaller tumor size. Patients with Fas positive tumors exhibited longer disease‐free survival than those with Fas‐negative carcinoma while FasL did not influence patient outcome. These relationships indicate that benign and malignant mammary lesions are characterized by differential cellular expression of Fas and FasL and suggest that a neoplastic Fas negative/FasL positive phenotype may be linked to breast cancer progression. Int. J. Cancer (Pred. Oncol.) 89:127–132, 2000.

Second primary cancer following Hodgkin's disease: updated results of an Italian multicentric study.

The risk of second primary cancer (SPC) was evaluated in 947 patients treated for Hodgkins disease (HD) during the period January 1969 to December 1979. The median follow-up of this series was 10.5 years (range, 9 to 19). Treatment categories included radiotherapy (RT) alone (115 patients, 12%), chemotherapy (CHT) alone (161 patients, 17%), combined RT plus CHT (381 patients, 40%), and salvage treatment for resistant or relapsing HD (290 patients, 30.6%). Fifty-six SPCs were observed, occurring between 1 and 17 years from initial treatment. Among these, secondary acute nonlymphoid leukemia (s-ANLL) was the most frequent SPC (23 cases). Secondary non-Hodgkins lymphoma (s-NHL) occurred in 5 patients, whereas a secondary solid tumor (s-ST) was observed in 28 patients. The calculated actuarial risk (+/- SE) of developing SPC was 5.0% (+/- 0.9%) and 23.1% (+/- 5.8%) at 10 and 19 years, respectively. Concerning treatment modalities and s-ANLL risk, no cases were observed in the radiotherapy group, whereas CHT plus RT and salvage groups showed the highest actuarial risk. This was, in fact, at 10 and 19 years, 3.1% (+/- 0.9%) and 8.1% (+/- 4.0%) in the former group, and 1.8% (+/- 1.0%) and 16% (+/- 9.0%) in the latter. A statistically significant difference was observed when the CHT plus RT group was compared with CHT and RT groups (P = .04). Concerning the relationships with chemotherapeutic regimens, 12 s-ANLL cases occurred in the mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) plus RT group, and only one case in the group receiving doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus RT. A statistically significant difference of s-ANLL actuarial risk was found comparing patients receiving MOPP plus RT to all other treatment groups (P = .04). With respect to s-ST, the actuarial risk at 10 and 19 years was 2.0% (+/- 0.6%) and 13.0% (+/- 3.8%), respectively. No significant differences were found among groups treated with different modalities. These data were confirmed by a multivariate analysis, which indicated treatment modality and age as independent variables for s-ANLL and s-ST development, respectively. Based on the prolonged follow-up analysis, the actuarial SPC risk at 10 years hereby reported should reflect the real SPC incidence in our series.

Impact of Five Prophylactic Filgrastim Schedules on Hematologic Toxicity in Early Breast Cancer Patients Treated With Epirubicin and Cyclophosphamide

PURPOSE To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC). PATIENTS AND METHODS From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 x 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles +/- lonidamine +/- G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 microg/d subcutaneously days 8 to 14; (2) 480 microg/d days 8, 10, 12, and 14; (3) 300 microg/d days 8 to 14; (4) 300 microg/d days 8, 10, 12, and 14; and (5) 300 microg/d days 8 and 12. RESULTS All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non-G-CSF arms. CONCLUSION In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.

Addition of Either Lonidamine or Granulocyte Colony-Stimulating Factor Does Not Improve Survival in Early Breast Cancer Patients Treated With High-Dose Epirubicin and Cyclophosphamide

PURPOSE Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. PATIENTS AND METHODS From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). RESULTS Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non-G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non-G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). CONCLUSION EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Supracricoid partial laryngectomies after radiation failure: A multi‐institutional series

Radiation therapy (RT) is one of the gold standard treatments for early laryngeal cancer, and total laryngectomy is still the most applied surgical procedure after failure. Selected recurrences can be managed by supracricoid partial laryngectomies (SCPLs).

Acute leukaemia in patients treated for Hodgkin's disease

Fourteen acute non‐Iymphoid leukaemias (ANIL) were identified among 947 consecutive patients with Hodgkins disease (HD) treated in five collaborating centres in Italy between January 1969 and December 1979.

High serum IL‐2 levels are predictive of prolonged survival in multiple myeloma

Summary. In this study we analysed serum IL‐2 levels in 61 patients with multiple myeloma (MM). Patients serum IL‐2 levels were significantly higher than normal controls. Moreover, higher serum IL‐2 levels were associated with a prolonged actuarial survival. In particular, 87% of the MM patients with IL‐2 ≥ 10 U/ml are still alive at 5 years while only 13% of the remaining patients with IL‐2 < 10 U/ml are alive. The multivariate analysis confirmed these data indicating that high serum IL‐2 levels are the most useful predictor index of longer survival in MM patients. Furthermore, among the 50 patients in whom serum beta‐2‐microglobulin (SB2M) determination was available we observed that all patients with serum IL‐2 levels ≥ 10 U/ml had SB2M < 6 μg/ml, whereas in patients with serum IL‐2 < 10 U/ml SB2M ranged from 1.3 to 15 μg/ml. Using these two parameters we were able to identify three groups of patients with different survival duration. Group A (9 patients) defined by serum IL‐2 ≥ 10 U/ml and SB2M < 6 μg/ml in which all patients are alive; group B (26 patients) characterized by serum IL‐2 < 10 U/ml and SB2M < 6 μg/ml in which 24% of patients are alive and group C (15 patients) characterized by serum IL‐2 levels < 10 U/ml and SB2M ≥ 6 μg/ml in which the actuarial survival curve drops to 0 at 2.5 years. A statistically significant difference was observed between groups A and B (P < 0.05), groups A and C (P < 0.01) and groups B and C (P < 0.01). These data could reflect the existence of an active T cell control on B cell neoplasia and may suggest the opportunity of a more extensive use of recombinant biological modifiers such as IL‐2 in the therapeutic strategy of MM.