• Assessment of tumour vascularity as a prognostic factor in lymph node negative invasive breast cancer.

      Van Hoef, M E; Knox, W F; Dhesi, S S; Howell, Anthony; Schor, Ana M; Department of Medical Oncology, Paterson Institute for Cancer Research, Manchester, U.K. (1993)
      The association between tumour vascularity and relapse was examined in 93 patients with lymph node negative (LNN) invasive breast cancer. Factor VIII-related antibody was used to stain the microvessels. Vascularity was defined by the number of vessels per field counted in the area of highest vascular density at 100 x magnification. These vascular counts were divided into three groups of vascular density (group I: < 67, group 2: 68-100, group 3: > 101 vessels/field). Cross-tabulation analysis revealed a significant relationship between vascular density and tumour grade (P = 0.027). No association was found between vascularity and tumour size, tumour type, age or menopausal status. Survival analysis showed no association between vascularity and relapse-free (P = 0.92) or overall survival (P = 0.99). Significant associations between tumour grade and relapse-free (P = 0.0048) and overall survival (P = 0.0064) and between tumour size at the cut off of 15 mm diameter and relapse-free (P = 0.0097) and overall survival (P = 0.0271) were found. When grade was taken into account the effect of tumour size became non-significant (P = 0.059). Our results suggest that assessment of vascularity is not an independent prognostic factor in LNN invasive breast cancer.
    • Dose-escalating induction chemotherapy supported by lenograstim preceding high-dose consolidation chemotherapy for advanced breast cancer. Selection of the most acceptable regimen to induce maximal tumor response and investigation of the optimal time to collect peripheral blood progenitor cells for haematological rescue after high-dose consolidation chemotherapy.

      Van Hoef, M E; Baumann, Irith; Lange, C; Luft, T; De Wynter, Erika A; Ranson, Malcolm R; Morgenstern, Godfrey R; Yvers, A; Dexter, T Michael; Testa, Nydia G; et al. (1994-03)
      BACKGROUND: In advanced breast cancer high-dose consolidation chemotherapy with haematological rescue has resulted in prolonged disease free and overall survival in a small percentage of patients. Maximal reduction of the tumor burden by intensive induction treatment preceding the high-dose chemotherapy may favor that outcome. The aims of this study were to find a rapid highly effective induction regimen with acceptable toxicity and to examine the optimal time for peripheral blood progenitor cell (PBPC) collection for haematological rescue. SUBJECTS AND METHODS: Twenty-four patients received 4 cycles of FAC chemotherapy (5-FU, adriamycin, cyclosphamide), each followed by 10 micrograms/kg/d of lenograstim (glycosylated rHuG-CSF) s.c. day 2 to 11. Chemotherapy was administered at 4 dose intensity levels with 6 patients including at each level (level 1: 500(F)/50(A)/500(C) mg/m2/3wk, level 2: 500/50/500 mg/m2/2wk, level 3: 500/75/500 mg/m2/2wk, m2/2wk, level 4: 500/75/1000 mg/m2/2wk d1 i.v.). In addition lenograstim (10 micrograms/kg/d s.c.) was administered for a period of 10 days before (period X) and after (period Y) chemotherapy. In 16 patients (4 at each dose intensity level) assessment of PBPC was performed during period X and Y as well as during cycle 1 and 4. A single apheresis to collect PBPC was planned during chemotherapy cycle 1. RESULTS: The best response was obtained at dose intensity level 3 (all 6 patients responded, 3 of them achieved CR) with acceptable toxicity. Peak circulating numbers of total CFC/ml blood were median 5819 (period X), 4635 (cycle 1), 3807 (cycle 4) and 3519 (period Y) and occurred concurrently with peak circulating numbers of CD34+ cells. The and median 3.76 x 10(6)/kg CD34+ cells. Three patients received high-dose consolidation chemotherapy with PBPC support. Recovery of ANC > 0.5 x 10(9)/l occurred on median day 11 and of platelets > 20 x 10(9)/l on median day 10. CONCLUSION: Dose intensity level 3 is the best usable induction regimen in this study. The optimal time for apheresis is either during lenograstim before chemotherapy treatment or during the first cycle of chemotherapy. Rapid haematological recovery was obtained by reinfusion of PBPC as sole source of support in the patients receiving high-dose consolidation chemotherapy.
    • Mobilisation kinetics of primitive haemopoietic cells following G-CSF with or without chemotherapy for advanced breast cancer.

      Baumann, Irith; Swindell, Ric; Van Hoef, M E; Dexter, T Michael; De Wynter, Erika A; Lange, C; Luft, T; Howell, Anthony; Testa, Nydia G; Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK. (1996-12)
      BACKGROUND: The objective of this study was to determine the optimal conditions for blood progenitor cell harvest for transplantation, with main emphasis on the mobilisation kinetics of primitive, marrow repopulating cells. PATIENTS AND METHODS: Sixteen patients with advanced breast cancer were treated with 4 cycles of dose escalating FAC chemotherapy (5-fluorouracil, adriamycin, cyclophosphamide) each followed by 10 micrograms/kg/d G-CSF for 13 days. We assessed the number of colony-forming cells (CFC), and estimated the long-term culture initiating cells (LTC-IC) and CD34+ cells during the recovery phase of cycle 1 and 4 of chemotherapy, and during additional periods of G-CSF administration either preceding or following the full course of chemotherapy. RESULTS: The highest peak numbers of CFC per ml of blood (median 10489, range 860-39282) were mobilised after the first cycle of chemotherapy. The lowest peak numbers of CFC were obtained during the recovery phase from cycle 4 (median 4739, range 40-26789). In contrast, the numbers of CD34+ cells per ml of blood were significantly higher in cycle 4 (median 650, range 30-2600 x 10(2)) compared to those of cycle 1 (median 240, range 20-770 x 10(2)). The peak numbers of CFC mobilised by G-CSF before commencement and after the cessation of chemotherapy were equivalent, with a median of 5470 (range 1056-25669) and 5948 (range 2710-38975) per ml of blood, respectively. However, while mononuclear cells (MNC) collected at the days of maximal CFC mobilization following G-CSF administration before or after cycle 1 were similar to normal bone marrow MNCs in their ability to generate haemopoiesis when seeded onto performed irradiated stroma, those collected after cycle 4 or during G-CSF administration after the cessation of chemotherapy were markedly compromised in this respect. CONCLUSIONS: Our results indicate that repeated cycles of FAC chemotherapy followed by G-CSF result in a far lower number of LTC-IC than of CFC mobilised into the circulation. Furthermore although the combination of chemotherapy and G-CSF mobilised the highest numbers if CFC, G-CSF alone pre-chemotherapy was more effective at mobilising LTC-IC. These data indicate that neither the numbers of CFC mobilised nor the numbers of CD34+ cells are necessarily a reliable indicator for the putative marrow repopulating capability of the blood cells mobilised with chemotherapy plus G-CSF.
    • Urinary-derived monocyte-colony stimulating factor (P-100) following treatment with carboplatin and etoposide in small cell lung cancer (SCLC).

      Van Hoef, M E; Radford, John A; Jones, A; Smith, I E; Earl, H M; Woll, Penella J; Thatcher, Nick; CRC Dept Medical Oncology, Christie Hospital, Manchester, U.K. (1993-12)
      BACKGROUND: The hematopoietic growth factor P-100 is a monocyte-colony stimulating factor purified from human urine and has been reported to reduce neutropenia following chemotherapy. In this study the effect and toxicity of P-100 was evaluated in 26 patients receiving intensive chemotherapy for SCLC. STUDY DESIGN: Chemotherapy consisted of four 28 day cycles of carboplatin (C) 600 mg/m2 i.v. on day 1 of cycle 1 + 2 and 300 mg/m2 i.v. on day 1 of cycle 3 + 4 and etoposide (E) 120 mg/m2 i.v. on day 1-3 of each cycle. Patients were randomised to receive P-100 for ten days following chemotherapy during either the first or second cycle. 12 Patients received P-100 with the first and 12 with the second cycle. For each group cycles with P-100 were compared to cycles without P-100. RESULTS: P-100 was well tolerated but no significant differences between cycles with and without P-100 were seen in the administered chemotherapy dose, depth and duration of neutropenia, number of blood or platelet transfusions, WHO grade 3-4 infection or requirement for intravenous antibiotics. Of 24 evaluable patients 14 (58.3%) achieved CR and 4 (16.6%) PR. Patients achieving CR received radiotherapy. The median time to progression was 169 days (range 38-995+ days) and the median survival time was 305 days (range 42-1052+ days). Three patients are alive after 2 years (11.5%), 2 without relapse (7.7%). Alopecia, nausea and vomiting occurred in all patients but no treatment related deaths occurred. CONCLUSION: In this study P-100 did not significantly influence the myelotoxicity associated with carboplatin-etoposide chemotherapy in the treatment of SCLC.