• Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial

      Bahlis, Nizar; Corso, A; Mugge, LO; Shen, ZX; Desjardins, P; Stoppa, AM; Decaux, O; De Revel, T; Granell, M; Marit, G; et al. (Springer Science and Business Media LLC, 2017-11-01)
      © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. The phase 3, randomized Frontline Investigation of Revlimid and Dexamethasone Versus Standard Thalidomide (FIRST) trial investigating lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) vs melphalan, prednisone and thalidomide for 12 cycles (MPT) and Rd for 18 cycles (Rd18) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) showed that Rd continuous prolonged progression-free survival and overall survival compared with MPT. A subanalysis of the FIRST trial was conducted to determine the benefits of Rd continuous in patients with NDMM based on depth of response. Patients randomized 1:1:1 to Rd continuous, Rd18 or MPT were divided into subgroups based on best response: complete response (CR; n=290), ≥ very good partial response (VGPR; n=679), ≥ partial response (PR; n=1 225) or ≤ stable disease (n=299). Over 13% of patients receiving Rd continuous who achieved ≥ VGPR as best response did so beyond 18 months of treatment. Rd continuous reduced the risk of progression or death by 67%, 51% and 35% vs MPT in patients with CR, ≥ VGPR and ≥ PR, respectively. Similarly, Rd continuous reduced the risk of progression or death by 61%, 54% and 38% vs Rd18 in patients with CR, ≥ VGPR and ≥ PR, respectively. In patients with CR, ≥ VGPR or ≥ PR, 4-year survival rates in the Rd continuous arm (81.1%, 73.1% or 64.6%, respectively) were higher vs MPT (70.8%, 59.8% or 57.2%, respectively) and similar vs Rd18 (76.5%, 67.7% and 62.5%, respectively). Rd continuous improved efficacy outcomes in all responding patients, including those with CR, compared with fixed duration treatment.
    • Down-regulation of nitric oxide production by droloxifene and toremifene in human breast cancer cells.

      Martin, Jan H.; Symonds, A.; Chohan, S. (Spandidos Publications Ltd, 2003)
      We investigated the effect of tamoxifen, 4-OH tamoxifen, toremifene droloxifene, interferon-alpha2a, interferon-alpha2b and interferon-alpha2c, singly and in combination, for their effect on nitric oxide production by MCF-7 and ZR-75-1 human breast cancer cells. Tamoxifen and 4-OH tamoxifen singly had no effect on nitric oxide production by either cell line. However, treatment with droloxifene or toremifene significantly reduced nitric oxide production by both MCF-7 and ZR-75-1 human breast cancer cell lines. Combination treatment with anti-estrogens and interferon-alpha2a interferon-alpha2b or interferon-alpha2c had no synergistic or additive effect compared to each drug singly.
    • Interleukin 6 expression by Hodgkin/Reed-Sternberg cells is associated with the presence of 'B' symptoms and failure to achieve complete remission in patients with advanced Hodgkin's disease.

      Reynolds, Gary; Billingham, Lucinda; Gray, Laura; Flavell, Joanne R.; Najafipour, Sohrab; Crocker, John; Nelson, Paul N.; Young, Lawrence S.; Murray, Paul G. (Blackwell Synergy, 2002)
      Interleukin 6 (IL-6) is a potent immunomodulatory cytokine that has pathogenic and prognostic significance in a number of disorders. Previous studies in Hodgkin's disease (HD) have demonstrated the association between elevated serum levels of IL-6 and unfavourable prognosis, including advanced stage and the presence of 'B' symptoms and with reduced survival. Although IL-6 expression has been demonstrated in both the malignant Hodgkin/Reed-Sternberg (HRS) cells and in the various non-malignant cells present in HD biopsies, a relationship between expression of IL-6 by the tumour and outcome measures has not been established. The study group comprised of 97 patients with advanced HD who were recruited to two related clinical trials. IL-6 expression was determined on paraffin-wax sections of biopsy material by means of an immunohistochemical assay. Of the 97 patients, 27 (28%) showed staining for IL-6 in HRS cells. IL-6 expression by HRS cells was significantly correlated with a decreased likelihood of achieving a complete response to chemotherapy (P = 0.02) and with an increased prevalence of 'B' symptoms (P = 0.04). IL-6 expression by HRS cells was not associated with Epstein-Barr virus status (P = 0.57). In summary, the results suggest that IL-6 expression by HRS cells may contribute to the presence of 'B' symptoms and to a decreased likelihood to achieve a complete remission in HD patients.
    • Panobinostat in combination with bortezomib and dexamethasone in multiply relapsed and refractory myeloma; UK routine care cohort

      Maouche, Nadjoua; Kishore, Bhuvan; Bhatti, Zara; Basu, Supratik; Karim, Farheen; Sundararaman, Sharadha; Collings, Freya; Tseu, Bing; Leary, Heather; Ryman, Noel; et al. (Public Library of Science, 2022-07-07)
      The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the PANORAMA-1 trial which investigated this triplet in early relapse. In routine clinical care, PanBorDex is used primarily in later relapses and is commonly administered in attenuated dosing schedules to mitigate the treatment-related toxicity. We set out to evaluate efficacy and safety outcomes with PanBorDex later in the disease course and evaluate the role of attenuated dosing schedules. This was a retrospective evaluation of patients treated in routine clinical practice between 2016–2019 across seven heamatology centres in the UK; patients who received at least one dose of PanBorDex were eligible for inclusion. The dosing schedule of panobinostat (10mg, 15mg or 20mg, twice or three times a week) and bortezomib (0.7mg/m2, 1mg/m2 or 1.3mg/m2 once or twice weekly) was as per treating physician choice. Patients received treatment until disease progression or unacceptable toxicity. The primary outcome is response rates according to IMWG criteria. Key secondary endpoints include progression-free survival (PFS) and overall survival (OS). Other secondary endpoints include rates of adverse events according to CTCAE criteria. In total, 61 patients were eligible for inclusion and received PanBorDex primarily as ≥5th line of treatment. One third of patients received PanBorDex at full dose, for the remaining two thirds, treatment was given in reduced dose intensities. The overall response rate was 44.2%, including 14.7% very good partial response (VGPR) rates; 68.8% of patients derived clinical benefit with stable disease or better. The median PFS was 3.4 months; non-refractory patients and those who achieved VGPR benefited from prolonged PFS of 11.4 months and 17.7 months, respectively. The median OS was 9.5 months. The triplet was associated with 45% and 18% incidence of grade 3–4 thrombocytopenia and diarrhea, respectively.
    • Preoperative mitomycin, ifosfamide, and cisplatin followed by esophagectomy in squamous cell carcinoma of the esophagus: pathologic complete response induced by chemotherapy leads to long-term survival.

      Darnton, S.J.; Archer, V.R.; Stocken, D.D.; Mulholland, P.J.; Casson, A.G.; Ferry, David R. (American Society of Clinical Oncology, 2003)
      PURPOSE: Squamous cell carcinoma of the esophagus remains an aggressive disease with a poor prognosis, even after curative-intent surgery. This article analyzes the impact of preoperative chemotherapy with mitomycin, ifosfamide, and cisplatin (MIC) on a cohort of 68 patients. PATIENTS AND METHODS: From 1988 to 1994, 68 patients with potentially operable squamous cell carcinoma of the esophagus were entered onto two phase II trials of neoadjuvant chemotherapy with mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 and received between two and four cycles of treatment at 3-weekly intervals. Two patients were removed from the analysis when they were found to have malignancy other than squamous cell carcinoma of the esophagus. RESULTS: Forty (61%) of 66 patients had a radiologic response to chemotherapy (18 complete responses and 22 partial responses), and 52 (79%) of 66 patients went on to have the primary tumor resected. There were nine pathologic complete responders, seven of whom remain fit and well after at least 60 months of follow-up. The overall median survival was 12.4 months (95% confidence interval, 9.6 to 18.8 months). The complete response and node-negative patients survived significantly longer than those in other categories (log-rank chi2 = 18.8; P <.001): on average 13 months longer than the node-positive or nonresected category (22.0 v 9.4 months). The toxicity of the regimen was low. CONCLUSION: MIC is an easily administered, well-tolerated, and efficacious regimen as neoadjuvant therapy for patients with squamous cell carcinoma of the esophagus. These results warrant further investigation.
    • Synergistic antitumour effect of a combination of toremifene and interferon-alpha on ZR-75-1 human breast cancer cells: dependence on interferon-alpha subtype.

      Martin, Jan H.; Symonds, A. (Spandidos Publications Ltd, 2002)
      We investigated the effect of toremifene, interferon-alpha2a, interferon-alpha2b and interferon-alpha2c, singly and in combination for their effect on the growth of ZR-75-1 human breast cancer cells. Median effect analysis was used to determine synergistic or additive effects. Anti-proliferative studies showed that the growth of ZR-75-1 cells was inhibited to a greater extent by combination treatment with toremifene plus interferon-alpha2a, resulting in a synergistic interaction (CI <1) for all concentrations tested. A combination of toremifene plus interferon-alpha2b resulted in a synergistic interaction (CI <1) for the two highest concentrations of toremifene (10(-6) and 10(-7) M) and an additive effect (CI approximately equal to 1) for the lower concentrations (10(-8) to 10(-10) M). When toremifene was combined with interferon-alpha2c no additive or synergistic interaction was determined.