• 11-week course of sequential methotrexate, thoracic irradiation, and moderate-dose cyclophosphamide for "limited"-stage small-cell bronchogenic carcinoma. A study from the Manchester Lung Tumour Group.

      Thatcher, Nick; Barber, Philip V; Hunter, Robin D; Carroll, K B; Jegarajah, S; Wilkinson, Peter M; Crowther, Derek (1982-05-08)
      55 patients with inoperable but "limited"-stage small-cell carcinoma were treated sequentially with methotrexate, radiotherapy, and high doses of cyclophosphamide. The treatment was completed over 11 weeks and no maintenance chemotherapy was given. Follow-up lasted 9-29 months. Toxicity was acceptable, despite doses of cyclophosphamide of 1.5-3.5 g/m2. The complete response rate was 53%. Median survival for the total patient group was 12 months, range 2-29+. Patients who attained a complete response had a 17 month median survival; 17 patients remained in complete remission, 9 of whom first underwent treatment 14-29 months previously. Karnofsky performance scores improved after treatment and most patients were able to resume normal activity. The results are similar to those obtained with prolonged combination chemotherapy.
    • Advanced recurrent squamous cell carcinoma of the head and neck. Results of a chemotherapeutic regimen with adriamycin, bleomycin, 5-fluorouracil, methotrextate, and vitamin A.

      Thatcher, Nick; Blackledge, G; Crowther, Derek (1980-09-15)
      Twenty-five patients with advanced squamous cell carcinoma of the head and neck were entered into this study. All patients had previously been irradiated and the majority had also undergone surgery for recurrent tumor. A low-dose regimen consisting of adriamycin, bleomycin, 5-fluorouracil, methotrexate, and vitamin A was prescribed, the median number of courses was four and a total of 95 were administered. Ten patients (40%) achieved objective responses (7 partial, 3 complete). The median duration of response was 14 weeks (range, nine to 60 weeks) with a median survival time of 38.5 weeks (range, eight to 72 weeks). The nonresponding patient group's survival time was significantly reduced (P = 0.002; median, 12 weeks; range, three to 40 weeks). The treatment was given on an outpatient basis and no serious hematologic toxic reactions were encountered. Mucositis was uncommon. This regimen produced an acceptable response rate without serious side-effects. The use of Vitamin A may have helped to prevent further impairment of the patient's nutritional status by ameliorating drug-induced mucositis.
    • Blood and neoplastic diseases. A rational approach to the chemotherapy of human malignant disease. I.

      Crowther, Derek; Christie Hospital and Holt Radium Institute, Manchester (1974-10-19)
    • Chemoimmunotherapy for metastatic malignant melanoma using vincristine (NSC-67574), DTIC (NSC-45388) and Bacillus Calmette-Guerin.

      Thatcher, Nick; Blackledge, G; Palmer, Michael K; Crowther, Derek; Cancer Research Campaign Department of Medical Oncology, University of Manchester, Christie Hospital and Holt Radium Institute, Wilmslow Road, Manchester M20 9BX, United Kingdom. (1981-04)
    • Chemotherapy of metastatic carcinoma of the breast.

      Hancock, B; Todd, Ian D; Wilkinson, Peter M; Departments of Radiotherapy and Clinical Pharmacology, Christie Hospital and Holt Radium Institute, Withington, Manchester, UK (1980-07)
      Thirty-four patients with metastatic breast carcinoma were treated with the following combination: methotrexate 60 mg/m2 i.v. days 1 and 8,5-fluorouracil 500 mg/m2 i.v. days 1 and 8, cyclophosphamide 100 mg/m2 daily for 14 days, and prednisolone 25 mg b.d. by mouth daily for 14 days. In 21/34 (62%) patients regression of tumour was maintained for at least three months and in six (18%) this was complete. The median duration of response was 15 months (range 6--33) and there was a significant difference in survival between responders and non-responders (P<0.01). Toxicity was acceptable although dose reduction was necessary in eight patients and in three patients treatment had to be discontinued.
    • Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer.

      Jones, P H; Christodoulos, K; Dobbs, N; Thavasu, P; Balkwill, Frances; Blann, A D; Caine, G J; Kumar, Shant; Kakkar, A J; Gompertz, N; et al. (2004-07-05)
      Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg(-1) for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.
    • A comparison between a single agent short course chemotherapy regimen and a quadruple prolonged course regimen for small-cell bronchogenic carcinoma of limited extent.

      Carroll, K B; Moussalli, H; Brown, D; Thatcher, Nick; Regional Cardiothoracic Unit, Wythenshawe Hospital, Southmoore Road, Manchester 23 UK. (1983-04)
      Sixty-eight patients with inoperable but 'limited' stage small-cell carcinoma of the bronchus were treated with two different chemotherapy regimens. Thirty-four patients received methotrexate, cyclophosphamide, procarbazine and vincristine in standard dose over a 2-year schedule. Thirty-four patients received cyclophosphamide alone over a period of 3 months. The groups were evenly balanced with respect to clinical details which are fully described. Toxicity was acceptable. The median actual survival for the whole group was 11 months, the 1-year, 2-year and 4-year survival being 48%, 30% and 1.5% respectively. There was no statistically significant difference in survival between those classified as responders and those as non-responders, nor between the groups treated with the two different regimens. There was a high local recurrence rate.
    • The effect of combination chemotherapy on ovarian function in women treated for Hodgkin's disease.

      Whitehead, E; Shalet, Stephen M; Blackledge, G; Todd, Ian D; Crowther, Derek; Beardwell, Colin G; Christie Hospital and Holt Radium Institute, Wilmslow Rd, Manchester. (1983-09-15)
      Ovarian function has been studied in 44 adult females who previously received quadruple chemotherapy (MVPP) for Hodgkin's disease. The median age at treatment was 23 years, and the length of time between completion of treatment and study ranged from 6 months to 10 years (median, 30 months). Seventeen women maintained regular menses, 10 developed oligomenorrhea, and 17 developed amenorrhea. At treatment, the 17 women who subsequently developed amenorrhea were significantly older (median, 30 years) than those who maintained regular menses (median, 22 years) or developed oligomenorrhea (median, 23 years). All patients older than 36 years at the start of treatment stopped menstruating during chemotherapy. The cause of the menstrual disturbance in these patients was chemotherapy-induced ovarian damage characterized by high serum gonadotrophin and low serum estradiol concentrations. After completion of treatment there were 17 pregnancies, which resulted in 9 normal infants, 3 terminations, and 4 spontaneous abortions. Nine patients took the combination oral contraceptive pill throughout chemotherapy; however, subsequently 4 developed amenorrhea and 3 oligomenorrhea, suggesting that these patients had not been protected from chemotherapy-induced ovarian damage. Estrogen replacement therapy was of definite benefit in the symptomatic patients with premature ovarian failure.
    • Effects of cancer chemotherapy on gonadal function of patients.

      Shalet, Stephen M; Department of Endocrinology, Christie Hospital and Holt Radium Institute, Manchester, UK. (1980-09)
    • The effects of Hodgkin's disease and combination chemotherapy on gonadal function in the adult male.

      Whitehead, E; Shalet, Stephen M; Blackledge, G; Todd, Ian D; Crowther, Derek; Beardwell, Colin G; Christie Hospital, Manchester, England (1982-02-01)
      The effects of Hodgkin's disease and quadruple chemotherapy on gonadal function have been investigated in 92 male patients with Hodgkin's disease. Nineteen men were studied before they received chemotherapy. Fifteen of the 19 had a sperm count of 20 million/ml or greater and motility was at least 40% in all 15. In the remaining 74 men, gonadal function was studied after completion of chemotherapy (6 months--8 years). Semen was obtained from 49 men who had received six of more courses of MVPP. Forty-two were azoospermic and five of the remaining seven had a sperm count below 1 million/ml. Decreased libido and sexual activity was common during treatment but in the majority of men these returned to normal after completion of chemotherapy. The median FSH and LH levels and the median increments in serum FSH and LH levels after LHRH administration were significantly elevated compared with an age-matched control group. The mean testosterone level of the patients was significantly lower than in controls suggesting Leydig cell damage but androgen replacement therapy was not indicated in any individual patient. No evidence of hyperprolactinaemia as a result of MVPP therapy was found. These results suggest that sperm storage before chemotherapy represents the main possibility for these patients to have children after completing chemotherapy. Before starting chemotherapy, advice should be given to these patients concerning possible changes in sexual behavior during treatment and the very high incidence of permanent infertility following treatment.
    • The effects of sex steroid replacement therapy on an expanded panel of IGF-related peptides.

      Renehan, Andrew G; Frystyk, Jan; Howell, Anthony; O'Dwyer, Sarah T; Shalet, Stephen M; Flyvbjerg, Allan; Department of Surgery, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. arenehan@picr.man.ac.uk (2007-06)
      BACKGROUND: Oral estrogen alone (EA) decreases concentrations of total IGF-I while increasing IGFBP-1, but data on other IGF-related peptides are inconsistent and/or sparse. Combined oral estrogen and progestin (EP) may have differential effects on IGF-related peptides dependent on its progestin-associated androgenic activity. The aim of this study was to clarify these relationships, as circulating IGF-related peptides are potential surrogates of predisposition to common chronic diseases. DESIGN: Using an open-labelled cross-sectional design within a bowel cancer screening trial (aged 55-64 years), we determined total IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in fasted serum from 210 healthy women and free IGF-I (by ultrafiltration), insulin, IGFBP-1 and IGFBP-1:IGF-I binary complex in a selected subset of 92 women. Unadjusted and adjusted (using generalized linear models) means were compared. RESULTS: Among EA users, mean concentrations for total IGF-I (adjusted P=0.004) and free IGF-I (P<0.001) were reduced, whereas mean concentrations of IGFBP-1 (P=0.001) and binary complex (P=0.01) were increased compared with non-users. Taken as a whole group, EP use was not associated with differences in concentrations of IGF-related peptides, but on sub-group analyses, mean concentrations associated with the use of progestins with reduced androgenic activity reflected the use of EA. By contrast, mean IGFBP-2 concentrations were significantly reduced among both EA (P=0.008) and EP (P=0.002) users, irrespective of androgenic activity. Neither EA nor EP influenced mean concentrations of IGF-II, insulin and IGFBP-3. CONCLUSIONS: The uses of oral sex steroid replacements are associated with significant changes in several IGF-related analytes in a preparation-specific manner, suggesting different regulatory mechanisms. However, the directions of these changes do not fit simple correlative models of predisposition to common diseases.
    • Evaluation of adjuvant therapy in soft tissue sarcoma. A collaborative multidisciplinary approach.

      Pinedo, H; Vendrik, C; Bramwell, Vivien H C; van Slooten, E; Deakin, David P; van Unnik, J; Staquet, M; Sylvester, R; Bonadonna, G (1979-05)
    • Follow-up of pituitary tumor volume in patients with acromegaly treated with pegvisomant in clinical trials.

      Jimenez, Camilo; Burman, Pia; Abs, Roger; Clemmons, David R; Drake, William M; Hutson, Kent R; Messig, Michael; Thorner, Michael O; Trainer, Peter J; Gagel, Robert F; et al. (2008-11)
      OBJECTIVE: We examined pituitary tumor volumes in patients treated with pegvisomant for 18 months or longer, and in whom the tumors were monitored for at least 3 years. We present details on 9 of 304 patients in clinical trials with pegvisomant who experienced tumor growth within the first year of treatment. METHOD: Magnetic resonance images prior to start of pegvisomant and at last follow-up were examined in 43 patients (14% of participating patients). Twenty-nine had received prior radiation therapy (18% of irradiated patients) and all but five received somatostatin analogs between periods of pegvisomant treatment. RESULTS: At follow-up, the median tumor volume was 0.6 cc (range 0.0-19.7 cc), in comparison with 1.6 cc (0.0-19.7 cc) at baseline (P<0.001). Twenty-five patients, of which 23 received radiation therapy, had tumor volume reduction. Seventeen patients had no significant change. One patient, who had not received radiation therapy, had an increase in tumor volume from 1.61 to 1.93 cc. Of the nine patients with tumor growth, six had progressive growth before initiating pegvisomant. Two patients with stable tumors while on octreotide experienced enlargement after octreotide discontinuation but remained stable on long-term pegvisomant therapy. CONCLUSION: The present data indicate that pegvisomant does not promote tumor growth and suggest that the nine observed cases of tumor progression, which occurred within 8 months after commencing pegvisomant, are likely rebound expansions after discontinuation of somatostatin analogs and/or the natural history of aggressively growing pituitary tumors. Continued long-term surveillance of tumor volume, particularly in non-irradiated patients, is recommended.
    • Gonadal function after combination chemotherapy for Hodgkin's disease in childhood.

      Whitehead, E; Shalet, Stephen M; Jones, P H Morris; Beardwell, Colin G; Deakin, David P; Christie Hospital, Manchester (1982-04)
      The effect of quadruple chemotherapy (mustine, vincristine, procarbazine, and prednisolone) on gonadal function was investigated in 15 males and 2 females treated for Hodgkin's disease during childhood. The 2 females have regular menstrual cycles with evidence of ovulation in one. Twelve of the males have shown normal progression of pubertal development since completing their treatment. Nine out of 10 late pubertal or adult subjects had small testes but only one developed gynaecomastia. All 4 prepubertal subjects had normal basal and peak gonadotrophin responses to luteinising hormone-releasing hormone. Nine of the 12 subjects studied during puberty or adulthood had either an increased basal serum follicle-stimulating hormone (FSH) level or an exaggerated FSH response to luteinising hormone-releasing hormone. Each of the 6 males who provided semen for analysis was azoospermic after an interval of between 2.4 and 8 (mean 5.3) years after completion of treatment. We conclude that severe testicular damage is common after treatment with mustine, vincristine, procarbazine, and prednisolone in childhood. The germinal epithelium is particularly vulnerable and the resultant azoospermia is likely to be irreversible. The Leydig cells are less susceptible to cytotoxic-induced damage. Pubertal development is normal and there is no indication for androgen replacement therapy.
    • Gonadotrophin-releasing hormone analogues: a novel treatment for premenstrual asthma.

      Murray, Robert D; New, J P; Barber, Philip V; Shalet, Stephen M; Dept of Endocrinology, Christie Hospital, Manchester, UK. (1999-10)
      Premenstrual exacerbation of asthma, as reflected by a reduction in peak expiratory flow rate (PEFR), has been demonstrated in 40-100% of female asthmatics. Epidemiological data demonstrate that admission to hospital with an exacerbation of asthma occurs more frequently perimenstrually. Therapeutic interventions aimed at modifying this precipitating factor, however, remain limited. We report on a 32-yr old female with asthma in whom a marked increase in symptoms and reduction in PEFR occurred premenstrually, necessitating recurrent admissions to hospital. Frequent severe exacerbations resulted in the chronic use of oral maintenance corticosteroids. In order to suppress gonadotrophin secretion and ovarian function, a long-acting gonadotrophin-releasing hormone analogue was administered with a view to inducing a reversible menopause. This resulted in improvement in respiratory symptoms, the absence of PEFR dips premenstrually, a reduction in maintenance prednisolone dosage and no further hospital admissions during a follow-up period of 14 months. The authors propose that gonadotrophin-releasing hormone-analogue therapy is a rational and innovative adjuvant treatment worthy of further study in cases of severe premenstrual asthma.
    • Hodgkin's disease: a curable malignancy.

      Crowther, Derek; Cancer Research Campaign Department of Medical Oncology, Manchester University and Christie Hospital and Holt Radium Institute, Manchester (1981-05)
    • In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation.

      Kottaridis, Panagiotis D; Milligan, Donald W; Chopra, Rajesh; Chakraverty, Ronjon; Chakrabarti, Suparno; Robinson, Stephen P; Peggs, Karl S; Verfuerth, Stephanie; Pettengell, Ruth; Marsh, Judith C W; et al. (2000-10-01)
      A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days -8 to -4; fludarabine, 30 mg/m(2) on days -7 to -3; and melphalan, 140 mg/m(2) on day -2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor-mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.
    • In vivo CAMPATH-1H prevents GvHD following nonmyeloablative stem-cell transplantation.

      Kottaridis, P D; Milligan, Donald W; Chopra, Rajesh; Chakraverty, R K; Chakrabarti, S; Robinson, S; Peggs, Karl S; Verfuerth, S; Pettengell, Ruth; Marsh, Judith C W; et al. (2001)
      BACKGROUND: We have investigated a novel nonmyeloablative conditioning regimen in 44 patients with hematological malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. METHODS: Recipient conditioning consisted of CAMPATH-1H 20 mg/day on Days -8 to -4, fludarabine 30 mg/m(2) on Days -7 to -3 and melphalan 140 mg/m(2) on Day -2. Thirty-six recipients received unmanipulated G-CSF mobilized PBSC from HLA identical siblings and eight received unmanipulated BM from MUD. GvHD prophylaxis was with CYA alone for 38 patients and CYA plus MTX for six sibling recipients. RESULTS: Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite PCR indicate that 18 of 31 patients studied were full donor chimeras, while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range, 3-29 months) 33 patients remain alive in CR, or with no evidence of disease progression. Seven patients relapsed or progressed post-transplant and four of them subsequently died. Four patients died from regimen-related complications. There were no cases of Grades III-IV acute GvHD. Only two patients developed Grade II acute GvHD and only one had chronic GvHD. The estimated probability of non-relapse mortality at 1 year was 11%.Results: Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity and low incidence of GvHD.
    • Intensive combination chemotherapy with vincristine, adriamycin and prednisolone (VAP) in the treatment of diffuse histology non-Hodgkin's lymphoma. (A report of 89 cases with extensive disease from the Manchester Lymphoma Group).

      Blackledge, George; Bush, H; Chang, James; Crowther, Derek; Deakin, David P; Dodge, O G; Garrett, J V; Palmer, Michael K; Pearson, D; Scarffe, J Howard; et al. (1980-11)
    • Intermittent high-dose cyclophosphamide with and without prednisolone: a study of the relationships between toxicity, response and survival in metastatic lung cancer.

      Thatcher, Nick; Wagstaff, John; Wilkinson, Peter M; Palmer, Michael K; Crowther, Derek; Cancer Research Campaign, Department of Medical Oncology, University of Manchester, Manchester, England. (1982-09-15)
      Fifty-seven patients with metastatic lung carcinoma were treated with either high-dose cyclophosphamide (Cy) alone or with a combination of high dose Cy and prednisolone (Pred) 100 mg/m2 orally daily for two days. The Cy was given IV on three occasions, at 1.5 g/m2, 2.5 g/m2 and 3.5 g/m2 with three-week intervals between courses. The overall response rate was 57% (18% CR), a median survival of 24 weeks (range, 6--130) for Cy alone, and 24% (3% CR), a median of 14 weeks (range, 1--94) for Cy + Pred. Patients with small cell carcinoma given Cy alone had a 69% response rate (19% CR), a median survival of seven months, and with non-small cell pathologic conditions 42% (16% CR), a median survival of 16 weeks. Performance scores and survival were better for responding patients. Addition of Pred did not improve the therapeutic efficacy of high dose Cy or ameliorate toxicity. No marked or unexpected toxicity was observed with the high-dose Cy regimen. The blood counts had returned to normal by three weeks in the great majority of patients. A short course of high-dose Cy was not associated with unacceptable side effects and the therapeutic results obtained were superior to those described for Cy at conventional dosage. High-dose Cy is of value to patients with metastatic lung cancer, and the incorporation of the regimen into chemotherapeutic combinations could be advantageous.