New perspectives in lung cancer. 4. Haematopoietic growth factors and lung cancer treatment.
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Erythropoietin↗
Biomedical subjects
N Thatcher
Publications and source records attributed to N Thatcher.
Novel approaches with ifosfamide in small cell lung cancer.
During the past 5 years, ifosfamide has been used increasingly in combination chemotherapy for small cell lung cancer (SCLC). The high activity and favorable toxicity spectrum (with the uroprotector mesna) will encourage further use. A policy of no dosage reduction is feasible in patients receiving combination chemotherapy with ifosfamide given as a 24-hour intravenous (IV) infusion, which is much more convenient than the more commonly used 4- to 5-day fractionated regimen. This policy has resulted in actual 2-year survivals of 22% to 33% among SCLC patients not intensively staged. The stability of ifosfamide and its high bioavailability have allowed its use in chronic, 7-day ambulatory IV infusions, with decreased toxicity and hospitalization. Recently, oral and subcutaneous administration also have been tried, again allowing outpatient treatment. The first studies with hemopoietic growth factor support, eg, granulocyte colony-stimulating factor, conducted with combination chemotherapy with ifosfamide-containing regimens in SCLC, demonstrated significant reduction in neutropenia, infections, and antibiotic use. It is clear that the dosage of ifosfamide can be intensified in the future. The broad versatility of the drug will allow interesting new studies, including those to be conducted with outpatients.
Antineoplastic Combined Chemotherapy Protocols↗
O6-alkylguanine-DNA alkyltransferase depletion and regeneration in human peripheral lymphocytes following dacarbazine and fotemustine.
O6-Alkylguanine-DNA alkyltransferase (ATase) levels were measured in peripheral blood lymphocytes of 13 patients with advanced malignant melanoma treated with sequential dacarbazine (DTIC) and fotemustine. Wide interindividual variation in the pretreatment levels and in depletion and regeneration of ATase activity was noted. Depletion of ATase was seen within the first h after DTIC administration with values ranging from 44 to 92% of pretreatment levels. In 10 patients, progressive depletion of ATase activity occurred with nadir activity occurring at about 4 to 6 h with values ranging from 0 to 67% of pretreatment activity; at 18 h after DTIC infusion. ATase activity varied from 6 to 81%. No significant difference was seen between the rates of ATase depletion or regeneration between the two groups of patients receiving either 500 or 800 mg/m2 of DTIC with the same dose of fotemustine (100 mg/m2). In one patient, maximum depletion occurred within 1 h and no ATase activity was detectable over the next 18 h. In another patient, maximum depletion occurred at 2 h after DTIC followed by recovery of ATase activity to 71% at 18 h. In 2 patients who returned for subsequent cycles of chemotherapy, an increase in pretreatment ATase activity was seen. Overall, the extent of depletion of ATase following DTIC/fotemustine was directly proportional to the initial ATase level.
Adenosine Triphosphatases↗
Recombinant human GM-CSF in small cell lung cancer: a phase I/II study.
Seventeen patients with small cell lung cancer were entered into a dose ranging phase I-II study using rhGM-CSF (Glaxo). In the phase I study patients received 50, 150, 300 or 500 micrograms/m2 GM-CSF for 10 days by daily subcutaneous injection. Full blood counts were performed thrice weekly. After 4 days off all therapy patients then received chemotherapy with doxorubicin 50 mg/m2 i.v. bolus, day 1, ifosfamide 5 g/m2 with mesna 5 g/m2 over 24 h by continuous infusion followed by mesna 3 g/m2, and etoposide 120 mg/m2 i.v. on days 1-3. A total of six courses of chemotherapy were given. In the phase II study patients received the same dose of GM-CSF as in the phase I. GM-CSF was given 24 h after the last dose of chemotherapy for 14 days. Full blood counts were checked thrice weekly and the incidence of infections noted. Patients were randomised to receive GM-CSF with either odd or even courses of chemotherapy. The leucocyte count rose from a mean of 8.7 to 21.6 x 10(9)/l at the 50 micrograms/m2 GM-CSF dosage and from 11.4 to 39.4 x 10(9)/l at the 500 micrograms/m2 dosage during the phase I study. Phase I toxicity was: bone pain in 65% of patients, rash in 47%, fever in 24%, lethargy in 12% and diarrhoea in 12%. In the phase II study the duration of neutropenia was less during the chemotherapy courses with GM-CSF (p = 0.04) but the number of infections was similar.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
A phase II study of ifosfamide and a2b-interferon in advanced non-small-cell lung cancer.
A total of 45 patients with advanced non-small-cell lung cancer were treated with a combination of 1.5 g/m2 ifosfamide given on days 1-5 every 3 weeks for four courses with 3 million IU a2b-interferon (Intron A) given s.c. three times a week for 12 weeks. Nine objective responses were seen, including two complete responses (CRs) and seven partial responses (PRs). Haematological and non-haematological toxicities were generally mild and did not necessitate discontinuation of therapy.
Adult↗
A randomised study of intravenous bolus versus continuous infusion of ifosfamide and doxorubicin with oral etoposide for small-cell lung cancer.
159 "poor risk" patients with previously untreated small cell lung cancer were entered into a randomised study of intravenous bolus versus continuous infusion chemotherapy with doxorubicin on weeks 1, 3, 5 and ifosfamide with mesna on weeks 2, 4, 6. Oral etoposide was given on days 1-5, 15-19, and 29-33. There was no difference in response rate or survival. However, patients treated with continuous infusion therapy had significantly less haematological toxicity (P = 0.0007), and less nausea and vomiting (P = 0.03).
Administration, Oral↗
The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.
Dose fractionation is known to reduce the toxicity of ifosfamide and also results in an increased production of alkylating metabolites. Administration by slow infusion using the convenience of ambulatory pumps is therefore of interest. We used HPLC to investigate the stability of ifosfamide in aqueous solution (either alone, solution A, or mixed with mesna, solution B) under various conditions over a 9-day period. At both ambient temperature in daylight and 27 degrees C in a dark environment, there was no evidence of ifosfamide decay in either solution. However, at 37 degrees C in a dark environment, a fall was detected in both solutions, which at 9 days amounted to a loss of 7% of the amount of ifosfamide present at time zero. At 70 degrees C, levels of ifosfamide in both solutions fell within 72 h to markedly lower levels than controls, thus confirming that the methods used were indicative of stability. We conclude that ifosfamide, either alone or mixed with mesna, is stable for 9 days at temperatures up to 27 degrees C; even at 37 degrees C, the measured loss is small. The continuous infusion of ifosfamide over 7 days by ambulatory pump is now a practical proposition.
Ambulatory Care↗
Ifosfamide and mitomycin in combination for the treatment of patients with progressive advanced non-small cell lung cancer.
42 patients with progressive and advanced non-small cell lung cancer received chemotherapy comprising ifosfamide 1.5 g/m2, mesna 1.5 g/m2 and mitomycin 1.2 mg/m2 daily for 5 days. Only those patients with symptoms and progressive disease were selected for treatment. Partial response was achieved in 10/42 patients (23.8%) and stable disease in 25/42 (59.5%). The Karnofsky performance status (KP) improved in 10/42 patients (23.8%) and a subjective respiratory symptom score improved in 12 patients (28.6%). In addition 27 patients (64.3%) had stabilisation of both the KP and respiratory score following chemotherapy. These results indicate that the ifosfamide and mitomycin combination is active in non-small cell lung cancer in this selected group of patients with antitumour and symptom control activity.
Adenocarcinoma↗
Phase II study with mitomycin, ifosfamide and carboplatin in inoperable non-small cell lung cancer.
In a phase II study of non-small cell lung cancer a new chemotherapy combination of mitomycin 6 mg/m2 intravenously on day 1, carboplatin 400 mg/m2 intravenously on day 1 and ifosfamide with mesna 5 g/m2 intravenously over 24 hours on day 1 was evaluated. A maximum of four chemotherapy cycles was given at intervals of 4 weeks to 34 patients with progressive, inoperable disease. 1 complete and 10 partial remissions were documented, the overall response rate being 32.4%. In a further 13 patients (38.2%) the previously progressing tumours remained stable for at least 6 weeks. The median time to progression for responding patients was 184 days. The median survival time for the whole group has not yet been reached at 293 days. A considerable but easily manageable myelosuppression was the principal toxicity despite a "no dose reduction" policy. Indeed, the dose intensity of the chemotherapy actually given was extremely close (97%) to that intended on protocol. In conclusion, the regimen is active in patients with advanced non-small cell lung cancer but requires regular haematological monitoring to prevent morbidity resulting from myelotoxicity.
Aged↗
Viridans streptococcal bacteraemia in patients with haematological and solid malignancies.
Thirty-three episodes of septicaemia caused by viridans streptococci are reported in 32 adults under treatment for malignant diseases. The underlying diseases were acute leukaemia (17), lymphoma (4), myeloma (1), small cell carcinoma of the bronchus (6), carcinoma of the breast (2) and carcinoma of the stomach (2). Important predisposing factors included severe neutropenia and oral mucositis due to intensive chemotherapeutic regimens. There was a poor response to standard empirical antibiotics and a mortality of 12%. A role for prophylactic penicillin in high risk groups is suggested.
Adolescent↗
Recombinant interleukin-2 in metastatic renal cell carcinoma--a European multicentre phase II study.
This multinational, multicentre study represents the introduction of recombinant interleukin-2 (rIL-2) in Europe. From December 1987 to June 1989, 57 eligible patients with metastatic renal cell cancer were treated with rIL-2 administered as continuous intravenous infusion. 8 out of 51 evaluable patients responded (16%), 2 complete remission (CR) and 6 partial remission (PR). 10 patients had no change (20%). The response duration for CR was 209 and 394+ days. The median response duration for PR was 371 (range 140-506+) days. Dose-limiting grade 3-4 toxicities were hypotension in 52% of the patients, arrhythmia (4%), dyspnoea (8%), creatinine rise (4%), peripheral neurotoxicity (10%) and central neurotoxicity (10%). Toxicities most often recovered solely on interrupted therapy. 2 patients died due to catheter-related septicaemia and one patient died of rIL-2 induced renal failure. The study confirmed the antitumour efficacy of rIL-2 in renal cell cancer. Toxicities were numerous, but manageable by close observation in a normal oncology ward without routine use of an intensive care unit.
Adult↗
High dose combination chemotherapy with ifosfamide, cyclophosphamide or cisplatin, mitomycin C and mustine with autologous bone marrow support in advanced non-small cell lung cancer. A phase I/II study.
Twenty-three patients with advanced NSCLC were treated with high dose chemotherapy using four agents and autologous bone marrow reinfusion. Ten patients received two bolus doses of cyclophosphamide (maximum tolerated total dose 10 G m-2), ifosfamide as a 24 h infusion (11 G m-2) followed by mitomycin C (70 mg m-2) as a subsequent 24 h infusion and mustine as two boluses (total dose 30 mg m-2). Another 13 patients received the same agents except cisplatin was substituted for cyclophosphamide, two doses (total dose 100 mg m-2) being given in a 24 h period. The median time of recovery to greater than or equal to 20,000 platelets was 21 days and of neutropaenia greater than or equal to 500 was 12-15 days. Unusual non-haematological toxicity e.g. cardiomyopathy, colitis, veno occlusive disease was not noted, all patients being given regular selenium and other trace elements. Three patients died in the first 2 weeks. There were five complete responses (22%) and 12 partial responses (52%) with four patients (2CR, 2PR) still alive at 27, 48, 73 and 82 weeks. The patient's Karnofsky performance in the cisplatin regimen improved over pretreatment values when compared a month after the end of treatment. The high dose regimen was associated with a high (74%) response rate, but with an overall median survival of only 6 months. The regimen has no advantage over conventional doses with the same agents in patients with metastatic NSCLC.
Adult↗
Recombinant interleukin-2 and other types of treatment of advanced malignant melanoma.
Interleukin-2 has demonstrated significant and consistent activity against melanoma even in patients who have been treated previously with other modalities. This paper reviews local treatment, systemic treatment with single-agent, combination, and high-dose chemotherapy, and new agents; biologic modifier therapy, including tumor vaccines and active specific immunization, and interferons; and recombinant interleukin-2, which has activity when used alone, with lymphokine-activated killer cells, chemotherapy, or biologic modifiers. Tumor response, predictors of response, and survival are also discussed.
Antineoplastic Agents↗
The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.
1. We investigated the pharmacokinetics of ifosfamide 5 g m-2 given by two regimens. Six patients (one female), median age 55 (range 40-71) years, all with lung cancer received 5 g m-2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23-72) years were studied on seven treatment occasions with 5 g m-2 ifosfamide (median ifosfamide dose 8.88 g) as a 24 h intravenous infusion with mesna. Plasma was assayed for ifosfamide by gas liquid chromatography and for alkylating activity by the nitrobenzylpyridine method. 2. After ifosfamide 5 g m-2 infused over 0.5 h, the decay of the plasma ifosfamide concentration was monoexponential with a median (range) t1/2,z of 5.4 h (3.6-10.4 h). The median clearance was 60 ml min-1 (47-104) and the median volume of distribution was 388 (329-783) ml kg-1. Plasma nitrobenzylpyridine alkylating activity showed a biexponential decay in four patients and a monoexponential decay in two, with a median AUC of 102 (24-177) nmol nor nitrogen mustard eq h ml-1. 3. When ifosfamide 5 g m-2 was given as a 24 h infusion, the decay of the plasma ifosfamide concentration was monoexponential, the median (range) t1/2,z was 4.5 (3.4-6.1), the median volume of distribution was 563 (292-818) ml kg-1 and the median clearance was 79 (59-116) ml min-1. Plasma nitrobenzylpyridine alkylating activity decayed monoexponentially and the median AUC was 49 (45-131) nmol nor nitrogen mustard eq ml-1 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Intensive therapy for small-cell lung cancer using carboplatin alternating with cisplatin, ifosfamide, etoposide, mid-cycle vincristine, and radiotherapy.
Forty patients with small-cell lung cancer (31 patients with limited-stage [LS] disease, and nine patients with extensive-stage [ES] disease but of good performance status) have been treated with an intensive therapy composed of carboplatin alternating with cisplatin, ifosfamide, and etoposide with vincristine on day 14 of each carboplatin cycle. A maximum of six cycles were administered at 3 weekly intervals after the cisplatin combination and 4 weekly after the carboplatin combination. Prophylactic cranial irradiation was given with the first cycle of chemotherapy and thoracic irradiation with the third cycle. The median nadir for neutrophils was 0.47 x 10(9)/L and for platelets, 40 x 10(9)/L. Chemotherapy dosages were not reduced in response to myelosuppression, but treatment was delayed to allow blood count recovery. Sixty-eight percent of patients received all six cycles of chemotherapy, and there were four deaths associated with treatment-related neutropenia. Twenty-eight patients (70%) achieved a complete response (CR) when assessed 1 month after the end of treatment, and a further five patients (12.5%) had a partial response (PR). Median duration of CR was 16 months and of PR, 8 months. Cerebral metastases occurred in 20% of all patients and was the apparent sole site of relapse in 11% of the CR patients. The median survival of the total group was 14 months with an actual 2-year survival of 30% and a minimum follow-up of 28 months.
Adult↗
Current status of quality of life measurement in lung cancer patients.
Quality of life in patients with inoperable lung cancer receiving palliative treatment has become an important issue. As in other types of cancer, lack of standardization of quality of life data makes comparison between trials difficult, sometimes even impossible. Much effort is being given to the development of suitable instruments to measure quality of life and strategies to incorporate these measurements into clinical trials. The authors review studies in palliative lung cancer treatment where two crucial questions are being addressed: Do patients improve in performance status and symptom relief and does treatment toxicity outweigh disease palliation?
Clinical Trials as Topic↗
Comparison of epidermal growth factor receptor expression in lung cancer by immunohistochemical staining of both frozen and formalin fixed specimens.
Two monoclonal antibodies used to investigate the expression of the epidermal growth factor receptor (EGF-R) in 45 lung cancers were compared. The R1 antibody recognises the extracellular domain portion of the receptor and the F4 is directed against the cytoplasmic portion. The reactivities of the two antibodies have been compared in fresh frozen tumour specimens. In addition the staining activity of the F4 antibody (the first to EGF-R which can be used in archival material) was compared using frozen and paraffin sections from the same series of tumours. Comparisons of the numbers of cells staining with the R1 and F4 antibody showed only slight discrepancy when fresh material was examined. The discrepancy that existed could be explained by the heterogeneity of the tumours. Very similar results were obtained using the F4 antibody on paraffin embedded and fresh non-small cell lung cancer material. We conclude that the expression EGF-R can be detected reliably by the F4 antibody in both the fresh frozen and formalin fixed, paraffin embedded material and could be useful in assessing the clinical importance of EGF-R in archival tumour material.
Cytological Techniques↗
Growth factor-assisted chemotherapy--the Manchester experience.
Stimulation of red cell production by erythropoietin and of granulocyte production by granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-CSF (GM-CSF) has been demonstrated in several clinical studies. The first study to show that a human CSF could be used to shorten the period of neutropenia and reduce the risk of serious infection following intensive combination chemotherapy was carried out in Manchester using G-CSF. The period of neutropenia was significantly shortenened (by a median of 80%) and the neutrophil count levels were restored and above normal by 14 days after chemotherapy. In view of these results a further study was undertaken to examine the possibility of using intensive two weekly chemotherapy under cover of G-CSF. Treatment with Doxorubicin at doses of 75, 100, 125 and 150 mg/m2 was followed by infusion of G-CSF for 11 days. The neutrophil counts returned to normal within 12-14 days, allowing the delivery of up to three cycles of high dose chemotherapy at 14 day intervals. These studies demonstrated that intensive chemotherapy with dose-limiting myelodepression can be given with increased frequency under cover of G-CSF. Our studies using GM-CSF have also shown that administration by continuous i.v. infusion can reduce the period of life-threatening neutropenia following high dose Melphalan (120 mg/m2) without resort to autologous bone marrow transplantation (ABMT). In this study the period of granulocytopenia following Melphalan (less than 500 g x 10(9)/m2) was less than 15 days. This compares favourably with other series using high dose Melphalan followed by ABMT without CSF, where the duration of severe neutropenia was prolonged beyond three weeks. Although it appears that G-CSF and GM-CSF should be given either by continuous i.v. infusion or s.c. injection at doses between 3-10 micrograms/kg/day to obtain maximum biological effect, a great deal more work is required to determine optimum schedules and investigate the possibility of using more than one bioregulator.
Agranulocytosis↗