Chemotherapy

Abstract

Chemotherapy is the mainstay treatment modality in haematological cancers: 60% of childhood acute lymphocytic leukaemias and 30% of adult cases, 30-40% of acute myelogenous leukaemias in young and middle-aged adults, 80% of Hodgkin's disease, and 30% of intermediate-grade and high-grade non-Hodgkin lymphomas are cured by combination chemotherapy.1Löwenberg B Acute myelogenous leukemia and myelodysplasia.in: 4th ed. Baillière's clinical haematology. 9. Baillière Tindall, London1996: 1-203Google Scholar Many patients with solid tumours benefit from chemotherapy, which can cure some in the metastatic phase (eg, germ-cell and paediatric solid tumours). Chemotherapy prolongs overall survival of patients with several chemosensitive metastatic cancers, such as breast, ovarian, small-cell lung, and bladder cancers; in other less sensitive tumours, such as colorectal and non-small-cell lung cancers, the benefit is mostly limited to responding patients. Chemotherapy has its greatest impact when given as adjuvant treatment before and/or after a radical local therapy (eg, adjuvant chemotherapy in breast, colon, and childhood cancers).2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google ScholarNew drugsIn the past decade, we have witnessed extensive investigation of new molecules obtained by small modifications of known active compounds. Only a few of these drugs have substantial differences compared with their parent, either in different and more manageable toxicity (eg, carboplatin vs cisplatin), a different and larger spectrum of activity and different toxicity profile (ifosfamide vs cyclophosphamide), or a better therapeutic index (idarubicin vs daunorubicin). Carboplatin, being more manageable than cisplatin, has similar activity to cisplatin in advanced ovarian cancer, but not in other tumours such as germ-cell tumours, where cisplatin-based chemotherapy is still recommended. Ifosfamide has activity in sarcomas and in non-small-cell lung cancer, where its parent does not have substantial activity. Idarubicin has partly replaced daunorubicin in the first-line treatment of acute non-lymphocytic leukaemias and might replace daunorubicin entirely. In the past 5 years, new cytotoxic agents with activity primarily in solid tumours, and with new mechanisms of action, have been introduced (table).TableImportant characteristics of new anticancer agentsDrugMechanism of actionActivitySide-effectsRecommended dose and schedule as single agentToxanosPaclitaxelMicrotubuline disassembly inhibitorOvary, breast, lung (nonsmall-cell) bladderNeutropenia, peripheral neurotoxicity135 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per 24 h every 3 weeks or 200 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per 3 h every 3 weeksDocetaxelMicrotubuline disassemblyBreast, lung (nonsmall-cell), ovaryNeutropenia, peripheral neurotoxicity, fluid retention100 rng/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every 3 weeksCytarbine analogueGemcitabineInhibitor of DNA synthesisLung (nonsmall-cell), pancreas, ovaryInfluenza-like syndrome, liver1000 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar everyCamptothecansIrinotecanTopoisomerase I inhibitorLung, colonNeutropenia, diarrhoea100 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every week or 350 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every 3 weeksTopotecanTopoisomerase I inhibitorLung (small-cell), ovaryNeutropenia1.5 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per day for 5 days every 3 weeksVinca derivativeVinorelbineMicrotubuline inhibitorBreast, lung (nonsmall-cell)Leukopenla, neurotoxicity30 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every weekThymidylate-synthase inhibitorTomudexThymidylate synthase inhibitorColonNeutropenia, diarrhoea3.5 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every 3 weeksAdenosine analoguesFludarabineInhibitor of DNA polyrnerase and ribonucleotide reductaseCLL, low-grade NHL, hairy-cell leukaemiaNeutropenia, lymphopenia, immunodepression25-50 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per day for 2-5 days every 4 weeksCladribineInhibitor of DNA polymerase and ribonucleotide reductaseCLL, low-grade NHL, hairy-cell leukaemiaNeutropenia, lymphopenia, immunodepression01 mg/kg per day for 7 days by continuous infusion every 5 weeksCLL=chronic lymphocytic leukaemia, NHL=non-Hodgkin lymphoma Open table in a new tab The two taxanes,3Gelmon K The taxoids: paclitaxel and docetaxel.Lancet. 1994; 344: 1267-1272Abstract PubMed Scopus (211) Google Scholar paclitaxel and docetaxel, stimulate formation and inhibit disassembly of microtubules, which have an essential role in spindle formation during mitosis and in cell migration. For both drugs, neutropenia is the dose-limiting side-effect. Paclitaxel administration necessitates premedication to prevent severe hypersensitivity reactions. Prolonged use of docetaxel is characterised by fluid retention, which may mean therapy discontinuation; the use of oral dexamethasone limits the occurrence of this side-effect. Furthermore, for both drugs, peripheral neurotoxicity is a cumulative side-effect. These new agents are active in breast, ovary, bladder, and non-small-cell lung cancers, and in squamous cell carcinoma of the head and neck. They are being tested in combination with other agents. Paclitaxel has moved into first-line treatment of several malignant diseases, such as ovarian and breast cancers. The combination of paclitaxel with cisplatin has become first-line treatment of ovarian cancer, and paclitaxel plus doxorubicin appears to be one of the most active combinations for advanced breast cancer. The sequence and the duration of infusion of doxorubicin and paclitaxel may be important for deleterious side-effects, such as cardiotoxicity.4Gianni L Munzone E Capri G et al.Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.J Clin Oncol. 1995; 13: 2688-2699Crossref PubMed Scopus (544) Google Scholar Taxanes appear to have activity in patients who are refractory to platinum (eg, ovary and non-small-cell lung cancers) or anthracyclines (breast cancer).Gemcitabine is an antimetabolite analogue of cytarabine, with major activity in solid tumours rather than in haematological cancers. Gemcitabine is active in non-small-cell lung, bladder, and ovarian cancers5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google Scholar and in pancreatic cancer it improves quality of life and symptoms and survival compared with fluorouracil, despite a low response rate.6Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer a randomized trial. J Clin Oncol (in press).Google Scholar With a mild toxicity profile (influenza-like syndrome, transient increase of liver enzymes, and mild myelotoxicity), gemcitabine appears easy to combine with other agents. Interesting activities have been reported by combining gemcitabine with cisplatin in non-small-cell lung and ovarian cancers.Irinotecan (CPT-11) and topotecan are new topoisomerase I inhibitors and derivatives of camptothecin, a drug tested in the early 1970s and dismissed due to unpredictable and severe side-effects. These new derivatives have a more predictable toxicity profile and are active in a range of cancers.7Dancey J Eisenhauer EA Current perspectives on camptothecins in cancer treatment.Br J Cancer. 1996; 74: 327-328Crossref PubMed Scopus (143) Google Scholar Irinotecan has diarrhoea and neutropenia as major side-effects, whereas topotecan has mainly neutropenia. Irinotecan is active in advanced colon and lung cancers, whilst topotecan is active in small-cell lung and ovarian cancers that are resistant to platinum-containing chemotherapy.Vinorelbine is a vinca alkaloid, with mild neurotoxicity compared with other vinca alkaloids such as vincristine and vinblastine.8Pinedo HM Van Groeningen CJ Vinorelbine: a horse of a different color?.J Clin Oncol. 1994; 9: 1745-1747Google Scholar Vinorelbine is active in solid tumours, in which other vinca alkaloids have limited activity, in particular in breast and non-small-cell lung cancers.As a result of extensive research on thymidylate-synthase inhibitors, tomudex has recently been shown to be at least as active as the combination of fluorouracil plus folinic acid (leucovorin) in advanced colorectal cancer.5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google ScholarOther agents have specific activity in haematological cancers. New adenosine analogues have important activity in chronic lymphocytic and hairy-cell leukaemias, especially fludarabine and cladribine (2-chlorodeoxyadenosine).5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google Scholar Interferon-α prolongs remission in hairy-cell leukaemia, low-grade malignant lymphoma, chronic myeloid leukaemia, and multiple myeloma. Finally, tretinoin (all-trans retinoic acid) is a potent inducer of differentiation in leukaemic cells, with strong antileukaemic activity; it improves significantly the response and outcome of patients with acute promyelocytic leukaemia when given as an adjunct to chemotherapy.9Chomienne C Fenaux P Degos L Retinoid differentiation therapy in promyelocytic leukemia.FASEB J. 1996; 10: 1025-1030Crossref PubMed Scopus (121) Google ScholarHigh-dose chemotherapyIn retrospective studies in conventional dose ranges, the dose-intensity of chemotherapy appears to be related to effects (response rate and median survival) in several cancers, including breast, ovary, and colon and in haematological cancers. Far less convincing, however, are the prospective randomised trials. Acute myelogenous leukaemia is an exception in which well-designed randomised studies with cytarabine show that higher-dose regimens prevent relapse more effectively and may produce superior survival.10Bishop JF Matthews JP Young GA et al.A randomized study of high-dose cytarabine in induction in acute myeloid leukemia.Blood. 1996; 87: 1710-1717PubMed Google ScholarThe use of colony-stimulating factors allows only a modest increase in doses of chemotherapy by itself. Although side-effects associated with severe myelosuppression may be decreased, less evident is an improvement in efficacy with the addition of colony-stimulating factors in any tumour type, even in acute myelogenous leukaemia.High-dose chemotherapy plus haematopoietic stem-cell transplantation and colony-stimulating factors allows larger dose-escalation and has a definite place in the treatment of haematological cancers,11Attal M Harousseau JL Stoppa AM et al.A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.N Engl J Med. 1996; 335: 91-97Crossref PubMed Scopus (2577) Google Scholar, 12Löwenberg B Postremission treatment of acute myelogenous leukemia.N Engl J Med. 1995; 332: 260-262Crossref PubMed Scopus (33) Google Scholar and can also be effective in refractory testicular cancer.13Margolin K Doroshow JH Ch Ahn et al.Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support.J Clin Oncol. 1996; 14: 2631-2637Crossref PubMed Scopus (80) Google ScholarSo far, there is no evidence that high-dose chemotherapy has any impact on survival of patients with other metastatic solid tumours. The use of autologous bone-marrow transplantation has been progressively replaced by peripheral stem-cell transfusion, which circumvents general anaesthesia, is performed as an outpatient procedure, permits accelerated haematological recovery, and is cheaper. The studies with the best chance to prove the high-dose concept are probably those in early stages of disease—ie, as adjuvant treatment of patients at high-risk for relapse after adequate local treatment. Such studies are ongoing.Another approach to high-dose chemotherapy is to expose only localised parts of the body to very high concentrations of drug. This can be achieved by hepatic arterial or intracavitary chemotherapy. Accumulating data show that fluorouracil or doxifluridine (FUDR) given through the hepatic artery was more effective than the intravenous route in patients with liver metastases from colon carcinoma.14Meta-Analysis Group in CancerReappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer.J Natl Cancer Inst. 1996; 88: 252-258Crossref PubMed Scopus (465) Google Scholar Similarly, intraperitoneal chemotherapy appears to have a role in the treatment of ovarian cancer patients with minimal residual disease after surgery15Alberts DS Liu PY Hannigan EV et al.Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.N Engl J Med. 1996; 335: 1950-1955Crossref PubMed Scopus (1109) Google Scholar or induction chemotherapy. Isolated-limb perfusion with high-dose tumour necrosis factor-in combination with interferon-y and melphalan can achieve limb salvage in patients with non-resectable soft-tissue sarcomas of the extremities.16Eggermont AMM Schraffordt Koops H Liénard D et al.Isolated limb perfusion with high-dose tumor necrosis factor-α in combination with interferon-γ and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial.J Clin Oncol. 1996; 14: 2653-2665Crossref PubMed Scopus (364) Google ScholarDrug resistanceOver the past 10–15 years, our understanding of the causes of resistance to drugs has substantially improved. Gene alterations associated with resistance to specific drugs have been identified and genes have also been identified which, when altered, may lead to broad cross-resistance to several unrelated anticancer agents (multidrug resistance). The assessment of these genes or their products as predictors of tumour sensitivity to specific drugs, although promising (eg, lung resistance protein17Izquierdo MA Van der Zee AGJ Vermorken JB et al.Drug resistance-associated marker LRP for prediction of response to chemotherapy and prognosis in advanced ovarian carcinoma.J Natl Cancer Inst. 1995; 87: 1230-1237Crossref PubMed Scopus (232) Google Scholar and glutathione S-transferase2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar in platinum resistance, and thymidylate synthase in fluorouracil resistance19Peters GJ Van der Wilt CL Van Groeningen CJ et al.Thymidylate synthase inhibition after administration of 5-fluorouracil with or without leucovorin; implications for treatment with 5-fluorouracil.J Clin Oncol. 1994; 12: 2035-2042PubMed Google Scholar) appears to be of clinical relevance only in certain tumour types. The discovery that several non-cytotoxic substances may inhibit the activity of the gene products in the laboratory has led to the study of these multidrug-resistance reverters in the clinic in association with an anticancer agent. So far this strategy has not substantially improved management, perhaps because multiple mechanisms of drugs resistance may occur simultaneously in the same turnout. Furthermore, the expression of several of these genes is not necessarily causally linked to the development of drug resistance, but may be the expression of a more aggressive phenotype by themselves.20Pinedo HM Giaccone G P-Glycoprotein—a marker of cancer-cell behavior.N Engl J Med. 1995; 333: 1417-1419Crossref PubMed Scopus (91) Google Scholar Alterations in important genes for cell life and proliferation, such as TP53 and BCL-2, have an important impact on the development of resistance to a broad range of anticancer agents.21Harris CC Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies.J Natl Cancer Inst. 1996; 88: 1442-1455Crossref PubMed Scopus (646) Google ScholarHormonal treatmentHormones have a major role in the treatment of hormone-sensitive tumours. The use of tamoxifen for up to 5 years has become standard treatment for postmenopausal breast cancer patients with positive axillary lymph-nodes, in whom survival is substantially increased.22Swedish Breast Cancer Cooperative GroupRandomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer.J Natl Cancer Inst. 1996; 88: 1543-1549Crossref PubMed Scopus (267) Google Scholar Tamoxifen and several other hormonal preparations have an important place in the treatment of advanced breast carcinoma. Luteinising-hormone releasing-hormone agonists alone or in combinations with antiandrogens have largely replaced orchidectomy in the treatment of advanced prostatic cancer.Supportive measuresThe improvements in chemotherapy have also been due to improvements in the way chemotherapy can be administered. The use of 5-hydroxy-tryptamine antagonists and high-dose steroids as effective antiemetic drugs improves tolerance to several anticancer drugs, including cisplatin.23Karim F Roerig SC Saphier D Role of 5-hydroxytryptamine3 (5-HT3) antagonists in the prevention of emesis caused by anticancer therapy.Biochem Pharmacol. 1996; 52: 685-692Crossref PubMed Scopus (30) Google Scholar The introduction of prophylactic colony-stimulating factors (eg, granulocyte and granulocyte-macrophage colony-stimulating factors) and improved antibacterial and antifungal strategies has allowed in some studies the reduction of infective complications in patients undergoing myelosuppressive chemotherapy. Thrombopoietin will in the future also help in dealing with thrombocytopenia.The introduction of oral morphine preparations and new potent analgesic drugs (eg, transdermal fentanyl) allow better pain control. In this respect the use of bisphosphonates in patients with osteolytic bone metastases may achieve, besides pain reduction, a reduction of complications due to bone metastases (eg, fractures)24Hortobagyi GN Theriault RL Porter L et al.Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases.N Engl J Med. 1996; 335: 1785-1791Crossref PubMed Scopus (926) Google Scholar and also delay their occurrence. Treatment with radioactive strontium is less readily applicable but highly effective in selected patients with pain derived from extensive bone metastases that cannot be kept under control with analgesic drugs. Chemotherapy is the mainstay treatment modality in haematological cancers: 60% of childhood acute lymphocytic leukaemias and 30% of adult cases, 30-40% of acute myelogenous leukaemias in young and middle-aged adults, 80% of Hodgkin's disease, and 30% of intermediate-grade and high-grade non-Hodgkin lymphomas are cured by combination chemotherapy.1Löwenberg B Acute myelogenous leukemia and myelodysplasia.in: 4th ed. Baillière's clinical haematology. 9. Baillière Tindall, London1996: 1-203Google Scholar Many patients with solid tumours benefit from chemotherapy, which can cure some in the metastatic phase (eg, germ-cell and paediatric solid tumours). Chemotherapy prolongs overall survival of patients with several chemosensitive metastatic cancers, such as breast, ovarian, small-cell lung, and bladder cancers; in other less sensitive tumours, such as colorectal and non-small-cell lung cancers, the benefit is mostly limited to responding patients. Chemotherapy has its greatest impact when given as adjuvant treatment before and/or after a radical local therapy (eg, adjuvant chemotherapy in breast, colon, and childhood cancers).2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar New drugsIn the past decade, we have witnessed extensive investigation of new molecules obtained by small modifications of known active compounds. Only a few of these drugs have substantial differences compared with their parent, either in different and more manageable toxicity (eg, carboplatin vs cisplatin), a different and larger spectrum of activity and different toxicity profile (ifosfamide vs cyclophosphamide), or a better therapeutic index (idarubicin vs daunorubicin). Carboplatin, being more manageable than cisplatin, has similar activity to cisplatin in advanced ovarian cancer, but not in other tumours such as germ-cell tumours, where cisplatin-based chemotherapy is still recommended. Ifosfamide has activity in sarcomas and in non-small-cell lung cancer, where its parent does not have substantial activity. Idarubicin has partly replaced daunorubicin in the first-line treatment of acute non-lymphocytic leukaemias and might replace daunorubicin entirely. In the past 5 years, new cytotoxic agents with activity primarily in solid tumours, and with new mechanisms of action, have been introduced (table).TableImportant characteristics of new anticancer agentsDrugMechanism of actionActivitySide-effectsRecommended dose and schedule as single agentToxanosPaclitaxelMicrotubuline disassembly inhibitorOvary, breast, lung (nonsmall-cell) bladderNeutropenia, peripheral neurotoxicity135 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per 24 h every 3 weeks or 200 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per 3 h every 3 weeksDocetaxelMicrotubuline disassemblyBreast, lung (nonsmall-cell), ovaryNeutropenia, peripheral neurotoxicity, fluid retention100 rng/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every 3 weeksCytarbine analogueGemcitabineInhibitor of DNA synthesisLung (nonsmall-cell), pancreas, ovaryInfluenza-like syndrome, liver1000 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar everyCamptothecansIrinotecanTopoisomerase I inhibitorLung, colonNeutropenia, diarrhoea100 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every week or 350 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every 3 weeksTopotecanTopoisomerase I inhibitorLung (small-cell), ovaryNeutropenia1.5 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per day for 5 days every 3 weeksVinca derivativeVinorelbineMicrotubuline inhibitorBreast, lung (nonsmall-cell)Leukopenla, neurotoxicity30 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every weekThymidylate-synthase inhibitorTomudexThymidylate synthase inhibitorColonNeutropenia, diarrhoea3.5 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar every 3 weeksAdenosine analoguesFludarabineInhibitor of DNA polyrnerase and ribonucleotide reductaseCLL, low-grade NHL, hairy-cell leukaemiaNeutropenia, lymphopenia, immunodepression25-50 mg/m2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar per day for 2-5 days every 4 weeksCladribineInhibitor of DNA polymerase and ribonucleotide reductaseCLL, low-grade NHL, hairy-cell leukaemiaNeutropenia, lymphopenia, immunodepression01 mg/kg per day for 7 days by continuous infusion every 5 weeksCLL=chronic lymphocytic leukaemia, NHL=non-Hodgkin lymphoma Open table in a new tab The two taxanes,3Gelmon K The taxoids: paclitaxel and docetaxel.Lancet. 1994; 344: 1267-1272Abstract PubMed Scopus (211) Google Scholar paclitaxel and docetaxel, stimulate formation and inhibit disassembly of microtubules, which have an essential role in spindle formation during mitosis and in cell migration. For both drugs, neutropenia is the dose-limiting side-effect. Paclitaxel administration necessitates premedication to prevent severe hypersensitivity reactions. Prolonged use of docetaxel is characterised by fluid retention, which may mean therapy discontinuation; the use of oral dexamethasone limits the occurrence of this side-effect. Furthermore, for both drugs, peripheral neurotoxicity is a cumulative side-effect. These new agents are active in breast, ovary, bladder, and non-small-cell lung cancers, and in squamous cell carcinoma of the head and neck. They are being tested in combination with other agents. Paclitaxel has moved into first-line treatment of several malignant diseases, such as ovarian and breast cancers. The combination of paclitaxel with cisplatin has become first-line treatment of ovarian cancer, and paclitaxel plus doxorubicin appears to be one of the most active combinations for advanced breast cancer. The sequence and the duration of infusion of doxorubicin and paclitaxel may be important for deleterious side-effects, such as cardiotoxicity.4Gianni L Munzone E Capri G et al.Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.J Clin Oncol. 1995; 13: 2688-2699Crossref PubMed Scopus (544) Google Scholar Taxanes appear to have activity in patients who are refractory to platinum (eg, ovary and non-small-cell lung cancers) or anthracyclines (breast cancer).Gemcitabine is an antimetabolite analogue of cytarabine, with major activity in solid tumours rather than in haematological cancers. Gemcitabine is active in non-small-cell lung, bladder, and ovarian cancers5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google Scholar and in pancreatic cancer it improves quality of life and symptoms and survival compared with fluorouracil, despite a low response rate.6Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer a randomized trial. J Clin Oncol (in press).Google Scholar With a mild toxicity profile (influenza-like syndrome, transient increase of liver enzymes, and mild myelotoxicity), gemcitabine appears easy to combine with other agents. Interesting activities have been reported by combining gemcitabine with cisplatin in non-small-cell lung and ovarian cancers.Irinotecan (CPT-11) and topotecan are new topoisomerase I inhibitors and derivatives of camptothecin, a drug tested in the early 1970s and dismissed due to unpredictable and severe side-effects. These new derivatives have a more predictable toxicity profile and are active in a range of cancers.7Dancey J Eisenhauer EA Current perspectives on camptothecins in cancer treatment.Br J Cancer. 1996; 74: 327-328Crossref PubMed Scopus (143) Google Scholar Irinotecan has diarrhoea and neutropenia as major side-effects, whereas topotecan has mainly neutropenia. Irinotecan is active in advanced colon and lung cancers, whilst topotecan is active in small-cell lung and ovarian cancers that are resistant to platinum-containing chemotherapy.Vinorelbine is a vinca alkaloid, with mild neurotoxicity compared with other vinca alkaloids such as vincristine and vinblastine.8Pinedo HM Van Groeningen CJ Vinorelbine: a horse of a different color?.J Clin Oncol. 1994; 9: 1745-1747Google Scholar Vinorelbine is active in solid tumours, in which other vinca alkaloids have limited activity, in particular in breast and non-small-cell lung cancers.As a result of extensive research on thymidylate-synthase inhibitors, tomudex has recently been shown to be at least as active as the combination of fluorouracil plus folinic acid (leucovorin) in advanced colorectal cancer.5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google ScholarOther agents have specific activity in haematological cancers. New adenosine analogues have important activity in chronic lymphocytic and hairy-cell leukaemias, especially fludarabine and cladribine (2-chlorodeoxyadenosine).5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google Scholar Interferon-α prolongs remission in hairy-cell leukaemia, low-grade malignant lymphoma, chronic myeloid leukaemia, and multiple myeloma. Finally, tretinoin (all-trans retinoic acid) is a potent inducer of differentiation in leukaemic cells, with strong antileukaemic activity; it improves significantly the response and outcome of patients with acute promyelocytic leukaemia when given as an adjunct to chemotherapy.9Chomienne C Fenaux P Degos L Retinoid differentiation therapy in promyelocytic leukemia.FASEB J. 1996; 10: 1025-1030Crossref PubMed Scopus (121) Google Scholar In the past decade, we have witnessed extensive investigation of new molecules obtained by small modifications of known active compounds. Only a few of these drugs have substantial differences compared with their parent, either in different and more manageable toxicity (eg, carboplatin vs cisplatin), a different and larger spectrum of activity and different toxicity profile (ifosfamide vs cyclophosphamide), or a better therapeutic index (idarubicin vs daunorubicin). Carboplatin, being more manageable than cisplatin, has similar activity to cisplatin in advanced ovarian cancer, but not in other tumours such as germ-cell tumours, where cisplatin-based chemotherapy is still recommended. Ifosfamide has activity in sarcomas and in non-small-cell lung cancer, where its parent does not have substantial activity. Idarubicin has partly replaced daunorubicin in the first-line treatment of acute non-lymphocytic leukaemias and might replace daunorubicin entirely. In the past 5 years, new cytotoxic agents with activity primarily in solid tumours, and with new mechanisms of action, have been introduced (table). CLL=chronic lymphocytic leukaemia, NHL=non-Hodgkin lymphoma The two taxanes,3Gelmon K The taxoids: paclitaxel and docetaxel.Lancet. 1994; 344: 1267-1272Abstract PubMed Scopus (211) Google Scholar paclitaxel and docetaxel, stimulate formation and inhibit disassembly of microtubules, which have an essential role in spindle formation during mitosis and in cell migration. For both drugs, neutropenia is the dose-limiting side-effect. Paclitaxel administration necessitates premedication to prevent severe hypersensitivity reactions. Prolonged use of docetaxel is characterised by fluid retention, which may mean therapy discontinuation; the use of oral dexamethasone limits the occurrence of this side-effect. Furthermore, for both drugs, peripheral neurotoxicity is a cumulative side-effect. These new agents are active in breast, ovary, bladder, and non-small-cell lung cancers, and in squamous cell carcinoma of the head and neck. They are being tested in combination with other agents. Paclitaxel has moved into first-line treatment of several malignant diseases, such as ovarian and breast cancers. The combination of paclitaxel with cisplatin has become first-line treatment of ovarian cancer, and paclitaxel plus doxorubicin appears to be one of the most active combinations for advanced breast cancer. The sequence and the duration of infusion of doxorubicin and paclitaxel may be important for deleterious side-effects, such as cardiotoxicity.4Gianni L Munzone E Capri G et al.Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.J Clin Oncol. 1995; 13: 2688-2699Crossref PubMed Scopus (544) Google Scholar Taxanes appear to have activity in patients who are refractory to platinum (eg, ovary and non-small-cell lung cancers) or anthracyclines (breast cancer). Gemcitabine is an antimetabolite analogue of cytarabine, with major activity in solid tumours rather than in haematological cancers. Gemcitabine is active in non-small-cell lung, bladder, and ovarian cancers5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google Scholar and in pancreatic cancer it improves quality of life and symptoms and survival compared with fluorouracil, despite a low response rate.6Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer a randomized trial. J Clin Oncol (in press).Google Scholar With a mild toxicity profile (influenza-like syndrome, transient increase of liver enzymes, and mild myelotoxicity), gemcitabine appears easy to combine with other agents. Interesting activities have been reported by combining gemcitabine with cisplatin in non-small-cell lung and ovarian cancers. Irinotecan (CPT-11) and topotecan are new topoisomerase I inhibitors and derivatives of camptothecin, a drug tested in the early 1970s and dismissed due to unpredictable and severe side-effects. These new derivatives have a more predictable toxicity profile and are active in a range of cancers.7Dancey J Eisenhauer EA Current perspectives on camptothecins in cancer treatment.Br J Cancer. 1996; 74: 327-328Crossref PubMed Scopus (143) Google Scholar Irinotecan has diarrhoea and neutropenia as major side-effects, whereas topotecan has mainly neutropenia. Irinotecan is active in advanced colon and lung cancers, whilst topotecan is active in small-cell lung and ovarian cancers that are resistant to platinum-containing chemotherapy. Vinorelbine is a vinca alkaloid, with mild neurotoxicity compared with other vinca alkaloids such as vincristine and vinblastine.8Pinedo HM Van Groeningen CJ Vinorelbine: a horse of a different color?.J Clin Oncol. 1994; 9: 1745-1747Google Scholar Vinorelbine is active in solid tumours, in which other vinca alkaloids have limited activity, in particular in breast and non-small-cell lung cancers. As a result of extensive research on thymidylate-synthase inhibitors, tomudex has recently been shown to be at least as active as the combination of fluorouracil plus folinic acid (leucovorin) in advanced colorectal cancer.5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google Scholar Other agents have specific activity in haematological cancers. New adenosine analogues have important activity in chronic lymphocytic and hairy-cell leukaemias, especially fludarabine and cladribine (2-chlorodeoxyadenosine).5Peters GJ Ackland SP New antimetabolites in preclinical and clinical development.Exp Opin Invest Drugs. 1996; 5: 637-679Crossref Scopus (64) Google Scholar Interferon-α prolongs remission in hairy-cell leukaemia, low-grade malignant lymphoma, chronic myeloid leukaemia, and multiple myeloma. Finally, tretinoin (all-trans retinoic acid) is a potent inducer of differentiation in leukaemic cells, with strong antileukaemic activity; it improves significantly the response and outcome of patients with acute promyelocytic leukaemia when given as an adjunct to chemotherapy.9Chomienne C Fenaux P Degos L Retinoid differentiation therapy in promyelocytic leukemia.FASEB J. 1996; 10: 1025-1030Crossref PubMed Scopus (121) Google Scholar High-dose chemotherapyIn retrospective studies in conventional dose ranges, the dose-intensity of chemotherapy appears to be related to effects (response rate and median survival) in several cancers, including breast, ovary, and colon and in haematological cancers. Far less convincing, however, are the prospective randomised trials. Acute myelogenous leukaemia is an exception in which well-designed randomised studies with cytarabine show that higher-dose regimens prevent relapse more effectively and may produce superior survival.10Bishop JF Matthews JP Young GA et al.A randomized study of high-dose cytarabine in induction in acute myeloid leukemia.Blood. 1996; 87: 1710-1717PubMed Google ScholarThe use of colony-stimulating factors allows only a modest increase in doses of chemotherapy by itself. Although side-effects associated with severe myelosuppression may be decreased, less evident is an improvement in efficacy with the addition of colony-stimulating factors in any tumour type, even in acute myelogenous leukaemia.High-dose chemotherapy plus haematopoietic stem-cell transplantation and colony-stimulating factors allows larger dose-escalation and has a definite place in the treatment of haematological cancers,11Attal M Harousseau JL Stoppa AM et al.A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.N Engl J Med. 1996; 335: 91-97Crossref PubMed Scopus (2577) Google Scholar, 12Löwenberg B Postremission treatment of acute myelogenous leukemia.N Engl J Med. 1995; 332: 260-262Crossref PubMed Scopus (33) Google Scholar and can also be effective in refractory testicular cancer.13Margolin K Doroshow JH Ch Ahn et al.Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support.J Clin Oncol. 1996; 14: 2631-2637Crossref PubMed Scopus (80) Google ScholarSo far, there is no evidence that high-dose chemotherapy has any impact on survival of patients with other metastatic solid tumours. The use of autologous bone-marrow transplantation has been progressively replaced by peripheral stem-cell transfusion, which circumvents general anaesthesia, is performed as an outpatient procedure, permits accelerated haematological recovery, and is cheaper. The studies with the best chance to prove the high-dose concept are probably those in early stages of disease—ie, as adjuvant treatment of patients at high-risk for relapse after adequate local treatment. Such studies are ongoing.Another approach to high-dose chemotherapy is to expose only localised parts of the body to very high concentrations of drug. This can be achieved by hepatic arterial or intracavitary chemotherapy. Accumulating data show that fluorouracil or doxifluridine (FUDR) given through the hepatic artery was more effective than the intravenous route in patients with liver metastases from colon carcinoma.14Meta-Analysis Group in CancerReappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer.J Natl Cancer Inst. 1996; 88: 252-258Crossref PubMed Scopus (465) Google Scholar Similarly, intraperitoneal chemotherapy appears to have a role in the treatment of ovarian cancer patients with minimal residual disease after surgery15Alberts DS Liu PY Hannigan EV et al.Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.N Engl J Med. 1996; 335: 1950-1955Crossref PubMed Scopus (1109) Google Scholar or induction chemotherapy. Isolated-limb perfusion with high-dose tumour necrosis factor-in combination with interferon-y and melphalan can achieve limb salvage in patients with non-resectable soft-tissue sarcomas of the extremities.16Eggermont AMM Schraffordt Koops H Liénard D et al.Isolated limb perfusion with high-dose tumor necrosis factor-α in combination with interferon-γ and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial.J Clin Oncol. 1996; 14: 2653-2665Crossref PubMed Scopus (364) Google Scholar In retrospective studies in conventional dose ranges, the dose-intensity of chemotherapy appears to be related to effects (response rate and median survival) in several cancers, including breast, ovary, and colon and in haematological cancers. Far less convincing, however, are the prospective randomised trials. Acute myelogenous leukaemia is an exception in which well-designed randomised studies with cytarabine show that higher-dose regimens prevent relapse more effectively and may produce superior survival.10Bishop JF Matthews JP Young GA et al.A randomized study of high-dose cytarabine in induction in acute myeloid leukemia.Blood. 1996; 87: 1710-1717PubMed Google Scholar The use of colony-stimulating factors allows only a modest increase in doses of chemotherapy by itself. Although side-effects associated with severe myelosuppression may be decreased, less evident is an improvement in efficacy with the addition of colony-stimulating factors in any tumour type, even in acute myelogenous leukaemia. High-dose chemotherapy plus haematopoietic stem-cell transplantation and colony-stimulating factors allows larger dose-escalation and has a definite place in the treatment of haematological cancers,11Attal M Harousseau JL Stoppa AM et al.A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.N Engl J Med. 1996; 335: 91-97Crossref PubMed Scopus (2577) Google Scholar, 12Löwenberg B Postremission treatment of acute myelogenous leukemia.N Engl J Med. 1995; 332: 260-262Crossref PubMed Scopus (33) Google Scholar and can also be effective in refractory testicular cancer.13Margolin K Doroshow JH Ch Ahn et al.Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support.J Clin Oncol. 1996; 14: 2631-2637Crossref PubMed Scopus (80) Google Scholar So far, there is no evidence that high-dose chemotherapy has any impact on survival of patients with other metastatic solid tumours. The use of autologous bone-marrow transplantation has been progressively replaced by peripheral stem-cell transfusion, which circumvents general anaesthesia, is performed as an outpatient procedure, permits accelerated haematological recovery, and is cheaper. The studies with the best chance to prove the high-dose concept are probably those in early stages of disease—ie, as adjuvant treatment of patients at high-risk for relapse after adequate local treatment. Such studies are ongoing. Another approach to high-dose chemotherapy is to expose only localised parts of the body to very high concentrations of drug. This can be achieved by hepatic arterial or intracavitary chemotherapy. Accumulating data show that fluorouracil or doxifluridine (FUDR) given through the hepatic artery was more effective than the intravenous route in patients with liver metastases from colon carcinoma.14Meta-Analysis Group in CancerReappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer.J Natl Cancer Inst. 1996; 88: 252-258Crossref PubMed Scopus (465) Google Scholar Similarly, intraperitoneal chemotherapy appears to have a role in the treatment of ovarian cancer patients with minimal residual disease after surgery15Alberts DS Liu PY Hannigan EV et al.Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.N Engl J Med. 1996; 335: 1950-1955Crossref PubMed Scopus (1109) Google Scholar or induction chemotherapy. Isolated-limb perfusion with high-dose tumour necrosis factor-in combination with interferon-y and melphalan can achieve limb salvage in patients with non-resectable soft-tissue sarcomas of the extremities.16Eggermont AMM Schraffordt Koops H Liénard D et al.Isolated limb perfusion with high-dose tumor necrosis factor-α in combination with interferon-γ and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial.J Clin Oncol. 1996; 14: 2653-2665Crossref PubMed Scopus (364) Google Scholar Drug resistanceOver the past 10–15 years, our understanding of the causes of resistance to drugs has substantially improved. Gene alterations associated with resistance to specific drugs have been identified and genes have also been identified which, when altered, may lead to broad cross-resistance to several unrelated anticancer agents (multidrug resistance). The assessment of these genes or their products as predictors of tumour sensitivity to specific drugs, although promising (eg, lung resistance protein17Izquierdo MA Van der Zee AGJ Vermorken JB et al.Drug resistance-associated marker LRP for prediction of response to chemotherapy and prognosis in advanced ovarian carcinoma.J Natl Cancer Inst. 1995; 87: 1230-1237Crossref PubMed Scopus (232) Google Scholar and glutathione S-transferase2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar in platinum resistance, and thymidylate synthase in fluorouracil resistance19Peters GJ Van der Wilt CL Van Groeningen CJ et al.Thymidylate synthase inhibition after administration of 5-fluorouracil with or without leucovorin; implications for treatment with 5-fluorouracil.J Clin Oncol. 1994; 12: 2035-2042PubMed Google Scholar) appears to be of clinical relevance only in certain tumour types. The discovery that several non-cytotoxic substances may inhibit the activity of the gene products in the laboratory has led to the study of these multidrug-resistance reverters in the clinic in association with an anticancer agent. So far this strategy has not substantially improved management, perhaps because multiple mechanisms of drugs resistance may occur simultaneously in the same turnout. Furthermore, the expression of several of these genes is not necessarily causally linked to the development of drug resistance, but may be the expression of a more aggressive phenotype by themselves.20Pinedo HM Giaccone G P-Glycoprotein—a marker of cancer-cell behavior.N Engl J Med. 1995; 333: 1417-1419Crossref PubMed Scopus (91) Google Scholar Alterations in important genes for cell life and proliferation, such as TP53 and BCL-2, have an important impact on the development of resistance to a broad range of anticancer agents.21Harris CC Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies.J Natl Cancer Inst. 1996; 88: 1442-1455Crossref PubMed Scopus (646) Google Scholar Over the past 10–15 years, our understanding of the causes of resistance to drugs has substantially improved. Gene alterations associated with resistance to specific drugs have been identified and genes have also been identified which, when altered, may lead to broad cross-resistance to several unrelated anticancer agents (multidrug resistance). The assessment of these genes or their products as predictors of tumour sensitivity to specific drugs, although promising (eg, lung resistance protein17Izquierdo MA Van der Zee AGJ Vermorken JB et al.Drug resistance-associated marker LRP for prediction of response to chemotherapy and prognosis in advanced ovarian carcinoma.J Natl Cancer Inst. 1995; 87: 1230-1237Crossref PubMed Scopus (232) Google Scholar and glutathione S-transferase2Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Annual 17 (in press).Google Scholar in platinum resistance, and thymidylate synthase in fluorouracil resistance19Peters GJ Van der Wilt CL Van Groeningen CJ et al.Thymidylate synthase inhibition after administration of 5-fluorouracil with or without leucovorin; implications for treatment with 5-fluorouracil.J Clin Oncol. 1994; 12: 2035-2042PubMed Google Scholar) appears to be of clinical relevance only in certain tumour types. The discovery that several non-cytotoxic substances may inhibit the activity of the gene products in the laboratory has led to the study of these multidrug-resistance reverters in the clinic in association with an anticancer agent. So far this strategy has not substantially improved management, perhaps because multiple mechanisms of drugs resistance may occur simultaneously in the same turnout. Furthermore, the expression of several of these genes is not necessarily causally linked to the development of drug resistance, but may be the expression of a more aggressive phenotype by themselves.20Pinedo HM Giaccone G P-Glycoprotein—a marker of cancer-cell behavior.N Engl J Med. 1995; 333: 1417-1419Crossref PubMed Scopus (91) Google Scholar Alterations in important genes for cell life and proliferation, such as TP53 and BCL-2, have an important impact on the development of resistance to a broad range of anticancer agents.21Harris CC Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies.J Natl Cancer Inst. 1996; 88: 1442-1455Crossref PubMed Scopus (646) Google Scholar Hormonal treatmentHormones have a major role in the treatment of hormone-sensitive tumours. The use of tamoxifen for up to 5 years has become standard treatment for postmenopausal breast cancer patients with positive axillary lymph-nodes, in whom survival is substantially increased.22Swedish Breast Cancer Cooperative GroupRandomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer.J Natl Cancer Inst. 1996; 88: 1543-1549Crossref PubMed Scopus (267) Google Scholar Tamoxifen and several other hormonal preparations have an important place in the treatment of advanced breast carcinoma. Luteinising-hormone releasing-hormone agonists alone or in combinations with antiandrogens have largely replaced orchidectomy in the treatment of advanced prostatic cancer. Hormones have a major role in the treatment of hormone-sensitive tumours. The use of tamoxifen for up to 5 years has become standard treatment for postmenopausal breast cancer patients with positive axillary lymph-nodes, in whom survival is substantially increased.22Swedish Breast Cancer Cooperative GroupRandomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer.J Natl Cancer Inst. 1996; 88: 1543-1549Crossref PubMed Scopus (267) Google Scholar Tamoxifen and several other hormonal preparations have an important place in the treatment of advanced breast carcinoma. Luteinising-hormone releasing-hormone agonists alone or in combinations with antiandrogens have largely replaced orchidectomy in the treatment of advanced prostatic cancer. Supportive measuresThe improvements in chemotherapy have also been due to improvements in the way chemotherapy can be administered. The use of 5-hydroxy-tryptamine antagonists and high-dose steroids as effective antiemetic drugs improves tolerance to several anticancer drugs, including cisplatin.23Karim F Roerig SC Saphier D Role of 5-hydroxytryptamine3 (5-HT3) antagonists in the prevention of emesis caused by anticancer therapy.Biochem Pharmacol. 1996; 52: 685-692Crossref PubMed Scopus (30) Google Scholar The introduction of prophylactic colony-stimulating factors (eg, granulocyte and granulocyte-macrophage colony-stimulating factors) and improved antibacterial and antifungal strategies has allowed in some studies the reduction of infective complications in patients undergoing myelosuppressive chemotherapy. Thrombopoietin will in the future also help in dealing with thrombocytopenia.The introduction of oral morphine preparations and new potent analgesic drugs (eg, transdermal fentanyl) allow better pain control. In this respect the use of bisphosphonates in patients with osteolytic bone metastases may achieve, besides pain reduction, a reduction of complications due to bone metastases (eg, fractures)24Hortobagyi GN Theriault RL Porter L et al.Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases.N Engl J Med. 1996; 335: 1785-1791Crossref PubMed Scopus (926) Google Scholar and also delay their occurrence. Treatment with radioactive strontium is less readily applicable but highly effective in selected patients with pain derived from extensive bone metastases that cannot be kept under control with analgesic drugs. The improvements in chemotherapy have also been due to improvements in the way chemotherapy can be administered. The use of 5-hydroxy-tryptamine antagonists and high-dose steroids as effective antiemetic drugs improves tolerance to several anticancer drugs, including cisplatin.23Karim F Roerig SC Saphier D Role of 5-hydroxytryptamine3 (5-HT3) antagonists in the prevention of emesis caused by anticancer therapy.Biochem Pharmacol. 1996; 52: 685-692Crossref PubMed Scopus (30) Google Scholar The introduction of prophylactic colony-stimulating factors (eg, granulocyte and granulocyte-macrophage colony-stimulating factors) and improved antibacterial and antifungal strategies has allowed in some studies the reduction of infective complications in patients undergoing myelosuppressive chemotherapy. Thrombopoietin will in the future also help in dealing with thrombocytopenia. The introduction of oral morphine preparations and new potent analgesic drugs (eg, transdermal fentanyl) allow better pain control. In this respect the use of bisphosphonates in patients with osteolytic bone metastases may achieve, besides pain reduction, a reduction of complications due to bone metastases (eg, fractures)24Hortobagyi GN Theriault RL Porter L et al.Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases.N Engl J Med. 1996; 335: 1785-1791Crossref PubMed Scopus (926) Google Scholar and also delay their occurrence. Treatment with radioactive strontium is less readily applicable but highly effective in selected patients with pain derived from extensive bone metastases that cannot be kept under control with analgesic drugs.