Cancer pain management necessitates the use of opioids when pain is moderate or severe. Opioids need to be versatile and effective. Newer formulations may improve patient compliance and may be more conducive to the management of transient flares of pain; they also may be tailored to treat certain special populations and may be particularly effective in certain clinical situations. For example, newer opioids have been developed for transdermal, nasal, and nebulized administration, providing a ‘needle-less’ means of controlling pain in those unable to take oral medications. However, newer opioid formulations are not a substitute for good pain management strategies and will not control pain unless provided in adequate doses and schedules. Newer opioid formulations have niche roles in clinical practice, and pain and palliative specialists need to be aware of new developments in opioids and delivery systems. This state-of-the-art review provides a synopsis of recent advances and evolving technologies.
Hairy cell leukemia is a B cell malignancy, accounting for 2% of all leukemias. Patients typically have splenomegaly, pancytopenia and an indolent course. Diagnosis requires identification of malignant cells in the bone marrow and peripheral blood with cytoplasmic projections and characteristic surface antigens. Splenectomy and interferon α were early treatments which have palliative value in the salvage setting. The purine analogs pentostatin and cladribine were found over 10 years ago to induce durable complete remissions in a high percentage of patients. Both are generally well tolerated, although with significant toxicity to CD4+ T cells and possibly hematopoietic stem cells, and it is unknown whether they differ in terms of long-term efficacy, safety, or association with secondary malignancies. Cladribine can induce complete remission with one cycle and is most commonly used. However, patients in complete remission can have minimal residual disease (assessed by immunologic studies) and its presence can increase the risk of early relapse. Molecular studies show that cladribine cannot eradicate the malignant hairy cell clone, and the lack of plateau in the disease free survival curve over time suggests that the present therapy cannot cure the disease. While retreatment with purine analogs is often successful, at least 25 to 35% of patients with HCL either initially or eventually become unresponsive and can succumb to infections and bleeding. The characteristic bright expression of several B-cell antigens on malignant cells, including CD20, CD22 and CD25, has led to the development of targeted therapy which is showing promising results in early clinical studies. Rituximab has activity, although duration and rates of response in clinical trials remain unclear. Recombinant immunotoxins LMB-2 and BL22 targeting CD25 and CD22, respectively, with truncated Pseudomonas exotoxin induce responses in 80 to 100% of patients who are resistant to purine analogs, and BL22 has a >60% complete remission rate in this setting. Further work is proceeding to increase the options for patients with hairy cell leukemia and to determine whether this disease can be cured.
Acute promyelocytic leukemia (APL) represents approximately 10–15% of all adult cases of acute myeloid leukemia and is characterized by a unique genetic abnormality and frequent association with a severe hemorrhagic diathesis. An arsenic trioxide formulation for intravenous infusion has been developed and is currently licensed for the induction of remission and consolidation in adult patients with relapsed/refractory APL. Several studies have shown that arsenic trioxide is highly effective in the treatment of relapsed/refractory patients with APL, achieving remission rates of >80%, high rates of molecular remission, and durable periods of disease-free survival. Furthermore, recent studies indicate that arsenic trioxide may also have a role in the treatment of newly diagnosed patients, either as a single agent or in combination with tretinoin. These studies suggest a synergistic effect when arsenic trioxide and tretinoin are administered in combination, reducing the time to complete remission and rapidly reducing promyelocytic leukemia/retinoic acid receptor-α protein transcripts. Arsenic trioxide is generally well tolerated with a manageable adverse-event profile. The most common adverse events occur during the induction cycle and are often associated with the APL differentiation syndrome. Other common adverse events include leucocytosis, prolongation of the QT/corrected QT interval, peripheral neuropathy, neutropenia, thrombocytopenia, hyperglycemia, and hypokalemia.
Standard adjuvant polychemotherapy for patients with breast cancer significantly improves their survival and is used for this patient group worldwide. In the beginning of this era, mainly CMF (cyclophosphamide, methotrexate and fluorouracil) was used but CMF is nowadays often replaced by anthracycline containing regimens after results favoring anthracyclines were published. The role of taxanes in the adjuvant setting is not yet fully understood; however, this should become clearer following the results from several ongoing randomized studies. In addition to the question of which drugs to use, dosage recommendations are a more complex issue. Low dosage regimens have been associated with inferior survival results compared with standard dosages in the adjuvant setting. High dosage regimens of anthracyclines have not been associated with better survival in some studies, although some investigators have shown the opposite. The use of very high doses requiring autologous bone marrow support have not resulted in survival gains in randomized studies. The body surface area (BSA) method is used to calculate doses. This method fails to standardize the marked interpatient variation in pharmacokinetics for most cytotoxic drugs. BSA is not correlated to hepatic function. Hepatic function varies widely among different persons and most drugs are excreted through the liver, which is one of the reasons for the difference in toxicity among different people. When patients experience toxicity from chemotherapy, a dose reduction is considered but when patients experience no toxicity the dose is seldom increased. It has been shown that patients treated with adjuvant chemotherapy doses causing a low leukocyte nadir have significantly better disease free survival and overall survival than those with higher nadir. One way to treat patients with breast cancer in the adjuvant setting is to use the tailored regimen described in this article. The aim of this regimen is to produce similar hematological toxicity for all patients and to achieve this the patients are treated at six different dose levels. This tailored treatment regimen has shown significantly better 3-year relapse-free survival than high dose treatment combined with autologous stem cell transplantation. Many facts support the idea of tailored treatment as being more effective than standard doses calculated with the help of BSA. An ongoing study is comparing standard FEC (fluorouracil, epirubicin, cyclophosphamide) with tailored FEC. This study will hopefully contribute to the knowledge on how to give chemotherapy in the most optimal way.
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Most patients still present late in the course of the disease so that curative therapy is rarely possible. Strategies developed to improve the prognosis include primary prevention, directed at the underlying liver diseases, secondary prevention by cancer surveillance and early intervention, and more effective therapies. Only childhood vaccination against hepatitis B (HBV) infection has been clearly documented to reduce the incidence of HCC. Eradication of the hepatitis B and C viruses by interferon in noncirrhotic patients may reduce the incidence of HCC. Removal of iron by phlebotomy in noncirrhotic patients with genetic hemochromatosis will largely prevent HCC. Many physicians offer secondary prevention by surveillance and early intervention involving repeated abdominal ultrasound and serial serum α-fetoprotein estimations in order to identify early malignant lesions, but such strategies have yet to be proven to reduce mortality from HCC. Nonetheless, early detection would seem to offer a greater chance for application of potentially curative therapy. Different surveillance strategies may be necessary in different patient groups. For example, in chronic hepatitis C the increased risk of HCC seems to be confined to patients with established cirrhosis, whereas even noncirrhotic patients with HBV have a substantially increased risk of HCC. In high-risk patients, such as those with cirrhosis following chronic viral hepatitis, several factors can be identified which appear to confer additional risk. Examples are hepatocyte dysplasia found on biopsy, or non-neoplastic vascular nodules on computed tomography scanning. The management of such patients needs urgent resolution. Potentially curative treatment options include resection, liver transplantation, and alcohol injection or radiofrequency ablation. Resection in ideal candidates may provide up to 60% survival at 5 years. Liver transplantation may result in a 5-year survival of up to 70%. However, the shortage of organ donors means that tumor progression while on the waiting list will disqualify some patients, while others will die before an organ becomes available. Local ablation has been reported to be as effective as resection and is applicable to a larger proportion of patients. Of the palliative forms of therapy only chemoembolization has been shown to provide a significant improvement in life-span, although other forms of adjuvant and palliative therapy are under investigation.
Worldwide about half a million new cases of cervical cancer occur each year. The incidence is about three times higher in resource-poor countries compared with more developed countries. The disease is reasonably well controlled in countries where routine cervical cytology for detection of premalignant precursors (cervical intraepithelial neoplasia; CIN) is available. Since the causal link between infection by so-called high-risk types of human papillomaviruses (HPV 16, 18 and others) and cervical cancer has been firmly established, the development of virus-specific vaccines has become a major activity both in the academic and corporate sectors. During the natural history of cervical cancer, there are different possible windows for vaccination: (i) prevention of infection that is conferred by neutralizing antibodies can be achieved by immunization with virus-like particles (VLP). Clinical trials with HPV 16 VLPs in humans demonstrated the safety and immunogenicity of the vaccine. Analysis of clinical endpoints such as prevention of infection, CIN and ultimately cervical cancer will require a longer follow-up time; (ii) HPV-as-sociated cervical diseases can also possibly be prevented by postexposure vaccination. As persistent HPV infection appears to be a prerequisite for the development of a malignant tumor, the viral proteins expressed during this state (e.g. E6, E7) are potential targets for cytotoxic T-cell responses to eliminate the infection. Since the target population for this vaccination strategy will consist of mostly young sexually active women that are at risk for reinfection or are potential carriers of infectious virus, it seems to be reasonable to induce a protective immunity via neutralizing antibodies as well. Chimeric virus like particles (CVLP) containing both the L1 (with or without L2) and E7 proteins are promising tools to achieve this goal; and (iii) treatment of cervical cancer by HPV E6/E7-specific immune therapy will most likely only be successful as an adjuvant strategy along with other therapies. On the other hand, based on the data from the first clinical trials, the option of curing precursor lesions by HPV-specific vaccination is considered promising.
Hypercalcemia of malignancy (HCM) is the most common cause of elevated serum calcium in hospitalized patients and is found with varying frequency in patients with various types of cancer. Calcium homeostasis is finely regulated with day-to-day variations of less than 2%, and the development of HCM stems from various anomalies in homeostatic mechanisms. Hypercalcemia often produces a number of clinical symptoms, including alterations in central nervous system function, symptoms of dehydration and renal dysfunction. Whenever possible and appropriate, the goals of treatment of HCM should therefore be to return the patient to a euvolemic state, to normalize serum calcium and to treat the underlying cause. Almost invariably, however, HCM is a particularly adverse complication for patients with cancer and is almost always associated with a dismal prognosis. Older treatments like mithramycin and calcitonin have recently been replaced with newer management strategies, mostly involving bisphosphonates. These agents are potent inhibitors of osteoclasts which have been found to normalize serum calcium levels in a high proportion of patients with HCM. Emerging therapeutic approaches include monoclonal antibodies to parathyroid hormone related peptide (PTHrP), inhibition of RANK ligand through the use of a soluble form of its receptor osteoprotegerin, analogues of Vitamin D and selective inhibiton of the Ras-Raf-MAPK-ERK signalling pathway. In this article, we review the pathophysiology of tumour osteolysis leading to hypercalcemia of malignancy, and we discuss the physiological basis for the clinical symptoms of hypercalcemia. Past, current and future therapeutic approaches are also reviewed.
In recent years, important progress has been made in understanding the pathophysiology, and in improving the diagnosis and treatment, of chronic lymphocytic leukemia (CLL). The characteristics of the B lymphocyte clone are now better defined and disclose great heterogeneity in the mechanisms involved in the development of lymphocytic tumours: both proliferative and apoptotic abnormalities are involved, and a single or recurrent triggering feature is not recognized. Accordingly, the course of the disease is highly variable. Although treatment abstention or deferral for a long period is convenient for many patients, others who present with, or progress to, active CLL will ultimately die from the disease. Clinico-hematological staging systems have greatly clarified the prognostic factors of interest to clinicians, but they remain imprecise in a large category of patients. Recently, other characteristics such as cytogenetics, immunoglobulin gene sequencing, and serum levels of soluble CD23, thymidine kinase and lymphocyte p27 have been recognized as powerful prognostic factors and should now be evaluated in prospective clinical trials. It remains unclear whether any of the available treatments, when indicated, could offer long-term survival benefits for patients. Chlorambucil, purine analogues (including fludarabine or cladribine) and anthracyclinecontaining regimens [i.e. cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)] have been evaluated in large prospective controlled trials, which demonstrated some differences according to response rates, but which failed to disclose any survival advantage, irrespective of the first-line drug treatment allocated. These disappointing results emphasize the need to develop other treatment strategies. Progress could be anticipated in two main ways. Firstly, new, effective and well tolerated treatments with greater specificity are now, or should soon be, available in the clinic: monoclonal antibodies, apoptotic inducers and vaccine systems. Preliminary data suggest that the best use of such treatments is as adjuvant therapy for patients with residual disease, thus complementing the results of chemotherapy. Secondly, intensive treatments with stem-cell rescue (autologous or allogenic) have provided evidence that clonal extinction is an obtainable goal in selected patients, some of whom remain free of any clonal molecular signal for many years. Whether such patients could be considered cured is still unresolved, and this point deserves longer follow-up. Controlled trials are currently exploring this important question. Finally, optimum therapy also aims to improve quality of life, and clinical trials dealing with this important issue, especially in elderly patients, are needed.
The extraordinary development of powerful screening methods to define molecular signatures from resected patient tissues is increasingly paving the way towards molecular staging concepts of tumors. However, the quality of resected patient tissues can dramatically influence the quality of results gained from molecular screening. In our experience, establishing and conducting a tumor bank is an interdisciplinary challenge requiring considerable effort from different disciplines (e.g. surgical and especially pathology departments) and personnel, specific equipment, consent of the patient, ethics approval, documentation, consideration of logistics, and continuous quality control. This article gives practical advice as to how to establish tumor tissue banking.
Adjuvant tamoxifen has a significant survival benefit in early breast cancer but current data suggest that there is no further benefit beyond 5 years’ treatment. Extended adjuvant therapy with oral letrozole 2.5mg daily following 5 years of tamoxifen in postmenopausal women with hormone receptor-positive breast cancer was shown to significantly reduce the risk of recurrence compared with placebo in the MA-17 trial (predicted 4-year disease-free survival 95% vs 90%). A small but significant overall survival benefit has also emerged in the subset of patients with node-positive disease.
Objective:To determine the effects on menopausal symptoms and quality of life of switching from tamoxifen to anastrozole as adjuvant endocrine treatment for early breast cancer patients.
The clinical and biological heterogeneity of the myelodysplastic syndromes (MDS) has engendered new expectations that therapy must be individualized. As a consequence, anemia management strategies for patients with MDS have evolved from a long-standing reliance upon supportive measures to active treatment guided by the risks posed by the disease. Median survival for a patient with MDS ranges from several months to ≥5 years with differing treatment goals, such as the promotion of hematopoiesis with recombinant cytokines to reducing the risk of leukemic transformation or death with agents such as azacitidine. As further insight into the molecular pathogenesis of these disorders has emerged, significant progress has been made in identifying new drug targets. Among these promising new agents are the farnesyl transferase inhibitors, immunosuppressive therapy, small-molecule tyrosine kinase inhibitors, and angiogenesis inhibitors. Phase I and II trials have shown encouraging activity with these agents and larger randomized trials are expected to define their place in the management of MDS.
