Γδ T Cell-Based Immunotherapy in Melanoma: State of the Art.

Metastatic melanoma is still associated with a poor prognosis, and there is increasing interest in immunotherapy alone or in combination with other adjuvant therapies. Γδ T lymphocytes play a pivot role in the immune response against cancer, but while γδ-based immunotherapy is already a clinical reality for several solid tumors, data on melanoma are still limited and fragmented. This systematic review presents preclinical and clinical evidence for a role of γδ T lymphocytes in immunotherapeutic strategies for advanced melanoma and discusses research state of the art and future perspectives. Current strategies focus on in vivo stimulation, and ex vivo adoptive therapy and vaccination; results are promising, but further studies are needed to better investigate the interactions in tumoral microenvironment and to improve clinical efficacy of immunotherapeutic protocols.

Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers.

BACKGROUND: Biliary tract cancers are uncommon tumors with a poor prognosis and most patients present with invasive and inoperable disease at diagnosis. Chemotherapy represents a palliative treatment, with poor response rates and a median survival of less than 6 months. Oxaliplatin and gemcitabine have shown an interesting activity as single agents in this group of patients. PATIENTS AND METHODS: We carried out a multicenter phase II study to evaluate the efficacy and safety of combined oxaliplatin and gemcitabine in locally advanced and metastatic biliary tract carcinoma. The schedule of chemotherapy included oxaliplatin 100 mg/m(2) on day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8, every 21 days. RESULTS: All the 24 patients were evaluable for response and toxicity. According to RECIST criteria we observed one complete response and 11 partial responses for an overall response rate of 50%. Overall survival for all the patients on study was 12 months (range 2-30). According to WHO criteria, three patients (12.5%) suffered grade 3 neutropenia and three patients (12.5%) grade 3 thrombocytopenia. Only two patients (8%) suffered grade 3 neuropathy. CONCLUSIONS: Oxaliplatin and gemcitabine chemotherapy seems to be effective with a favorable safety profile in first-line chemotherapy of advanced biliary tract cancers.

Detection and quantification of mammaglobin in the blood of breast cancer patients: can it be useful as a potential clinical marker? Preliminary results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Mammaglobin is expressed mainly in mammary tissue, overexpressed in breast cancer (BC) and rarely in other tissue. The aim of this study was to assess the sensitivity and specificity of transcript MGB1 detection and to evaluate the role of MGB1 as potential clinical marker for the detection of disseminated cancer cells in the blood of BC patients. PATIENTS AND METHODS: A consecutive series of 23 BC tissues, 36 peripheral blood BC samples and 35 healthy peripheral blood samples was prospectively recruited to investigate MGB1 expression by means of a quantitative Real Time RT-PCR assay. RESULTS: MGB1 overexpression in tissue samples of BC patients is significantly associated only with high level of Ki67 (P <0.05). None of the samples from peripheral blood of 35 healthy female individuals were positive for MGB1 transcript. In contrast MGB1 mRNA expression was detected in three of 36 (8%) peripheral blood of BC patients. CONCLUSIONS: Our preliminary results demonstrate that the detection of MGB1 transcript in peripheral blood of BC patients was specific but with low sensitivity. MGB1 overexpression by itself or in combination with Ki67 might be considered an index of BC progression.

Paclitaxel in metastatic breast cancer: a trial of two doses by a 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines.

BACKGROUND: To date, anthracyclines are the most active drugs against breast tumors, and the taxane paclitaxel (Taxol) looks very promising. Both classes of drugs are affected by cellular multidrug-resistance mechanisms, and therefore their sequential use raises the possibility of clinical cross-resistance. It is therefore important to assess the activity of paclitaxel in patients with clinical resistance to anthracyclines. PURPOSE: We assessed the safety and efficacy of paclitaxel administered by the logistically convenient 3-hour infusion to breast cancer patients who had disease progression within 12 months since prior therapy with anthracyclines. METHODS: Fifty-one patients with metastatic breast cancer who had all relapsed or whose disease had progressed within 12 months from completion of an anthracycline-containing chemotherapy protocol (six receiving adjuvant therapy, 19 receiving neoadjuvant therapy, and 26 receiving treatment for metastatic disease) were enrolled in this phase II trial from June 1992 to May 1994. After medication to prevent type I acute hypersensitivity reactions, paclitaxel was given intravenously over 3 hours at 175 mg/m2 to the first 15 patients and at 225 mg/m2 to the next 36 patients. The median age was 50 years (range, 31-62 years), and the median Eastern Cooperative Oncology Group performance status was 0 (range, 0-2). RESULTS: Patients received a median of five cycles (range, one to 11 cycles). After initial doses of 175 and 225 mg/m2, paclitaxel could be increased by 25 mg/m2 in 73% and 58% of cycles, respectively. Among 50 assessable patients, seven achieved a complete response and 12 achieved a partial response (response rate, 38% [95% confidence interval = 25%-53%]). The median duration of response was 7 months (range, 4-16 months), and the median time to disease progression for all patients was 5 months. Grade 4 neutropenia occurred in 3% of the cycles and in 12% of the patients and was never associated with fever and infection. Common toxic effects were myalgia and arthralgia (94% of the patients; 4% grade 3), peripheral neuropathy (92% of the patients; 8% grade 3), and alopecia (all patients). Pruritus and neuropathy were significantly more frequent and severe, respectively, with the higher dose (P < .01 by chi 2 test). Frequency and severity of other toxic effects were similar at either starting dose. Ten patients had symptoms of neuro-optic toxicity. Only one patient had a grade 2 hypersensitivity reaction. CONCLUSIONS: Paclitaxel at starting doses of 175 and 225 mg/m2 given as a 3-hour infusion can safely be administered to, and is active in women whose disease has progressed after prior treatment with anthracyclines. There was evidence of increased toxicity at the higher dose but no suggestion of better efficacy. IMPLICATION: Paclitaxel by a 3-hour infusion in combination with doxorubicin should be investigated in patients with metastatic breast cancer. Unless randomized trials demonstrate greater efficacy of the more toxic higher dose, it is suggested that a dose of 175-200 mg/m2 be administered with the 3-hour infusion schedule.

Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.

PURPOSE: To evaluate the clinical benefits of switching from morphine to oral methadone in patients who experience poor analgesia or adverse effects from morphine. PATIENTS AND METHODS: Fifty-two consecutive cancer patients receiving oral morphine but with uncontrolled pain and/or moderate to severe opioid adverse effects were switched to oral methadone administered every 8 hours using different dose ratios. Intensity of pain and adverse effects were assessed daily, and the symptom distress score (DS) was calculated before and after switching. RESULTS: Data were analyzed for 50 patients. Switching was considered effective in 80% of the patients; results were achieved in an average of 3.65 days. In the 10 patients who switched to methadone because of uncontrolled pain, a significant reduction in pain intensity (P <.005) and an average of a 33% increase in methadone doses necessary (P <.01) were found after an average of 3.5 days. DS significantly decreased from an average of 8.4 to 4.5 (P <.0005). In the 32 patients switching because of uncontrolled pain and morphine-related adverse effects, significant improvement was found in pain intensity (P <.0005), nausea and vomiting (P <.03), constipation (P <.001), and drowsiness (P <.01), but a significant increase in the methadone dose of an average of 20% (P <.004) was required. CONCLUSION: In most patients with cancer pain referred for poor pain control and/or adverse effects, switching to oral methadone is a valid therapeutic option. In the clinical setting of poor pain control, higher doses of methadone are necessary with respect to the equianalgesic calculated dose ratios previously published.

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.

PURPOSE: To define the maximum-tolerated dose (MTD) and better tolerated sequence of paclitaxel by 3-hour infusion plus bolus doxorubicin (DOX) and to evaluate antitumor efficacy. PATIENTS AND METHODS: Thirty-five women with metastatic breast cancer (dominant visceral metastases in 56%, and involvement of > or = three sites in 67%) who never received chemotherapy of any type were studied. Paclitaxel every 3 weeks (125 mg/m2 starting dose) was increased by 25-mg/m2 steps in subsequent cohorts of patients. DOX (60 mg/m2 fixed dose) was administered 15 minutes before the start of or after the end of paclitaxel for a maximum of eight cycles. Subsequently, patients in continuous response could receive single-agent paclitaxel (175 to 200 mg/m2 every 3 weeks). The drug sequence was alternated in consecutive patients and in the first two cycles. RESULTS: Severe neutropenia that lasted greater than 7 days (n = 4), febrile neutropenia (n = 7) and grade III oral mucositis (n = 6) defined the MTD of paclitaxel at 200 mg/m2 in 34 assessable patients. Grade II peripheral neuropathy occurred in 33% of patients. Six women (18%) developed clinically reversible congestive heart failure (CHF) after a median of 480 mg/m2 total DOX. Drug sequence had no effect on toxicities. High efficacy on all metastatic sites in 32 assessable patients accounted for a 41% complete response (CR) rate (95% confidence interval [CI], 24% to 59%) and 94% overall-response rate (95% CI, 79% to 99%). After a median follow-up of 12 months (range 3 to 18), the median response duration is 8 months (range, 2+ to 18+) for complete responders and 11 months (range 1+ to 15+) for partial responders. CONCLUSION: The rate of CR and incidence of CHF may be an expression of therapeutic and toxic enhancement due to the schedule used in this trial. Until clarification of this possibility, this promising combination should be used in investigational trials.

Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.

Outpatient treatment of deep vein thrombosis (DVT) has become a common practice in uncomplicated patients. Few data are still present in patients with comorbidity (such as cancer) or concomitant symptomatic pulmonary embolism. Cancer patients with DVT are often excluded from home treatment because they have a higher risk of both bleeding and recurrent DVT. We tested the feasibility and safety of the Home Treatment (HT) program for acute DVT a PE in cancer patients. Patients were treated as outpatients unless they required admission for other medical problems, were actively bleeding or had pain that requires parenteral narcotics. Outpatient treatment was with low molecular weight heparin (LMWH) followed by warfarin or with LMWH alone. An educational program for patients was implemented. Two-hundred and seven patients with cancer were evaluated, 36 (17.4%) of whom had metastatic disease. Treatment with LMWH and warfarin was prescribed to 106 (51.2%) and LMWH alone to 102 (48.8%). One hundred and twenty-seven patients (61.3%) were entirely treated at home. There were no differences between patients treated at home and hospitalized patients with regard to gender, mean age, site of cancer, presence of metastases, and treatment. After 6 months, recurrent thrombo-embolism occurred in 8.7% of patients treated at home and in 5.6% of hospitalized patients (P=0.58); major bleeding in 2.0% and 1.5%, respectively (P=0.06). Twenty-seven patients (33%) in the hospitalized, and 33 (26%) in the home-treatment group, died after a follow-up of 6 months. These results indicate that, regarding cancer patients with acute DVT and/or PE, there is no difference between hospitalised and home-treated patients in terms of major outcomes.

The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers.

Zoledronic acid is a bisphosphonate that is effective in the treatment of complications of metastatic bone disease. We have carried out a perspective study on 24 consecutive patients with prostate cancer metastatic to bone to verify the effect of zoledronic acid on analgesic response and a possible relationship with the levels of bone metabolism biomarkers. Eligibility for this study required prostate cancer patients with metastatic bone disease and pain not controlled by analgesics. Patients were excluded from the study if they were receiving cytotoxic chemotherapy or radiation therapy within three months. Eighteen patients (75%) were considered responder to acid zoledronic, only 6 patients did not respond. Before starting treatment (T0) mean Visual Analogue Scale was 7.8 (SE +/- 0.29), after 1 month therapy (T1) was 3.6 (SE +/- 0.3) and after three months (T2) was 3.1 (SE +/- 0.4) with a significant difference between T0 and T1 (p<0.0005) and between T0 and T2 (p<0.0005). Visual Analogue Scale improvement was positively correlated with decrease of C-telopeptide and bone phosphatase alkaline (p<0.05) serum levels.

A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis.

The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain has been well established in the treatment of mild pain and in association with opioids in the treatment of moderate to severe pain. The aim of this study was to verify the effects of NSAIDs on morphine escalation in advanced cancer patients with pain followed-up at home and to assess the pharmacoeconomic implications. A prospective randomised controlled study was carried out in 156 consecutive advanced cancer patients with pain followed-up at home in the period December 1999-December 2000. In this group of patients, 47 were selected with pain progression after 1 week of opioid stabilisation. Patients were randomly assigned to one of two groups: group 'O' patients were treated with continuing opioid escalation according to their clinical needs; group 'OK' received ketorolac 60 mg/daily orally (p.o.) in three doses and then continued opioid escalation according to their clinical situation. Performance status, doses of morphine before and after starting treatment, mean weekly pain intensity (assessed by means of a numerical scale from 0 to 10), mean weekly symptoms intensity, adverse effects and pain mechanisms were recorded. Moreover, drug costs per day in both groups were calculated. Patients who received ketorolac in addition to morphine showed a better analgesia after a week in comparison to the group treated with morphine only (P=0.005). Thereafter, morphine escalation was slower and the maximum morphine dose was lower in the group treated with ketorolac. The incidence and the severity of gastric discomfort was more evident in patients treated with ketorolac, while constipation was significantly increased in patients who received morphine only. Drug costs per day were similar in both groups; statistical differences were observed in patients who started on lower morphine doses (<100 mg/daily) in the two groups (4.3 in the ketorolac-morphine group versus 3.4 in the morphine group; P=0.012). The use of NSAIDs reduces the need for an opioid dose escalation or allows the use of lower doses. Their use is associated with a more intense gastric discomfort, but results in less opioid-related constipation. The eventual additive cost for NSAIDs therapy is negligible, especially in patients taking high doses of morphine.

The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials.

Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour-induced hypercalcemia, Paget's disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients' compliance, are well-tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.

The role of taxanes in the treatment of breast cancer.

The taxanes paclitaxel and docetaxel are undergoing extensive evaluation in women with breast cancer in the United States and in Europe. Their dose-limiting toxicity is neutropenia. Paclitaxel also causes peripheral neuropathy, while docetaxel can cause unpredictable and severe skin toxicity, as well as edema and effusions due to a capillary leak syndrome. Due to threshold pharmacodynamics and nonlinear pharmacokinetics, tolerability of paclitaxel is schedule dependent. Single-agent paclitaxel was very active in multiple phase II trials in patients with different numbers and types of prior chemotherapy and disease extent (20% to 60% complete plus partial responses). Effective doses ranged from 135 to 250 mg/m2. Activity was observed with all infusion schedules (1, 3, and 24 hours) and in women with anthracycline-resistant tumors (25% to 38%). The use of a 96-hour infusion schedule was very active in anthracycline-refractory patients (48%) and in women who failed short infusion taxanes. The drug is undergoing extensive evaluation in combination with doxorubicin, cyclophosphamide, cisplatin, and antimetabolites. Very promising efficacy was observed for paclitaxel by 3-hour infusion plus bolus doxorubicin (approximately 40% complete responses and 50% partial responses). The combination also caused a high incidence of clinically reversible congestive heart failure(14% to 18%). Docetaxel also has very good efficacy in breast cancer, with approximately 70% major responses in untreated patients and more than 50% in anthracycline-resistant tumors. There is no evidence that efficacy and tolerability are schedule dependent as is the case for paclitaxel. At recommended doses (100 or 75 mg/m2 by 1-hour infusion every 3 weeks), docetaxel causes a fluid retention syndrome that may affect quality of life. Its common onset after multiple cycles may limit the use of docetaxel for palliation in metastatic breast cancer. These results clearly indicate that the taxanes will become a standard component of initial chemotherapy for women with breast cancer. The definition of their actual role still requires an answer to the unresolved questions of their optimal dose and combination with other anticancer agents. Most importantly, the drugs should be prospectively evaluated in a randomized study using comparable doses and schedules to assess which of the two has the better therapeutic index in breast cancer.

DNA ploidy and S-phase fraction, but not p53 or NM23-H1 expression, predict outcome in colorectal cancer patients. Result of a 5-year prospective study.

PURPOSE: The aim of this study was to determine TP53 and NM23-H1 immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160 patients undergoing resective surgery for primary operable colorectal cancer (CRC) and to establish whether these alterations have any clinical value in predicting CRC patients' prognosis. METHODS: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. RESULTS: The median follow-up time in our study group was 71 months (range 34-115 months). P53 protein expression was associated with distal tumors (P<0.05) and DNA aneuploid tumors (P<0.05) tumors. DNA-aneuploidy was associated with distal tumors (P<0.01), histological grade (G3) (P<0.05), advanced Dukes' stage (C and D) (P<0.01), lymph node metastases (P<0.01) and high SPF (>18.3%) (P<0.01). The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA-aneuploidy, and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. CONCLUSIONS: Our results indicate that DNA aneuploidy and high SPF are associated in CRC with a poor clinical 5-year outcome, while in contrast the prognostic role of TP53 and NM23-H1 expression is still to be clarified.

The course of symptom frequency and intensity in advanced cancer patients followed at home.

Four hundred consecutive patients who were referred to a home palliative care program were prospectively surveyed to estimate the prevalence and severity of common symptoms according to the changes in the performance status. Patients were admitted for the presence of different symptoms and psychosocial support. Common symptoms included in a standard form were rated for severity (absent 0, mild 1, moderate 2, severe 3) for each visit. Pain intensity was rated on a numerical scale (0-10). For each level of Karnofsky performance score (K), the frequency and the worse symptom intensity were recorded until patient's death. Data from 370 patients were analyzed. Pain was effectively controlled. In the final stage, it was also less frequently observed, despite the use of lower analgesic doses in the last days of life. The peak of opioid consumption and symptom frequency and severity was found at K40. This was also the most frequent K level at admission. Some symptoms, such as nausea and vomiting, dry mouth, gastric pyrosis, and diarrhea reached a peak in frequency and severity, then decreased with the advanced stage of the disease. Other symptoms, such as dyspnea, drowsiness, weakness, and confusion tended to further increase and to have a peak at the lowest levels of K. Dysphagia and constipation progressively increased in frequency and intensity, but decreased at the end. These findings clarify the actual frequency and intensity of symptoms in a non-selected home care population with advanced cancer.

Opioid responsiveness-primary diagnosis relationship in advanced cancer patients followed at home.

The aim of this study was to evaluate the influence of the primary cancer on pain characteristics and opioid response, in terms of analgesia and adverse effects, in advanced cancer patients followed at home. A prospective study was carried out in a sample of 434 consecutive advanced cancer patients who required opioids during the last four weeks of life. One hundred eighty-one patients received opioids for longer than the four weeks and were considered for this analysis. Demographic data, primary diagnosis, and pain mechanisms were recorded, and mean opioid doses, pain intensity, and symptoms were assessed at weekly intervals during the last four weeks of life. In the group of 181 patients, somatic pain was associated with lung, head and neck, breast, and prostate cancer (p < 0.0005), while visceral pain was associated with colorectal, gastric, liver, pancreatic, and uterine cancer (p < 0.0005). Considering all primary diagnoses, there was a significant increase in the mean opioid dose (p < 0.0005) across the four weekly periods. There was a significant decrease in pain intensity scores (p < 0.0005) in all cases. A significant dose increase was observed only for mesothelioma (p = 0. 027) when compared with other types of cancer. In all 181 cases, a significant worsening in symptom intensity was observed during the last two weeks of life (p < 0.01). This study shows that primary cancer may have an influence on pain characteristics and opioid response. Patients with some kinds of cancer may be at risk of developing severe pain syndromes or more adverse effects.

Investigation of an opioid response categorization in advanced cancer patients.

The aim of this study was to investigate a possible distinction in three categories of opioid response and to identify possible factors associated with a poor response. A prospective survey was carried out in 105 consecutive patients requiring morphine for at least 4 weeks before death. Mean pain intensity, opioid doses and symptom intensity at weekly intervals, pain syndromes, and the presence of psychological distress were assessed. Opioid escalation index (OEI%) was calculated from the parameters recorded. Three categories were considered, including (1) patients with slow increments of opioid dose and a mean analgesic 10-cm visual analogue scale (VAS) less than 4 (responders), (2) patients with an OEI% more than 5 but a mean VAS less than 4 (partial responders), and (3) patients with a mean VAS more than 4 (poor responders). Treating physicians were asked to make a judgment on the pain treatment difficulties on a numerical scale (0-10). Significant differences in opioid starting dose (OSD), opioid dose at--4 weeks, nausea and vomiting at--1 week, opioid maximum doses, mean VAS, and OEI were found in the three categories of response. Significant correlations with the physician judgment were found for opioid maximum dose, mean VAS, VAS at the different time intervals, the doses used at the different intervals, OEI, and confusion. Neuropathic pain was significantly associated with a judgment of poor pain outcome. The correlation between the physician judgment and the categories of opioid response was highly significant. Seven of the 12 patients in the third category (poor response) were considered as having a relevant psychological distress. The categorization of the opioid response used in this study could be used in clinical research and as an audit tool, and could be tested in other settings to compare different treatments.

Carcinoid somatostatinoma of the duodenum.

Carcinoid somatostatinoma is a rare neuroendocrine malignant tumour and the duodenal location is an atypical site of presentation of which only few cases have been reported in the literature. A case of duodenal carcinoid somatostatinoma metastatic to lymph nodes in a 66-year-old patient is presented with an update of the literature. No relevant signs or symptoms were associated to the retrogastric lymph-node mass, which deformed but did not infiltrate the stomach wall. At the first and third portion of the duodenum, two polipoid endoluminal nodules (size 1 cm) were found with adjacent adenopathy partially adherent to the head of the pancreas and with thickening of the antropyloric wall. The patient underwent antrectomy duodenum mobilization and lymphadenectomy in the hepatic artery region. The treatment was successful and, over 3 years after diagnosis, there has been no clinical or radiological evidence of relapse. Duodenal somatostatinoma is rare and its diagnosis is often incidental. Surgery would be the appropriate treatment in the early stage of the disease with good chances of cure.

Alternatives to oral opioids for cancer pain.

Although the optimal route of administration of opioids is by mouth, some patients may require alternative routes during the course of their illnesses for several reasons. These include bowel obstruction, severe emesis, or severe dysphagia. In these cases, the alternatives include the subcutaneous or rectal route. The transdermal route also provides a simple, comfortable method that produces stable blood drug concentrations. The high potency and lipid solubility of fentanyl make it suitable for this route of administration. Iontophoresis can provide a rapid drug delivery rate, but no clinical studies exist to document the long-term effectiveness of this method in controlling pain. The transmucosal route is recommended only for those opioids with high solubility, such as buprenorphine, the fentanyl series, and methadone. Oral transmucosal fentanyl (Actiq) provides a rapid onset of pain relief and is appropriate for treating episodes of breakthrough pain.

Role of pamidronate disodium in the treatment of metastatic bone disease.

AIMS AND BACKGROUND: Bone metastases are a common feature of advanced neoplastic disease and are considered to be among the most frequent causes of pain and complications in oncologic patients. The main objective of the treatment of such patients is to control their symptoms and improve their quality of life. Pamidronate disodium is a second-generation bisphosphonate capable of inhibiting bone resorption (particularly osteoclast activity) without affecting bone remineralization. After a brief introduction concerning the pathophysiology of bone metastases and neoplastic bone pain, we herein present data on the clinical pharmacology and toxicity of bisphosphonates in general, and pamidronate in particular. We conclude by reviewing the literature on the use of pamidronate in phase II and III trials involving patients with metastatic bone disease. METHODS: The paper is based on a review of articles published between 1984 and 1997 selected from the Cancerline and Medline databases. RESULTS: In the considered phase II and III studies involving patients with bone metastases (breast cancer and multiple myeloma in particular), pamidronate proved to be efficacious in reducing the incidence of pain and skeletal complications, decreasing the excretion of metabolic markers of bone resorption and improving the quality of life. Intravenous infusions of 60-90 mg over a period of 2 hr every 3-4 weeks did not cause any significant toxic effects and was easily managed. CONCLUSIONS: Pamidronate is a bisphosphonate that is efficacious in the treatment of symptomatic bone metastases and can be considered an important therapeutic option in association with systemic treatments, radiotherapy and normal supportive care, especially in patients with breast cancer and multiple myeloma. Further randomized studies are necessary to confirm the positive preliminary results in other neoplasms, analyze the cost/benefit ratio of the treatment, and verify the possibility that, in addition to being used for palliative purposes, pamidronate may also prevent or delay the appearance of bone metastases.

Pattern of drug use by advanced cancer patients followed at home.

UNLABELLED: The aim of this study was to document the drugs most commonly prescribed to control symptoms in advanced cancer patients being followed at home. We analyzed data for 128 patients admitted to a home palliative care program from January 1993 to January 1995. All patients were followed at home until death by a team consisting of doctors and nurses, and were given two or three medical examinations a week. The most frequently prescribed drugs were analgesics and drugs commonly used to prevent NSAID-induced gastric toxicity. Slow-release morphine was the analgesic used most often. Most patients received more than four drugs. Younger people received morphine more often than did older patients. CONCLUSIONS: Drug monitoring is a useful audit tool for verifying the quality and quantity of drugs prescribed for advanced cancer patients being followed at home. Pharmacological usage should be reviewed periodically and should reflect evidence-based practice.