Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system that primarily afflicts young adults. Approximately 400,000 people in the United States are affected by MS. Although several forms of MS exist, the most common course is known as relapsing-remitting MS (RRMS), which affects about 85% of MS patients. This form of MS is characterized by relapses of neurologic symptoms followed by periods of recovery. Progression of disease can lead to increasingly severe disability. Since the introduction of immunomodulatory biologic agents, such as interferon betas and glatiramer acetate, treatment has helped to change the course of the disease. Under budgetary constraints, health services payers are challenged to differentiate the economic value of these agents for formulary selection and/or placement. OBJECTIVE: The primary objective of this analysis was to evaluate the 2-year cost-effectiveness of 4 disease modifying drugs (DMDs) used as first-line treatment of RRMS: glatiramer acetate, interferon (IFN) Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b SC injection. METHODS: An Excel-based model was developed to compare the relative effectiveness and cost components of relapses, disability progression, and DMDs in the treatment of RRMS over a 2-year time horizon. The relative risk reduction (RRR) method was used to compare reduction in relapse rates and disease progression data from pivotal randomized double-blind placebo-controlled clinical trials of the DMDs. RRRs for relapses and disability progression, respectively, were calculated as the relative difference (treatment vs. placebo) in relapse rates and disease progression rates from placebo-controlled clinical trials. These RRRs were applied to the weighted average rates of relapse and number of disability progression steps seen in the placebo arms of the pivotal studies. The evaluation was conducted from the perspective of a U.S. health care payer (only direct medical costs considered). Medical savings were calculated as costs saved due to relapses avoided and prevention in disability progression steps. In the base case analysis, we assumed 89.4% persistence, a cost per relapse of $4,682, and a cost per disability progression step of $1,788. Monthly cost of therapy was defined as wholesale acquisition cost ($0 contractual discounts and $25 patient copayment assumed in the base case analysis) plus routine monitoring costs as assessed by an expert panel. The primary economic endpoint was cost per relapse avoided. Costs and outcomes occurring in the second year were discounted 3% to bring to 2008 present values. Oneway and multiway probabilistic (Monte Carlo) sensitivity analyses were conducted on key input variables to assess their impact on cost per relapse avoided. RESULTS: Without DMD treatment, patients were predicted to experience 2.55 relapses and 0.44 disability progression steps over a 2-year period (discounted values). The 2-year reductions in clinical relapses for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.66, 0.42, 0.74, and 0.70, respectively. The 2-year reductions in disability progression steps for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.05, 0.15, 0.12, and 0.11, respectively. In the base case analysis, IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate had the most favorable costs per relapse avoided ($80,589; $87,061; and $88,310; respectively) and IFN Beta-1a IM injection had the least favorable cost-effectiveness ratio ($141,721 per relapse avoided). Sensitivity analyses showed that these results were robust to changes in key input parameters, such as the number of relapses and disease progression steps in untreated patients, the RRR in clinical relapse and progression rates, the rate of persistence, the average cost of relapse, and the average cost of a disease progression step. CONCLUSION: This evaluation suggests that IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate represent the most cost-effective DMDs for the treatment of RRMS, where cost-effectiveness is defined as cost per relapse avoided, assuming that (a) the RRR in relapses and disease progression steps calculated from multiple DMD placebo-controlled clinical trials reflect real differences among DMDs over 2 years; and (b) resource unit costs derived from published sources reflect economic consequences of relapses and disease progression.

Preoperative embolization of bone metastases from renal cell carcinoma.

The purpose of this study was to correlate the effectiveness of preoperative embolization with the blood loss and transfusion requirement during surgery for bone metastases from renal cell carcinoma. Twenty-eight preoperative embolizations in 26 patients with renal cell carcinoma metastatic to bone were retrospectively evaluated and divided into two groups: Group A included the embolizations that resulted in complete devascularization of the lesion as defined by the post-embolization arteriograms, and group B included those with an incomplete result. The two groups were compared with regard to blood loss and transfusion requirement during surgery, by unpaired two-tailed Student's t-test. Where complete embolization was effected (group A, 10 cases), there was a mean blood loss of 535 +/- 390 ml. When a less than complete embolization was achieved (group B, 18 cases), the mean blood loss was 1.247 +/- 1.047 ml (p = 0.049). The red blood cell transfusion in group A was 1.3 +/- 1 units, whereas in group B it was 2.4 +/- 1.2 (p = 0.03). Preoperative embolization of bone metastases from renal cell carcinoma with subsequent complete devascularization leads to significant reduction of blood loss during surgery. Interventional radiologists should pursue and embolize every feeder to the metastasis, because any less than complete devascularization increases the amount of blood loss and the amount of red blood cell transfusion during surgery.

Cellular and humoral immune responses to adenovirus and p53 protein antigens in patients following intratumoral injection of an adenovirus vector expressing wild-type. P53 (Ad-p53).

The immune responses of 10 patients with advanced non-small cell lung cancer receiving monthly intratumoral injections of a recombinant adenovirus containing human wild-type p53 (Ad-p53) to adenovirus and transgene antigens were studied. The predominate cellular and humoral immune responses as measured by lymphocyte proliferation and neutralizing antibody (Ab) formation were to adenovirus serotype 5 vector antigens, with increased responses in posttreatment samples. Consistent alterations in posttreatment cellular and humoral immune responses to p53 epitopes were not observed, and cytotoxic Abs to human lung cancer cells were not generated. Patients in this study had evidence of an antitumoral effect of this treatment with prolonged tumor stability or regression; however, neither Abs to p53 protein nor increased lymphocyte proliferative responses to wild-type or mutant p53 peptides have been consistently detected.

Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer.

PURPOSE: To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS: Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.

BACKGROUND: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. METHODS: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. RESULTS: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. CONCLUSIONS: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Gene therapy for non-small cell lung cancer: a preliminary report of a phase I trial of adenoviral p53 gene replacement.

The identification of genetic lesions that lead a normal cell to become malignant presents us with the opportunity of targeting those lesions as a means of therapy. Given the key role played by the tumor suppressor gene p53 in cell cycle regulation and apoptosis, and the evidence linking p53 mutations with non-small cell lung cancer, attempts at p53 replacement are a logical approach to therapy in this disease. In a phase I study, administration of an adenoviral p53 vector (Adp53) to 21 patients with advanced non-small cell lung cancer produced little toxicity. Up to six intratumoral injections at monthly intervals were well-tolerated. Expression of the p53 transgene was evident, along with potentially useful clinical responses. Time to disease progression in the indicator lesion treated with Adp53 appears to be enhanced by higher doses of vector, concomitant cisplatin therapy, and evidence of apoptosis on tumor biopsy specimens. Phase II trials should now be undertaken to determine the response rate to Adp53.

Intraperitoneal immunotherapy of peritoneal carcinomatosis.

Carcinomas that originate in the ovary or from different sites in the gastrointestinal tract frequently develop metastases that involve the peritoneal and serosal surfaces. Carcinomatous involvement of the peritoneum is a significant cause of morbidity and mortality. Advances in our understanding of the immunobiology of the peritoneal cavity and the availability of technically advanced immunotherapeutic agents are providing an important opportunity for the intraperitoneal delivery of these agents. This review describes newer concepts in tumor immunology that have a bearing on the further development of intraperitoneal immunotherapy; delivery systems for and issues to be resolved in intraperitoneal immunotherapy, and results of studies with recombinant interferons alpha and gamma and interleukin (IL)-2, cellular therapies including lymphokine-activated killer cells, tumor-infiltrating lymphocytes, monoclonal antibodies, and intraperitoneal radioimmunotherapy. New trials of intraperitoneal immunotherapy employing novel agents, including IL-12 and genetically modified tumor vaccines, are discussed, as are issues related to the integration of immunotherapy with standard chemotherapy agents. A number of immunotherapy agents have been tested intraperitoneally and have shown promising clinical activity with acceptable toxicity. Complete responses have been documented at surgical restaging, and intraperitoneal treatments with these agents may soon be included in the therapeutic armamentarium for patients with peritoneal carcinomatosis.

Two-phase study of hepatic artery vascular occlusion with microencapsulated cisplatin in patients with liver metastases from neuroendocrine tumors.

OBJECTIVE: We conducted a two-phase trial in which 100-micron polylactic acid microcapsules with a cisplatin payload (manufactured at our institution [the M. D. Anderson Cancer Center]) were used for hepatic artery occlusion therapy for symptomatic patients who had liver metastases from neuroendocrine tumors. SUBJECTS AND METHODS: Between January 1993 and December 1995, 20 patients with advanced, unresectable, symptomatic neuroendocrine tumors with liver metastases received repeated hepatic artery occlusion therapy using encapsulated cisplatin. The dose of encapsulated cisplatin was increased in a stepwise fashion. Selective angiography was used to occlude the portion of the hepatic vasculature that had the most metastases with encapsulated cisplatin microcapsules. In each patient, hepatic artery occlusion therapy was repeated in 6-8 weeks and responses were evaluated. Subsequent vascular occlusions were performed on the basis of the level of palliation achieved and the persistence of symptoms. RESULTS: Of the 20 patients, 17 patients had carcinoid tumors and three had islet cell tumors. The median percentage of liver replacement was approximately 50%. Fifteen of the 20 patients had received prior therapy and 17 patients had hormonal syndrome at the beginning of therapy. One patient had tumor bulk-related symptoms. Nineteen patients had elevated peptides markers that could be followed serially Six patients received encapsulated cisplatin at 50 mg/m2, four patients at 75 mg/m2, and 10 patients at 100 mg/m2 of body surface area. The median number of vascular occlusive procedures per patient was three. All patients were assessable for toxicity and 18 were assessable for response (the other two patients were not assessable because of loss of follow-up). The median follow-up time was 14 months. Twelve (67%) of 18 patients had a median reduction in symptoms of 50%. Eleven (73%) of 15 patients with elevated 24-hr-urine levels of 5-hydroxyindoleacetic acid had a median reduction of 64% for this symptom. We observed objective reduction in the tumors of 14 of the 18 patients. In six of the 14 patients, we noted a partial response. In eight, we observed a minor response. In four of the 18 patients, we noted no response. One treatment-related death resulted from hepatorenal syndrome. Other major complications included hepatic pain (100%), fever (100%), nausea (100%), and vomiting (95%). Also all patients had a transient elevation of liver enzymes. Five of the 20 patients died of disease during our study. CONCLUSION: Hepatic artery vascular occlusion therapy using encapsulated cisplatin is feasible, can palliate symptoms, and can produce biochemical and objective responses in liver metastases from neuroendocrine tumors. The maximum tolerated dose appears to be 100 mg/m2 of body surface area per treatment. Polylactic acid capsules have potential because they can incorporate multiple agents. With surface coating, such capsules can also be used to target specific receptors.

Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.

A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.

Therapy of locally recurrent renal cell carcinoma after nephrectomy.

PURPOSE: We evaluated the outcome of patients with locally recurrent renal cell carcinoma treated at our university. MATERIALS AND METHODS: We retrospectively analyzed 16 cases of locally recurrent renal cell carcinoma in the renal fossa treated with surgical resection alone or in combination with biological therapy. RESULTS: Complete resection was possible in 15 patients of whom 3 had positive surgical margins. Of the 12 patients with negative margins 6 are free of disease while the 3 with positive margins had involvement of a remaining ipsilateral adrenal gland and distant metastasis. Of all 16 patients 12 are alive a median of 23.5 months after the diagnosis of locally recurrent renal cell carcinoma. Of those treated with the combination of biological therapy and surgery 50% have no evidence of disease compared to 25% of those treated with surgery alone. CONCLUSIONS: Long-term survival can be achieved with an aggressive surgical approach. Incomplete resection or positive surgical margins are associated with a high risk of local or distant failure, and combined treatment with immunotherapy and surgery may offer a benefit compared to surgery alone.

Prolonged stabilization of progressive endometrial stromal sarcoma with prolonged oral etoposide therapy.

We report the case of a patient who has a 23-year history of endometrial stromal sarcoma (ESS). She initially underwent tumor-reductive surgery followed by adjuvant radiotherapy. The pelvic tumor recurred nearly 8 years later, obstructing the ureter and directly invading the bladder. It propagated into the vena cava as a thrombus and finally spread into the right heart chambers, leading to cardiac failure 13 years after the recurrence. The patient was treated with hormonal therapy, multiple resections of the pelvic tumor, chemoembolization, and systemic chemotherapy with doxorubicin and cyclophosphamide. She developed recurrent intractable symptoms and was started on prolonged oral etoposide therapy, which stabilized the size of the pelvic tumor and relieved her symptoms for 3 years. Her quality of life has markedly improved without significant morbidity. We review the options for treating recurrent ESS and suggest that use of prolonged oral etoposide therapy warrants further study in this setting.

A large lumen microcatheter for oncologic intervention.

A newly available Tracker-325 catheter (Target Therapeutics, Fremont, CA, USA), modified from the Tracker-18 catheter, has the same outer diameter but a larger lumen. This catheter was used in 15 patients during a 7-month period for superselective arterial catheterization when conventional catheters could not be placed successfully. Arterial embolization (n = 7), chemoembolization (n = 5), and chemoinfusion (n = 3), were performed. The increased luminal diameter of the Tracker-325 allowed an increased flow rate for diagnostic arteriography, accommodated larger embolic particles, and improved the ability to achieve a super-selective position.

Management of tracheal and bronchial stenoses with the Gianturco stent.

Thirty-six cancer patients with symptomatic tracheobronchial stenoses received Gianturco tracheobronchial stents over a 9-year period. Symptoms improved in 28 patients (78%). The overall median survival was 1 month 3 weeks (range, 4 days to 35 months). The median survival for patients who showed improvement after receiving stents was 3 months compared with 1 week for those who did not respond. Complications were minimal. The Gianturco stent may palliate symptoms of tracheobronchial compression in selected cancer patients.

Intraperitoneal catheters: percutaneous placement with fluoroscopic guidance.

PURPOSE: The authors reviewed their experience with percutaneous placement of catheters into the peritoneal cavity for the administration of intraperitoneal chemotherapy to determine if their approach resulted in a lower complication rate than the reported 12%-16% rate and to demonstrate the technical advantages over surgically placed catheters. PATIENTS AND METHODS: Seventy-six patients with gastrointestinal or gynecologic malignancies underwent 152 procedures during a 20-month period. The catheters were used to deliver antineoplastic agents and, in some patients, to drain ascites. Catheter insertion was performed with local anesthesia and a modified Seldinger technique. A 5-F catheter was used in 89% of procedures; in the remainder, the catheter was of a larger caliber. RESULTS: The procedure was successful in 145 (95%) instances and failed in seven (5%) attempts because of peritoneal adhesions. The catheters remained in place for less than 2 days in 56%, 2-10 days in 25%, and more than 10 days in 19% of patients. One catheter remained in place for 15 weeks. Complications occurred in seven procedures (5%). Four cases of mild peritonitis responded to a brief course of intravenously administered antibiotics, and severe pain in two patients required premature catheter removal. A single case of inadvertent transcolonic catheter placement occurred without adverse sequelae to the patient. CONCLUSIONS: Intraperitoneal catheterization can be performed with local anesthesia by using a simple technique with a very low complication rate. The catheters can remain in place for prolonged periods without significant risks.

Fine-needle aspiration cytology of sarcomatoid renal cell carcinoma: a morphologic and immunocytochemical study of 15 cases.

Sarcomatoid renal cell carcinoma (SRCC), which accounts for 5% of all renal cell carcinomas (RCC), has a worse prognosis than conventional nonsarcomatoid RCC, making accurate diagnosis important. This study reports on the morphologic and immunocytochemical features of 15 cases of SRCC (9 primary tumors and 6 metastases) diagnosed by fine-needle aspiration (FNA) biopsy. All but three cases showed a dimorphic cell population consisting of varying proportions of a high-grade epithelial component, either clear or granular-cell type and a spindle cell (sarcomatoid) component, of either fibrosarcomatous, malignant fibrous histiocytoma (MFH), or unclassified types. The sarcomatoid component in the biphasic and monophasic tumors stained positively for cytokeratin in 12 of 14 (85%) cases, for vimentin in 10 of 11 (91%) cases, and for muscle-specific action in 4 of 11 (36%) cases. Of note, the three cases that demonstrated a purely sarcomatoid morphology stained positively for cytokeratin. Unlike in studies performed on surgically resected specimens, neither the proportion of the sarcomatoid component nor the presence of necrosis had prognostic significance, the discrepancy most likely being related to the sampling. We conclude that SRCC, both primary and metastatic, can be accurately diagnosed by FNA when cytologic features are evaluated in conjunction with immunocytochemical findings.

Fine-needle aspiration cytology of sclerosing hemangioma of the lung: case report with immunohistochemical study.

Sclerosing hemangioma of the lung (SHL) is a rare benign neoplasm, usually found incidentally on a routine chest X-ray. We present a case of SHL initially diagnosed by fine-needle aspiration cytology. Cytomorphologic characteristics were confirmed by a cell block examination and immunohistochemical findings. The differential diagnoses of the fine-needle aspiration are discussed.

Percutaneous lymph node biopsy.

Advances in imaging modalities for detecting lymphadenopathy, the ease, safety, and accuracy of the tools and techniques, and the addition of refined ancillary studies for cytologic analysis will continue to increase the acceptance and use of percutaneous lymph node biopsy (PLNB) by fine-needle aspiration (FNA), especially in lymphomas.

Two chromosomal locations for human ornithine decarboxylase gene sequences and elevated expression in colorectal neoplasia.

The polyamines are known to be essential for cellular proliferation. Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the synthesis of these amines, and activity is elevated in colorectal tumors and polyps. Two ODC genes (designated ODC1 and ODC2) were localized by somatic cell hybridization and in situ techniques to 2p25 and 7q31-qter, respectively. Investigation of the expression of ODC in colorectal neoplasia reveals a consistent increase in mRNA expression compared with normal adjacent mucosa and control mucosa, ranging from 1.3- to 12.2-fold. No amplification of the loci was seen. Comparison of ODC mRNA expression with ODC activity from the same samples revealed no direct correlation, suggesting that regulation of ODC in this system occurs at the posttranscriptional level.

Percutaneously placed endovascular grafts for aortic aneurysms: feasibility study.

This limited study addressed the feasibility of treating aneurysms with a new transcatheter endoprosthesis. Aortic aneurysms were experimentally created in six dogs and subsequently bridged with nylon-covered, self-expanding metallic stents. The dogs were followed up for as long as 7 months (median, 22 weeks). In each dog, the graft effectively reconstituted the aortic lumen, excluding the aneurysm. One dog exhibited minimal (less than 1-mm) residual dilatation at the site of the aneurysm 7 months after graft placement. The nylon material acted as a support and template for neointimal encasement, enabling the formation of a new vascular lumen. It also remained porous at the origin of aortic side branches, preserving the visceral blood supply. One of the endovascular grafts failed to expand completely at its distal end, which promoted thrombus formation within the graft and resulted in the occlusion of both renal arteries. The dog was found comatose 48 hours after graft placement and was killed at that time.