Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance).

LESSONS LEARNED: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma.Patients treated with 10 mg per day dose were most likely to require dose reductions.Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. BACKGROUND: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). METHODS: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. RESULTS: A total of 53 patients were enrolled in cohort 1 (n = 24) and cohort 2 (n = 29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. CONCLUSION: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.

Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks.

PURPOSE: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. METHODS: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. RESULTS: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. CONCLUSIONS: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed.

Intracranial low-grade gliomas in adults: 30-year experience with long-term follow-up at Mayo Clinic.

The purpose of this study was to evaluate long-term survival in patients with nonpilocytic low-grade gliomas (LGGs). Records of 314 adult patients with nonpilocytic LGGs diagnosed between 1960 and 1992 at the Mayo Clinic, Rochester, Minnesota, were retrospectively reviewed. The Kaplan-Meier method estimated progression-free survival (PFS) and overall survival (OS). Median age at diagnosis was 36 years. Median follow-up was 13.6 years. Operative pathology revealed pure astrocytoma in 181 patients (58%), oligoastrocytoma in 99 (31%), and oligodendroglioma in 34 (11%). Gross total resection (GTR) was achieved in 41 patients (13%), radical subtotal resection (rSTR) in 33 (11%), subtotal resection in 130 (41%), and biopsy only in 110 (35%). Median OS was 6.9 years (range, 1 month-38.5 years). Adverse prognostic factors for OS identified by multivariate analysis were tumor size 5 cm or larger, pure astrocytoma histology, Kernohan grade 2, undergoing less than rSTR, and presentation with sensory motor symptoms. Statistically significant adverse prognostic factors for PFS by multivariate analysis were only tumor size 5 cm or larger and undergoing less than rSTR. In patients who underwent less than rSTR, radiotherapy (RT) was associated with improved OS and PFS. A substantial proportion of patients have a good long-term prognosis after GTR and rSTR, with nearly half of patients free of recurrence 10 years after diagnosis. Postoperative RT was associated with improved OS and PFS and is recommended for patients after subtotal resection or biopsy.

Melanoma-induced brain metastases.

Brain metastases are a common site of metastasis from malignant melanoma, and are associated with a poor prognosis. Diagnosis of brain metastasis may also have significant implications for quality of life, and management can be difficult due to rapid progression of disease and resistance to conventional therapies. In this article, we will review the published evidence for treatment modalities for melanoma-induced brain metastases and outline future directions for research. In brief, surgical management of solitary or acutely symptomatic lesions appears to alleviate symptoms and provide the possibility of local control of disease. Stereotactic radiosurgery is an increasingly utilized technique for patients with a limited number of metastases, and presents a less invasive alternative to craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, though combined chemotherapy with external-beam radiation is being investigated. Future directions include combined-modality therapy, the incorporation of novel agents, and careful consideration of the structure of clinical trials for this disease.

Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3.

BACKGROUND: Lamotrigine, an antiepileptic agent, has been reported as being effective in reducing symptoms of neuropathy associated with various etiologies. Based on such data, a multicenter double-blind, placebo-controlled, randomized trial was conducted to evaluate the effect of lamotrigine on pain and other neuropathic symptoms due to chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Patients with symptomatic CIPN with symptom scores of either 1) >3 on a 0-10 Numerical Rating Scale (NRS) or 2) >1 on the 0-3 the Eastern Cooperative Oncology Group (ECOG) neuropathy scale (ENS) were eligible (higher numbers corresponding to greater severity of symptoms in both scales). Patients were randomly assigned to receive lamotrigine (target dose of 300 mg/day) or placebo for 10 weeks. Endpoints were measured biweekly. RESULTS: In all, 131 patients were enrolled. Both groups were well matched at baseline. Over the 10-week period of the trial, the average pain scores (NRS) for the lamotrigine and placebo arms declined in both arms, with no statistically significant difference noted between the changes in the 2 groups (0.3 and 0.5 unit reduction from baseline, respectively; P=.56). Similarly, decreases in the ENS with therapy were not statistically different (0.4 and 0.3, respectively; P=.3). Changes in other subjective symptom scales were also not found to be statistically different between the 2 groups. Toxicities were mild and similar in each group. CONCLUSIONS: The results suggest that lamotrigine is not effective for relieving neuropathic symptoms in patients because of CIPN.

The Paclitaxel acute pain syndrome: sensitization of nociceptors as the putative mechanism.

PURPOSE: Paclitaxel therapy often result in a unique subacute pain syndrome, commonly termed "myalgia" or "arthralgia." The pathophysiology of this syndrome is unknown and has not been demonstrated to be associated with any structural alteration of muscles or joints. We hypothesized that this syndrome was caused by a neuropathic nerve injury from paclitaxel. Herein, we characterize the clinical characteristics of this syndrome using detailed patient interviews and consider the putative mechanism(s) for these symptoms. METHODS: Oncology patients who were treated with paclitaxel and developed a subacute pain syndrome were questioned using a detailed structured interview. Data were tabulated descriptively. RESULTS: Eighteen patients were interviewed. The symptoms (ie, pain) typically began 1-2 days after the infusion and lasted for a median of 4-5 days. Pain was most commonly located in the back, hips, shoulders, thighs, legs, and feet, with the most common descriptors used being "aching" or "deep pain." Commonly used adjectives to describe the pain were radiating, shooting, aching, stabbing, and pulsating. Some patients described increased pain with weight bearing, walking, or tactile contact. When asked directly whether the pains appeared to be specifically localized to either joints or muscles, 15 of 18 patients denied localization. DISCUSSION: Based on the nature and temporal occurrence of the paclitaxel acute pain syndrome symptoms, we infer that the paclitaxel acute pain syndrome occurs as a result of sensitization of nociceptors, their fibers, or the spinothalamic system. This proposed neurologic etiology of this pain may also explain the subsequent development in some patients of a symmetric length-dependent sensorimotor polyneuropathy. The mechanism of this syndrome needs further study.

Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3).

BACKGROUND: The antiepileptic agent, gabapentin, has been demonstrated to relieve symptoms of peripheral neuropathy due to various etiologies. On the basis of these data, a multicenter, double-blind, placebo-controlled, crossover, randomized trial was conducted to evaluate the effect of gabapentin on symptoms of chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Patients with symptomatic CIPN who complained of 'average' daily pain scores of either 1) >/=4 on a 0-10 numerical rating scale (NRS); or 2) >/=1 on the 0-3 Eastern Cooperative Oncology Group neuropathy scale (ENS) were eligible (higher numbers indicate greater severity of symptoms in both scales). Patients were randomized to receive gabapentin (target dose, 2700 mg) or placebo for 6 weeks. Crossover occurred after a 2-week washout period. CIPN-related symptoms were evaluated weekly by questionnaires. Statistical methods followed established methods for crossover designs, including Student t tests to compare average intrapatient differences between treatments and linear models to adjust for potential concomitant covariates. RESULTS: There were 115 patients who were randomly assigned to the treatment or control arm. Both groups were well matched by symptoms at study entry. Changes in symptom severity were statistically similar between the 2 groups during the study. Adverse events were mild and similar in both groups. CONCLUSIONS: This trial failed to demonstrate any benefit to using gabapentin to treat symptoms caused by CIPN.

Chemotherapy-induced neuropathy.

Peripheral neuropathy is a common dose-limiting toxicity of chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) causes numerous debilitating symptoms, impairs functional capacity, and results in dose reductions or possible cessation of chemotherapy. Analgesic or neurotropic agents are only modestly effective in treating neuropathic symptoms. Animal and human studies into the pathogenesis of CIPN have demonstrated heterogeneity in the mechanism(s) of nerve injury caused by individual agents, which may partly explain the wide variation in the resultant symptoms. Development of optimal therapeutic measures to treat CIPN requires continued research into the pathophysiologic basis of nerve injury, identification of risk factors for individual patients, development of reproducible and easy-to-use measurement scales, and finally, the performance of appropriately designed clinical trials to evaluate potentially promising agents.

Innovation in the management of brain metastases.

Metastatic lesions to the brain occur commonly in oncology patients and portend a very poor outcome, as they often occur in the setting of progressive systemic metastatic disease and can result in neurologic deterioration that may preclude therapy. Therapy of patients with brain metastases requires a combination of measures to achieve local control at the site of metastasis (e.g., with surgical resection or radiosurgery) and to reduce the subsequent risk of recurrences elsewhere in the brain (e.g., with whole-brain radiation). Successful therapy of extracranial systemic metastases is required for optimal outcomes. Clinical trials are currently underway to define the optimal role of whole-brain radiation and radiosurgery in different subsets of patients. Novel therapies to enhance radiation responsiveness are also under investigation. In the current review, we discuss recent developments in the management of patients with brain metastases.

Malignant melanoma in the 21st century, part 2: staging, prognosis, and treatment.

Critical to the clinical management of a patient with malignant melanoma is an understanding of its natural history. As with most malignant disorders, prognosis is highly dependent on the clinical stage (extent of tumor burden) at the time of diagnosis. The patient's clinical stage at diagnosis dictates selection of therapy. We review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. Although much work remains to be done to improve the survival of patients with melanoma, clinically meaningful results seem within reach.

Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis.

Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.

Peptide vaccination of patients with metastatic melanoma: improved clinical outcome in patients demonstrating effective immunization.

OBJECTIVES: Therapeutic peptide vaccines for melanoma continue to only demonstrate anecdotal success. We set out to evaluate the impact of low-dose GM-CSF emulsified in Montanide ISA-51 on the immunogenicity of HLA-A2 restricted melanoma differentiation antigen peptide vaccines (MART-1, gp100 and tyrosinase) administered in separate subcutaneous injections. METHODS: We conducted a randomized phase II clinical trial of HLA-A2+ patients with metastatic melanoma that were immunized every 3 weeks with one of the following vaccine preparations: (A) peptides + Montanide ISA-51; (B) peptides + Montanide ISA-51 + GM-CSF (10 microg); (C) peptides + Montanide ISA-51 + GM-CSF (50 microg). Immunization efficacy was determined by quantification of vaccine specific tetramer positive cytotoxic T cells in peripheral blood. Global assessment of immune competence was ascertained using DTH testing to common recall antigens as well as peripheral blood immunophenotyping. RESULTS: Twenty-five eligible patients were equally distributed across all 3 treatment groups. Only 9 patients demonstrated evidence of immunization. Most commonly, immune response was achieved to the gp100 peptide. The addition of low-dose GM-CSF did not impact immunization efficacy. DTH reactivity to Candida appeared predictive of successful immunization. Successful immunization with the peptide vaccines was associated with improved clinical outcomes. CONCLUSIONS: The addition of low dose GM-CSF to peptide vaccines did not enhance immunogenicity. Higher doses of GM-CSF may be needed to achieve this effect and this is a testable hypothesis. Likewise, better patient selection based on immunologic status (DTH reactivity) may be helpful to better understand the clinical impact of therapeutic cancer vaccines.

Current strategies in treatment of oligodendroglioma: evolution of molecular signatures of response.

Oligodendroglioma frequently (> or = 70%) responds to radiation and chemotherapy, and is the first CNS neoplasm in which a genetic signature (1p and 19q deletion) has been associated with outcome within the context of large clinical trials. Current translational investigations focus on deletions or mutations of potential tumor suppressor genes, epigenetic alterations, amplification or mutation of growth factor and regulatory genes, and characterization of signaling events and regulatory protein expression. The most compelling data has involved 1p and 19q loss, which is observed in over 50% of anaplastic oligodendrogliomas. In two randomized phase III trials (Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951), the addition of neoadjuvant or adjuvant procarbazine, lomustine, and vincristine (PCV; respectively) to radiotherapy did not produce superior survival as compared with radiotherapy alone. A modest increase in progression-free survival was observed with the addition of PCV, but at the cost of increased toxicity. Combined 1p and 19q loss identified a favorable prognostic group in both studies, which appeared to be independent of treatment arms. However, it is unclear whether these deletions represent surrogate markers of a favorable biologic tumor behavior, or are predictive of outcome after specific treatment. Currently, there is insufficient data to allow therapeutic decisions to be made solely on the basis of 1p and 19q gene deletion status. Future phase III trials are evaluating other chemotherapeutic and targeted agents, including temozolomide, and include correlative investigations of aberrant molecular events in these neoplasms, which may lead to future therapeutic strategies that are based on specific molecular signatures.

Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma.

BACKGROUND: Patients with metastatic melanoma (MM) have very few therapy options. Based on reports of responses to paclitaxel and carboplatin (PC), 31 patients with MM were treated with PC. METHODS: Data regarding patients treated with PC were abstracted from medical records. Clinical outcomes as determined by the treating oncologist were used for this analysis. Response determination was retrospectively confirmed using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Thirty-one patients with MM were treated with PC. Patients had a median of 2 previous therapies, with the majority (29; 94%) having failed prior temozolomide (TMZ) or dacarbazine (DTIC) therapy. The most commonly used regimen was weekly paclitaxel (at a dose of 100 mg/m(2)) and carboplatin (area under the curve 2) administered on Days 1, 8, and 15 of a 28-day cycle. An objective partial response was noted in 8 patients (26%) with an additional 6 patients (19%) having stable disease; therefore, a clinical benefit was noted in 45% of those patients treated. The median time to disease progression for the entire group was 3 months (range, 0-7 mos), with a median overall survival of 7.8 months (range, 1-14 mos). The clinical benefit derived by the 14 patients, which lasted for a median of 5.7 months (range, 2.5-7.3 mos), was considered to be clinically significant. At the time of last follow-up, eight patients continued to receive PC therapy. CONCLUSIONS: The PC combination appears to have definite and clinically meaningful activity when used as second-line therapy after TMZ or DTIC. Further evaluation of this regimen, alone or as a 'backbone' for other agents, needs to be considered.

Treatment options for brain metastases from melanoma.

Brain metastases are a common complication of metastatic malignant melanoma, conferring an exceedingly poor prognosis. Diagnosis of brain metastasis often has significant implications for duration and quality of life, and management can be difficult due to rapid progression of disease and resistance to conventional therapies. This review focuses primarily on the published evidence for treatment modalities for brain metastases from melanoma, emerging technologies and outlines future directions for research. In summary, external-beam radiation alone appears effective in palliating symptoms. Surgical management of solitary or acutely symptomatic lesions appears to alleviate symptoms and provide the possibility of local control of disease. Stereotactic radiosurgery is an increasingly utilized technique for patients with a limited number of metastases and presents a less-invasive alternative to craniotomy. Chemotherapy alone is relatively ineffective, although combined chemotherapy with external-beam radiation is being investigated. Future directions include combined modality therapy, the incorporation of novel agents and careful consideration of the structure of clinical trials for this disease.

Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells.

Elevated epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) signaling are known to contribute to the malignant properties of glioblastoma multiforme (GBM), which include uncontrolled cell proliferation and evasion of apoptosis. Small molecule inhibitors that target these protein kinases have been evaluated in multiple clinical trials for cancer patients, including those with GBM. Here we have examined the cellular and molecular effects of a combined kinase inhibition of mTOR (rapamycin) and EGFR (EKI-785) in U87 and U251 GBM cells. Simultaneous treatment with rapamycin and EKI-785 results in synergistic antiproliferative as well as proapoptotic effects. At a molecular level, rapamycin alone significantly decreases S6 phosphorylation, whereas EKI-785 alone promotes substantially reduced signal transducer and activator of transcription (STAT3) phosphorylation. Treatment with rapamycin alone also increases Akt phosphorylation on Ser-473, but this effect is blocked by a simultaneous administration of EKI-785. Individually, EKI-785 diminishes while rapamycin promotes the binding of the translation inhibitor eukaryotic initiation factor 4E binding protein (4EBP1) to the eukaryotic translation initiation factor 4E (eIF4E). In spite of these opposing effects, the highest level of 4EBP1-eIF4E binding occurs with the combination of the two inhibitors. These results indicate that the inhibition of EGFR and mTOR has distinct as well as common signaling consequences and provides a molecular rationale for the synergistic antitumor effects of EKI-785 and rapamycin administration.

Phase II trial of carmustine, cisplatin, and oral etoposide chemotherapy before radiotherapy for grade 3 astrocytoma (anaplastic astrocytoma): results of North Central Cancer Treatment Group trial 98-72-51.

PURPOSE: To evaluate the efficacy of preradiotherapy (RT) chemotherapy with carmustine, cisplatin, and oral etoposide combined with RT in the treatment of newly diagnosed anaplastic astrocytoma. METHODS AND MATERIALS: Therapy consisted of carmustine (40 mg/m(2)/d) on Days 1-3, oral etoposide (50 mg/d) on Days 1-21 and 29-49, and cisplatin (20 mg/m(2)/d i.v.) on Days 1-3 and 29-31. The regimen was repeated every 8 weeks for three cycles, with conventionally fractionated RT (5000 cGy with a 1000-cGy boost) delivered concurrently with the third cycle. RESULTS: A total of 29 patients were enrolled between December 1999 and March 2001. For varying reasons (e.g., progression, refusal, death, or toxicity), only 48% completed the chemotherapy regimen and 76% completed RT. Grade 3-4 toxicities were observed in 14 patients (48%). The primary study endpoint was the 23-month (700-day) survival, the median survival of patients with anaplastic astrocytoma in a previous North Central Cancer Treatment Group trial. To be considered an active treatment, a maximum of 9 patient deaths (of the first 25) were allowed before 700 days. However, 14 patients had died by 700 days after therapy. CONCLUSION: Our results have demonstrated that pre-RT chemotherapy with this regimen is insufficiently active in patients with anaplastic astrocytoma.

Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents.

Highly specific signal transduction inhibitors are being developed as anti-cancer agents against an array of molecular targets, with the promise of increased selectivity and lower toxicity than classic cytotoxic chemotherapy agents. Rapamycin and its analogues are a promising class of novel therapeutics that specifically inhibit signaling from the serine-threonine kinase, mammalian target of rapamycin (mTOR). mTOR is a key intermediary in multiple mitogenic signaling pathways and plays a central role in modulating proliferation and angiogenesis in normal tissues and neoplastic processes. Rapamycin potently inhibits T-cell proliferation, and is approved for clinical use as an immuno-suppressant following kidney transplantation. Hyperactivation of mTOR signaling has been implicated in tumorigenesis, and promising pre-clinical studies in several tumor types suggest that the anti-proliferative and anti-angiogenic properties of rapamycin may be useful in cancer therapy. These studies have led to several clinical trials evaluating the safety and efficacy of rapamycin analogs in cancer therapy. The goal of this article is to review the mechanism of action of rapamycin as an anti-cancer agent, and to review the clinical experience with rapamycin and rapamycin analogs as immunosuppressive and anti-neoplastic therapeutic agents.