Showing papers in "Oncology in 1999"

Management of brain metastases.

Abstract: Brain metastases are the most common type of brain tumor in adults and are an increasingly important cause of morbidity and mortality in cancer patients. In recent years, important advances have been made in the diagnosis and management of brain metastases. These advances include the widespread use of magnetic resonance imaging (MRI), enabling small metastases to be detected; the introduction of stereotactic radiosurgery; and the performance of studies that have clarified the role of surgery and postoperative radiation therapy for single brain metastases. As a result, most patients receive effective palliation, and the majority do not die from their brain metastases. However, further studies are needed to define the optimal role of conventional treatments and to develop more effective novel therapies.

An Early Phase II Study of Oral S-1, a Newly Developed 5-Fluorouracil Derivative for Advanced and Recurrent Gastrointestinal Cancers

Abstract: 5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to alpha-fluoro-beta-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4-68.1% and C 8.4-30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and these responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3%) (G) and 13 (43.3%) (C) patients, and in 6 (21. 4%) (G) and 7 (23.3%) (C) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35. 7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastrointestinal cancer.

S100B Protein Detection in Serum Is a Significant Prognostic Factor in Metastatic Melanoma

Abstract: The serum detection of S100B, a new melanoma marker, has shown clinical significance in early studies. The aim of our study of 1, 339 serum samples from 412 different melanoma patients and 107 control patients was to prove the prognostic value of serum S100B levels in melanoma patients at different stages of disease and at follow-up (median: 30 months). Using a cutoff level of 0.2 microgram/l S100B, 5 of 286 patients (1.7%) with primary tumors (stage I/II), 14/73 (19.2%) patients with locoregional metastasis (stage III) and 57/84 (67.9%) patients with advanced disease (stage IV) were S100B positive (statistically significant differences for stage I/II vs. III, I/II vs. IV, and III vs. IV, p /=0.2 microgram/l), which was independent of the stage of disease (I-IV). Regarding prognosis, we were furthermore able to distinguish different subgroups among stage III and IV patients using S100B serum levels (p < 0.01). Patients with different cutaneous non-melanoma diseases served as S100B-negative controls. S100B serum evaluations using the Sangtec(R)100 IRMA are highly specific and sensitive for the detection of metastatic melanoma. S100B has been shown to be a relevant prognostic factor for survival in a study with a large sample size of melanoma patients including close follow-up evaluations.

Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience.

Abstract: Topotecan, a water-soluble analogue of camptothecin, is a newly available cytotoxic agent which acts as an inhibitor of topoisomerase I, an enzyme necessary for DNA replication. Topotecan is a semisyn

Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis.

Abstract: The relation between tumor-associated macrophage (TAM) density and the density of microvessels was investigated in specimens from 113 patients with pulmonary adenocarcinoma, as was the influence of TAM density on prognosis. The rank correlation test revealed a significant relation between TAM density and microvessel density (y = 14.418 + 0.863x, r = 0.454, p > 0.0001). A significant difference in patient survival rate was detected between tumors with a TAM density defined as high and those with a TAM density defined as low (p < 0.01). Multivariate analysis also showed that TAM density was significantly related to survival (p < 0.05). These data indicate that TAM infiltration may contribute to tumor angiogenesis, and that TAM density is a useful prognostic marker in pulmonary adenocarcinoma.

Possible interactions between dietary antioxidants and chemotherapy.

Abstract: Many patients treat themselves with oral antioxidants and other alternative therapies during chemotherapy, frequently without advising their conventional health care provider. No definitive studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants in humans. However, there is sufficient understanding of the mechanisms of action of both chemotherapeutic agents and antioxidants to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation. This article will describe these potential interactions and areas of concern, based on the available data. It will also suggest several potential courses of action that clinicians may take when patients indicate that they are taking or plan to use alternative therapies.

Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers.

Abstract: Expression of several members of the Bcl-2 family proteins was investigated by means of both immunohistochemical analysis in 30 invasive ductal adenocarcinomas and 23 intraductal papillary-mucinous tumors (IPMTs) and immunoblot analysis in 6 cancer tissues and 7 pancreatic cancer cell lines. We found that Bcl-2 was expressed in 23%, Bax in 53%, Bcl-X in 90%, and Mcl-1 in 90% of the invasive ductal adenocarcinomas. In intraductal papillary-mucinous adenocarcinomas, the expression rate of Bax was 44% and those of Bcl-XL and Mcl-1 were 88%; these values were higher than those for intraductal papillary-mucinous adenomas. Immunoblot analysis identified Bcl-XL as the predominant form of the Bcl-X protein in both pancreatic cancer tissues and cell lines, and demonstrated that both Bcl-XL and Mcl-1 protein levels were uniformly high in all cell lines. These results suggest that an imbalance between antiapoptosis proteins (such as Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (such as Bax and Bcl-Xs) is involved in the distinctive biologic features of adenocarcinomas of the pancreas. Furthermore, predominantly high expressions of Bcl-XL and Mcl-1 in intraductal papillary-mucinous adenocarcinomas might be involved in the carcinogenesis in IPMT of the pancreas.

p53 tumor suppressor gene therapy for cancer.

Abstract: Gene therapy has the potential to provide cancer treatments based on novel mechanisms of action with potentially low toxicities. This therapy may provide more effective control of locoregional recurrence in diseases like non-small-cell lung cancer (NSCLC) as well as systemic control of micrometastases. Despite current limitations, retroviral and adenoviral vectors can, in certain circumstances, provide an effective means of delivering therapeutic genes to tumor cells. Although multiple genes are involved in carcinogenesis, mutations of the p53 gene are the most frequent abnormality identified in human tumors. Preclinical studies both in vitro and in vivo have shown that restoring p53 function can induce apoptosis in cancer cells. High levels of p53 expression and DNA-damaging agents like cisplatin (Platinol) and ionizing radiation work synergistically to induce apoptosis in cancer cells. Phase I clinical trials now show that p53 gene replacement therapy using both retroviral and adenoviral vectors is feasible and safe. In addition, p53 gene replacement therapy induces tumor regression in patients with advanced NSCLC and in those with recurrent head and neck cancer. This article describes various gene therapy strategies under investigation, reviews preclinical data that provide a rationale for the gene replacement approach, and discusses the clinical trial data available to date.

Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in gastric carcinoma.

Abstract: The prognostic value of preoperative serum levels of CEA, CA 19-9 and CA 72-4 tumor markers was investigated in 153 patients resected for gastric cancer. The positivity rates for CEA, CA 19-9 and CA 7

Artificial neural networks applied to survival prediction in breast cancer.

Abstract: In this study, we evaluated the accuracy of a neural network in predicting 5-, 10- and 15-year breast-cancer-specific survival. A series of 951 breast cancer patients was divided into a training set of 651 and a validation set of 300 patients. Eight variables were entered as input to the network: tumor size, axillary nodal status, histological type, mitotic count, nuclear pleomorphism, tubule formation, tumor necrosis and age. The area under the ROC curve (AUC) was used as a measure of accuracy of the prediction models in generating survival estimates for the patients in the independent validation set. The AUC values of the neural network models for 5-, 10- and 15-year breast-cancer-specific survival were 0.909, 0.886 and 0.883, respectively.The corresponding AUC values for logistic regression were 0.897, 0.862 and 0.858. Axillary lymph node status (N0 vs. N+) predicted 5-year survival with a specificity of 71% and a sensitivity of 77%. The sensitivity of the neural network model was 91% at this specificity level. The rate of false predictions at 5 years was 82/300 for nodal status and 40/300 for the neural network. When nodal status was excluded from the neural network model, the rate of false predictions increased only to 49/300 (AUC 0.877). An artificial neural network is very accurate in the 5-, 10- and 15-year breast-cancer-specific survival prediction. The consistently high accuracy over time and the good predictive performance of a network trained without information on nodal status demonstrate that neural networks can be important tools for cancer survival prediction.

Amplification of c-myc in hepatocellular carcinoma: correlation with clinicopathologic features, proliferative activity and p53 overexpression.

Abstract: Expression of the proto-oncogene c- myc has been implicated in liver regeneration and hepatocarcinogenesis. The biologic significance of c- myc gene amplification i

Two Consecutive Phase II Studies of 5-Fluorouracil/Leucovorin/Mitomycin C and of Gemcitabine in Patients with Advanced Biliary Cancer

Abstract: Introduction: Carcinoma of the biliary system is a rare tumor entity, and patients with advanced disease face a dismal prognosis. Because of the absence of standard chemotherapy for

Diagnosis and treatment of depression in cancer patients.

Abstract: Depression is a common complication of cancer, occurring in about 25% of all patients. If left untreated, depression can contribute to poor treatment compliance, increased hospital stays, and mortality. Medical issues, as well as psychosocial stressors, can complicate the diagnosis of depression in people with cancer. This article describes the clinical presentation of depression in cancer patients, reviews the differential diagnosis, and discusses various treatment options, including antidepressants.

Complications of Subcutaneous Infusion Port in the General Oncology Population

Abstract: Subcutaneous infusion ports (SIPs) represent a valid method for long-term chemotherapy. The SIPs have several advantages over other methods of venous access: they are easy to implant under local anaes

Plasma insulin-like growth factor-I and serum IGF-binding protein 3 can be associated with the progression of breast cancer, and predict the risk of recurrence and the probability of survival in African-American and Hispanic women.

Abstract: In vitro studies have shown that insulin-like growth factor (IGF) is a mitogen for breast cancer cells. However, the associations of plasma IGF-I with tumor histopathology in high-risk groups need further investigation. We hypothesize that plasma IGF-I and serum IGFBP3 concentrations in breast cancer patients may provide useful information on the progression of their disease, and determine the probability of recurrence and survival. We have carried out a retrospective study on 130 minority breast cancer patients. Plasma IGF-I and serum IGFBP3 were correlated with tumor histopathology, menopausal status, treatment modality, recurrence rates, and probability of survival. Plasma IGF-I and serum IGFBP3 were measured by radioimmunoassay. Our studies show that breast cancer patients have elevated plasma IGF-I and serum IGFBP3 levels. In addition we observed the following: IGF-I did not correlate with age and nodal stage. IGF-I and IGFBP3 increased with tumor size (T4). IGF-I did not correlate with estrogen receptor status, but did increase in progesterone-receptor-positive patients. IGF-I levels were higher in premenopausal patients and in women with cancer recurrence. Tamoxifen reduced IGF-I levels significantly and reduced the risk of recurrence. The survival probability was greater in patients with plasma IGF-I levels <120 ng/ml. In conclusion, lowering of plasma IGF-I may offer the following benefits: (a) reduce the risk of developing breast cancer in high-risk groups; (b) slow the progression of breast cancer in patients at early stages of cancer; (c) lower the risk of recurrence, and (d) increase the probability of survival.

A Comparative Study of Intraperitoneal Carboplatin versus Intravenous Carboplatin with Intravenous Cyclophosphamide in Both Arms as Initial Chemotherapy for Stage III Ovarian Cancer

Abstract: Cisplatin (C) or carboplatin (CBP) plus cyclophosphamide (CTX) was until recently considered standard chemotherapy for advanced ovarian cancer (OC). Attempts to maximize platinum and its analog activi

Sentinel lymph node mapping in breast cancer

Abstract: Sentinel lymph node (SLN) biopsy is a rapidly emerging treatment option for patients with early-stage invasive breast cancer and a clinically negative axilla. In the era of mammographic detection, SLN biopsy has the potential to eliminate axillary dissection for the enlarging cohort of breast cancer patients who are node-negative. Using radioisotope, blue dye, or both methods, experienced surgeons can successfully localize SLNs in more than 90% of cases. The effects of isotope and blue dye may be additive. Sentinel lymph node biopsy reliably predicts axillary node status in 98% of all patients and 95% of those who are node-positive. The operation is best learned under a formalized protocol in which a backup axillary dissection is performed to validate the technique during the surgeon's early experience. Enhanced pathologic analysis, including serial sections and immunohistochemical (IHC) staining, is an essential element of the procedure. In experienced hands, SLN biopsy has less morbidity and greater accuracy than conventional axillary dissection.

Radiosensitization by gemcitabine.

Abstract: Gemcitabine is a potent radiosensitizer in both laboratory studies and in the clinic. Initial laboratory studies showed that gemcitabine radiosensitizes a wide variety of rodent and human tumor cells in culture. Maximum

Efficacy of continuous hyperthermic peritoneal perfusion for the prophylaxis and treatment of peritoneal metastasis of advanced gastric cancer: evaluation by multivariate regression analysis.

Abstract: Thirty-two patients with advanced gastric cancer underwent continuous hyperthermic peritoneal perfusion (CHPP) combined with surgery: to prevent peritoneal recurrence in 15 patients without peritoneal metastasis (prophylactic CHPP) and to treat 17 patients with peritoneal metastases (therapeutic CHPP). The postoperative outcome was compared with that of control patients treated with surgery alone. Peritoneal recurrence was less frequent (26%) and the 5-year survival rate was significantly higher (39%) in the patients with prophylactic CHPP than in 40 control patients (42 and 17%, respectively). The patients with therapeutic CHPP showed significantly better median survival than did 20 control patients (11 vs. 6 months). Cox multivariate regression analysis revealed that CHPP was an independent prognostic factor in the prophylactic study (hazard ratio = 0.3965), and that the independent prognostic factor in the therapeutic study was not CHPP but complete resection of the peritoneal metastasis. Thus, CHPP has no marked benefit for established peritoneal metastasis. CHPP for the prevention of peritoneal recurrence may have a beneficial effect on long-term survival, but a prospective randomized trial is needed to clarify its prognostic value.

Immunohistochemical analysis of midkine expression in human prostate carcinoma.

Abstract: Midkine (MK) is a growth/differentiation factor frequently expressed at high levels in some types of human malignancies. To investigate whether MK is a useful marker in prostate carcinogenesis, immunohistochemical analysis was performed on samples of both latent and clinical prostate cancers of various stages, as well as on specimens of normal gland and prostatic intraepithelial neoplasia (PIN). Of the 80 clinical cancers examined, 69 specimens (86.3%) were immunoreactive for MK, with metastatic lesions generally showing higher expression than the corresponding primaries; normal prostate tissues were negative or showed only weak staining. Midkine was also detected in 12 of 15 latent cancers (80%) and in 12 of 16 cases of PIN (75%). In sections of whole prostate, MK showed variable expression through tumorous sections, probably in reflection of heterogeneous cell populations. The results demonstrate the possible value of MK as a marker for early and latent disease, as well as for more advanced clinical stages of prostate cancer.

Review: Gonadotropins and Development of Ovarian Cancer

Abstract: An epidemiological correlation between infertility therapy and ovarian cancer development has been reported in 1992; consequently, the possible role of gonadotropins in ovarian carcinogenesis has received much attention. Here, we review the effect of gonadotropins on epithelial ovarian carcinoma and ovarian surface epithelium (OSE), which is the histogenetic origin of carcinomas. Recent studies have demonstrated that gonadotropin receptors are expressed in OSE and in approximately half of the ovarian carcinomas. Gonadotropins have also been reported to stimulate cell proliferation and to inhibit apoptosis in OSE and ovarian cancer cells. These data suggest that gonadotropins play an important role in the development, progression, and/or chemoresistance of ovarian carcinomas. Hormonal therapy against gonadotropins may be applicable for patients with ovarian carcinoma.

Prognostic value of p27(Kip1) and CyclinD1 expression in esophageal cancer.

Abstract: It has recently been reported that the reduced expression of p27(Kip1) is a negative prognostic marker in several carcinomas. In this study, we examined the expression of p27(Kip1) in esophageal squamous cell carcinomas in order to understand its prognostic role. We also examined the expression of cyclinD1, which is believed to be correlated with the prognosis. Of the 128 cases, 64 cases (50.0%) showed low grade p27(Kip1) immunostaining and 64 cases (50.0%) high grade immunostaining; there was no significant difference in survival (p = 0.0915) between the two groups. On the other hand, 51 of the 156 cases (32.7%) were classified as the high cyclinD1 group, and 105 of the 156 cases (67.3%) as the low group, thus representing prognostic significance with regard to survival (p = 0.0161). Multivariate analysis indicated that gender, lymph node metastasis and positive cyclinD1 were independent prognostic factors. Our results revealed that cyclinD1 was a significant prognostic predictor of esophageal squamous cell carcinomas, whereas p27(Kip1) was not a significant prognostic factor.

Toxicity of 5-Fluorouracil

Abstract: Fluorouracil (5-FU) is a relatively unique drug in oncology because administration in different doses and schedules results in dramatically different patterns of qualitative toxicity. In the 41 years 5-FU has been available to the clinical oncologist, a wide variety of doses and schedules of this agent have been used. Infusional schedules are associated with less myelosuppression but may have more gastrointestinal and skin toxicity. Bolus schedules cause myelotoxicity, and bolus schedules including calcium folinate are associated with diarrhea, mucositis, and, in some schedules, myelosuppression. The availability of various doses and schedules of 5-FU for administration allows clinicians to choose a 5-FU regimen with the most acceptable pattern of toxicity for individual cases. Also, the study of 5-FU in various groups of patients has demonstrated that relatively increased drug toxicity may be expected in patients above the age of 70 years and in female patients.

Molecular Bases for the Actions of Ovarian Sex Steroids in the Regulation of Proliferation and Apoptosis of Human Uterine Leiomyoma

Abstract: Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. In order to characterize the molecular mechanism of sex

Hypermethylation of the p16 gene in sporadic T3N0M0 stage colorectal cancers: association with DNA replication error and shorter survival.

Abstract: Hypermethylation in the promoter region of the p16 gene was suspected to be involved in the tumorigenesis of colorectal cancers, although its clinical and biological significance remains obscure. In this study, we collected 84 T3N0M0 stage primary colorectal cancers that were curatively resected. The clinicopathologic data were reviewed. p16 hypermethylation was determined by a methylation-specific polymerase chain reaction (PCR). p53 overexpression was detected by immunocytochemistry (ICC). The point mutations in the 12 and 13 codons of the K-ras gene were screened by restriction enzyme analysis. Loss of heterozygosity (LOH) of the DCC (Deleted in Colorectal cancer) gene was examined by PCR using primers of the DCC (18q21) microsatellite marker. The DNA replication error (RER) was examined using 7 microsatellite markers at distinct chromosomal loci. p16 hypermethylation, regarded as an indication of p16 inactivation, was evident in 24 (28.6%) of the tumors. No correlation was found between p16 hypermethylation and various clinicopathologic factors, includinig age, sex, tumor location, tumor size, growth pattern, tumor differentiation, mucin production, vascular and/or lymphatic invasion, lymphocyte infiltration of the tumor, and serum level of carcinoembryonic antigen. There was no association between p16 hypermethylation of K-ras gene mutation, p53 overexpression and LOH of the DCC gene. However, p16 hypermethylation was significantly associated with DNA RER (p = 0.01). Survival analysis revealed a significant survival disadvantage of p16-hypermethylated versus non-p16-hypermethylated tumors (p = 0.0001). These findings indicate that p16 hypermethylation plays a role in the carcinogenesis of a subset of colorectal cancers; and the presence of p16 hypermethylation predicts shorter survival in T3N0M0 stage colorectal cancers.

Chronic myelogenous leukemia: Update on biology and treatment

Abstract: Chronic myelogenous leukemia (CML) is a myeloproliferative disorder that follows a characteristic clinical course in which a chronic phase of variable duration precedes an accelerated, and ultimately blastic, phase, which is generally fatal. This disorder results from a clonal expansion of transformed hematopoietic progenitor cells and includes myeloid, monocytic, erythroid, megakaryocytic, and lymphoid lineages. At the molecular level, CML is characterized by the bcr-abl fusion gene, which results from the reciprocal translocation t(9;22)(q34;q11), creating the Philadelphia (Ph) chromosome. Chronic myelogenous leukemia was the first human disease for which a specific karyotype abnormality was demonstrated and could be linked to pathogenetic events of leukemogenesis. The outlook for patients with CML has changed dramatically over the last decade. The median survival time of patients has doubled to 5 to 7 years, with up to 50% of patients alive at 5 years. This development is due to refinements in allogeneic stem-cell transplantation and growing expertise in the use of interferon-alfa (Intron A, Roferon-A), a biological agent that has been shown to suppress the leukemic clone and to prolong survival in patients with CML. This review provides a concise update of the biology of CML, as well as current therapeutic options and management strategies.

Discussing disease progression and end-of-life decisions.

Abstract: Because most patients now want to know the truth about their diagnosis and prognosis, the ability to discuss the cancer diagnosis, disease recurrence, or treatment failure, and to solicit patients' views about resuscitation or hospice care, are important verbal skills for oncologists and other oncology health care providers. Moreover, the ability to clearly articulate a treatment plan or elicit patient preferences for treatment are a prerequisite to informed consent. Despite these imperatives, clinicians do not routinely receive training in key communication skills that could enable them to accomplish these tasks. A body of literature is available, however, that identifies communication strategies that can (1) facilitate the establishment of a close rapport with the patient, (2) identify the patient's information preferences, (3) ensure comprehension of key knowledge and information, (4) address the patient's emotions in a supportive fashion, (5) elicit the patient's key concerns, and (6) involve the patient in the treatment plan. In this article, we use dialogues between a physician and a hypothetical patient with advanced ovarian cancer to illustrate how communication techniques can be applied to accomplish these goals. We identify important benefits of the use of these techniques for both the physician and patient, and pose several questions regarding the training of physicians in this area.

Stereotactic Radiosurgery for Brain Metastases

Abstract: Worldwide, approximately 100,000 patients have undergone stereotactic radiosurgery for a variety of intracranial lesions, of which brain metastases represent the most common treatment indication. This article summarizes the major issues surrounding the management of brain metastases, and also analyzes 21 independent reports of Gamma Knife– or linear accelerator–based radiosurgery, representing over 1,700 patients and more than 2,700 lesions. Variable reporting in the studies precludes a definitive, rigorous analysis, but the composite data reveal an average local control rate of 83% and median survival of 9.6 months, both of which are comparable to results in recent surgical reports. The most important prognostic factors for survival appear to be fewer than three lesions, controlled extracranial disease, and Karnofsky performance score (KPS). The exact impact of dose has not been clarified, but a dose-response relationship, especially for ³ 18 Gy, is emerging. The role of whole-brain radiotherapy remains unresolved. It may enhance local control but does not convincingly improve survival and, in some series, is associated with an increased risk of late complications. Chronic steroid dependence and increased intracranial edema do not appear to be common problems. This is an opportune time for the completion of ongoing randomized trials to validate these observations. [ONCOLOGY 13(10):1397-1409,1999]

DNA topoisomerase I-targeting drugs as radiation sensitizers.

Abstract: Combination chemoradiation, alone or as an adjuvant to surgery, has been shown to improve treatment outcomes in a number of human malignancies, but may be limited by normal tissue toxicities. A primary challenge in radiation oncology is the development of drugs that can selectively enhance the cytotoxicity of ionizing radiation against tumor cells. Mammalian DNA topoisomerase I is the major cytotoxic target of a number of newly developed anticancer drugs that have shown efficacy against solid tumors, including colon cancer, ovarian cancer, lung cancer, cancer of the head and neck, and pediatric cancers. Topoisomerase I-targeting drugs exert their cytotoxic effect by producing enzyme-mediated DNA damage, rather than by directly inhibiting enzyme catalytic activity. DNA topoisomerase I recently has been established as a biochemical mediator of radiosensitization in cultured mammalian cells by camptothecin derivatives. Interestingly, this sensitization appears to be schedule-dependent, cell cycle phase-specific, cell line-dependent, and not strictly dependent on drug cytotoxicity. Clinical chemoradiation trials using camptothecin derivatives are currently ongoing. Future studies aimed at better understanding the underlying mechanisms of molecular radiosensitization with topoisomerase I-targeting drugs are pivotal to the clinical application of these agents, as well as in guiding the development of more effective radiosensitizers.