Re: Incidence of initial local therapy among men with lower-risk prostate cancer in the United States.
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Age Factors↗
Biomedical subjects
Bhadrasain Vikram
Publications and source records attributed to Bhadrasain Vikram.
A core curriculum for RTTs (radiation therapists/radiotherapy radiographers) designed for developing countries under the auspices of the international atomic energy agency (IAEA).
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Curriculum↗
Flt3L therapy following localized tumor irradiation generates long-term protective immune response in metastatic lung cancer: its implication in designing a vaccination strategy.
Flt3 ligand (Flt3L) therapy that expands dendritic cells in vivo in combination with local tumor radiotherapy (RT) significantly improved survival and induced a long-term tumor-specific immune response in a murine model of Lewis lung carcinoma (3LL). The irradiated tumor cells were able to significantly restimulate the splenocytes of the RT + Flt3L cohort in vitro. The restimulated splenocytes demonstrated increased cytotoxic response, lymphocytic proliferation and elevated levels of Th type I cytokines (IL-2, IL-12, IFN-gamma and TNF-alpha). The combination therapy of RT + Flt3L induced a long-term protective immunity in the disease-free animals. The protective effect was further enhanced when the disease-free animals were vaccinated with irradiated tumor cells. The vaccinated animals had significantly greater protection compared to the nonvaccinated group against subsequent challenge with 3LL cells. Taken together, these results indicate that the release of tumor antigens by irradiated dying tumors and concomitant administration of Flt3L was able to facilitate the generation of a tumor-specific long-term immune response against a poorly immunogenic tumor. This effect was further boosted by vaccination with irradiated tumor cells.
Adjuvants, Immunologic↗
Inhibition of human neuroblastoma cell growth by CAY10404, a highly selective Cox-2 inhibitor.
Neuroblastomas constitute about 10% of childhood cancers and are responsible for 15% of pediatric cancer mortality. We evaluated the efficacy and the mechanism of cell death induced by CAY10404, a selective cyclooxygenase-2 (Cox-2) inhibitor in four human neuroblastoma cell lines (SH-EP, SH-SY5Y, SK-N-MC and MSN). Treatment with CAY10404 in the range of 15-115 microM revealed a dose-dependent decrease in cell number and an average IC50 (inhibitory concentration 50%) of 60 microM. About 20-30% of the cells were terminal deoxynucleotidyltransferase-mediated UTP nick-end-labeling (TUNEL) positive 48 h after treatment. Western blot analysis of CAY10404-treated cells showed poly(ADP-ribose) polymerase (PARP) cleavage and cleaved caspase-3 signifying caspase activity and apoptotic cell death. Inhibitor-of-apoptosis proteins including X-linked inhibitor-of-apoptosis protein (XIAP) and survivin did not change significantly after CAY10404 treatment. Fluorescence activated cell sorter (FACS) analysis performed in two different cell lines 48 h following CAY10404 treatment showed a reduction in the number of cells in the G1 phase of the cell cycle and an increase in the number of cells in the G2 phase. When radioresistant SH-EP cells were treated with CAY10404, a 49% decrease in cell viability was observed relative to DMSO-treated cells; pretreatment with CAY10404 followed by ortho-voltage irradiation further enhanced cell death (58%) suggesting radiosensitization by CAY10404.
Apoptosis↗
Extended-field radiotherapy and high-dose-rate brachytherapy in carcinoma of the uterine cervix: clinical experience with and without concomitant chemotherapy.
BACKGROUND: It has long been recognized that many patients with locally advanced carcinoma of the cervix harbor occult paraaortic metastases. A randomized study demonstrated that elective paraaortic irradiation improved survival and reduced distant metastases. More recently, concomitant chemotherapy with pelvic irradiation has improved survival among patients with locally advanced carcinoma of the cervix. This has led to a reexamination of the role of extended-field irradiation. An important issue is the toxicity of concomitant chemotherapy and extended-field radiotherapy. The authors report a retrospective analysis of their experience with extended-field radiotherapy and high-dose-rate brachytherapy with or without concomitant chemotherapy. METHODS: The authors treated 54 women with biopsy-confirmed carcinoma of the cervix using extended-field radiotherapy and high-dose-rate brachytherapy with or without concomitant chemotherapy. The histology was squamous cell carcinoma in 49 patients (91%) and nonsquamous cell carcinoma in 5 patients (9%). The median size of the primary tumor was 7 cm (range, 3-10 cm). Each patient received 45 grays (Gy) of external beam radiotherapy to the pelvis and the paraaortic region, followed by a parametrial boost (9 Gy) in the patients with disease extension to the parametrium or the pelvic side wall(s). Each patient also underwent two applications of high-dose-rate brachytherapy, 1 week apart. The median dose delivered to Point A from each application was 9 Gy. Forty-four of the 54 patients (81%) received concomitant chemotherapy (cisplatin, 20 mg/m(2)/day for 5 days) during the first and the fourth weeks of external beam radiotherapy, and once after the second high-dose rate application. Chemotherapy was not assigned randomly. RESULTS: One of the 10 patients (10%) treated without chemotherapy experienced acute toxicity, whereas 41 of 44 patients (93%) who received chemotherapy suffered from acute toxicity, including hematologic toxicity, gastrointestinal toxicity, and deep venous thrombosis. During a median follow-up period of 28 months (range, 12-70 months), 6 of the 54 patients have died (11%). The actuarial rate of local control at 3 years is 100% among the patients treated without chemotherapy, compared with 85% among those receiving chemotherapy. No one failed in the paraaortic region. The actuarial rates of freedom from distant metastases are 90% and 95% among the patients treated without and with chemotherapy, respectively. The actuarial incidence of late toxicity is 10% among the patients treated without chemotherapy and 6% among those receiving chemotherapy. CONCLUSIONS: The regimen of extended-field radiotherapy with concomitant cisplatin and high-dose-rate brachytherapy produced substantial acute toxicity, but its long-term toxicity is low and the preliminary tumor control excellent, albeit with limited follow-up. Only prospective, randomized trials can evaluate whether these results are truly better than those of pelvic radiotherapy with concomitant chemotherapy, or those of other regimens of extended-field radiotherapy with concomitant chemotherapy. Cancer 2003;97:1781-8.
Adult↗
A candidate metastasis-associated DNA marker for ductal mammary carcinoma.
BACKGROUND: Molecular genetic markers to identify the 13% lymph node-negative mammary carcinomas that are prone to develop metastases would clearly be of considerable value in indicating those cases in need of early aggressive therapy. METHODS: Representational difference analysis was used in an attempt to identify genetic alterations related to breast cancer metastasis by comparing genomic DNA from microdissected normal cells and from metastatic cells of ductal breast carcinoma patients. RESULTS: Representational difference analysis products yielded 10 unique metastasis-associated DNA sequences (MADS), i.e. products apparently lost in metastatic cell DNA. Of these sequences, MADS-IX was found to be lost in the transition from primary to metastasis in two out of five ductal breast carcinoma cases. This sequence was localized on chromosome 10q21 by radiation hybrid mapping and fluorescence in situ hybridization. The PTEN gene, which is also located on chromosome 10q, was detected to be present by PCR in all five cases. On the contrary, a breast carcinoma cell line, HCC-1937, which has homozygous loss of a region encompassing the PTEN gene, showed the presence of MADS-IX. PCR screening of three additional breast carcinoma cell lines with known losses in specific chromosomal regions also showed the presence of MADS-IX. CONCLUSION: These data suggest that MADS-IX possibly is part of a novel candidate metastasis-associated gene located close to the PTEN gene on chromosome 10q. The first set of PCR screening in five patient samples indicates that it could be used as a molecular marker for ductal mammary metastasis.
Breast Neoplasms↗
Cancers of the head and neck region in developing countries.
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Developing Countries↗
Microsatellite dinucleotide (T-G) repeat: a candidate DNA marker for breast metastasis.
A dinucleotide (T-G) repeat sequence was isolated by comparing DNA from metastatic lymph node and matched normal breast samples from a ductal mammary carcinoma patient using representational difference analysis (RDA) method. Our present study used this metastasis associated DNA sequence (MADS) as a diagnostic probe to screen five patient samples by slot blot method. A new approach to isolate single cells by microdissection, namely single cell microdissection (SCM) was developed to obtain homogeneous population of tumor cells (approximately 1000) from matched primary tumors and corresponding positive lymph nodes of five patients. We isolated DNA from these homogeneous tumor cells and used for the RDA and DNA slot blot experiments. The screening of patient samples showed loss of this MADS in the transition from primary to metastasis in four out of five cases (80%) suggesting its possible role in breast metastasis.
Biomarkers, Tumor↗
Predictive value of linear-quadratic model in the treatment of cervical cancer using high-dose-rate brachytherapy.
PURPOSE: To determine whether a dose-response relationship exists between the biologic effective dose (BED) at Point A and the bladder and rectum and the clinical outcomes in our experience with external beam radiotherapy (EBRT) and high-dose-rate brachytherapy in the treatment of cervical carcinoma. METHODS AND MATERIALS: This was a retrospective study. A total of 49 patients with cervical cancer were treated with a combination of EBRT (median 45 Gy, range 41.4-50.4) and high-dose-rate brachytherapy (median 18 Gy; range 18-19, in two fractions). Twenty-three patients received concomitant cisplatin-based chemotherapy. The cumulative BEDs were calculated at Point A (BED10) and at bladder and rectal reference points (BED3) using the linear-quadratic equation. The BED10 values, after incorporating a time factor (BED10tf) in the formula, were also calculated. RESULTS: In patients treated with RT alone, the local failure rate was 10% (1 of 10) and 19% (3 of 16) in patients receiving a BED10 >89 Gy10 or <89 Gy10 to Point A, respectively (p = 0.2). The corresponding local failure rates were 20% (3 of 15) and 0% (0 of 8) in patients treated with concomitant chemotherapy (p = 0.3). In patients treated with RT alone, the local failure rate was 7.7% (1 of 13) and 23% (3 of 13) in patients with a BED10tf >64 Gy10 or <64 Gy10 (p = 0.1), respectively. The median BED3 values at the rectal and bladder point was 95.5 Gy3 and 103.6 Gy3, respectively. Only 1 case of Grade 2 late rectal toxicity (2%) and no late bladder toxicity occurred. CONCLUSION: In patients treated with RT alone, a BED10 >89 Gy and a BED10tf >64 Gy indicated a trend toward a better local control rate. This difference was not observed in patients receiving chemotherapy. A BED3 <100 Gy3 was associated with negligible late toxicity. Although the BED10 in our study was about 10-15 Gy10 less than that in the published data, the 4-year local control rate of 80% and 83% and disease-free survival rate of 75% and 70% with and without chemotherapy, respectively, compare well with the rates in other studies in the literature.
Adenocarcinoma↗
Two fractions of high-dose-rate brachytherapy in the management of cervix cancer: clinical experience with and without chemotherapy.
PURPOSE: In recent years, high-dose-rate brachytherapy has become popular in the management of carcinoma of the uterine cervix, because it eliminates many of the problems associated with low-dose-rate brachytherapy. However, the optimum time-dose-fractionation remains controversial. Two fractions of high-dose-rate brachytherapy are convenient for patients, but most radiation oncologists in the United States do not use them, because of fear that they could lead to excessive rectal or bladder toxicity. Here we present our experience, which suggests that a two-fraction regimen is indeed safe and effective. METHODS: We treated 49 patients with Stages I-III biopsy-proven carcinoma of the uterine cervix by external beam radiation therapy (EBRT), plus two fractions of high-dose-rate brachytherapy. The histology was squamous cell carcinoma in 43 patients (88%) and nonsquamous in 6 (12%). The median size of the primary tumor was 6 cm (range: 3-10 cm). Each patient received EBRT to the pelvis to a median dose of 45 Gy (range: 41.4-50.4 Gy), followed by a parametrial boost when indicated. Thirty patients (61%) also received irradiation to the para-aortic lymph nodes to a dose of 45 Gy. After EBRT, each patient underwent two applications of high-dose-rate brachytherapy, 1 week apart. The dose delivered to point A was 9 Gy per application for 49 applications (50%) and 9.4 Gy for 43 applications (44%), and it varied from 7 to 11 Gy for the rest (6%). The total dose to the rectum from both high-dose-rate brachytherapy applications ranged from 4.7 to 11.7 Gy (median: 7.1 Gy), and the total dose to the bladder from 3.8 to 15.5 Gy (median: 10.5 Gy). Twenty-five of the 49 patients (51%) received concomitant chemotherapy (cisplatin 20 mg/m(2)/day for 5 days) during the first and fourth weeks of EBRT and once after the second high-dose-rate brachytherapy application. Chemotherapy was not assigned in a randomized fashion. The use of chemotherapy increased during the time period spanned by this study as increasing evidence supporting the use of chemotherapy began to appear. RESULTS: The observed survival rates after 2, 3, and 5 years were 83%, 78%, and 78%, respectively. The surviving patients have been followed up for a median of 3 years (range: 2-6 years). Eight of the 49 patients suffered local failures. Among patients treated without chemotherapy, the 3-year local control rate was 77%; it was 88% among those receiving chemotherapy. There have been no regional failures. Four patients developed distant metastases. At 3 years, 91% of the patients in each group were free of distant metastases. Ten of the 49 patients (20%) suffered Grade 3 acute toxicity; 11 (22%) had Grade 4. Among the 24 patients treated without chemotherapy, only 1 (4%) suffered Grade 3 toxicity. Among the 25 patients receiving chemotherapy, in contrast, 8 (32%) suffered Grade 3 and 12 (48%) Grade 4 acute toxicity. Only 2 patients suffered late toxicity: One suffered Grade 2 and the other Grade 3 late toxicity. The actuarial risk of Grade 2 or worse late toxicity was 5%, with or without chemotherapy. CONCLUSIONS: Our experience suggests that two fractions of high-dose-rate brachytherapy are safe and effective in the management of cervix cancer, even in conjunction with concomitant cisplatin. The fears that the use of two fractions would lead to excessive rectal or bladder toxicity proved unfounded. Guidelines for ensuring a low complication rate are discussed.
Adult↗
Phase I clinical trial of parenteral hydroxyurea in combination with pelvic and para-aortic external radiation and brachytherapy for patients with advanced squamous cell cancer of the uterine cervix.
PURPOSE: Oral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix. METHODS: This Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity. RESULTS: At dose level 1 (0.25 mg/m(2)/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m(2)/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m(2)/min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU. CONCLUSIONS: The maximal tolerated dose of parenteral HU was 0.375 mg/m(2)/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.
Aged↗
Normal hepatocytes correct serum bilirubin after repopulation of Gunn rat liver subjected to irradiation/partial resection.
The treatment of inherited metabolic liver diseases by hepatocyte transplantation (HT) would be greatly facilitated if the transplanted normal hepatocytes could be induced to proliferate preferentially over the host liver cells. We hypothesized that preparative hepatic irradiation (HIR) should inhibit host hepatocyte proliferation in response to partial hepatectomy (PH). Normal nonirradiated hepatocytes transplanted in this setting should have a selective growth advantage over the host liver cells and should progressively repopulate the liver. To test this hypothesis, we transplanted 5 million hepatocytes from normal Wistar-Roman High Avoidance (RHA) rats into the livers of congeneic bilirubin-uridine 5'-diphosphoglucuronate glucuronosyltransferase (UGT1A1)-deficient jaundiced Gunn rats by intrasplenic injection after one of the following treatments: (1) 68% PH, (2) HIR (50 Gy), or (3) HIR + PH. In rats receiving either PH or HIR alone before HT, serum bilirubin concentrations declined by 25% to 30% in 28 weeks. In contrast, serum bilirubin levels were normalized completely in rats receiving HIR + PH before HT. Massive repopulation of the Gunn rat liver by the UGT1A1-positive Wistar-RHA hepatocytes was shown by UGT1A1 enzyme assay, immunoblot analysis, and immunohistochemical staining of the recipient liver. High-performance liquid chromatography analysis of the bile collected from Gunn rats 5 months after PH, HIR, and HT showed normalization of the pigment profile, with bilirubin diglucuronide and monoglucuronide as the predominant pigments. In conclusion, a preparative regimen of HIR + PH results in massive repopulation of the liver with functionally normal transplanted hepatocytes, resulting in complete correction of a metabolic deficiency. Noninvasive strategies to replace PH for providing proliferative stimuli to the transplanted cells should make this regimen valuable in augmenting the effects of HT for the treatment of liver diseases.
Animals↗
Intensity-modulated radiation therapy for head and neck cancer: emphasis on the selection and delineation of the targets.
The head and neck contain many critical, noninvolved structures in close vicinity to the targets. The tightly conformal doses produced by intensity-modulated radiation therapy (IMRT), and the lack of internal organ motion in the head and neck, provide the potential for organ sparing and improved tumor irradiation. Many studies of treatment planning for head and neck cancer have demonstrated the dosimetric superiority of IMRT over conventional techniques in these respects. The initial results of clinical studies demonstrate reduced xerostomia. They suggest an improvement in tumor control, which needs to be verified in larger studies and longer follow-up. Critical issues for successful outcome of head and neck IMRT are accurate selection of the neck lymph nodes that require adjuvant treatment, and accurate delineation on the planning computed tomography (CT) of the lymph-node bearing areas and subclinical disease adjoining the gross tumor. This review emphasizes these topics and provides some guidelines.
Head and Neck Neoplasms↗
7-Hydroxystaurosporine (UCN-01) preferentially sensitizes cells with a disrupted TP53 to gamma radiation in lung cancer cell lines.
Mutations in TP53 occur in more than 50% of the lung cancer patients and are associated with an increased resistance to chemotherapy and radiotherapy. The human lung adenocarcinoma cell lines A549 and LXSN contain a wild-type TP53 and were growth arrested at both the G(1)- and G(2)-phase checkpoints after irradiation. However, a TP53-disrupted cell line, E6, was arrested only at the G(2)-phase checkpoint. UCN-01 (7-hydroxystaurosporine), a CHEK1 inhibitor that abrogates the G(2) block, has been reported to enhance radiation toxicity in human lymphoma and colon cancer cell lines. In this study, UCN-01 preferentially enhanced the radiosensitivity of the TP53-disrupted E6 cells compared to the TP53 wild-type cells. This effect was more pronounced in cells synchronized in early G(1) phase, where the E6 cells showed a higher resistance to radiation in the absence of drug. These results indicate that the combination of UCN-01 and radiation can more specifically target resistant TP53 mutated cancer cells and spare TP53 wild-type normal cells.
Adenocarcinoma↗
Breast cancer in limited-resource countries: treatment and allocation of resources.
Treating breast cancer under the constraints of significantly limited health care resources poses unique challenges that are not well addressed by existing guidelines. We present evidence-based guidelines for systematically prioritizing cancer therapies across the entire spectrum of resource levels. After consideration of factors affecting the value of a given breast cancer therapy (contribution to overall survival, disease-free survival, quality of life, and cost), we assigned each therapy to one of four incremental levels--basic, limited, enhanced, or maximal--that together map out a sequential and flexible approach for planning, establishing, and expanding breast cancer treatment services. For stage I disease, basic-level therapies are modified radical mastectomy and endocrine therapy with ovarian ablation or tamoxifen; therapies added at the limited level are breast-conserving therapy, radiation therapy, and standard-efficacy chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF], or doxorubicin and cyclophosphamide [AC], epirubicin and cyclophosphamide [EC], or 5-fluorouracil, doxorubicin, and cyclophosphamide [FAC]); at the enhanced level, taxane chemotherapy and endocrine therapy with aromatase inhibitors or luteinizing hormone-releasing hormone (LH-RH) agonists; and at the maximal level, reconstructive surgery, dose-dense chemotherapy, and growth factors. For stage II disease, the therapy allocation is the same, with the exception that standard-efficacy chemotherapy is a basic-level therapy. For locally advanced breast cancer, basic-level therapies are modified radical mastectomy, neoadjuvant chemotherapy (CMF, AC, or FAC), and endocrine therapy with ovarian ablation or tamoxifen; the therapy added at the limited level is postmastectomy radiation therapy; at the enhanced level, breast-conserving therapy, breast-conserving whole-breast radiation therapy, taxane chemotherapy, and endocrine therapy with aromatase inhibitors or LH-RH agonists; and at the maximal level, reconstructive surgery and dose-dense chemotherapy and growth factors. For metastatic or recurrent disease, basic-level therapies are total mastectomy for ipsilateral in-breast recurrence, endocrine therapy with ovarian ablation or tamoxifen, and analgesics; therapies added at the limited level are radiation therapy and CMF or anthracycline chemotherapy; at the enhanced level, chemotherapy with taxanes, capecitabine, or trastuzumab, endocrine therapy with aromatase inhibitors, and bisphosphonates; and at the maximal level, chemotherapy with vinorelbine, gemcitabine, or carboplatin, growth factors, and endocrine therapy with fulvestrant. Compared with the treatment of early breast cancer, the treatment of advanced breast cancer is more resource intensive and generally has poorer outcomes, highlighting the potential benefit of earlier detection and diagnosis, both in terms of conserving scarce resources and in terms of reducing morbidity and mortality. Use of the scheme outlined here should help ministers of health, policymakers, administrators, and institutions in limited-resource settings plan, establish, and gradually expand breast cancer treatment services for their populations.
Aromatase Inhibitors↗
Radiotherapy for breast cancer in countries with limited resources: program implementation and evidence-based recommendations.
Radiotherapy is an essential part of the multimodality treatment of breast cancer. Applying safe and effective treatment requires appropriate facilities, staff, and equipment, as well as support systems, initiation of treatment without undue delay, geographic accessibility, and completion of radiotherapy without undue prolongation of the overall treatment time. Radiotherapy can be delivered with a cobalt-60 unit or a linear accelerator (linac). In early stage breast cancer, radiotherapy is an integral part of breast-conserving treatment. Standard treatment includes irradiation of the entire breast for several weeks, followed by a boost to the tumor bed in women age 50 years or younger or those with close surgical margins. Mastectomy is an appropriate treatment for many patients. Postmastectomy irradiation with proper techniques substantially decreases local recurrences and improves survival in patients with positive axillary lymph nodes. It is also considered for patients with negative nodes if they have multiple adverse features such as a primary tumor larger than 2 cm, unsatisfactory surgical margins, and lymphovascular invasion. Many patients present with locally advanced or inoperable breast cancer. Their initial treatment is by systemic therapy; after responding to systemic therapy, most will require a modified radical mastectomy followed by radiotherapy. For those patients in whom mastectomy is still not possible after initial systemic therapy, breast and regional irradiation is given, followed whenever possible by mastectomy. For patients with distant metastases, irradiation may provide relief of symptoms such as pain, bleeding, ulceration, and lymphedema. A single fraction of irradiation can effectively relieve pain from bone metastases. Radiotherapy is also effective in the palliation of symptoms secondary to metastases in the brain, lungs, and other sites. Radiotherapy is important in the treatment of women with breast cancer of all stages. In developing countries, it is required for almost all women with the disease and should therefore be available.
Breast Neoplasms↗