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Biomedical subjects

D Raghavan

Publications and source records attributed to D Raghavan.

At least 73 records · Page 4Linked to original sources
PubMed1992

Combination chemotherapy with cisplatin, vindesine and mitomycin-C for advanced, inoperable non-small-cell lung cancer.

OBJECTIVES: To assess the activity of chemotherapy with cisplatin, vindesine and mitomycin-C (PVM) in advanced non-small-cell lung cancer (NSCLC) and to test the feasibility of preemptive therapy with PVM. DESIGN AND SETTING: A phase II clinical trial of PVM in patients with NSCLC treated at the Royal Prince Alfred Hospital between June 1987 and July 1990. PATIENTS: Forty-one patients with advanced, inoperable or recurrent NSCLC--22 women, 19 men, with a median age of 51 years. Thirteen patients had been treated previously with radiotherapy and/or surgery; 18 had extrathoracic metastases. Four patients previously deemed inoperable were treated preemptively with PVM before proceeding to radical surgery. INTERVENTIONS: Cisplatin 100 mg/m2, vindesine 5 mg and mitomycin-C 8 mg/m2, all given intravenously on Day 1, with vigorous hydration and antiemetic therapy. Cycles were repeated every four weeks. MAIN OUTCOME MEASURES: Objective tumour response to treatment, patient survival time, time to treatment failure, and treatment toxicity. RESULTS: There was one complete tumour response to PVM and 15 partial responses; 14 patients had stable disease and nine had progressive disease--yielding an objective response rate (complete plus partial responses) of 39% (16/41; 95% confidence interval [CI], 24%-56%). Responses were documented in all histological subgroups, in both locally advanced and disseminated disease, and in recurrent disease. Median survival of the group was six months (95% CI, 5-10 months; range, 0.5-19+ months), and is unchanged by exclusion of the four patients treated before surgery. Seven of the 41 patients (17%) survived 12 months or longer. Median time to treatment failure in patients who had an objective response was six months (95% CI, 5-10 months). Grade 3 or 4 nausea and vomiting occurred in 21 patients (51%). Haematological, renal and neurological toxicity were not major problems; there were no deaths from treatment toxicity. CONCLUSION: PVM is an active regimen in advanced NSCLC and can produce durable remissions. The potential palliative effects of PVM in incurable disease must be weighed against the risk of subjective toxicity.

Adult↗
PubMed1992

Detection of a rare point mutation in Ki-ras of a human bladder cancer xenograft by polymerase chain reaction and direct sequencing.

This paper represents the first report of a codon 59 mutation in Ki-ras from a spontaneous human transitional cell carcinoma of the bladder. Point mutations have the potential to activate the ras genes if they occur in critical coding regions. These include the sequences of codons 12, 13, 59, 61 and 63. Mutations in codons 12, 13 and 61 have been reported in a wide variety of human cancers, including transitional cell carcinoma of the bladder. However mutations in codon 59 have been reported only in retroviral Ki-ras and as a result of in vitro mutagenesis experiments. We have used the polymerase chain reaction and direct sequencing to detect mutations of Ki-ras, and allele-specific restriction analysis to detect mutations of N-ras in xenografts and continuous cell lines established from bladder cancer biopsies of ten different patients as well as in direct biopsy specimens from five human bladder tumours. For studies of Ki-ras, a 139 bp fragment which spanned the critical codons 12 and 13 and a 128 bp fragment that spanned the sequences of codon 59, 61 and 63 were enzymatically amplified and then sequenced. No N-ras mutations were detected. A heterozygous mutation of Ki-ras at codon 59 GCA----G/ACA was detected in one line. This mutation is being expressed and appears stable as it was detected over several xenograft passages and was present in paraffin-embedded tissue from the primary tumour of the patient. The biological significance of the mutation in bladder cancer is currently under study.

Animals↗
PubMed1992

Phase II clinical trial of recombinant alpha-2 interferon for biopsy-proven metastatic or recurrent renal carcinoma.

Twenty patients with histologically confirmed metastatic or recurrent renal carcinoma were treated in a phase II study with alpha-interferon (2-5 x 10(6) U/m2 subcutaneously, 3 times a week). Nineteen patients had multiple sites of disease and 18 had previously undergone nephrectomy; 9 had an ECOG performance status of 0.1, and 11 had a performance status of 2-3. There was one partial response, yielding an overall response rate of 5%. Treatment was well tolerated, although 7 patients developed influenza-like symptoms, and in 2 cases this was sufficiently severe for the patients to request cessation of treatment. As a single agent at this dose schedule, alpha-interferon has minimal activity in the treatment of renal carcinoma and cannot be recommended as standard therapy. The difference in outcome between this and some published series may reflect the stringent requirement for histological proof of the presence of metastases.

Adult↗
PubMed1992

Spinal cord compression in prostate cancer. A 10-year experience.

Of 478 patients treated at a single institution for prostate cancer, 29 developed spinal cord or cauda equina compression. In 5 patients, spinal cord compression was the first evidence of malignancy. Clinical features were predominantly pain, weakness, sensory and sphincter disturbance. The median duration of symptoms was 2 weeks, although the diagnosis was made rapidly at presentation. Clinical diagnosis correlated well with myelographic findings. Only 1 patient suffered neurological deterioration as a consequence of myelography. The functional outcome was dependent on the ability to walk prior to treatment. The median survival in those who were bedridden following treatment was 6 weeks (range 3.5-13) and 21 weeks (range 7-110+) in those who were ambulant following therapy.

Cauda Equina↗
PubMed1992

Initial combination chemotherapy with cisplatin, methotrexate and vinblastine in locally advanced transitional cell carcinoma--response rate and pitfalls. MRC Subgroup in Advanced Bladder Cancer (on behalf of the MRC Urological Working Party).

A total of 51 patients with locally advanced transitional cell carcinoma of the bladder were entered into a phase II study to evaluate the effect of initial cisplatin (100 mg/m2, Day 2) combined with methotrexate (30 mg/m2, Days 1 and 8) and vinblastine (4 mg/m2, Days 1 and 8). Of 44 evaluable patients, 25 (57%) achieved an objective response of their primary bladder tumour (complete response (CR): 4 patients; partial response (PR): 21 patients); 30 of the 36 patients with micturition disturbances obtained relief. Toxicity was acceptable, but dose modifications due to haematological or renal toxicity were required in 153 of the 690 drug courses. Non-protocol dose modifications were performed 45 times. The experience gained in this trial emphasises the need for improved co-operation between urologists, radiologists and clinical oncologists in such multicentre phase II studies. Difficulties were observed in adhering to dose modification rules, assessing pre-treatment tumour size (due to variation in quality of measure and in timing relative to initial transurethral resection (TUR)) and defining response to chemotherapy (due to failure to perform mandatory investigations at the right time). This study also illustrates that the accepted criteria for assessing response in the primary bladder tumour are difficult to apply in practice and that the results of any study using this indicator lesion require caution in their interpretation.

Aged↗
PubMed1992

A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.

PURPOSE: A prospective randomized trial was performed to determine if the addition of methotrexate, vinblastine, and doxorubicin to cisplatin (M-VAC) imparted a response rate or a survival advantage over single-agent cisplatin in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: From October 1984 through May 1989, 269 patients with advanced urothelial carcinoma were entered onto this international intergroup trial and randomized to receive intravenous (IV) cisplatin (70 mg/m2) alone or with methotrexate (30 mg/m2 on days 1, 15, 22), vinblastine (3 mg/m2 on days 2, 15, 22) plus doxorubicin (30 mg/m2 on day 2). Cycles were repeated every 28 days until tumor progression or a maximum of six cycles. There were 246 fully assessable patients of whom 126 were randomized to cisplatin alone and 120 were randomized to the M-VAC regimen. RESULTS: As expected, the M-VAC regimen was associated with a greater toxicity, especially leukopenia, mucositis, granulocytopenic fever, and drug-related mortality. Response rates were superior for the M-VAC regimen compared with single-agent cisplatin (39% v 12%; P less than .0001). Similarly, the progression-free survival (10.0 v 4.3 months) and overall survival (12.5 v 8.2 months) were significantly greater for the combined therapy arm. CONCLUSION: Although a more toxic regimen, we found M-VAC to be superior to single-agent cisplatin with respect to response rate, duration of remission, and overall survival in patients with advanced urothelial carcinoma.

Adult↗
PubMed1992

Hypercholesterolemia after chemotherapy for testis cancer.

PURPOSE: The study was designed to determine prospectively the prevalence of fasting serum lipid abnormalities in patients who were treated with cisplatin-based chemotherapy for germ cell tumors. We unexpectedly had demonstrated hypercholesterolemia in 20 of 30 nonfasting patients in a prior study of long-term toxicity of chemotherapy for germ cell tumors. The present study was designed to explore this phenomenon further. PATIENTS AND METHODS: Seventeen unselected patients with biopsy-proven germ cell tumors, who underwent cisplatin-based chemotherapy and who had no prior history of cardiac disease nor known hypercholesterolemia, were studied. In addition to the standard staging tests, blood was drawn for a pretreatment fasting lipid screen, which included cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoproteins A1, B, and (a). Repeat samples were drawn 24 hours after the administration of cisplatin and at intervals of 6 to 24 months after the completion of treatment. RESULTS: Seven of 17 patients (41%) had higher than desirable levels of total serum cholesterol and low-density lipoprotein cholesterol. Two of them had normal levels before treatment, four had preexisting hypercholesterolemia that increased further, and one patient had an elevated pretreatment level that did not alter. Absolute increases in serum cholesterol were noted in 14 of 17 patients. No consistent patterns of change beyond the reference ranges were found for other serum lipids. CONCLUSIONS: We have confirmed our initial observation that serum cholesterol increases in patients who received cisplatin-containing chemotherapy regimens for germ cell tumors. Further studies will be necessary to define whether other lipid abnormalities occur and the biologic significance of these findings.

Adolescent↗
PubMed1992

Toxicity of treatment of germ cell tumors.

Great progress has been made in the management of testicular cancer in the past 15 years, with the attainment of the expectation of cure for most patients. In all of the efforts to reduce the toxicity of treatment, one governing principle should be retained: we must not reduce the chance of successful treatment in our attempts to avoid toxicity. Continued progress will only be achieved by the meticulous implementation of carefully structured trials with appropriate follow-up schedules. If future studies are effected in an unstructured and uncontrolled fashion, physicians could become the most common cause of death of patients with testicular cancer.

Antineoplastic Agents↗
PubMed1992

Carboplatin-containing regimens for small cell lung cancer: implications for management in the elderly.

The efficacy and toxicity of two regimens based on etoposide/carboplatin with or without cyclophosphamide/vincristine in the management of small cell lung cancer (SCLC) were assessed by the Australian Lung Cancer Study Group. Response rates of 77% and 85% were noted for the two- and four-drug regimens, respectively, among patients with limited disease (LD). Response rates among patients with extensive disease (ED) were 58% and 79%, respectively. The profiles of nonhematologic toxicity were modest; myelosuppression was dose-limiting when colony-stimulating factors were not used. Twenty-six patients (14%) were older than 70 years of age. Although hematologic toxicity was more severe in the elderly group, there was no significant difference in nonhematologic toxicity, response rate, or overall survival between the geriatric and younger groups. When LD only was considered, 33% of those younger than 70 were alive at 2 years; no patients aged 70 years or older with LD were alive beyond 2 years. In patients with ED, there was no age-related difference in survival. Cytotoxic regimens based on etoposide/carboplatin constitute useful treatment for SCLC, with high response rates and manageable toxicity, irrespective of patient age.

Adult↗
PubMed1992

Management of advanced bladder cancer in the elderly.

Patients over the age of 70 years will become an increasingly important component of uro-oncologic practice. Although few published studies have specifically addressed this population, it is clear that the elderly can expect outcomes similar to younger patients in the management of advanced bladder cancer provided care is taken in planning. Of particular importance is an understanding of the pathophysiology of aging, of the possible implications of the causative factors for bladder cancer, and of the potential impact of advanced age on the biology of urothelial malignancy. Future studies should specifically address the problems of older patients with this malignancy to ensure the optimal possible outcome and definition of the most appropriate balance of toxicity and efficacy.

Aged↗
PubMed1991

Neoplastic venous involvement and pulmonary embolism in patients with germ cell tumors.

Inferior vena caval (IVC) obstruction and pulmonary embolism (PE) were observed in three patients with untreated germ cell tumors. A review of the literature revealed nine similar cases. The clinical presentation and specific management of IVC occlusion and PE may delay or interfere with definitive treatment of the tumor. The occurrence of this complication before starting cytotoxic chemotherapy has implications with regard to other types of vascular disease observed in patients with these tumors.

Adolescent↗
PubMed1991

Growth and metastasis of human bladder cancer xenografts in the bladder of nude rats. A model for intravesical radioimmunotherapy.

A potentially useful therapeutic approach to the treatment of human bladder cancer is intravesical therapy with radiolabelled monoclonal antibodies (MAbs). We have established an animal model to study this approach. Inoculation of cloned 2B8 cells derived from the human bladder cancer cell line, UCRU-BL-17, into the bladder wall of nude rats pre-irradiated with 900 rads, resulted in local tumour growth in 39/40 (97.5%) animals, with invasion or metastases to distant organs in 25% of cases. Both the bladder tumours and the metastases were morphologically similar to the original biopsy sample from which the cell line, UCRU-BL-17, was established. The cells were of human origin, as shown by expression of HLA antigens, Alu probing, and cytogenetic analysis. Preliminary studies indicated that i.p. injection of anti-human bladder cancer monoclonal antibody (MAb), BLCA-38, radiolabelled with either iodine 131 or samarium 153 (153Sm), resulted in tumour localisation, with tumour-to-blood ratios of 5.04 (131I), and 4.3 and 3.1 (153Sm) respectively. We now aim to examine the efficacy of the intravesical route for radioimmunotherapy in the nude rat model. This model will also serve for preclinical studies on the efficacy of systemically injected radioimmunoconjugates for control of metastatic growth.

Aged↗
PubMed1991

Epirubicin: a phase II study in recurrent small-cell lung cancer.

Epirubicin (4'-epidoxorubicin), an analogue of doxorubicin (Adriamycin), has established activity in the treatment of small-cell lung cancer (SCLC) when used at doses of 75 to 120 mg/m2 in previously untreated patients. We completed a phase II study of epirubicin (85 mg/m2 given intravenously at 3-week intervals) in 20 patients with recurrent SCLC, all of whom had received prior combination chemotherapy. Of 19 patients who were assessable for response, 2 achieved a complete response and 2 a partial response, for an overall response rate of 4/19 (21%); 95% confidence interval, 8%-43%). Myelosuppression and alopecia were the most frequent toxicities; epirubicin was otherwise well tolerated, with other toxicities such as nausea and vomiting being infrequent or mild. Epirubicin at a dose of 85 mg/m2 exhibits modest single-agent activity in previously treated SCLC and is generally well tolerated. Given as a single agent or in combination with other well-tolerated drugs, epirubicin would be suitable in cases in which palliation of symptoms without undue toxicity is required in the management of previously treated SCLC.

Aged↗
PubMed1991

Retrospective review of chemotherapy for small cell lung cancer in the elderly: does the end justify the means?

Between 1978 and 1983, 72 patients aged 70 years or older (median 72, range 70-80) were treated for biopsy-proven, small cell lung cancer (SCLC). Intercurrent disorders were common, including ischaemic heart disease, peripheral vascular disease, chronic airflow limitation and second malignancies. 26 patients (36%) had limited extent of disease, and 46 (64%) had extensive disease. "Intensive" chemotherapy incorporating vincristine, cyclophosphamide and doxorubicin (OCA regimen) was administered to 32 patients [complete response (CR) + partial response (PR) = 84%]; less rigorous regimens (e.g. single agent chemotherapy, planned dose reductions, radiotherapy only) were used in 34 cases (CR + PR = 52%); and 6 received no active treatment. In the intensively treated group, there were 3 treatment-related deaths and 26 episodes of WHO grade 3-4 toxicity. In the less intensively treated group, there were no treatment-induced deaths and only 1 episode of severe toxicity. The overall median survival was 25 weeks (36 weeks for intensive treatment, 16 weeks with less intense treatment). For patients with limited disease only, the median survival in each group was 43 and 26 weeks, respectively. Intensive treatment for elderly patients with small cell lung cancer is associated with substantially increased toxicity and higher response rates than for gentle treatment, but without a major survival benefit.

Age Factors↗
PubMed1991

Keynote address: a critical assessment of trials of neoadjuvant (preemptive) chemotherapy for bladder cancer: lesson for future studies of combined modality treatment.

The 5-year survival of patients with invasive, clinically non-metastatic bladder cancer (Stages T2-4N2Mo) is less than 50%, whether treated by radical radiotherapy, radical cystectomy, or combinations of the two modalities. Cytotoxic regimens, incorporating single agents or combination protocols, produce objective response rates of 10-30 and 10-70%, respectively. Hence, it has been postulated that the use of cytotoxics before or with radiotherapy or surgery ("neoadjuvant", "preemptive", or "concurrent" chemotherapy) could improve the cure rate of invasive bladder cancer. Initial Phase I-II clinical trials have shown such approaches to be feasible, with mild to moderate toxicity. To date, few randomized trials that compare conventional treatment with these new approaches have been initiated or completed, with the majority of eligible patients being treated in increasingly complex Phase II studies. Accordingly, progress has been retarded, and after a decade of investigation, the true role of preemptive or concurrent chemotherapy for invasive bladder cancer is not known. Patients should be entered into well designed, randomized clinical trials in which new approaches to treatment are compared to standard therapy.

Clinical Trials as Topic↗
PubMed1991

Benign prostatic hyperplasia--video image analysis and its relationship to androgen and epidermal growth factor receptor expression.

Androgens are essential for the development and maintenance of the prostate. However, prostatic growth may be mediated by epidermal growth factor (EGF) and the expression of the EGF receptor (EGFR) may be influenced by the androgenic milieu. We have characterized the expression of cytosolic androgen receptor (ARc), nuclear salt extractable androgen receptor (ARn) and EGFR in 89 consecutive cases of benign prostatic hyperplasia, 84 of which were treated by transurethral prostatic resections. Image analysis morphometry was performed on the histological sections to determine the epithelial content of the gland. Our results indicate that there is a vast heterogeneity of receptor expression in benign prostatic hyperplasia. Expression of ARc ranged from zero to 1312 fmol/gm. tissue (mean +/- SD 265 +/- 290), ARn ranged from zero to 531 fmol/gm. tissue (mean +/- SD 145 +/- 98) and EGFR ranged from zero to 316 fmol/gm. tissue (mean +/- SD 121 +/- 76). A statistically significant association was found between expression of ARn and EGFR, and these were both significantly correlated with the epithelial content of the gland.

Cell Nucleus↗