Perioperative chemotherapy for invasive bladder cancer--what should we tell our patients?
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
D Raghavan
Publications and source records attributed to D Raghavan.
Systemic Therapy for Invasive Bladder Cancer.
BACKGROUND: Bladder cancer is one of the most common malignancies in Western society. In the United States, approximately 10,000 of these patients present with invasive disease, and more progress from superficial bladder cancer. METHODS: The authors review the literature on systemic treatment for both localized and metastatic bladder cancer, and they include their experience in defining approaches to various stages of disease. RESULTS: Cisplatin-based combination chemotherapy is the most effective systemic approach for advanced bladder cancers, although few patients are cured. Neoadjuvant, perspective, and adjuvant trials, as well as concurrent chemoradiation studies, are in progress to attempt to demonstrate better outcomes. CONCLUSIONS: The combination of systemic chemotherapy and definitive local therapy may have a useful role in the management of locally advanced bladder cancers, but optimal schedules and true survival benefit have not been established.
Journal Article↗
Management of hormone-resistant prostate cancer: an Australian trial.
The management of metastatic prostate cancer that has relapsed after initial hormonal manipulation remains a major problem, with the majority of patients dying within 12 months. Their clinical course is frequently characterized by progressive debilitation, pain, and other tumor-related symptoms. A phase II, non-randomized multicenter clinical trial was carried out in Australia in 1985-1986 to assess the efficacy and toxicity of mitoxantrone. Substantial anticancer activity was shown against hormone-refractory prostate cancer, indicated by reduction in tumor-related symptoms, improvement in quality of life indices, and a median survival of 10 months in patients with a heavy tumor burden. Although it is not possible to equate this nonrandomized series more fully with current experience since routine prostate-specific antigen measurement was not performed, the median survival of 10 months was equivalent to or better than the survival times reported from most other institutional reports of the time. Even more importantly, however, major improvements were noted in such subjective indices as reduction in pain, weight gain, and performance status. Toxicity was also acceptable, with the major side effect being asymptomatic myelosuppression.
Aged↗
Early phase studies with paclitaxel/low-dose carboplatin in patients with solid tumors.
In preparation for the design of phase II studies in lung cancer, low-dose carboplatin, fixed at a target area under the concentration-time curve (AUC) of 4.0 or 4.5 mg x min/mL, has been combined with escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in a series of studies to establish the maximum tolerated dose of the combination. In patients who had received prior chemotherapy, the maximum tolerated paclitaxel dose was 135 mg/m2 (carboplatin target AUC 4.0); the dose-limiting toxicity was febrile neutropenia. Without granulocyte colony-stimulating factor support in chemotherapy-naive patients (carboplatin target AUC 4.5), and with granulocyte colony-stimulating factor in chemotherapy-pretreated patients, the current paclitaxel dose is 290 mg/m2. The maximum tolerated dose has not been defined. In a study in which paclitaxel was given by 1-hour infusion with carboplatin (target AUC 4.5), a 205 mg/m2 dose was poorly tolerated. No evidence of pharmacokinetic interactions between paclitaxel and carboplatin was found. Twenty-one evaluable patients with lung cancer have been treated to date. There have been two partial responses, one minor response, and 10 patients with stable disease at paclitaxel doses of 100 to 270 mg/m2.
Antineoplastic Agents, Phytogenic↗
Novel bifunctional anthracycline and nitrosourea chemotherapy for human bladder cancer: analysis in a preclinical survival model.
A hybrid drug [N-2-chloroethylnitrosoureidodaunorubicin (AD312)] that combines structural and functional features of both anthracyclines and nitrosoureas was evaluated in a preclinical survival model of human bladder cancer. To measure the therapeutic activity of AD312, UCRU-BL13 transitional cell carcinoma cells were grown as xenografts in nude mice, and tumor growth rates were compared after i.v. administration of the drug at three dose levels. AD312 treatment at 45 and 60 mg/kg achieved 7-10-fold inhibition of tumor growth and increased host survival by 156 and 249%, respectively. Doses of 60 mg/kg showed optimal therapeutic efficacy, with sustained tumor growth inhibition, an over 2-fold increase in life span, and 40% of mice tumor free ("cured") at 120 days. Tumors were unresponsive to maximum tolerated doses of doxorubicin, a standard anthracycline used as a single agent and in combination therapies for bladder cancer. 1,3-Bis-[2-chloroethyl]-1-nitrosourea was used as a control for the apparently enhanced response of human tumors in murine hosts to nitrosoureas. 1, 3-Bis-[2-chloroethyl]-1-nitrosourea administered in three injections of 20 mg/kg did not cure mice but temporarily inhibited tumor growth by 70% and prolonged survival by 55%; its activity in this model suggests that it may be included in the repertoire of alkylating agents currently used for treatment of bladder cancers. AD312 showed increased antitumor activity with less toxicity than doxorubicin, and its bifunctional properties provide the opportunity for simultaneous treatment of individual cancer cells with two cytotoxic modalities as well as treatment of heterogeneous populations typical of bladder cancers. This novel cytotoxic drug cured doxorubicin-refractory disease and should be investigated for the clinical management of bladder cancer.
Animals↗
Neoadjuvant chemotherapy of stage III-A and B lung carcinoma using the PACCO regimen.
Previously, we reported an effective chemotherapeutic combination regimen for non-small cell lung carcinoma (NSCLC): cisplatinum, doxorubicin, cyclophosphamide, CCNU, and vincristine (PACCO). Forty-one patients with a diagnosis of NSCLC Stages III-A and III-B were entered into the protocol of neoadjuvant PACCO chemotherapy. Following two courses of chemotherapy, the patients were evaluated for surgical therapy. The overall response rate to the chemotherapy was 60%. Subsequently, 65% of the patients underwent surgical resection. The overall estimated median survival was 18 months. The survival of patients in III-A was 36 months and that of III-B was 18 months (95% confidence lower bounds for III-A: 8 months and for III-B: 13 months). There was one chemotherapy-related mortality but no surgical mortality. Neoadjuvant chemotherapy with PACCO regiment offers an alternative to chemoradiation therapy, without increasing the surgical mortality, and should be validated in a randomized clinical trial. For successful neoadjuvant chemotherapy of Stage III NSCLC, chemotherapy combination which would give a high response rate without significant side effects must be chosen.
Adult↗
Intracellular glutathione and cytotoxicity of platinum complexes.
Although there have been a number of reports correlating cellular GSH levels with cytotoxicity of platinum agents, none has examined the relationship between GSH concentrations and cytotoxicity. In this study, using a highly specific HPLC method for measuring GSH and expressing GSH as concentration and also per cell number, we evaluated the correlation between GSH levels and the cytotoxicity to five agents in ten human tumor cell lines. The five platinum agents included the platinum(II) complexes cisplatin, carboplatin and oxaliplatin and platinum(IV) complexes iproplatin and tetraplatin. The correlation between intracellular GSH concentration and cytotoxicity was highly significant only for iproplatin (P = 0.002) followed by tetraplatin, which demonstrated a trend toward statistical significance (P = 0.06). Cytotoxicity of the other platinum complexes showed no relation to GSH concentration, cisplatin itself showing a P-value of 0.09. In contrast, the GSH levels normalized to cell number showed a statistically significant correlation with the cytotoxicity of four of the five platinum agents, the exception being carboplatin; the strongest correlation observed was that for iproplatin and tetraplatin. Glutathione-S-transferase (GST) activity in these cell lines showed no correlation with cytotoxicity of any of the platinum complexes. Our results, from the analyses of both GSH concentration as well as GSH per cell number, suggest a significantly higher interaction between GSH and iproplatin compared with the other platinum agents. Moreover, our data suggest that relationships between cytotoxicity and GSH levels on a per-cell basis may not persist when differences in cell volume are taken into account.
Antineoplastic Agents↗
Phase I study of paclitaxel and carboplatin: implications for trials in head and neck cancer.
An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.
Adenocarcinoma↗
Adjuvant systemic therapy of prostate cancer.
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Antineoplastic Agents↗
Phase I and pharmacokinetic evaluation of floxuridine/leucovorin given on the Roswell Park weekly regimen.
A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (> 200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified.
Adult↗
Operation and intracavitary photodynamic therapy for malignant pleural mesothelioma: a phase II study.
From April 1991 to May 1993, 23 patients entered a phase II clinical study of surgical resection and adjuvant intracavitary photodynamic therapy for malignant pleural mesothelioma. Two days preoperatively, patients received an intravenous injection of 2 mg/kg of the photosensitizer Photofrin. Six patients underwent a pleuro-pneumonectomy, and 15 patients a pleurectomy, after which intracavitary photodynamic therapy was administered. A total light energy dose of 20 to 25 J/cm2 was given. In 2 patients the tumor was unresectable due to intrapericardial invasion. Postoperative complications were noted in more than 50 percent of patients; 2 patients died of postoperative complications. Postoperative survival was analyzed according to intraoperative staging proposed by the American Joint Committee for Cancer Staging, published in 1992. The overall estimated median survival is 12 months; that of stage III and IV patients is 7 months. Five patients with stage I and II diseases (who had grossly complete resection by pleurectomy) are alive, disease-free, for 11, 17, 18, 21, and 33 postoperative months. Intraoperative staging is important in carrying out further clinical studies of malignant pleural mesothelioma.
Adult↗
Karyotypic analysis of a heterogeneous human transitional cell carcinoma of the bladder.
The UCRU-BL-17 (BL-17) series of xenografts, tissue culture sublines, and cloned cell lines (Fig. 1) shows a range of heterogeneous growth characteristics both in vitro and in vivo (Table 1) and represents a model of human bladder cancer heterogeneity. Cytogenetic analysis was undertaken to determine if specific chromosome changes correlated with particular aspects of the heterogeneous phenotypes. The BL-17 sublines and cloned cell lines shared many common chromosome abnormalities. Indeed, the cloned cell lines showed nearly identical karyotypes despite their marked differences in growth characteristics. Karyotypic evolution with passage through the nude mice was apparent, however. This evolution occurred at the specific chromosome regions of 1p12, 3cen-3p21, and 6cen-6q21. Whether the heterogeneity of karyotype between the BL-17 cell lines resulted from the existence of multiple clones in the original patient tumor or from karyotypic instability through passage in nude mice is uncertain, but in either case the specificity of karyotypic evolution observed suggests that 1p12, 3cen-3p21, and 6cen-6q21 are hotspots for rearrangement in the BL-17 tumor. No specific correlations between chromosome abnormalities and biologic characteristics could be made, but several unique karyotypic features arose in the progression to two of the sublines, BL-17/23 alpha and BL-17/0/X2A, coinciding with a loss of anchorage-independent growth by BL-17/23 alpha and a change in growth in vivo from a solid tumor to a fluid-filled tumor by BL-17/0/X2A.
Aged↗
Multiple atypical nevi: a cutaneous marker of germ cell tumors.
PURPOSE: This study assessed whether a specific association exists between atypical nevi and germ cell tumors (GCT). METHODS: A prospective comparison was performed on a cohort of 129 unselected patients with GCT and a series of 153 healthy men. Three or more of the following criteria were required for diagnosis of multiple atypical nevi: greater than 5 mm in diameter; variegated color, often speckled black/brown, with irregularly distributed pigmentation; irregular outline or indistinct border; and at least three such lesions. RESULTS: Prevalences for multiple atypical nevi in patients with GCT and in healthy controls were 37% and 15%, respectively (P < .01). Two patients with these lesions also had documented malignant melanoma. In contrast, 16% of patients with GCT had a history of testicular maldescent (the most common known risk factor), compared with 5% of healthy controls (P < .01). CONCLUSION: Multiple atypical nevi occur with a statistically significant increased prevalence in patients with GCT as compared with healthy controls, and constitute one of the most common known clinical associations with this malignancy. These data may be of relevance for our understanding of the biology of GCT and of malignant melanoma, in the design of screening programs for testis cancer, and in the follow-up evaluation of patients with each of these disorders.
Adolescent↗
The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma.
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Antineoplastic Combined Chemotherapy Protocols↗
Carboplatin for small cell lung cancer: progress toward greater efficacy and reduced toxicity.
Small cell lung cancer, an aggressive malignancy characterized by early dissemination, is highly responsive to radiotherapy and cytotoxic chemotherapy. Since the introduction of combined-modality regimens that incorporate both radiotherapy and chemotherapy, the median survival time for patients with localized disease has increased to 12 to 15 months, but median length of survival of patients with extensive disease has remained at a plateau of only 6 to 8 months. New cytotoxic agents, such as ifosfamide, etoposide, and carboplatin, have contributed to a reduced toxicity profile and an increase in complete response rates to combination regimens of 40% to 50%, but they have not contributed to any major increase in long-term survival. Potential strategies for improving efficacy and reducing toxicity of the chemotherapy of small cell lung cancer are reviewed.
Antineoplastic Combined Chemotherapy Protocols↗
Quantum leaps in treatment of high-risk breast cancer? Prove it!
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Antineoplastic Combined Chemotherapy Protocols↗
A randomised cross-over trial of antiemetic therapy for platinum-based chemotherapy. Improved control with an intensive multiagent regimen.
In a partially blinded randomised cross-over trial, 78 patients receiving cisplatinum based chemotherapy were assigned to receive two forms of antiemetic therapy: SAD, a regimen composed of serenace (haloperidol), ativan (lorazepam), and dexamethasone followed by low dose maxolon (metoclopramide) and STADMAX, a regimen composed of scopolamine (hyoscine), tavegyl (clemastine), ativan, dexamethasone and high dose maxolon. Each antiemetic regimen was given in random order, with the first and second cycles of cytotoxic chemotherapy. 66 (85%) patients completed both cycles of antiemetic therapy and were available for the cross-over comparison. Significantly less acute vomiting, as assessed by nurse observer (P < 0.0001), and less delayed vomiting, as assessed by patient diary (P = 0.03), were seen with STADMAX. In the first 18 h, complete control of vomiting (no episodes) was achieved in 30 (45%) patients with STADMAX compared with 10 (15%) receiving SAD. Overall, major control of emesis (< or = 2 episodes) was achieved in 56 (85%) patients with STADMAX compared with 35 (53%) receiving SAD. Vomiting was also better controlled on STADMAX in the week after this initial 18 hour period based on the 7 day patient diary with no vomiting episodes in 18/65 (28%) on STADMAX vs. 13/65 (20%) on SAD. However, no significant differences in appetite, nausea or vomiting were found when based on linear analogue self assessment (LASA) scales recorded by patients. Significant differences in side effects of the two antiemetic regimens were noted on LASA scales with more dry mouth (P = 0.01), blurred vision (P = 0.03) and diarrhoea (P = 0.04) associated with STADMAX and more restlessness (P = 0.002) associated with SAD. Significantly, no episodes of dystonic reactions were seen among patients on either regimen. In the 68 patients who completed both cycles and were in a position to express a preference, 46 (68%) preferred STADMAX compared with only 20 (29%) who preferred SAD (P = 0.001), while 2 patients expressed no preference. It is concluded that STADMAX is the preferred regimen to SAD for the control of cisplatinum-related emesis. It has a role, both where specific serotonin 3 antagonists are not available and as a model for building more effective combinations where these agents are available.
Adult↗
Characterization of a new human bladder cancer cell line, UCRU-BL-28.
A new human bladder cancer cell line, UCRU-BL-28 has been established and characterized from a relapsed, cisplatin resistant, grade II, stage T4 tumor. This line is tumorigenic in nude mice and reflects the pathology of the original tumor. The morphology, the expression of tumor-associated antigens and EGF receptors, and the ability to grow both in an anchorage independent manner and in the absence of serum is explored. The BL-28 line has 71-74XXY chromosomes, with del 5q, der(9) and i(19q). Further studies on the molecular basis of bladder cancer, chemosensitivity to cisplatin, growth factor production and tissue invasion are under way.
Biomarkers, Tumor↗