The cancer journal from Scientific American最新文献

Purpose: 9-cis retinoic acid (ALRT 1057; 9cRA) is a promising new retinoid that binds to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoic acid or all-trans retinoic acid. It has been shown to be at least as active as all-trans retinoic acid as a differentiation-inducing and antiproliferative agent in both in vivo and in vitro tumor model systems.

Methods: The New York Gynecologic Oncology Group undertook a prospective, multi-institutional phase II clinical and pharmacokinetic trial of 9cRA in patients with advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix. Patients received daily oral doses of 140 mg/m2 of 9cRA. 9cRA and its metabolites were determined by reversed-phase HPLC in plasma samples drawn at 0.5 to 8 hours.

Results: Sixteen patients with advanced or recurrent carcinoma of the cervix were enrolled. Therapy was well tolerated with no unexpected toxicities. There were no complete or partial responses observed, indicating that a response rate of 20% or greater to this agent could be ruled out with 95% confidence. Pharmacokinetic parameters for 9cRA on day 1 were in agreement with previous studies. The area under the plasma versus time curves for 9cRA declined by 69% between days 1 and 8 with daily 9cRA dosing and remained at this low level in those patients evaluated on day 28. 4-oxo-9-cis retinoic acid (4-oxo-9cRA) was identified as a major plasma metabolite of 9cRA. Plasma levels of 4-oxo-9-cRA were initially 71% of those of 9cRA, but in contrast to 9cRA, there was no decline in plasma levels on days 8 and 28. The ratio of the area under the curve for the 4-oxo metabolite relative to that of the parent compound increased from less than 1 on day 1 to approximately 2.4 on days 8 and 28. Thus, despite early induction of its own metabolism, levels of total retinoid metabolites persisted at pharmacologic levels at day 28.

Conclusions: 9cRA with this dose and schedule was inactive in women with advanced carcinoma of the cervix. Despite a decline in plasma levels of 9cRA over time, levels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest that the lack of clinical activity in this patient population may not be attributable exclusively to suboptimal pharmacokinetic parameters.

Purpose: The value of treating prostate cancer has been questioned, and some insist that a survival benefit is demonstrated to justify treatment. Prospective dose-escalation studies with three-dimensional conformal radiotherapy technique have demonstrated improvement in biochemical freedom from disease and local control. We report the outcomes of high-dose treatment with three-dimensional conformal radiotherapy compared with low-dose treatment for biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival.

Patients and methods: The study design was retrospective, involving pairs matched on independent prognostic variables in which each patient treated with low-dose radiotherapy was matched with a patient treated with high-dose radiotherapy. Outcomes were compared for two groups of patients: Group I: Three-dimensional conformal radiotherapy treatment--296 patients treated with more than 74 Gy matched on stage, grade, and prostate-specific antigen level, to 296 patients treated with less than 74 Gy. Group II: Three-dimensional conformal radiotherapy treatment--357 patients treated with more than 74 Gy matched on stage and grade to 357 patients treated with less than 74 Gy.

Results: Univariate analysis showed that dose is a significant predictor of biochemical freedom from disease, freedom from distant metastasis, and cause-specific survival for group I and biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival for group II. Multivariate analysis showed that dose is a significant independent predictor in group I for biochemical freedom from disease and freedom from distant metastasis and for biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival in group II.

Discussion: These data provide strong support for the definitive treatment of prostate cancer with high-dose (> 74 Gy) three-dimensional conformal radiotherapy. These doses can be safely delivered with three-dimensional conformal radiotherapy techniques. Various institutions and industry must collaborate to expand the technology allowing the use of high-dose three-dimensional conformal radiotherapy in the national practice beyond centers of technological excellence.

Purpose: To evaluate the feasibility, toxicity, and therapeutic efficacy of 1-hour paclitaxel, carboplatin, continuous low-dose infusional 5-fluorouracil, and concurrent radiation therapy administered preoperatively in patients with localized esophageal cancer.

Patient and methods: Forty-nine patients with localized esophageal cancer, of either squamous cell carcinoma or adenocarcinoma histology, were enrolled into this phase II trial. All patients were candidates for surgical resection and received the following neoadjuvant therapy: paclitaxel, 200 mg/m2, 1 hour IV on days 1 and 22; carboplatin, AUC 6.0, IV on days 1 and 22; 5-fluorouracil, 225 mg/m2/day, continuous IV infusion on days 1 to 42; and radiation therapy, 45 Gy, administered by 1.8-Gy daily fractions beginning on day 1 of chemotherapy. Upon completion of this neoadjuvant regimen, patients were reevaluated, and all responding patients were resected within 6 weeks of completing neoadjuvant treatment.

Results: Administration of this combined modality regimen was associated with moderate toxicity and was tolerated by most patients. Leukopenia (65%) and esophagitis (31%) were the most common toxicities. Most patients did not require nutritional support. There were no treatment-related deaths during neoadjuvant therapy; however, three patients (9%) experienced postoperative death. Preliminary assessment of treatment efficacy is encouraging, with 17 of 37 evaluable patients (46%) achieving pathologic complete remission and an additional 11 patients (30%) having only microscopic residual disease.

Conclusions: This novel, combined-modality neoadjuvant approach for the treatment of localized esophageal carcinoma is feasible and can be administered with toxicity that compares favorably to previously reported neoadjuvant regimens containing high-dose cisplatin. Preliminary assessment of efficacy is also encouraging, with 46% of patients having pathologic complete response. Further follow-up and larger numbers of patients are required to assess efficacy more definitively.

Purpose: Oral administration of etoposide represents a pharmacokinetic advantage over the traditional intermittent intravenous usage of this drug. This phase II trial was undertaken to determine its activity against gastric adenocarcinoma in chemotherapy-naive patients.

Patients and methods: Patients with measurable, unresectable, metastatic gastric carcinoma with performance status < or = 2 by Zubrod scale were eligible. Patients had to have normal liver, renal, and bone marrow functions. Written informed consent was obtained from all patients. The starting dose of etoposide was 50 mg/m2/day, given orally daily for 21 days, followed by a 7-day rest period. Oral etoposide was repeated every 28 days. Response was evaluated after two courses.

Results: Twenty-eight patients were registered. The median number of courses was two (range, 1 to 12; total, 69 courses). Twenty-six patients were evaluable for response and toxicity. Five patients (19%; 95% confidence interval, 3% to 35%) achieved a partial response. The median duration of response was 3.5 months. There was no treatment-related death. Toxic effects were mild to moderate.

Conclusions: Oral etoposide is modestly active against gastric carcinoma. It is well tolerated by patients. Further studies in combination with other active agents against gastric carcinoma may be warranted.

Purpose: To determine the role of the two angiogenic peptides, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) (the latter also being a target enzyme for cytotoxicity of 5-fluorouracil and methotrexate), and conventional prognostic factors in predicting relapse-free survival (RFS) and overall survival (OS) probabilities in two cohorts of patients with node-positive breast cancer (NPBC) treated with either adjuvant chemotherapy (CMF [cyclophosphamide, methotrexate, 5-fluorouracil] schedule) or hormone therapy (tamoxifen).

Patients and methods: We studied two groups of 137 and 164 patients with NPBC, median follow-up of 72 months for both, treated with adjuvant chemotherapy or hormone therapy, respectively. The cytosolic levels of VEGF and TP were determined in the primary tumor by original immunometric methods. The association between VEGF and TP and of these angiogenic peptides with other prognostic indicators were tested by using the Spearman correlation coefficient (for continuous variables) or the Kolmogorov-Smirnov test (for dichotomous variables). Results of the clinical outcome were analyzed by both univariate and multivariate (for RFS only) Cox regression models in which VEGF and TP were treated as continuous variables.

Results: In the CMF group, the concentrations of VEGF and TP ranged from 5.8 to 7798 pg/mg of protein (median, 87.5 pg/mg) and from 1.2 to 904 U/mg (median, 138.2 U/mg), respectively. There was no significant association between the two angiogenic peptides. VEGF was not associated with any other variable, whereas TP showed a positive association with age and an inverse association with the number of involved nodes. In the tamoxifen group, the concentrations of VEGF (5.9-2482; median, 79.3 pg/mg protein) and TP (6.1-1542; median, 146.5 U/mg) were similar to those of the CMF group, and the two angiogenic peptides were not correlated. VEGF was positively associated with age and was inversely associated with estrogen receptor and progesterone receptor, whereas TP was not associated with any other variable. Univariate analysis in the CMF group showed that VEGF and TP were significantly predictive of both RFS and OS. Likewise, the number of involved axillary nodes was significantly associated with both RFS and OS. Univariate analysis in the tamoxifen group showed that TP did not significantly influence either RFS or OS. On the contrary, VEGF levels were significantly predictive of both RFS and OS, as were the number of involved nodes, estrogen receptor concentrations, and progesterone receptor concentration. In the multivariate analysis on RFS in the CMF group, VEGF, TP, their first-order interaction term, and age were significant and independent predictive factors. In the tamoxifen group, only VEGF and the number of involved nodes were significant and independent predictive factors.

Discussion: The results of our s