低剂量粒—巨噬细胞集落刺激因子在肺癌化疗中的应用

３１例肺癌患者大剂量化疗４０例次，采用配对法分成加用低剂量粒－巨噬细胞集落刺激因子（ＧＭ－ＣＳＦ）的治疗组及不加用的对照组（二组均为２０例次）。结果表明，低剂量ＧＭ－ＣＳＦ明显缩短化疗所致白细胞低下的时间：治疗组为１４．５±９．４９天，对照组为１９．４±８．８５天（Ｐ＝０．０２），同时提高白细胞下降最低值：治疗组为３．３５×１０９／Ｌ±１．３７×１０９／Ｌ，对照组为２．９×１０９／Ｌ±１．１８×１０９／Ｌ。低剂量ＧＭ－ＣＳＦ的主要不良反应为发热（８０％）及肌痛、骨痛（１０％）。结果提示：低剂量ＧＭ－ＣＳＦ能支持癌症患者的大剂量化疗及连续化疗     

Daily CT localization for correcting portal errors in the treatment of prostate cancer

Introduction: Improved prostate localization techniques should allow the reduction of margins around the target to facilitate dose escalation in high-risk patients while minimizing the risk of normal tissue morbidity. A daily CT simulation technique is presented to assess setup variations in portal placement and organ motion for the treatment of localized prostate cancer.

Methods and Materials: Six patients who consented to this study underwent supine position CT simulation with an alpha cradle cast, intravenous contrast, and urethrogram. Patients received 46 Gy to the initial Planning Treatment Volume (PTV₁) in a four-field conformal technique that included the prostate, seminal vesicles, and lymph nodes as the Gross Tumor Volume (GTV₁). The prostate or prostate and seminal vesicles (GTV₂) then received 56 Gy to PTV₂. All doses were delivered in 2-Gy fractions.

After 5 weeks of treatment (50 Gy), a second CT simulation was performed. The alpha cradle was secured to a specially designed rigid sliding board. The prostate was contoured and a new isocenter was generated with appropriate surface markers. Prostate-only treatment portals for the final conedown (GTV₃) were created with a 0.25-cm margin from the GTV to PTV. On each subsequent treatment day, the patient was placed in his cast on the sliding board for a repeat CT simulation. The daily isocenter was recalculated in the anterior/posterior (A/P) and lateral dimension and compared to the 50-Gy CT simulation isocenter. Couch and surface marker shifts were calculated to produce portal alignment. To maintain proper positioning, the patients were transferred to a stretcher while on the sliding board in the cast and transported to the treatment room where they were then transferred to the treatment couch. The patients were then treated to the corrected isocenter. Portal films and electronic portal images were obtained for each field.

Results: Utilizing CT–CT image registration (fusion) of the daily and 50-Gy baseline CT scans, the isocenter changes were quantified to reflect the contribution of positional (surface marker shifts) error and absolute prostate motion relative to the bony pelvis. The maximum daily A/P shift was 7.3 mm. Motion was less than 5 mm in the remaining patients and the overall mean magnitude change was 2.9 mm. The overall variability was quantified by a pooled standard deviation of 1.7 mm. The maximum lateral shifts were less than 3 mm for all patients. With careful attention to patient positioning, maximal portal placement error was reduced to 3 mm.

Conclusion: In our experience, prostate motion after 50 Gy was significantly less than previously reported. This may reflect early physiologic changes due to radiation, which restrict prostate motion. This observation is being tested in a separate study. Intrapatient and overall population variance was minimal. With daily isocenter correction of setup and organ motion errors by CT imaging, PTV margins can be significantly reduced or eliminated. We believe this will facilitate further dose escalation in high-risk patients with minimal risk of increased morbidity. This technique may also be beneficial in low-risk patients by sparing more normal surrounding tissue.     

Radiation therapy in the management of desmoid tumors

Purpose: To evaluate the outcome of patients with extra-mesenteric desmoid tumors treated with radiation therapy, with or without surgery.

Methods and Materials: The outcome for 75 patients receiving radiation for desmoid tumor with or without complete gross resection between 1965 and 1994 was retrospectively reviewed utilizing univariate and multivariate statistical methods.

Results: With a median follow-up of 7.5 years, the overall freedom from relapse was 78% and 75% at 5 and 10 years, respectively. Of the total, 23 patients received radiation for gross disease because it was not resectable. Of these 23 patients, 7 sustained local recurrence, yielding a 31% actuarial relapse rate at 5 years. Radiation dose was the only significant determinant of disease control in this group. A dose of 50 Gy was associated with a 60% relapse rate, whereas higher doses yielded a 23% relapse rate (p < 0.05). The other 52 patients received radiation in conjunction with gross total resection of tumor. The 5- and 10-year relapse rates were 18% and 23%, respectively. No factor correlated significantly with disease outcome. There was no evidence that radiation doses exceeding 50 Gy improved outcome. Positive resection margins were not significantly deleterious in this group of irradiated patients. For all 75 patients, there was no evidence that radiation margins exceeding 5 cm beyond the tumor or surgical field improved local-regional control. Ultimately, 72 of the 75 patients were rendered disease-free, but 3 required extensive surgery (amputation, hemipelvectomy) to achieve this status. Significant radiation complications were seen in 13 patients. Radiation dose correlated with the incidence of complications. Doses of 56 Gy or less produced a 5% 15-year complication rate, compared to a 30% incidence with higher doses (p < 0.05).

Conclusions: Radiation is an effective modality for desmoid tumors, either alone or as an adjuvant to resection. For patients with negative resection margins, postoperative radiation is not recommended. Patients with positive margins should almost always receive 50 Gy of postoperative radiation. Unresectable tumors should be irradiated to a dose of approximately 56 Gy, with a 75% expectation of local control.     

Improved freedom from PSA failure with whole pelvic irradiation for high-risk prostate cancer

Purpose: To determine the impact of whole pelvic irradiation on the risk of PSA failure in prostate cancer patients, at high predicted risk for lymph node involvement, receiving definitive radiotherapy.

Materials and Methods: Between October 1987 and December 1995, 506 patients with clinically localized prostate cancer were treated with definitive radiotherapy at UCSF and affiliated institutions. Treatment consisted of 4-field whole pelvic irradiation followed by a prostate-only boost, or prostate-only treatment (median follow-up was 35 months and 30 months, respectively). PSA failure was defined as: 1. a PSA value ≥ 1 ng/ml; or 2. a PSA value that rose ≥ 0.5 ng/ml in ≤ 1 year posttreatment on two consecutive measurements, with the first rise defined as the time of failure. The calculated risk of lymph node positivity (%rLN+) was defined as (iPSA) + 10(GS-6), and high risk was defined as %rLN+ ≥ 15%. Univariate and multivariate analyses were performed.

Results: A total of 201 high-risk patients were identified. High-risk patients who received whole pelvic irradiation had significantly improved freedom from PSA failure compared to those who received prostate-only treatment (median PFS = 34.3 months vs. 21.0 months; p = 0.0001). Potential confounding variables, including initial PSA, Gleason score, T stage, radiation dose, year of treatment, use of three-dimensional (3D) conformal techniques, and use of hormone therapy, did not account for the observed difference in time to PSA failure. Multivariate analysis revealed type of radiation treatment to be the most significant independent predictor of outcome.

Conclusion: Whole pelvic radiotherapy significantly improves the PSA failure-free survival in patients with a high calculated risk of lymph node positivity.     

Allosteric effectors of hemoglobin as modulators of chemotherapy and radiation therapy in vitro and in vivo

Introduction: A series of molecules designed to be allosteric effectors of hemoglobin were examined for their potential as radiation sensitizers in vitro and in vivo and for their potential as chemosensitizers in vivo as well as for their antimetastatic effect. Results: At a concentration of 100 μM for 1 h prior to, during and for 1.5 h after radiation exposure, the allosteric effectors decreased the shoulder of the radiation survival curve of normally oxygenated EMT-6 cells and increased the slope of the radiation survival curves of hypoxic EMT-6 cells resulting in dose-modifying factors of 1.8 to 2.1. In vivo the allosteric effectors had antitumor activity against the Lewis lung carcinoma and produced primarily additive tumor growth delay when administered along with fractionated radiation therapy. When administered on days 4 through 18 after tumor implantation, the allosteric effectors, especially JP-7, RSR-13 and RSR-4, were highly effective antimetastatic agents in animals bearing Lewis lung carcinoma. In cell culture, simultaneous exposure to the allosteric effectors (at 100 μM ) effectively sensitized EMT-6 cells to the effects of 4-hydroperoxycyclophosphamide, thiotepa and carboplatin. The allosteric effectors were not very cytotoxic toward EMT-6 tumor cells from tumors treated in vivo with single doses of each molecule nor were these agents very cytotoxic toward bone marrow CFU-GM taken from the same animals. Conclusions: It is likely that the allosteric effectors have a molecular target in addition to hemoglobin. Other possible targets include hydroxymethyl-glutaryl-CoA reductase or microsomal cytochrome b₅. Received: 27 June 1997 / Accepted: 8 October 1997     

The results of radiotherapy for brainstem tumors

Objective: This analysis was performed to examine the outcome of adult and pediatric patients with brainstem tumors. Methods and materials: Forty patients with brainstem glioma were evaluated retrospectively. Included were 24 females and 16 males ranging in age from 3 to 81 years (median, 29.5 years). These patients were treated with various combinations of surgery, chemotherapy, and ratiotherapy (RT). The length of follow-up in survivors ranged from 0.6 to 20 years (median: 3.2 years, mean: 6 years). Survival rates were calculated with the Kaplan Meier method and differences between survival curves were calculated using the log-rank test. Results: The overall 2 and 5-year survival rates were 44% and 34%, respectively. The median survival time was 19 months. The 5-year survival rate was 54% for patients with tumors outside the pons compared to 21% for those with tumors involving the pons (p=0.04). The 5-year survival rate was 59% for patients with exophytic tumors as compared to 23% for those with intrinsic tumors (p=0.05). Patients undergoing subtotal resection had a 5-year survival rate of 53% compared to 28% for those having only a biopsy or no surgical intervention (p=0.04). None of the other potential prognostic or treatment related factors evaluated [patient age, tumor grade, tumor histology, radiotherapy parameters (including BID fractionation, 3-D treatment planning, or the use of doses > 55 Gy), or the administration of adjuvant chemotherapy] evaluated were associated with patient survival. Conclusions: Brainstem gliomas generally occur in younger individuals. The survival rates were better for patients with exophytic tumors, those involving sites other than the pons, and tumors amenable to subtotal resection. Improvements in the outcome of patients with brainstem gliomas will require new therapeutic approaches.     

Vinorelbine, bleomycin and methotrexate as a salvage therapy for patients with head and neck squamous carcinoma in relapse after cisplatin/fluorouracil

Background: Cisplatin (CDDP) and 5-fluorouracil (5-FU) represent the standard chemotherapy for advanced/recurrent head and neck squamous carcinoma (HNSC); however, the duration of response is often short, with a median survival of only five to six months.Patients and methods: Patients with HNSC were treated with vinorelbine 20 mg/m² and methotrexate 50 mg/m² every week and bleomycin 15 mg/m² every two weeks. All patients were previously treated with a CDDP/5-FU regimen.Results: Forty-eight patients were evaluable for response and toxicity. After a median follow-up of 15 months, 16 patients are still alive and 32 have died. We had one complete response (2%), 12 partial responses (25%) (overall response rate 27%; 95% CI: 14%–39%), 11 stabilizations (23%) and 24 progressions (50%) of disease. Neutropenia grade 3–4 was seen in 12 patients; peripheral neurotoxicity in two patients. There were no toxic deaths.Conclusions: This regimen, administered in an outpatient setting, revealed some activity as a second-line treatment in patients with HNSC, with acceptable toxicity.     

Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification

Malignant gliomas have been associated with a high rate of glycolytic activity which is believed necessary to sustain cellular function and integrity. Since lonidamine (LND) is believed to reduce tumor glucose utilization by inhibition of the mitochondrially-bound glycolytic enzyme hexokinase (HK), ³¹P magnetic resonance spectroscopy (MRS) was used to noninvasively follow the effects of LND on both tumor pH and the high-energy phosphate metabolites; ATP, phosphocreatine (PCr) and inorganic phosphate (P_i) in subcutaneous rat 9L gliosarcomas. ³¹P tumor spectra acquired in 5 min intervals pre- and post LND administration of 50 and 100 mg/kg, i.p. revealed an acidotic pH shift of – 0.25 and – 0.45 pH units, respectively within 30 min post administration. The ATP/P_i ratio of 9L tumors decreased to 40% of control and P_i levels increased to 280% of control over a 3 hr period. LND exerted no effect on tumor blood flow and mean arterial blood pressure. Brain and muscle metabolite levels and pH were also unaffected by LND. In vitro measurements of cultured 9L tumor cell intra- and extracellular lactate, pentose phosphate pathway (PPP) and hexokinase (HK) activities suggest that the mode of action of LND involves inhibition of lactate efflux and intracellular acidification. The selective reduction of tumor energy metabolites and pH by LND may be exploitable for sensitizing gliomas to radiation, chemotherapy or hyperthermia.     

Postoperative adjuvant radiotherapy and 5-fluorouracil chemotherapy for rectal carcinoma

Postoperative combined modality therapy with radiotherapy and 5-fluorouracil (5FU) chemotherapy is an effective adjuvant approach that reduces locoregional and distant metastatic disease in patients with high-risk rectal carcinoma. However, this approach results in a treatment regimen of at least 6 months’duration. The present prospective study investigates the integration of radiotherapy and 5FU chemotherapy in a protocol designed to minimize toxicity and reduce the overall treatment time. A total of 40 patients with TNM stage II or III disease received postoperative radiotherapy at four fractions per week with weekly 5FU bolus injections delivered on the fifth non-radiotherapy day. Patients also received systemic chemotherapy with leucovorin both before and after pelvic irradiation, with the total treatment duration extending for only 18 weeks. Patients were able to complete radiotherapy in 90% of cases, while the delivery of full-dose chemotherapy was achievable in the vast majority. The incidence of haematologic and gastrointestinal toxicities requiring the cessation of treatment was acceptable. With a median follow-up of 20.9 months among surviving patients, the estimated progression-free and overall survival at 2 years were 71 % and 79%, respectively.     

维甲酸在肺癌放疗中应用的近期临床观察

目的本文报道分析了维甲酸联合放射治疗与单纯放射治疗，对中晚期肺腺癌的疗效及放射治疗期间的毒副反应。方法从１９９４年１月至１９９５年１月收治中晚期肺腺癌２０例，１０例维甲酸加放疗，１０例单纯放射治疗，两组均用直线加速器，常规分割放射治疗，肿瘤量６０～７０Ｇｙ／６～７周，维甲酸加放疗组，放疗前１０～２０分钟口服维甲酸３０～６０ｍｇ／ｍ２。从放疗开始连服４６天为１周期，放疗结束后休息７～１４天重复１个周期。结果维甲酸加放疗组：ＣＲ６０％，ＰＲ２０％，Ｓ２０％；单纯放疗组：ＣＲ４０％，ＰＲ４０％，Ｓ２０％。在治疗过程中观察血象，肝、肾功能、胃肠道反应两组均未发现明显毒反映。结论结果显示放疗加维甲酸治疗中晚期肺腺癌疗效优于单纯放射治疗，其机理在于维甲酸使Ｇ１期延滞和Ｇ２～Ｓ期转换受到抑制，使癌细胞阻断于对放射线敏感的Ｇ１期增加放疗效果，使肿瘤消失变快