Intracranial metastases: behavioral patterns related to primary site and results of treatment by whole brain irradiation

Three hundred and fifty cases of tumors that metastasized to the brain and treated by radiotherapy were reviewed. The majority of patients had either lung (46 % I or breast (42 % ) primaries. Eighty percent of the patients had other sites of metastatic involvement. Seventy-five percent of the patients improved after cranial irradiation. The median survival was less than 6 months, regardless of the primary disease or the dose employed. No subgroup could be identified that might benefit from a more aggressive treatment regimen. Radiation treatment in the range of 2,000 rad in one week or 3,000 rad in two weeks is recommended for palliation of metastatic cancer to the brain.     

Breast-conserving therapy with partial or whole breast irradiation: Ten-year results of the Budapest randomized trial

Background and purpose

To report the long-term results of a single-institution randomized study comparing the results of breast-conserving treatment with partial breast irradiation (PBI) or conventional whole breast irradiation (WBI).

Patients and methods

Between 1998 and 2004, 258 selected women with pT1 pN0-1mi M0, grade 1–2, non-lobular breast cancer without the presence of extensive intraductal component and resected with negative margins were randomized after BCS to receive 50 Gy WBI (n = 130) or PBI (n = 128). The latter consisted of either 7 × 5.2 Gy high-dose-rate (HDR) multi-catheter brachytherapy (BT; n = 88) or 50 Gy electron beam (EB) irradiation (n = 40). Primary endpoint was local recurrence (LR) as a first event. Secondary endpoints were overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and cosmetic results.

Results

After a median follow up of 10.2 years, the ten-year actuarial rate of LR was 5.9% and 5.1% in PBI and WBI arms, respectively (p = 0.77). There was no significant difference in the ten-year probability of OS (80% vs 82%), CSS (94% vs 92%), and DFS (85% vs 84%), either. The rate of excellent-good cosmetic result was 81% in the PBI, and 63% in the control group (p < 0.01).

Conclusions

Partial breast irradiation delivered by interstitial HDR BT or EB for a selected group of early-stage breast cancer patients produces similar ten-year results to those achieved with conventional WBI. Significantly better cosmetic outcome can be achieved with HDR BT implants compared with the outcome after WBI.     

Treatment of spinal cord ependymomas by surgery with or without postoperative radiotherapy

Purpose: To evaluate the effectiveness of complete resection and postoperative radiotherapy in spinal cord ependymomas. Methods and materials: We conducted a retrospective study over 20 patients (13 males and 7 females) with histologically confirmed spinal cord ependymomas between July 1985 and April 2001. Among them, 13 patients had ependymomas, 6 had myxopapillary ependymomas, and 1 had anaplastic ependymoma. All patients received radical surgery for tumor removal with 13 patients achieving complete resection and 7 incomplete resection due to technical difficulty. Among those with incomplete resection, 6 patients received postoperative radiotherapy to tumor bed and only one patient with anaplastic ependymoma received surgery alone. The total tumor dose ranged from 50 to 60 Gy. Results: Among the 20 patients, 19 patients were alive and showed local control. The median survival time of all patients was 109 months, with 104 months in the complete resection alone group and 135 months in the incomplete resection with postoperative radiotherapy group. One patient with anaplastic ependymoma and no postoperative radiotherapy developed leptomeningeal seeding 9 months after surgery. Salvage therapy of radiotherapy and chemotherapy maintained normal neurological functions. The patient expired 34 months from the initial diagnosis due to progression of leptomeningeal seeding. Conclusion: Complete resection alone in spinal cord ependymoma can achieve excellent local control and survival. Patients should receive complete resection if technically possible. Postoperative radiotherapy is not recommended for complete resection. For incomplete resection, postoperative local radiotherapy is recommended and it can also achieve excellent local control and survival. Local radiotherapy with 50-60 Gy is effective and safe. Salvage radiotherapy improves quality of life for local recurrence or leptomeningeal seeding patients.     

Breast-conserving treatment with partial or whole breast irradiation for low-risk invasive breast carcinoma--5-year results of a randomized trial

PURPOSE: To report the 5-year results of a randomized study comparing the survival and cosmetic results of breast-conserving treatment with partial breast irradiation (PBI) or conventional whole breast irradiation (WBI). METHODS AND MATERIALS: Between 1998 and 2004, 258 selected patients with T1 N0-1mi, Grade 1-2, nonlobular breast cancer without presence of extensive intraductal component and resected with negative margins were randomized after breast-conserving surgery to receive 50 Gy/25 fractions WBI (n = 130) or PBI (n = 128). The latter consisted of either 7 x 5.2 Gy high-dose-rate (HDR) multicatheter brachytherapy (BT; n = 88) or 50 Gy/25 fractions electron beam (EB) irradiation (n = 40). RESULTS: At a median follow-up of 66 months, the 5-year actuarial rate of local recurrence was 4.7% and 3.4% in the PBI and WBI arms, respectively (p = 0.50). There was no significant difference in the 5-year probability of overall survival (94.6% vs. 91.8%), cancer-specific survival (98.3% vs. 96.0%), and disease-free survival (88.3% vs. 90.3%). The rate of excellent to good cosmetic result was 77.6% in the PBI group (81.2% after HDR BT; 70.0% after EB) and 62.9% in the control group (52.2% after telecobalt; 65.6% after 6-9-MV photons; p(WBI/PBI) = 0.009). CONCLUSIONS: Partial breast irradiation using interstitial HDR implants or EB to deliver radiation to the tumor bed alone for a selected group of early-stage breast cancer patients produces 5-year results similar to those achieved with conventional WBI. Significantly better cosmetic outcome can be achieved with carefully designed HDR multicatheter implants compared with the outcome after WBI.     

Intracranial ependymomas treated with radiotherapy: long-term results from a single institution

The purpose of the study is to report long-term outcomes following surgery and radiotherapy for intracranial ependymoma. We retrospectively reviewed the medical records of patients treated with radiotherapy for localized intracranial ependymomas from 1964 to 2006. Patients with subependymomas and ependymoblastomas, and those undergoing re-irradiation, were excluded. Our study population is 44 patients: 37 infratentorial lesions, 7 supratentorial. All patients had postoperative radiotherapy; most received sub-total resection and one-third received gross total resection. Most patients received local radiotherapy alone (median tumor dose 55 Gy); one-quarter received craniospinal irradiation (median dose 35 Gy). The 5- and 10-year local-control rates for all patients were 60 and 46%, respectively; 23% of local recurrences occurred after 5 years. Ninety-five percent of the patients recurred at the primary site; 5% had spinal seeding with no evidence of disease at the primary site. No patient who received craniospinal irradiation recurred in the spine. The 5- and 10-year disease-free survival and overall-survival rates for all patients were 60 and 42% and 57 and 43%, respectively. On multivariate analysis, age ≥18 years, gross total resection and infratentorial site were associated with improved local control. No patient with continuous local control had grade 4 or 5 toxicities; 27% of patients had grade 2 or 3 toxicities. One patient developed a radiation-induced meningioma >20 years after radiotherapy. Maximal safe resection followed by adjuvant radiotherapy provided local control in one-half of patients at 10 years. Age, extent of surgery, and location were identified as major independent prognostic factors in patients with intracranial ependymomas.     

Postoperative whole lung irradiation with or without adriamycin in osteogenic sarcoma

Thirty-six patients with histologically proven osteogenic sarcoma of the extremities, treated between September 1975 and April 1978, are the subject of this report. The primary tumor was treated with radical surgery. Patients received 2000 cGy whole lung irradiation postoperatively in an attempt to control micrometastases to the lung. Twenty-nine of the patients were given Adriamycin (60 mg/m2 IV every 6 weeks for a total dose of 550 mg/m2) in addition to the irradiation. The median, disease-free interval was 118 days for the seven patients treated with lung irradiation only. The median overall survival for these patients is 241 days, with one patient alive with disease. All patients developed lung metastasis. For the 29 patients treated with postoperative lung irradiation and Adriamycin, the median disease-free interval was 372 days, and the median overall survival is 843 days. Nineteen of the patients recurred (65.5%). The differences are statistically significant (p less than or equal to 0.003, median disease-free survival and p less than or equal to 0.03, median survival). This study supports the role of whole lung irradiation plus Adriamycin, in the control of micrometastases in osteogenic sarcoma of the extremities and suggests that additional clinical trials are warranted.     

Lumpectomy plus tamoxifen or anastrozole with or without whole breast irradiation in women with favorable early breast cancer

PURPOSE: In women with favorable early breast cancer treated by lumpectomy plus tamoxifen or anastrazole, it remains unclear whether whole breast radiotherapy is beneficial. METHODS AND MATERIAL: Between January 1996 and June 2004, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) randomly assigned 869 women to receive breast radiotherapy +/- boost (n = 414) or not (n = 417) after breast-conserving surgery (ABCSG Study 8A). Favorable early breast cancer was specified as tumor size <3 cm, Grading 1 or 2, negative lymph nodes, positive estrogen and/or progesterone receptor status, and manageable by breast-conserving surgery. Breast radiotherapy was performed after lumpectomy with 2 tangential opposed breast fields with mean 50 Gy, plus boost in 71% of patients with mean 10 Gy, in a median of 6 weeks. The primary endpoint was local relapse-free survival; further endpoints were contralateral breast cancer, distant metastases, and disease-free and overall survival. The median follow-up was 53.8 months. RESULTS: The mean age was 66 years. Overall, there were 21 local relapses, with 2 relapses in the radiotherapy group (5-y rate 0.4%) vs. 19 in the no-radiotherapy group (5.1%), respectively (p = 0.0001, hazard ratio 10.2). Overall relapses occurred in 30 patients, with 7 events in the radiotherapy group (5-y rate 2.1%) vs. 23 events in the no-radiotherapy group (6.1%) (p = 0.002, hazard ratio 3.5). No significant differences were found for distant metastases and overall survival. CONCLUSION: Breast radiotherapy +/- boost in women with favorable early breast cancer after lumpectomy combined with tamoxifen/anastrazole leads to a significant reduction in local and overall relapse.     

Prognostic models for patients with brain metastases after stereotactic radiosurgery with or without whole brain radiotherapy: a validation study

Gliomatosis cerebri (GC) comprises a rare widespread infiltrating growth pattern of diffuse gliomas. We explored the incidence patterns and survival rates of GC in a population-based registration sample from the Surveillance, Epidemiology and End, Results database (1973–2012). GC cases (n?=?176) were identified based on their International Classification of Diseases in Oncology (ICD-O-3) morphology code (9381). We calculated age-adjusted incidence rates (AIR) and evaluated temporal trends. Survival was assessed with Kaplan–Meier curves and Cox regression models. The annual AIR of GC was 0.1/million. We noted increasing trends in the preceding registration years (1973–2002; annually, +?7%) and a tendency of clinical/radiological approaches to substitute the gold-standard histological assessment for diagnosis. GC was diagnosed in the entire age spectrum (range 1–98 years), but higher incidence rates (0.43/million) were noted among the elderly (≥?65 years). A slight male preponderance was identified (male-to-female ratio: 1.4). Median overall survival was 9 months with a 5 year survival rate of 18%. Increasing age, primary tumor location not restricted to the cerebral hemispheres and rural residence at diagnosis were identified as negative prognostic factors, whereas receipt of radiotherapy, surgical treatment, race and method of diagnosis were not associated with outcome. This first comprehensive overview of GC epidemiology exemplifies the rarity of the disease, provides evidence for male preponderance and increased incidence among the elderly and shows lower survival rates compared to the published single center reports. Expansion of registration to histological and molecular characteristics would allow emergence of clinical prognostic factors at the population level.     

Integration of stereotactic radiosurgery or whole brain radiation therapy with immunotherapy for treatment of brain metastases

The prognosis of brain metastases(BM) is traditionally poor. BM are mainly treated by local radiotherapy,including stereotactic radiosurgery(SRS) or whole brain radiation therapy(WBRT). Recently, immunotherapy(i.e., immune checkpoint inhibitors, ICI) has demonstrated a survival advantage in multiple malignancies commonly associated with BM. Individually, radiotherapy and ICI both treat BM efficiently; hence, their combination seems logical. In this review, we summarize the existing preclinical a...     

Long-term evolution of renal function in patients with ovarian cancer after whole abdominal irradiation with or without preceding cisplatin

Background: The upper limit of the natural decline in creatinine clearance is 1 ml/min/year. To define the loss of renal function, we started a long-term assessment of patients with ovarian cancer treated by whole abdominal irradiation (WAI) with preceding cisplatin chemotherapy (CDDP) and second-look laparotomy (SLL).Patients and methods: We analyzed the creatinine clearance over time of 56 patients treated from 1982 to 1988 for ovarian cancer. Thirty-one of 56 patients had received WAI after their initial surgery, and 25 of 56 patients had undergone CDDP therapy followed by SLL, and then WAI after their initial surgery. Median follow-up was 99 months (7–156). Twenty of 56 patients accepted our invitation for additional assessment of tubular function, nine of the 31 patients without CDDP therapy and SLL, and 11 of the 25 patients with CDDP followed by SLL and WAI.Ten of twenty patients had received four to six cycles CDDP, 80 mg/m²/cycle, and one patient nine cycles. The median total dose for each kidney was 1450 cGy (480–1690).Results: The mean creatinine clearance decreased from 84 ml/min to 66 ml/min. Seventy-six percent of the 25 patients who had undergone CDDP therapy, SLL and WAI had declines of more than 1 ml/min/year, 64% of these patients of more than 2 ml/min/year. For the 31 patients who had received WAI after their initial surgery, the corresponding numbers were 71% and 55%, respectively. The tubular function of the 20 patients who had undergone the additional investigations was not impaired.Conclusion: The decline in renal function after WAI is more pronounced than in healthy subjects. The treatment with cisplatin and SLL prior to WAI does not seem to contribute to this loss of kidney function.     

不同EGFR突变肺腺癌脑转移患者WBRT分析

目的 探讨肺腺癌脑转移患者不同EGFR突变状态WBRT疗效差别。方法 回顾分析2010—2015年在本院诊治的89例肺腺癌脑转移患者,所有患者均行EGFR检测。脑转移一线6 MV X线外照射:WBRT30 Gy分10次或40 Gy分20次(≤3个脑转移灶IMRT同步加量40~45 Gy分10次或50~60 Gy分20次)。比较EGFR突变和野生型患者的有效率、IPFS、OS。Kaplan-Meier法计算IPFS、OS并Logrank检验和单因素分析,Cox模型多因素分析。结果 89例患者总有效率为62%,中位IPFS为7.0个月(95%CI为6.060~7.940),中位OS为12.0个月(95%CI为9.539~14.465)。单因素和多因素分析结果显示脑转移患者有效率与KPS评分、EGFR突变状态相关(P=0.009、0.035),KPS评分、EGFR突变状态是IPFS的影响因素(P=0.048、0.000),KPS评分、原发灶控制是OS的影响因素(P=0.000、0.031)。结论 肺腺癌脑转移患者WBRT后,EGFR突变较野生型有效率高,IPFS时间长,OS无差别。     

三维适形放疗配合全脑照射治疗脑转移瘤的疗效观察

Objective: To observe the recently therapeutic effects and toxicity of three-dimensional conformal radiotherapy combined with whole brain irradiation for patients with brain metastasis. Methods: 33 cases were treated by whole brain irradiation at first, the dose of which was 36-40 Gy (18-20 f). Then three-dimensional conformal radiotherapy was added to the focus with a total dose of 20-25 Gy, whose fractionated dose was 2-5 Gy/time, 5 times/week or 3 times/week. Results: Within 1 month after radiotherapy, according to imaging of the brain, the CR of all patients was 45.5%, PR 36.4%, NC 15.1%, and PD 3%. For the 32 cases with neural symptoms before radiation, the CR of the symptoms was 40.6% and PR 59.4%. All patients gained different increases in KPS grade. By the end of the follow-up period, there were 22 deaths with the mean survival time up to 9.3 months. Conclusion: Three-dimensional conformal radiotherapy combined with whole brain irradiation can not only effectively control brain metastases and improve life quality, but also tends to prolong survival time.     

Stereotaxic radiosurgery for brain metastases: the importance of adjuvant whole brain irradiation.

Stereotaxic radiosurgery delivered from a modified 4 MV linear accelerator was used to treat 47 brain metastases in 27 patients at Stanford. Response was assessed in 41 lesions. Histopathologies included adenocarcinoma (24 lesions), renal cell carcinoma (9 lesions), melanoma (6 lesions), and squamous cell carcinoma (2 lesions). Follow-up ranged from 1.0-16.5 months, with a median of 5.0 months. Radiographic local control was achieved in 88% of the lesions. Three patients developed enlarging contrast-enhancing lesions in the radiosurgical field; one of these was biopsied and revealed necrosis with no viable tumor. Adjuvant whole brain irradiation (10 patients) was associated with regional intracranial control in 80% of patients. This was statistically superior (p = 0.0007) to the regional intracranial control rate achieved when radiosurgery alone was employed (6 patients). Most patients reported resolution of their neurologic symptoms, and were able to discontinue dexamethasone without impairment of neurologic function.     

Effectiveness of stereotactic radiosurgery alone or in combination with whole brain radiotherapy compared to conventional surgery and/or whole brain radiotherapy for the treatment of one or more brain metastases: a systematic review and meta-analysis

PURPOSE: To assess the effectiveness of SRS alone or in combination with WBRT compared to surgery and/or WBRT in prolonging survival and improving the quality-of-life and functional status of patients with brain metastases. METHODS AND MATERIALS: A meta-analysis of randomized controlled trials and concurrent cohort studies examining SRS versus SRS + WBRT, SRS versus WBRT +/- surgical resection, SRS versus surgical resection only, or SRS + WBRT versus WBRT was conducted. Trial registers, bibliographic databases, and reference lists from selected studies and recent issues of relevant journals were searched. Neuro-oncology specialists were also contacted. All studies were analyzed independently by two reviewers, applying validated critical appraisal techniques. RESULTS: The review identified three RCTs and one cohort study. Among patients with multiple metastases, no difference in survival between those treated with WBRT + SRS and those treated with WBRT was found. However, in patients with one metastasis, a statistically significant difference, favoring those treated with WBRT + SRS, was observed. Regarding local tumor control at 24 months, rates were significantly higher in the WBRT + SRS treatment arm, regardless of the number of metastases. CONCLUSIONS: Adding SRS to WBRT improves survival in patients with one brain metastasis. Combining SRS and WBRT improves local tumour control and functional independence in all patients.     

Long-term results of breast cancer irradiation treatment with low-dose-rate external irradiation

PURPOSE: The aim of this study was to assess beam therapy with low-dose-rate (LDR) external irradiation in a group of patients with breast cancer. METHODS AND MATERIALS: This trial compared, from 1986 to 1989, patients with advanced breast cancer treated either by conventional fractionation or low-dose-rate (LDR) external radiotherapy (dose-rate 15 mGy/min, 5 sessions of 9 Gy delivered on 5 consecutive days). RESULTS: A total of 21 patients were included in the fractionated therapy arm. At follow-up 15 years after treatment, 7 local recurrences had occurred, 3 patients had died of cancer, 18 patients were alive, 10 were without evidence of disease, and 6 had evidence of disease. A total of 22 patients had been included in the LDR arm of the study. Of these, 11 had received a dose of 45 Gy; thereafter, in view of severe local reactions, the dose was reduced to 35 Gy. There was no local recurrence in patients who had received 45 Gy, although there were 2 local recurrences among the 11 patients after 35 Gy. The sequelae were severe in patients who received 45 Gy but were comparable to those observed in patients treated by fractionated radiotherapy who received 35 Gy. The higher efficacy of tumor control in patients treated by LDR irradiation as well as the lower tolerance of normal tissue are probably related to the lack of repopulation. CONCLUSION: Although the patient numbers in this study are limited, based on our study results we conclude that the data for LDR irradiation are encouraging and that further investigation is warranted.     

Intracranial ependymomas: an analysis of prognostic factors and patterns of failure

From 1965 to 1997, 49 patients were diagnosed and treated for intracranial ependymoma at one institution. Tumor location was infratentorial in two thirds, and pathology was low grade in 38 patients (78%). Gross total resection of the primary tumor was achieved in 21 (43%). Thirty-six patients received adjuvant radiotherapy; the entire neuraxis was treated in 14, whole brain in 10, and local field only in 12. Median follow-up was 9.6 years (range, 2-33 years). The 5-, 10-, and 15-year overall survival rates were 71.4%, 63.5%, and 63.5% for craniospinal radiotherapy, 60.0%, 60.0%, and 40.0% for whole brain radiotherapy, and 80.8%, 64.6%, and 64.6% for local field radiotherapy (p = 0.88). The 5-, 10-, and 15-year local control rates were 60.3%, 54.4%, and 48.9%. The prognostic factors for a better local control rate were gross total resection (p = 0.021) and low grade histology (p = 0.031). Seventeen of 43 (39.5%) M0 patients did not respond to treatment; all had local failure and 4 also had a spinal relapse. Spinal relapse developed in 3 of 31 (10%) M0 patients who did not receive spinal radiotherapy, whereas 1 of 12 (8%) who had spinal radiotherapy did not respond to treatment in the spine. The results of this study indicate that local radiotherapy is sufficient for M0 patients with intracranial ependymoma.     

Prospective study of stereotactic radiosurgery without whole brain radiotherapy in patients with four or less brain metastases: incidence of intracranial progression and salvage radiotherapy

This prospective study was conducted to evaluate the treatment outcome after stereotactic radiosurgery (SRS) alone with special attention to its influence on intracranial freedom from progression (FFP), local control, time to whole brain radiotherapy (WBRT), and survival. Forty-one patients with brain metastases who met the inclusion criteria were enrolled in this prospective cohort and treated by SRS alone between January 1998 and September 2001. The overall local control rate was 76%. The one year actuarial intracranial FFP was 33%. Ten patients (24%) had relapse at treated site. Twenty-three patients (56%) had intracranial progression with a median time of 4.25 months (1–24.6). Salvage radiotherapy was given in 21 patients (51%). Only 12 (29%) patients required WBRT with the median time to WBRT after SRS of 4.85 months. Nine patients (22%) underwent additional SRS at the median time of 5 months after the first procedure. The median survival was 10 months. At the time of follow up, 16 patients (39%) were still alive with a range of 6–31 months. This prospective study suggests that the omission of WBRT in the initial treatment of patients with SRS for four or less brain metastases may allow up to 70% of patients to avoid WBRT.     

Assessing perfusion changes during whole brain irradiation for patients with cerebral metastases

Purpose: To assess perfusion changes within brain and correlate these with clinical symptoms during whole brain radiotherapy (WBRT) for cerebral metastases. Materials and methods: Fourteen patients with cerebral metastases underwent dynamic CT perfusion scans during palliative whole brain irradiation. Perfusion scans were performed on Day 1 prior to initial radiotherapy treatment, then on Day 2, and on Day 5 immediately after completion of radiotherapy. Measurements of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and capillary surface area permeability product (PS) were performed for each perfusion scan, and daily symptom assessment was taken prior to initial perfusion scan and thereafter prior to each daily radiation treatment. Results: Utilizing Day 1 as baseline, a 19% increase (P=0.033) was noted in PS at Day 2, (median 1.47 ml/100 g/min), which returned to Day 1 range at Day 5 (median 1.31 ml/100 g/min). When symptoms were correlated with perfusion parameters, a statistically significant association between change in MTT with change in headache scores was observed, baseline to Day 2 (P=0.019), and a trend between change in nausea scores with change in CBV (P=0.059) as well as change in MTT (P=0.098), baseline to Day 5. Conclusion: This study has demonstrated the feasibility of a non-invasive technique to assess changes occurring within the human brain during a course of radiation treatment. Dynamic perfusion tomography provides insight into the pathophysiological processes taking place and allows correlation with patient symptomatology.     

Post-operative thoracic irradiation with or without levamisole in non-small cell lung cancer: results of a Radiation Therapy Oncology Group Study

The Radiation Therapy Oncology Group conducted a Phase III single blind trial to evaluate the addition of Levamisole to post-operative thoracic irradiation (200 cGy five times weekly to a total of 5000 cGy plus 1000 cGy boost) in patients with resected RTOG Stage II-III non-small cell lung cancer with positive nodes. Between February 1980 and February 1983, 74 patients from 18 RTOG institutions were randomized; accrual to this study was prematurely terminated due to poor accrual and the inferior survival observed in the levamisole-treated patients on another RTOG trial. Sixty-four patients were evaluable; 32 assigned to levamisole and 32 were assigned to placebo. Over 95% of the patients have been followed for a minimum of 4 years or to death. Two patients on placebo and 5 on levamisole experienced Grade 3 pneumonitis or esophagitis; 1 patient on placebo and 2 on levamisole experienced Grade 3 pulmonary fibrosis. Three patients on levamisole experienced other Grade 3 or 4 toxicity: 1 case of intractable nausea and vomiting and 2 with Grade 4 neutropenia (less than 500 per mm3). There were no fatal complications. Median disease-free survival was 13 months in the placebo group and 9 months for the levamisole group. Median time to distant metastases was 18 and 12 months, and median survival was 20 and 13 months, respectively. We concluded that this study failed to demonstrate an advantage for levamisole.