Abraham Kuten

External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study

BACKGROUNDnWe did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results.nnnMETHODSnFor this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1-2 prostatic adenocarcinoma with WHO histological grade 3 or T3-4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0-2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3·6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082.nnnFINDINGSnBetween May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9·1 years (IQR 5·1-12·6). 10-year clinical disease-free survival was 22·7% (95% CI 16·3-29·7) in the radiotherapy-alone group and 47·7% (39·0-56·0) in the combined treatment group (hazard ratio [HR] 0·42, 95% CI 0·33-0·55, p<0·0001). 10-year overall survival was 39·8% (95% CI 31·9-47·5) in patients receiving radiotherapy alone and 58·1% (49·2-66·0) in those allocated combined treatment (HR 0·60, 95% CI 0·45-0·80, p=0·0004), and 10-year prostate-cancer mortality was 30·4% (95% CI 23·2-37·5) and 10·3% (5·1-15·4), respectively (HR 0·38, 95% CI 0·24-0·60, p<0·0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0·60) and in those who did not (14 of 154 vs six of 145; p=0·25). Two fractures were reported in patients allocated combined treatment.nnnINTERPRETATIONnIn patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity.

Impact of the boost dose of 10 Gy versus 26 Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy : 10-year results of the randomised EORTC boost trial

PURPOSEnTo assess the impact of the boost dose in patients with involved surgical margins.nnnPATIENTS AND METHODSnIn the EORTC boost versus no boost trial, 251 patients with a microscopically incomplete tumour excision were randomised to receive either a low boost dose of 10 Gy (126 patients) or a high boost dose of 26 Gy (125 patients). Overall survival and the cumulative incidence of local recurrence as first event were compared by Logrank and Gray test, respectively (2-sided alpha=0.05), with a median follow-up of 11.3 years. The planned sample size was 660 patients, but only 251 were recruited.nnnRESULTSnThe median age at randomisation was 54 years. Thirty-seven patient initially relapsed locally. At 10 years, the cumulative incidence of local recurrence was 17.5% (95% CI: 10.4-24.6%) versus 10.8% (95% CI: 5.2-16.4%) for the low and high boost dose groups, respectively (HR=0.83, 95% CI: 0.43-1.57, Gray p>0.1). Overall, 64 patients have died (25.5%), 47 of them of breast cancer, without a difference in duration of survival between the two groups (HR=0.97, 95% CI=0.59-1.5, p>0.1). Severe fibrosis was palpated in the breast in 1% versus 5% and in the boost area in 3% versus 13% in the low and high boost dose groups, respectively.nnnCONCLUSIONSnThere was no statistically significant difference in local control or survival between the high boost dose of 26 Gy and the low boost dose of 10 Gy in patients with microscopically incomplete excision of early breast cancer. Fibrosis, however, was noted significantly more frequently in cases treated with the high boost dose.

Splenomegaly and solitary spleen metastasis in solid tumors

Metastasis to the spleen from various neoplasms is very rare. Most of the splenic metastases are found at autopsy, and are part of a widespread disease. Four patients had cervical cancer (1 patient), endometrial cancer (1 patient), lung carcinoma (1 patient), and malignant melanoma (1 patient). All patients had splenic involvement without pathologic evidence of lymph node metastasis, and all underwent splenectomy. Three of the four presented with painful splenomegaly. The time from diagnosis to the development of splenic metastasis varied from 20 to 24 months. Two of the four patients had postoperative radiotherapy, one patient received intraperitoneal chemotherapy, and the patient with the melanoma received adjuvant chemotherapy. The rarity of solitary spleen metastasis from solid tumors and the treatment modalities are discussed.

Increased emotional distress in daughters of breast cancer patients is associated with decreased natural cytotoxic activity, elevated levels of stress hormones and decreased secretion of Th1 cytokines

DBCP who are aware of their increased risk of developing breast cancer may suffer from high emotional distress. Chronic stress may interfere with NCA and low NCA is associated with increased cancer risk. We studied 80 DBCP and 47 age‐ and education‐matched healthy females (controls). Heparinized venous blood (30 ml) was drawn from all subjects between 8 and 9 A.M., and each participant answered a set of psychologic questionnaires. In addition, the first‐morning urine sample was collected. DBCP scored significantly higher in emotional distress compared to controls. Levels of stress hormones in DBCP were higher and in vitro secretion of IL‐2, IL‐12 and IFN‐γ lower compared to controls. NCA against NK‐resistant (MCF‐7, COLO‐205, U937) and NK‐sensitive (K562) cell lines was significantly lower in DBCP and much less augmented by in vitro preincubation with IL‐2 or IL‐12 compared to controls. NCA and in vitro Th1 cytokine secretion were inversely correlated with the degree of emotional distress and the level of stress hormones in blood or urine. High emotional distress and elevated levels of stress hormones are associated with impaired immune surveillance functions in DBCP. This may contribute to the increased risk of DBCP to develop breast cancer. An interventional trial to enhance coping and reduce stress levels may help to decrease the risk for breast cancer onset in DBCP.

Involvement of the central nervous system by ovarian carcinoma

Ovarian carcinoma rarely metastasizes to the central nervous system (CNS). Of 110 patients with epithelial ovarian carcinoma treated at the Northern Israel Oncology Center between the years 1979 and 1985, only five (4.5%) had CNS involvement. The median age of the patients was 54.5 years. All of them had treatment with cisplatin and Adriamycin (doxorubicin). The median duration from diagnosis to the development of brain involvement was 17 months. The median survival time was 28 months from diagnosis of carcinoma and 2 months from diagnosis of CNS disease. The increased incidence of this kind of metastasis in patients achieving local control of their advanced disease suggests that a change in the pattern of metastatic spread or the prolonged survival permits occult CNS metastases to become apparent. A routine computerized axial tomography (CAT) scan of the brain should therefore be performed on patients with ovarian carcinoma with prolonged survival.

Follicular carcinoma of the thyroid gland: prognostic factors, treatment, and survival.

Prognostic variables and treatment outcomes of 82 patients treated at the Northern Israel Oncology Center were reviewed. There were 59 women and 23 men in this series. The female/male ratio was 2.6/1. Median age was 46 years. Median follow-up was 11.4 (range: 3.8-24 years). Median tumor size was 3.6 cm. When first seen, 4 patients had lymph node involvement and 11 (13%) had distant metastases. Surgical treatment was total thyroidectomy in 37 patients (45%), subtotal thyroidectomy in 38 (46%), and lesser procedures in 7 (9%). Sixty-six patients (80%) were treated after surgery with 131I to ablate thyroid remnants. Doses ranged between 30 and 80 mCi. The 20-year overall actuarial survival rate was 65%. The actuarial survival rate of patients <40 years of age was 96% versus 33% in patients >50 years of age (p = 0.0008). Patients with distant metastases at presentation had inferior survival compared with patients without metastases. In conclusion, we found subtotal thyroidectomy followed by 131I and hormone therapy to provide survival similar to that with total thyroidectomy, with less morbidity. Risk factors include: age > or =40 at the time of diagnosis, presence of distant metastases, capsular invasion, tumor size > or =2 cm, and male gender.

TOTAL SKIN ELECTRON IRRADIATION. EVALUATION OF DOSE UNIFORMITY THROUGHOUT THE SKIN SURFACE

In this study, in vivo dosimetic data of 67 total skin electron irradiation (TSEI) treatments were analyzed. Thermoluminescent dosimetry (TLD) measurements were made at 10 different body points for every patient. The results demonstrated that the dose inhomogeneity throughout the skin surface is around 15%. The homogeneity was better at the trunk than at the extratrunk points, and was worse when a degrader was used. There was minimal improvement of homogeneity in subsequent days of treatment.

Cisplatin treatment triggers familial mediterranean fever attacks

A 42-year-old familial Mediterranean fever (FMF) patient who was treated with cisplatin-based chemotherapy for adenocarcinoma of the lung developed severe and frequent attacks of FMF during treatment. Abdominal pain, arthralgia and fever occurred for a few days following each cisplatin cycle. His FMF worsened, the abdominal pain and fever lasted longer and treatment with colchicine was ineffective. It has been hypothesized that the link between cisplatin treatment and FMF attacks lies in an increased production of serotonin, IL-6, IL-1, IL-8 and TNF-alpha. These inflammatory cytokines have been reported to be overproduced during cisplatin treatment and are known to play an important role in FMF relapse. The oncologist should be made aware of the possibility of disease aggravation in FMF patients during cisplatin-based chemotherapy.

Outcome and prognostic factors in endometrial stromal tumors: a Rare Cancer Network study

PURPOSEnTo provide further understanding regarding outcome and prognostic factors of endometrial stromal tumors (EST).nnnMETHODS AND MATERIALSnA retrospective analysis was performed on the records of 59 women diagnosed with EST and treated with curative intent between 1983 and 2007 in the framework of the Rare Cancer Network.nnnRESULTSnEndometrial stromal sarcomas (ESS) were found in 44% and undifferentiated ESS (UES) in 49% of the cases. In 7% the grading was unclear. Of the total number of patients, 33 had Stage I, 4 Stage II, 20 Stage III, and 1 presented with Stage IVB disease. Adjuvant chemotherapy was administered to 12 patients, all with UES. External-beam radiotherapy (RT) was administered postoperatively to 48 women. The median follow-up was 41.4 months. The 5-year overall survival (OS) rate was 96.2% and 64.8% for ESS and UES, respectively, with a corresponding 5-year disease-free survival (DFS) rate of 49.4% and 43.4%, respectively. On multivariate analysis, adjuvant RT was an independent prognostic factor for OS (p = 0.007) and DFS (p = 0.013). Locoregional control, DFS, and OS were significantly associated with age (≤60 vs. >60 years), grade (ESS vs. UES), and International Federation of Gynecology and Obstetrics stage (I-II vs. III-IV). Positive lymph node staging had an impact on OS (p < 0.001).nnnCONCLUSIONnThe prognosis of ESS differed from that of UES. Endometrial stromal sarcomas had an excellent 5-year OS, whereas the OS in UES was rather low. However, half of ESS patients had a relapse. For this reason, adjuvant treatment such as RT should be considered even in low-grade tumors. Multicenter randomized studies are still warranted to establish clear guidelines.

Low-dose iodine-131 metaiodobenzylguanidine therapy for patients with malignant pheochromocytoma and paraganglioma: single center experience.

The following is a report on the clinical experience of an Israeli referral center for iodine-131 metaiodobenzylguanidine (131-MIBG) therapy for malignant pheochromocytoma (MPCC) and malignant paraganglioma (MPGG). The charts of 10 patients with MPCC (n = 7) and MPGG (n = 3) treated between 2000 and 2008 were reviewed. Response to 131-MIBG therapy was evaluated by tumor, hormone, and symptomatic relief criteria. The median follow-up was 18 months (2–48 months). The number of 131-MIBG treatments ranged from 1 to 4 (mean: 2.1). The average single dose of 131-MIBG was 5.4 ± 0.2 GBq (145 ± 5.0 mCi). The average cumulative dose was 11.6 ± 1.6 GBq (310 ± 44.0 mCi). There were no complete responses. Three patients (30%) had partial tumor response, 5 (50%) had stable disease, and 2 (20%) progressed after therapy. Five patients (50%) experienced symptomatic response. Hormone response was noted in 5 patients (50%). Progression-free survival was 17.5 months (2–47 months). One patient (10%) had thrombocytopenia and 2 patients (20%) developed subclinical hypothyroidism. Hormonal and symptomatic relief can be achieved with 131-MIBG therapy in patients with MPCC and MPGG with minor side effects.