Brain metastases as late breast cancer relapse. Single institution experience and review of the literature.

PURPOSE: Approximately 40% of HER2-positive breast cancer patients will develop brain metastases, usually during the first 2-3 years following initial diagnosis and up to 2 years after overt metastatic spread. However, there are no data about brain metastases development as a late disease relapse. In addition, there are no data whether the high incidence of brain metastases is maintained in patients with HER2 overexpression even in late brain metastases. The aim of this paper was to determine the incidence of brain metastases and the HER2 status in patients who developed late relapse, at least 5 years after the initial diagnosis. PATIENTS AND METHODS: Among 384 consecutive breast cancer patients with late relapse, only 8 developed brain metastases. Archival pathological specimens of the primary tumors of those 8 patients were tested by immunohistochemistry (IHC) for HER2 status. RESULTS: The incidence of late brain metastases was 2% (8/384). None of these patients had HER2 3+ primary breast cancer. CONCLUSION: This study shows that the risk for brain metastases in HER2 3+ breast cancer patients is very low or might be even absent as a late relapse. Absence of late brain metastases in HER2 3+ breast cancer might be attributed to specific biological characteristics of HER2 3+ carcinomas to develop brain metastases mostly in the early course of metastatic disease.

[Preoperative chemoradiotherapy in locally advanced esophageal cancer].

Preoperative or definitive chemoradiotherapy defines today the standard treatment of patients with localized or locally advanced esophageal cancer. Preliminary results of our study are presented. 46 patients with locally advanced squamous cell esophageal cancer (T3-4, N0-1, M0) were enrolled. All patients recieved concomitant chemotherapy (Cisplatin/5FU/LV) and radiotherapy (45-50, 4Gy). Clinical response rate was 59% (3 patients (7%) complete response, 24 patients (52%) partial regression, 13 (28%) stabile disease, 6 patients (13%) disease progression). Out of 46 patients, 12 were operated (26%), all with R0 resection. Complete patohistolgical regression (TRG 1) was noted in 5 patients (42%). TRG 2 i TRG 3 in one (8%) and 3 patients (25%), and TRG 4 in 3 patients (25%). Mean survival time in operated group of patients was 9.3 months, and in nonoperated group 5.5 months. Studies show improved survival rate in patients with complete response to chemoradiotherapy and R0 resection. Individualy tailored therapy is essential.

[Combined hormono-radiotherapy in treatment of locally advanced prostate cancer].

Numerous questions regarding combined hormono-radiotherapy in the treatment of locally advanced prostate cancer still remain open. We present results of combined treatment in 133 our patients with locally advanced prostate cancer. All patients recieved hormonotherapy as neoadjuvant, concomitant with radiotherapy (tumor dose range 65-72 Gy), and adjuvant. In six months follow-up time, complete regression (CR) was noted in 120 patients (90%), partial regression (PR) in 6 (4.5%), stabile disease (SD) in 2 (1.5%) and progression of disease (PD) in 5 patients (4%). In mean follow up time of 17 months (6-77), 13 patients relapsed. Five-year time to progression was 70%. Five-year disease-free interval for CR patients was 70%. At the date of last control CR was noted in 116 patients (87%), PR in 2 patients (2%), SD in 7 patients (5%), and 8 patients (6%) had progressive disease. Second malignancy was noted in 4 patients. Multidisciplinary studies directed towards the optimisation of combined treatment are ongoing. There are no definitive conclusions.

The addition of bevacizumab to fluoropyrimidine, irinotecan and oxaliplatin-based therapy improves survival for patients with metastatic colorectal cancer (CRC): combined analysis of efficacy.

BACKGROUND: The primary objective of the analysis was to compare duration of survival in patients who received bevacizumab plus 5FU/LV, irinotecan or oxaliplatin based chemotherapy with the survival rate in a combined control groups of patients who received the same protocols alone, without bevacizumab. METHODS: Pooling of the data from the several studies allows evaluation of efficacy end points with greater statistical power to detect real differences between the groups of patients who were and were not treated with bevacizumab. The 10 studies have to be used for analysis were well designed, prospective trials conducted in patients with metastatic colorectal adenocarcinoma. RESULTS: The median duration of survival was 18/12/11 months median duration of progression free survival was 8.8/7/6.7 months and response rate was 34/14/12% in the 5-FU/LV/bevacizumab group, 5-FU/LV CI group, and bolus 5-FU/LV group, respectively. Difference in OS for patients who received bevacizumab with 5-FU/LV in comparison to 5-FU/LV alone is up to 7 months. The median duration of survival for bevacizumab plus irinotecan-based chemotherapy was 20 months, median duration of progression free survival was 11 months and response rate was 45%. Difference in OS, PFS and RR for patients who received bevacizumab plus irinotecan-based chemotherapy in comparison to irinotecan-based chemotherapy alone is up to 5 months, 4.5 months and 10%. For oxaliplatin-based protocols tumor response was 43-53%, overall survival was 16.4-19.4 months and the median progression free survival was 8-9 months. The median duration of survival was 26 months (benefit is up to 10 months), median duration of progression free survival was 19 months (benefit is up to 10 months) and response rate was 59% (benefit is up to 16%) were achieved for bevacizumab plus FOLFOX4 (oxaliplatin/inf.5FU/LV). CONCLUSIONS: Addition of bevacizumab to 5-FU/LV, irinotecan or oxaliplatin-based chemotherapy provided significantly and clinically meaningful improvement in overall survival, disease-free survival and response rate compared with 5-FU/LV, irinotecan or oxaliplatin-based chemotherapy alone in patients with metastatic CRC.

Chemotherapy by M-VAC protocol in progressive bladder carcinoma treatment.

Treatment of invasive bladder carcinoma is complex therapy procedure which means surgical and non-surgical treatment appliance. In spite of radical surgical treatment conduction, the gold standard in invasive bladder tumor therapy, about 30-40% patients spread metastasis in further disease course. The system chemotherapy in invasive bladder tumors treatments is marked with accent. Its fundamental aim is to correct results of surgical treatment. This therapy option very often means the only modality in bladder carcinoma treatment, for instance, in the diseminal disease faze. The adjuvant chemotherapy imposes a task to correct surgical treatments results in case where the high risk of recidive breaking out exists. As risks for recidive breaking out cite are: a) lymphatic and vascular invasion into the primary tumor; b) extravezical tumor extension-T3b; c) tumor invasion neighboring structures-T4; d) positive lgl findings-N+. After radical cystectomy caused by high level malignancy tumors - T3b,T4, is founded frequency of positive IgI of about 40-60%. Patients with positive lgl have badly prognosis. Only 17% they survive longer than two years, and 7% have surviving of five years.

Incomplete operative removal of colorectal liver metastases followed by chemotherapy decreases survival in comparison to chemotherapy alone.

Metastatic colorectal carcinoma (CRC) has an inevitable fatal outcome except in a small percentage of selected patients, approximately 10-20%, with good prognosis after successful complete operative removal of the liver metastases. In patients not eligible for surgical resection of the liver metastases, chemotherapy is currently the only widely available treatment option. Controversy still exists about the criteria for operability of CRC liver metastases, and some patients, still undergo ineffective, i.e. unnecessary surgery. The aim of this paper is to analyse and compare the overall survival (OS) and time to progression (TTP) in patients who underwent incomplete removal of liver CRC metastases followed by chemotherapy, and patients treated with chemotherapy alone. Seventy-three patients with CRC liver metastases underwent incomplete operative removal of the metastases followed by FOLFIRI (Cohort A - 27 patients) or with FOLFIRI alone (Cohort B - 46 patients). Patients received FOLFIRI until progression. FOLFOX4 was used as second line chemotherapy. The median OS in Cohort A was 8 months, the median TTP was 5 months, and the response rate was 44%; the median OS in Cohort B was 19 months, the median TTP was 8m, and the response rate was 39%. There was a significant difference in OS and in TTP (p < 0.01) in favour of the chemotherapy alone group (B). Patients undergoing incomplete removal of the liver metastases had shorter survival and TTP in comparison with patients treated with chemotherapy alone.

Radiotherapy in prostate cancer treatment.

Prostate cancer is a complex disease, with many controversial aspects of management in almost all stages of disease. The natural history of this tumor is variable and is influenced by multiple prognostic factors. Radical prostatectomy and radiotherapy are standard treatment options for disease limited to the prostate. The data in literature does not provide clear- cut evidence for the superiority of any treatment. Neo- adjuvant or adjuvant hormonal therapy improves local control and survival in locally advanced disease. The patients treated with radiotherapy would have a relatively long life expectancy, not great risk factors for radiation toxicity and a preference for radiotherapy. The advantages of radiotherapy are that it has a significant potential for cure, it is well tolerated in the majority of men especially when the modern techniques of conformal radiotherapy and intensity modulated therapy are used and it is non-invasive therapeutic options with no anesthesia risk. Expected complications like radiation cystitis, impotence and proctitis are registered in about 1% of patients.

Radio (chemo) therapy in locally advanced rectal cancer.

Radiotherapy has an role in combined treatment to lower local recurrence in resectable rectal cancer. Radiotherapy also has an established role in nonresectable rectal cancers to increase the operability, but radiochemotherapy is more efficient. Radiotherapy can be administered as a transcutaneous therapy on the megavoltage machines as well as brachytherapy and combined--transcutaneous and brachytherapy.

[Carcinoma of the anal canal--results of radical radiotherapy]. / Carcinoma of the anal canal--results of the radical radiotherapy.

From February 1995 to August 2001, 34 pts with squamous cell carcinoma of the anal canal (stage T2-35.3%, stage T3-44.1%, stage T4-20.6%, stage N1-29.4%) were treated prospectively by definitive radiotherapy only, delivered with megavoltage linear accelerator, combined with intracavitary brachytherapy in some patients, at the Institute for Oncology and Radiology of Serbia. Total tumor dose was range 55-75 Gy. Median follow-up time was 24.7 mounts (range 6-66 mounts). Overall survival and disease free survival at 5 years were 65.44% and 68.44%. Local control was 82.3% (28/34 pts). Eight pts had local or distant failure. Early and late complication rates were acceptable. In majority of patients the anal sphincter function was preserved.

[Role of radiotherapy in combined therapy of soft tissue sarcoma in children and adolescents]. / Uloga radioterapije u kombinovanom lecenju sarkoma meki tkiva kod dece i omladine.

Over last decades with modern approach to combined treatment of soft tissue sarcoma in children and adolescents, with effective systemic chemotherapy and adequate local control most frequently with conservative surgery and radiotherapy, or radiotherapy alone, results of treatment from 20% of a three-year overall survival to 75% were improved significantly. Nevertheless, combined treatment involves risk of acute radiation reactions and late side effects, so there is a need for precise radiotherapy planning with optimal schedule of fractionating, adequate radiation volume and optimal tumour dose. The purpose of our study was to evaluate the results of combined treatment of soft tissue sarcoma, role of radiotherapy in local control use of the optimal tumour dose and assessment of acute radiation reactions in an examined group of patients. A retrospective clinical study involved 47 patients treated with radiotherapy at the Institute of Oncology and Radiology of Serbia over the period from 1990 to 1997. The most frequent tumour sites were the head and neck and the extremities. According to the IRS classification most patients were in CS III (21 patients). Forty patients had histological type--Rhabdomyosarcoma (Table 1). All patients were treated with chemotherapy, and local therapy were surgery and radiotherapy or radiotherapy alone. Thirty one patients were operated on. All 47 patients were treated with radiotherapy; in 37 patients as primary treatment and in 10 patients as therapy for local relapse. Radiotherapy was planned according to tumour size, tumour site, age of the patient and type of surgery. Tumour dose from 45 Gy to 60 Gy was given in cases with a residual tumour. Lower tumour doses were used in cases of postoperative microscopic disease, in certain cases of local relapse treatment or when the size of residual tumour and patient's age allowed no delivery of higher tumour doses. Standard fractionating regimen was given to all patients, with daily fractions from 150 cGy to 214 cGy, five times per week. The majority of patients (24) were treated on Linear Accelerator machine with X photons of 10 MeV energy and with X photons of 6 MeV energy (13 patients) (Table 2). Statistical data processing was made by the following methods: Kaplan-Meier for survival rate and Long-rang and Wilcox test for assessment of the statistical significance in survival difference. In our group of patients treated over the period from 1990 to 1997 a three-year overall survival was 59.15%, and disease free survival was 46.68% (Figure 1). There were 21 patients (44.7%) without signs of the disease, 12 patients had a local disease (25.5%), 9 patients had both local and metastatic disease (19.1%) and 5 patients had only metastatic disease (10.50%). In the group of 47 patients who received radiotherapy, 24 patients received a tumour dose from 45 Gy to 60 Gy and 23 patients a tumour dose from 32 Gy to 45 Gy. The group of patients treated without tumour dose more than 45 Gy had a significantly better overall survival rate (p = 0.002) (Figure 2). Although the obtained results are in agreement with data from literature, a critical analysis is necessary. Namely, in addition to the group irradiated with a tumour dose from 32 Gy to 45 Gy, because of the postoperative microscopic disease, certain number of patients was irradiated with a "lower" dose because of an objective impossibility to administer a "higher" dose or this dose was planned for palliative reasons. The tumour dose of 45 Gy was delivered to 6 of 10 patients treated for local relapse. The tumour dose of 45 Gy was also used in four patients in CS IV, in two subjects for local control and in two as a palliative treatment. Seven patients in CS III received a tumour dose of 45 Gy, because the age of children, tumour site and tumour size permitted no higher tumour doses. That is when planning an adequate local therapy one must have in mind the initial tumour size, type of administered systematic chemo

[Radiotherapy of local recurrence of rectal carcinoma]. / Radioterapija lokalnih recidiva karcinoma rektuma.

In retrospective, non-randomized study were analyzed 45 patients with local recurrences of rectal carcinoma treated by combined external beam radiotherapy (EBRT) and "High dose rate (HDR) remote afterloading" brachytherapy in the period from January 1st, 1988 to May 1st, 1988. Depending on the localization of the local recurrent disease, 20 patients were with vaginal relapse, 13 with vaginal and presacral, 9 with perineal and 3 with presacral and rectal. Combined radiotherapy was applied as follows: 33 patients (73.3%) had EBRT with endovaginal brachytherapy, 3 (6.7%) EBRT plus intraluminal brachytherapy and 9 (20%) patients EBRT plus interstitial brachytherapy. Techniques with 3 and 4 field for EBRT were used and doses ranged 45-65 Gy with convenient fractionation were applied, combined with the doses ranged 15-35 Gy for brachytherapy. Radiotherapy was planned according to the computer tomography cross image on simulator with computer planning. Complete regression of the tumor was observed in 19 patients (42.2%), and partial in 23 patients (51.1%). Median follow-up period was 34 months (8-72). Acute radiation adverse effects were registered in 32 patients, and late sequels in 6 (13.3%). Overall 3-year survival rate was 54% and disease-free survival rate was 34% in the same period.

[Palliative irradiation in the treatment of breast carcinoma]. / Palijativno zracenje u lecenju karcinoma dojke.

It is considered that in 30% of female patients with breast cancer a certain form of evolutive disease occurs within 5 years from documented diagnosis. In these female patients, 58% develop distal metastases. Thus, a great number of these female patients enter the phase when hope for recovery is small. Then supportive therapy is used. It's main task is to alleviate the life of these patients. Palliative radiotherapy is one of the main elements of this therapy. It is directed to decrease the pain, and bleeding, to prevent fractures and decompression of the spinal cord, as well as many other evolution consequences of local or distal disease. The correct and timely definition of indications for radiotherapy, the optimal planning and conduction of the therapy should take into account the patient's characteristics as well as the main postulates on which radiotherapy is based. In this way the satisfying effects on patients with disseminated breast cancer, may be expected.

[Local recurrence after preoperative irradiation and radical surgery in patients with locally advanced breast carcinoma (clinical stage A)]. / Lokalni recidiv kod preoperaciono zracenih i radikalno operisanih bolesnica s lokalni napredovalim karcionomom dojke (klinicki stadijum tredji-A).

The rationale preoperative irradiation is expressed by the sound: eradication of sensitive tumour cells at the periphery of a lesion making complete resection more likely and dissemination of tumour cells by operative manipulation less likely. The dose of irradiation required is approximately 80 to 85% of the dose needed to permanently control the palpable disease, a dose which does not interfere with subsequent mastectomy, if 3 to 4 weeks elapse between the termination of irradiation and mastectomy. One hundred fifteen consecutively examined patients with stage IIIa breast cancer were treated over the period from January 1985 to December 1987 at the Institute of Oncology and Radiology, Belgrade, Serbia. We were interested in the local control of preoperatively irradiated and radically operated patients with the median follow-up of 82 months. Fifteen patients had local recidives, the local control was made in 87%, in the interval between 6 and 66 months (median 18 months). We analyzed the correlation between the local control and the grade of malignancy (GM) of the axillary lymph node and the T status of the tumour. GM was more important than T. Based on our results and on those of other authors, we believe that this multimodal regimen, which includes preoperative irradiation, radical mastectomy and adjuvant cheme-hormonotherapy, is satisfactory for patients with stage IIIa primary breast cancer.

[Combined radio-chemotherapy in solid tumour treatment of advanced bladder cancer (preliminary report)]. / Kombinovana radioterapija i hemoterapija kod bolesnika sa solidnim tumorima (prethodni izvestaj o lecenju napredovalih carcinoma mokracne besike).

Radiotherapy combined with platinum compounds in widely used despite unclear biological basis and mechanism of their potentiation. We started a prospective nonrandom study on January 1, 1991 with the aim to ameliorate local tumour control and possibility of curative treatment, and treatment of toxicyty. PATIENTS CHARACTERISTICS: 82 patients with locally advanced bladder cancer (stage T3 and localizet T4) were treated with radiochemotherapy. Median age was 62 years, and male female radio was 3.5:1. The whole group had transitpy cell carcinoma, grade III, with primary tumour in 56 patients and solitary tumour in 51 patients. TREATMENT: External beam radiotherapy was performed on linear accelerator with locoregional technique, conventional fractionating and tumour dose of 65 Gy. On the lifth day of radiotherapy a 20 mg i.v. bolus Cisplatin 1 hour prior radiotherapy was administered to 49 patients. Total dose of Cisplatin was 120 mg per course. Carboplatin was given (75 mg i.v.) to 12 patients in the same way like Cisplatin, with total dose od 450 mg. In 21 patients Carboplatin was administered in a dose of 150 mg (fifth day) during radiotherapy, and total dose was 900 mg. TOLERANCE: The toxicity was mild in both groups of patients: 2/49 patients in Cisplatin group experienced nausea and 2/49 experienced haematological toxicity grade II as wel as 5/33 patients from Carboplatin group. RESPONSE: Tumours complete regression was observed in 69.4% of patients in Cisplatin group and in 84.6% in Carboplatin group. Mean follow-up was 14 months in Cisplatin group and overall survival was 77% at a 2-year interval, these results are not-suphicicent for the binal conclusion conserning the late complications and the clinical benefit, but the treatment was well tolerated. We intend to increase Carboplatin dose in our fur ther study.