High-dose rate brachytherapy in the treatment of prostate cancer: acute toxicity and biochemical behavior analysis

Abstracts

OBJECTIVE: This study focuses on the biochemical response of the following variables: prostate volume, prostate-specific antigen (PSA) value, Gleason scores, staging, the risk of the disease, and hormonotherapy. MATERIALS AND METHODS: In the period between February of 1998 and July of 2001, 46 patients with prostate cancer were treated with radiotherapy, in a combination of teletherapy and high-dose rate brachytherapy (HDR). The age ranged from 51 to 79 years (averaging 66.4 years). T1c stage was the most frequent one: 30 (65%). The Gleason score was below 7 in 78% of the patients. PSA ranged from 3.4 to 33.3, being below 10 in 39% of the cases. The average prostatic volume was 32.3cc. Twenty-eight percent of the patients received hormonotherapy. Teletherapy dose ranged from 45 to 50.4 Gy, associated to four fractions of 4 Gy of HDR. RESULTS: The follow-up period varied from 6 to 43 months. Four patients missed the follow-up and four died (one due to the disease). Out of the 39 patients that were analyzed, 76% presented a less than 1.5 PSA. None of the analyzed variables were found to be of statistical significance (p>0.05) regarding biochemical control. CONCLUSION: The use of HDR brachytherapy was found to be effective in the treatment of prostate cancer and, in this study, the variables considered as prognostic factors did not interfere in the biochemical control.

Prostate cancer; Brachytherapy; Interstitial radiotherapy

OBJETIVO: Analisar a resposta bioquímica nas variáveis volume prostático, valor do antígeno prostático específico (PSA), escores de Gleason, estádio, risco da doença e hormonioterapia. MATERIAIS E MÉTODOS: No período de fevereiro de 1998 a julho de 2001, 46 pacientes com câncer de próstata foram tratados com radioterapia, numa combinação de teleterapia e braquiterapia de alta taxa de dose (BATD). A idade variou de 51 a 79 anos (média de 66,4 anos). O estádio T1c foi o mais freqüente: 30 (65%). O escore de Gleason era abaixo de 7 em 78% dos pacientes. O PSA variou de 3,4 a 33,3, estando abaixo de 10 em 39% das vezes. O volume prostático médio foi de 32,3 cc. Um total de 28% dos pacientes recebeu hormonioterapia. A dose de teleterapia variou de 45 a 50,4 Gy, associada a quatro frações de BATD de 4 Gy. RESULTADOS: O seguimento variou de 6 a 43 meses. Quatro pacientes perderam seguimento e quatro morreram (um por doença). Dos 39 pacientes analisados, 76% apresentaram PSA menor que 1,5. Nenhuma das variáveis analisadas foi estatisticamente significante (p > 0,05) com relação ao controle bioquímico. CONCLUSÃO: A utilização de BATD foi eficiente no tratamento do câncer de próstata e, neste estudo, as variáveis consideradas como fatores prognósticos não interferiram no controle bioquímico.

Câncer de próstata; Braquiterapia; Radioterapia intersticial

ORIGINAL ARTICLE

High-dose rate brachytherapy in the treatment of prostate cancer: acute toxicity and biochemical behavior analysis^*

Sérgio Carlos Barros Esteves^I; Antonio Carlos Zuliani de Oliveira^I; Herbeni Cardoso^I; Eduardo Komai Tagawa^I; Márcio D'Império^II; Roberto Castelo^III

^IMD Radiotherapists

^IIMD Urologist

^IIIMD Radiologist

^{Mailing address}

ABSTRACT

OBJECTIVE: This study focuses on the biochemical response of the following variables: prostate volume, prostate-specific antigen (PSA) value, Gleason scores, staging, the risk of the disease, and hormonotherapy.

MATERIALS AND METHODS: In the period between February of 1998 and July of 2001, 46 patients with prostate cancer were treated with radiotherapy, in a combination of teletherapy and high-dose rate (HDR) brachytherapy. The age ranged from 51 to 79 years (averaging 66.4 years). T1c stage was the most frequent one: 30 (65%). The Gleason score was below 7 in 78% of the patients. PSA ranged from 3.4 to 33.3, being below 10 in 39% of the cases. The average prostatic volume was 32.3 cc. Twenty-eight percent of the patients received hormonotherapy. Teletherapy dose ranged from 45 to 50.4 Gy, associated to four fractions of 4 Gy of HDR brachytherapy.

RESULTS: The follow-up period varied from 6 to 43 months. Four patients missed the follow-up and four died (one due to the disease). Out of the 39 patients that were analyzed, 76% presented a less than 1.5 PSA. None of the analyzed variables were found to be of statistical significance (p > 0.05) regarding biochemical control.

CONCLUSION: The use of HDR brachytherapy was found to be effective in the treatment of prostate cancer and, in this study, the variables considered as prognostic factors did not interfere in the biochemical control.

Keywords: Prostate cancer; Brachytherapy; Interstitial radiotherapy.

INTRODUCTION

Following surgery, brachytherapy was the therapeutic practice with greater impact on solid tumors at the early 20th century. At that time the teletherapy equipment (external radiotherapy) were of a low energy level and did not provide adequate doses at the required depth. On a comparative basis, brachytherapy provided high concentrated dose in restricted volumes, with normal surrounding structures receiving low radiation doses.

The first prostate implant in the United States of America was performed by Barringer in October, 1915 at the Memorial Hospital, using radioactive needles introduced through the perineum and guided by rectal touch.

There were many technical difficulties with the radioactive isotope. The professional was exposed to radiation, the decay produced toxic gases and one could not achieve an adequate distribution of the radioactive isotope in the entire prostate.

After World War II there were important technological breakthroughs with the discovery of new radioactive elements and the development of equipment with higher energy levels and penetration capabilities.

The linear accelerator appeared to be capable of solving the problems associated with the treatment of prostate carcinoma. However, the maximum tolerable dose for an acceptable level of complications (approximately 5%) is between 6,500 and 7,000 cGy. With brachytherapy, one can reach a twice as high dose level with the same complication rate.

Nowadays, the two techniques (teletherapy and brachytherapy) are greatly improved. Conformational teletherapy, with three dimensional planning, allows for higher doses (~8,000 cGy) with low toxicity⁽¹⁾. On the other hand, brachytherapy with the use of miniature sources, guided by remote control, allows the greater accuracy in the technique, without exposing the physician or the paramedics to radiations.

The prostate implant can be either permanent or temporary. In the permanent implants the most used isotopes are currently palladium-103 and iodine-125. In this study, temporary iridium-192 implants were applied, using high-dose rate (HDR) brachytherapy equipment associated with teletherapy (conformational therapy).

Several world centers, such as Kiel in Germany, Seattle in Washington, Royal Oak in Michigan and Long Beach in California started using HDR brachytherapy in the treatment of prostate carcinoma in the eighties⁽²⁾. In Brazil, some services have already treated hundreds of patients using this method.

The objective of this study was to evaluate the rate of biochemical response to prostate-specific antigen (PSA), the influence of several variables (age, prostate volume, PSA, Gleason, staging, risk and hormonotherapy) in the biochemical control and the acute and subacute complications of the procedures, according to the grading of the Radiation Therapy Oncology Group (RTOG)⁽³⁾.

MATERIALS AND METHODS

This clinical study, with a prospective character, included patients with prostate carcinoma with life expectancy > 10 years and Karnofsky > 70⁽⁴⁾, clinical stage T₁ to T₃, with staging examinations and prostatic volume < 60 cm³. The patients submitted to previous treatment (complete radiotherapy and/or surgery) clinical stage T4, prostatic volume > 60 cm³ and Karnofsky < 70 were excluded.

In the period between February of 1998 and July of 2001, 46 patients were treated with radiotherapy, associating teletherapy with HDR (high dose rate) brachytherapy.

The patients' age ranged from 51 to 79 years (averaging 66.4 years). Thirty patients were staged as T1c, seven as T2a, eight as T2b and one as T3a.

All patients had adenocarcinoma as histological type, with Gleason values (total) distributed as follows: Gleason 2, one patient; Gleason 3, two patients; Gleason 4, six patients; Gleason 5, ten patients; Gleason 6, 17 patients; Gleason 7, seven patients; Gleason 8, two patients. Gleason value remained unknown in only one patient. Initial PSA ranged from 3.4 to 33.1.

The pretreatment prostate volume ranged from 15 to 67 (average volume = 32.3 cc). Thirteen patients were submitted to previous hormone treatment (only as neoadjuvance) with central blockade in three patients, peripheral blockade in nine patients and complete blockade in three patients.

As far as risk is concerned, and according to Table 1, eight patients were classified as high risk, sixteen as intermediate risk and twelve as low risk^(5,6).

The external radiation dose was 5,040 cGy in 28 applications of 180 cGy, using a linear accelerator of 6 MV of photon energy, and conformational treatment technique. Six daily treatment fields were performed, with multileaf collimators or appropriate collimators (Figure 1).

For the brachytherapy implant, the patient is admitted on the previous day and is submitted to tricotomy and bowel cleaning.

The patient receives block anesthesia (spinal anesthesia) and is put in semilithotomy position. Prostatic examination under anesthesia and transrectal ultrasound in sagittal and coronal views are performed to assess the presence of lesions and to determine the prostatic volume. Prostatic examination under anesthesia and transrectal ultrasound in sagittal and coronal views is performed to assess the presence of lesions and determination of the prostatic volume. After this procedure, asepsis is performed, and a Foley 14-16 vesical probe is placed.

The needle procedure is guided by transrectal ultrasound and by the perineal template. The needles implantation is symmetrically performed in the whole prostatic volume, with the identification of each needle and its extension inside the prostate. After the needles are in place, the template is fixed on the patient's perineum with suture points.

Markers are introduced in the needles, and anteroposterior and lateral views x-rays are made (Figure 2).

The data is fed into the computer to calculate the best distribution of the sources and the dose to be applied on the target volume (Figure 3).

The needles are connected to the brachytherapy equipment and four fractions of 400 cGy are applied with a minimum interval of six hours. The patient is given antibiotics and analgesics (Figure 4).

At the end of the treatment, the template is removed along with the needles, with local compression for hemostasis.

The brachytherapy was performed between 10 and 15 days after the end of teletherapy treatment, with the exception of two patients that were submitted to brachytherapy before teletherapy.

The brachytherapy implant volume (target volume) was smaller than 50 cc in 43 patients (93.5%) and greater than 50 cc in three patients (6.5%).

The biochemical response analysis started within one month after the end of radiotherapy and after that every three months in the first year and every four months in the second year. For the patients with a satisfactory PSA evolution, the continuation of the control was once every six months.

The analyzed variables with regards to biochemical control were: age, histological grade (Gleason), clinical stage, PSA value, prostatic volume, hormonotherapy use and disease risk (high, intermediate and low).

The descriptive analysis was made by means of frequency tables for the category variables, and measurement of position and dispersion for the continuous variables. In order to compare proportions or to check for associations, the Fisher's exact test was used. For the comparison of continuous or orderable measurements between two groups, the Mann-Whitney test was used. The level of significance adopted was 5%.

RESULTS

The follow-up ranged from 6 to 43 months. Of the 46 patients treated with this technique of teletherapy and brachytherapy, 38 were adequately followed-up with PSA assessment. Four patients missed follow-up, and four died, one on account of the disease, one due to heart complications and two due to unknown causes.

Among the 39 analyzed patients up to the time of writing of this study, 26 had a nadir PSA below 1.0; three patients had PSA between 1.0 and 1.5; three patients between 1.5 and 2.0, six patients had PSA greater than 2.0 (among these, one eventually had PSA < 1.0).

Considering the PSA < 1.5, the current biochemical control is in 76.32% of the patients treated with radiotherapy.

Amongst the analyzed variables, none was of statistical significance relative to biochemical control, as shown on Table 2.

Only three patients presented toxicity in the genitourinary tract, with grade I in two patients (5.1%) and grade II in one patient (2.5%).

DISCUSSION

The HDR brachytherapy is a well established treatment for the therapeutics of gynecological tumorsin the literature⁽⁷⁾ and its effectiveness has been proved for other tumors such as the prostate ones⁽⁸⁾. Recent studies evaluating the biological effects of radiation show that the therapy with high rate doses can be superior to that with low rate doses, depending upon the target tissue⁽⁹⁾.

The ease of the method, the low cost when compared to permanent implants and its versatility should be considered as advantages over the other therapeutic approaches.

The procedure is well tolerated by patients, and the inherent complications of the treatment are very small.

The studied group had an average age of 66.4 years. The eldest patient was 69 years old. This shows that the tolerance to treatment is very good even among the elderly.

The majority of the patients (65.2%) were staged as T1c, a significant factor in patient selection, considering that substaging is relatively frequent as shown by anatomopathological findings. Certainly, among these patients staged as T1c, there are some with more advanced disease.

Eighty percent of the patients presented Gleason < 7. This situation is good for HDR brachytherapy, as the tumors with low histological grade are subject to greater biological effect of HDR brachytherapy⁽⁹⁾.

As an isolated factor, PSA was below 10 in 53% of the treated patients. In these cases, a smaller probability of disease dissemination is expected. Considering the other factors (stage and Gleason), the patients were stratified as low, intermediate and high risk. We have observed that the majority of the cases were of intermediate risk (44%) while 33% were of low risk and 22% were of high risk. The results could have been more satisfactory if we had a higher number of low risk patients⁽¹⁰⁾.

All analyzed variables did not demonstrate any significance with relation to biochemical control. This result may be related to the small number of studied patients, and also to the very short follow-up interval for the disease in study.

REFERENCES

Received April 30, 2004.

Accepted after revision June 17, 2005.

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*

Study developed at the Radiotherapy and Urology Services of Beneficência Portuguesa de São Paulo, Hospital São Joaquim, São Paulo, SP, Brazil.

Publication Dates

• Publication in this collection
  25 May 2006
• Date of issue
  Apr 2006

History

• Accepted
  17 June 2005
• Received
  30 Apr 2004