Early toxicity of combined treatment in localised and locally advanced prostate cancer:
hormone therapy with conformal radiotherapy
Artykuł opublikowany w Urologii Polskiej 2002/55/2.
Piotr Milecki 1, Grażyna Stryczyńska 1, Tomasz Stachowski 2, Zbigniew Kwias 2
- 1 Department of Radiotherapy, Wielkopolskie Cancer Centre, Poznań, Poland, Head of the Department: Grażyna Stryczyńska, PhD, MD.
2 Chair of Urology, University School of Medical Sciences, Poznań, Poland, Chair of Urology: Zbigniew Kwias, PhD, MD
stercz - rak gruczołu krokowego f radioterapia | leczenie hormonalne > ostra toksyczność
- Cel. Celem pracy byta ocena wczesnej toksyczności skojarzonego leczenia (hormonoterapia + radioterapia konformlna 3 D [3 D-CRTJ) u chorych z rakiem gruczołu krokowego.
- Materiał i metody. W okresie od kwietnia 1999 roku do grudnia 2000 roku w Wielkopolskim Centrum Onkologii w Poznaniu 42 chorych z rakiem gruczołu krokowego (T1-T3N0M0) zostało leczeniu podanych radioterapią konformalna 3 D w skojarzeniu z hormonoterapia. Analizowana grupa chorych obejmowała następujące stopnie zaawansowania klinicznego: Tl = 4 chorych, T2 = 11 chorych, T3 = 27 chorych. U żadnego z podanych analizie nie stwierdzono obecności przerzutów odległych. U wszystkich chorych przed rozpoczęciem leczenia napromienianiem, oraz w jego trakcie, zastosowano leczenie hormonalne, składające się z agonisty LHRH lub obustronnej orchidektomii w skojarzeniu z flutamidem. Leczenie napromienianiem prowadzono przy zastosowaniu fotonów 15 MV w dziennej dawce 1,8 Gy do średniej dawki całkowitej 71,7 Gy (67,8-72 Gy). Ostry odczyn popromienny był oceniany według klasyfikacji zaproponowanej przez Radiation Therapy Oncology Group (RTOG).
- Wyniki. Wszyscy chorzy ukończyli cały cykl napromieniania bez konieczności wprowadzania dodatkowych przerw z powodu nasilenia objawów ubocznych terapii. Do najczęstszych objawów ubocznych prowadzonego leczenia hormonalnego w analizowanej grupie zaliczono: „uderzenia gorąca\", poty, powiększenie gruczołów piersiowych, uczucie dyskomfortu w jamie brzusznej. Wszystkie powyższe dolegliwości miały niewielkie nasilenie i nie stanowił)\' znaczącego problemu u obserwowanych chorych. Istotne dolegliwości były natomiast związane z objawami ubocznymi prowadzonego leczenia napromienianiem. Objawy uboczne pojawiały się zwykle od 2. tygodnia radioterapii, a ustępowały w zwykle około kilku tygodni po zakończeniu radioterapii. Ze strony dróg moczowych ostry odczyn popromienny w stopniu 0. i 1. odnotowano u 80% chorych, a w stopniu 2. u 20%. Natomiast w dolnym odcinku przewodu pokarmowego ostry odczyn popromienny w stopniu 0. i 1. stwierdzono u 75% chorych, a w stopniu 2. u 25% chorych. Podsumowanie. Wstępne wyniki oceny wczesnej toksyczności skojarzonego leczenia (hormonoterapia + radioterapia konformal-na 3 D) sugerują dobrą tolerancję takiego sposobu postępowania u chorych z rakiem gruczołu krokowego.
The number of diagnosed cases of prostate cancer increases in Poland and for example the incidence rate for 1993 was 13.7 per 100.000 males, while the mortality was 10.3 per 100.000 . On the other hand, the proper management of patients who are not good candidates for radical prostatectomy is a challenge for both urologist and radiation oncologist .
The role of radiotherapy in the treatment of localised prostate cancer is well established, although there are still many controversies . Nowadays the three-dimensional conformal radiotherapy (3D-CRT) may lead to improvement in the outcome of treatment in prostate cancer. For example, Hanks and co-workers  showed an improvement of treatment outcomes from 48% to 79% based on PSA as an indicator of biochemical relapse. Zelefsky et al  using the 3-dimensional conformal radiotherapy with application of dose escalation to 81 Gy achieved after 18 months from the completion of radiotherapy normalization of PSA in 99% of Tl/TZb stage, in 90% of T2c stage, and in 81% of T3 stage. Because the 5-year biochemical disease-free survival rate of 3-D CRT is similar to that for radical prostatectomy, early and late morbidities have become increasingly important factors in a patient\\\\\\\'s decision-making process.
Recently, in our department, the high-dose 3-D conformal radiotherapy in conjunction with androgen depletion has been introduced in an attempt to improve the results of treatment. Data from literature has shown that the outcome of patients treated with hormone therapy and radiotherapy (combined treatment) were significantly better than results of radiotherapy alone [6,7].
The aim of this study was the evaluation of early toxicity of combined treatment: androgen ablation therapy (neo-adjuvant, during irradiation and adjuvant) with three-dimensional conformal radiotherapy (3-D CRT) for patients with prostate cancer.
MATERIAL AND METHODS
Between April 1999 and December 2000, at the Wielkopolskie Cancer Centre in Poznań, 42 patients with
prostate cancer (T1-T3N0M0) were treated with hormone therapy and high-dose 3 D-CRT (3-dimensional conformal radiotherapy). The median age of patients was 69 years (range, 55-76 years). All patients had a histological diagnosis of prostate adenocarcinoma, but only 33 out of 42 patients were classified according to the Gleason scoring system. The average level of PSA before radiotherapy was 14 ng/ml (range, 4 to 67 ng/ml). No patient had clinically detectable distant metastases (negative bone scan, chest X-ray - no abnormalities). All patients represented a localised disease (organ-limited) (Tl = 4 patients, T2 = 11 patients) and locally advanced stage of disease (T3 = 27 patients). Lymph nodes evaluation for all patients were based on diagnosis of computer tomography and ultrasonography. Only patients without any abnormalities in these examinations were treated with 3-D CRT We did not perform diagnostic pelvic lymphade-nectomy. In the group 32 out of 42 patients with high risk of metastases to lymph nodes, large pelvic fields which encompassed regional lymph nodes were introduced. Neo-adjuvant androgen ablation therapy (orchidectomy or LH-RH agonists and llulamide) was given to all patients. Orchidectomy was performed in 5 out of 42 patients. Indication for this treatment modality was T2 (1 patient) and T3 (4 patients) stage of disease when intercurrent diseases made it impossible to perform radical prostatectomy. All other patients received androgen depletion treatment (gosereline, 3.6mg/ 4 weeks) during and after completion of radiotherapy. An average time of androgen ablation was 6 months (range, 3 to 12 months). In each case the flutamide was added especially in the first phase of treatment by LHRH analogs (prior to LHRH treatment). The median time of treatment by flutamide was 5 months (range, 2-10 months).
All patients underwent CT scanning of the pelvis in the treatment position. Images were obtained at 5 mm increments throughout the treatment field. Radiotherapy was administered using 15 MV photons in daily fraction of 1.8 Gy to the total median dose of 71.7 Gy (range, 67.8 to 72 Gy) prescribed to the isocenter (ICRU point). The planning target volume (PTV) was defined as the gross target volume (GTV) plus 5 mm margins. GTV was represented as the prostate and the seminal vesicles with 10 mm margins around the prostate except for the posterior margin (prostate - rectum interface) where a margin of about 5 mm to decrease the risk of rectum morbidity was used. All plans consisted of anterior and two lateral fields. In case of T3 stage or PSA level higher than 20 ng/ml or Gleason score above 7, the elective irradiation of pelvic lymph nodes to the total dose of 45 Gy was introduced. In such cases, in the first phase of treatment, the four fields (box-technique) were used.
In this paper the definition of acute toxicities was based on the Radiation Therapy Oncology Group (RTOG) morbidity scoring scale and included side effects which arose during the irradiation time and within the first 90 days after completion of radiotherapy. The median follow-up was 11 months (range, 6 to 15 months). Patients, during evaluation period, were examined by the radiation oncologist (during irradiation time) and after completion of radiotherapy by both the radiation oncologist and the urologist at one month intervals.
All patients completed the entire course of radiotherapy and were assessable for evaluation of acute toxicities and the early biochemical outcome (PSA). No gaps during irradiation were introduced due to acute side effects of combined treatment. 5 out of 42 patients received less than 72 Gy due to breakdown of the therapeutic machine (1 patient = 67.8 Gy, 4 patients = 70.2 Gy).
The most common side effects of androgen ablation were „hot flushes\\\\\\\", gvnaecomastia, although these were mild. In addition, in the group for 4 out of 42 patients some discomfort in the abdomen probably due to intake of flutamide was observed.
Grade 1 toxicities indicated minimal symptoms requiring no medication. Grade 2 toxicities were slightly more severe and required medication. Loperamide was the most commonly prescribed drug and non-steroidal anti-flammatory agents (ibuprofen, diclofenac) were used to control GU and GI symptoms. The most prominent acute adverse effects [mild to moderate (grade 1 or 2)J noted in the gastro-intestinal tract (GI) were nausea, rectal discomfort, and diarrhoea. Diarrhoea occurred when the elective pelvic lymph nodes were irradiated, but the intensity of toxicity connected with introducing the irradiation of the pelvic lymph nodes was not a therapeutic problem. Only a small number of patients required short--time (two weeks) medication (loperamide) due to diarrhoea. Acute rectal side effects were observed at the end of the treatment. The GI toxicity grade 0 and 1 were observed in 75 % of patients and grade 2 in 25% of patients. Acute genitourinary (GU) symptoms included urgency, nocturia and dysuria. The GU toxicities were as follow: grade 0 and 1: 80% of patients and grade 2: 20% of patients. The urinary symptoms usually appeared during the third week of treatment and resolved within a few weeks after.
No grade 3 or 4 GI and GU toxicities were observed. Generally anti-inflammatory drugs were required for relief in 25% of patients. We observed that some early re-
action of irradiation could be associated with symptoms occurring before treatment.
Nowadays, three-dimensional treatment planning and conformal irradiation (3-D CRT) replaces 2-dime-nsional techniques (2D) in the treatment of many cancers, especially prostate cancer . The main advantages of such treatment are: the better delineation of target (tumour) and surrounding organs at risk (rectum, bladder) by application of the computer tomography. The 3-D radiotherapy treatment planning also gives more precise information about dose distribution because more sophisticated computer calculating systems were introduced. Since the radiation dose conforms better to the tumour at the same time as the dose to the neighbouring tissues decreases, thus it that allows the escalation of the dose to the tumour leading to the achievement of the therapeutic gain [9,10,11].
In our paper, early side effects of the combined treatment (androgen ablation therapy and 3D radiotherapy) of patients with localised and locally advanced prostate cancer (stage T1-T3 N0M0) were evaluated. We defined the acute toxicity, according to the RTOG morbidity scale, as side effects of treatment, which occurred during the course of irradiation and also 90 days after the ending of radiotherapy. Radiation oncologists generally accept this definition, but using a time factor as the criterion, which distinguishes acute and late morbidities, may realise the relative lack of knowledge regarding of the real nature of response in healthy tissues to irradiation. The prescribed average total dose to the target (tumour) was 72 Gy, but applied total dose was 71.7 Gy, and this treatment dose belongs to the middle range on the scale of dose escalation in radiotherapy of prostate cancer [17,18]. Each patient received androgen depletion treatment with LH-RH (goserelin) or bilateral orchiectomy plus flutamide. The daily dose of flutamide was in range of 0.5 g to 0.75 g. In the group of 4 patients the treatment with flutamide was connected probably with some liver dysfunction as mild pain in the right part of abdomen. We would like to underline that side effects induced by flutamide were not important in the comparison to the intensity of radiotherapy side effects. During irradiation and follow-up we did not observe any additional side effect except „hot flushes\\\\\\\" and gvnaecomastia, which are typical of the side effects of hormone therapy.
Introducing the 3-D radiotherapy treatment planning and then effecting of such treatment diminished side effects related to the radiotherapy. In such a case the whole rectum received only a small part of the prescribed total dose and even elective irradiation of pelvic lymph nodes did not significantly increase the dose because the posterior margin of fields used in our technique was small (0.5 cm). Generally, we have used large fields in the first phase of treatment (elective irradiation of pelviclymph nodes) and in the second phase small fields which encompassed the prostate and seminal vesicles. Thirty--two out of 42 patients were irradiated with the application of pelvic elective fields in the first phase of radiotherapy. There is still no agreement on introducing the elective irradiation of pelvic lymph nodes. According to numerous data from literature elective irradiation of pelvic lymph nodes does not change the overall survival time of patients with the localized stage of disease but the toxicity of the treatment is rather more pronounced [19,20]. On the other hand, five studies in the literature showed a survival benefit for whole pelvic irradiation. For example, Ranagala et al.  found increased failures when pelvic fields were less than 15 x 15 cm. Ploysonsang et al.  found a significant difference in both the 3-year DFS (57% vs. 30%) and 5-year OS (80% vs. 40%) for patients with stage C diseases receiving whole pelvic irradiation vs prostate only irradiation. The application of the small fields in the second phase of treatment which precisely encompassed the irradiated target (3 dimensional conformal radiotherapy) was probably one of the most important factors which meant that we did not observe more severe Gl side effects. The intensity of toxicities from gastro-intestinal tract (GI) observed in the investigated group of patients were in the same range as described by other authors . Ten of 22 patients experienced acute grade 1 GI morbidity. Only 25% of patients noted grade 2 acute toxicity from GI and no patient needed an intensive medical treatment. No patients experienced grade 3 or 4 morbidity.
The more pronounced side effects from genito-urin-ary tract (GU) were: nocturia, frequency, dysuria. We did not note any GU toxicities higher than grade 2. Similar observations were made by Pilepich et al  and by Soffen et al . These investigators applied higher total dose, even to 78 Gy or 81 Gy. We have to stress that in majority of cases we used small fields that involved the prostate and seminal vesicles and it could decrease the volume of irradiated tissue. Before the era of the three dimensional conformal radiotherapy the size of applied fields were significantly larger. Introduction of the sophisticated calculating software in planning of dose distribution and application of the computer tomography for planning allowed more accurate irradiation of the tumour and reduction of the fields size. It is known that side effects of radiotherapy in healthy tissue are more volume-dependent than dose dependent . The applied total dose for treatment of the prostate cancer in presented paper belongs to the middle range of dose escalation performed in radiotherapy treatment. Currently in our department the total dose of 73.8 Gy is introduced.
The second aspect of treatment presented in this paper was introduction of combined treatment which, was based on published data from literature that indicated that such treatment may lead to achieve a better results . For example, in the trial conducted by RTOG (RTOG 9202) neoadjuvant androgen ablation was introduced 2 months prior to irradiation and then was conti-
nued during radiotherapy and for 2 years alter ending of irradiation. In the group of patients treated with hormonal therapy and radiotherapy the 5-year overall survival was 80% vs 69% for patients without additional hormonotherapy . Another well documented trial which has shown a therapeutic gain was the trial conducted by Bolla et al. . In this investigation two modalities of treatment were compared: radiotherapy alone versus radiotherapy plus long-term adjuvant hormonotherapy (up to 3 years). This study confirmed that combined treatment resulted in increase of 5-years survival from 62% to 79% (p= 0.001). The mechanism of improvement of results of combined treatment and the question whether it represents sensitization of the radiation response by androgen deprivation or an additive therapeutic effect remains unknown. Many studies demonstrated statistically significant reductions in the volume of irradiated healthy tissue because neoadjuvant androgen suppression reduced the volume of prostate cancer tumour and the volume of prostate gland which is not changed by cancer . The tumour volume reduction may also result in an improvement of blood flow and in a decrease in the tumour cell hypoxia. Hypoxia is the most important factor which may lower response of irradiated cancer cells almost three times . Neoadjuvant androgen deprivation according to data presented by Zelefsky et al , appeared to have a significant impact on local control reducing the recurrence rate, but did not influence the overall survival. These data also indicated that combined treatment is associated with a higher incidence of treatment-induced impotence. Among the 159 patients who were potent (able to maintain a functional erection) before treatment the 2-year actuarial incidence of impotence was 43%, compared to 27%; for 385 patients who received radiation alone (p<0,001). Generally, combined treatment is a promising option of treatment because offers better results without overlapping toxicities .
We did not make any suggestions about an evaluation of early biochemical response (SA) due to small number of patients and short time of follow-up [26,27].
In this work we only evaluated early side effects of combined treatment, which concerned the course of radiotherapy and the 3 months period after completion of treatment. The resolve of combined side effects related to the course of radiotherapy was done at about 3 months of follow-up.
In our opinion the patient\\\\\\\'s quality of life even in such short observation time in relation to overall survival time after treatment is important and may influence making decision about treatment.
Preliminary results of combined treatment have suggested that such modality is well tolerated with only modest acute toxicities of GI and GU without severe toxicities. Neo-adjuvant therapy did not exacerbate radiation included toxicity. Longer follow-up is needed to evaluate
the longer-term tolerance of treatment that could seem more important from the patient point of view and outcome of treatment.
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