Volume 8, Issue 4, April – 2023 International Journal of Innovative Science and Research Technology

ISSN No:-2456-2165

Radiotherapy of Oligometastatic Prostate Cancer:

Experience of the Mohamed VI Center for Cancer
Treatment in Casablanca, Morocco
Ismael Coulibaly1, Meryem Zaouit1, Hanane Rida1, Chékrine Tarik1, Mouna Bourhafour1, Zineb Bouchbika1,
Nadia Benchakroun 1, Hassan Jouhadi1, Nezha Tawfiq1, Souha Sahraoui1
1
Mohamed VI Center for the treatment of cancers, CHU Ibn Rochd, hospital districts, 20360 Casablanca, Morocco

Abou Dao2
2
Joseph Ki-Zerbo University, UFR / SDS, Ouagadougou _ Burkina Faso

Corresponding Author :- Ismael Coulibaly1

Abstract :- hypofractionated and those irradiated in conventional

fractionation.
 Backgraound
Oligometastatic disease is an intermediate stage  Conclusion
between locally advanced disease and multi-metastatic The limit of our study lies in the small size of our
disease. We report the experience of the Mohamed VI sample but also in its retrospective nature. Prostate
Center for the Treatment of Cancers in the management radiation therapy remains a treatment option for de
of oligometastatic prostate cancers in a retrospective novo oligometastatic prostate cancer.
series from 2016 to 2019.
Keywords:- Prostate, Adenocarcinoma, Metastasis,
 Method Radiotherapy, Morocco.
We collected cases of de novo metastatic prostate
adenocarcinoma judged to be oligometastatic and having I. INTRODUCTION
benefited from radiotherapy on the prostate. The
primary endpoints were: progression-free survival and Hellman and Weichselbaum pioneered the concept of
overall survival at 2 and 3 years. The proportions were oligometastatic disease in 1995 [1]. It is an intermediate
compared by the CHI 2 test with a significance level of stage between locally advanced disease and multi-metastatic
0.05. The Kaplan Meier model was used to compare disease [2]. This concept of oligometastasis has largely
survivals. evolved with imaging techniques and therapeutic
possibilities. In practice, the qualification of oligometastasis
 Result uses various notions such as the metastatic mass, the number
We had recruited 37 patients with a median age of of metastases detectable in imaging, the number of organs
70 years. The initial PSA was between 11 ng/ml and 1635 affected, the number of subunits within an organ which can
ng/ml with an average of 160 ng/ml. The Gleason score be decisive in terms of therapeutic possibilities [3].
was between 8 and 10 in 46 % of patients. A secondary However, the definition of oligometastatic prostate cancer
bone location was present in 100% of cases and no varies in the literature [4]. It depends on the number of
patient had a visceral metastasis. The vertebral seat was metastases, the type of imaging, and the site of the
the most common secondary bone site (55%). The metastases. Most publications set the maximum number of
maximum number of metastatic sites was 3. The median metastases at 5. Conversely, in other clinical trials, a lower
follow-up is 38 months. Overall survival at 24 months number of secondary locations (< 3) was necessary to define
and 36 months, respectively, was 92% and 86%. The 2- oligometastatic cancer [5]. Our study aims to report the
year and 3-year progression-free survival was 84% and experience of the Mohamed VI Center for the Treatment of
79%, respectively. There was no statistically significant Cancers in the management of oligometastatic prostate
difference in either overall survival or progression-free cancers.
survival between patients who received radiation to the
prostate alone and those who received radiation to the II. METHOD
prostate plus the pelvis (p = 0.86). No significant
difference was observed in terms of survival between the We retrospectively collected all patients with de novo
patients who received in addition to local radiotherapy metastatic prostate cancer judged to be oligometastatic on
and primary palliative chemotherapy and those who the basis of CT and scintigraphy and who received
received only local radiotherapy. The low statistical radiotherapy to the prostate in the period from 2016 to 2019.
power of our sample did not allow us to obtain a Patient monitoring was quarterly by the PSA. Biological
significant difference between patients irradiated in progression was defined by the rise of the PSA to more than

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ISSN No:-2456-2165
2 ng/dl plus the nadir PSA. We used as a data collection in 38% and 49% of cases. No patient had visceral
source the computerized patient registration system of the metastasis. A secondary bone localization was present in
Mohamed VI center for the treatment of cancers in 100% of cases. A lumbo-aortic lymph node localization was
Casablanca. Data entry and analysis were performed using found in 3 patients in addition to the secondary bone
SPSS software version 21. The proportions were compared localization. The vertebral location was the most frequently
using the CHI 2 test. The ORs adjusted by a logistic encountered secondary bone site. The maximum number of
regression model were also presented with their 95% CIs secondary sites in a patient was 3. There were no more than
with a significance level of 0.05. We used the Kaplan Meier 2 vertebral levels affected in the same patient. On the whole
model to compare survival from the time of diagnosis. of the vertebral column there were no more than 3 vertebrae
affected. Half of the patients had only 2 bone secondary
III. RESULTS localization sites. For treatment, we found that 13 of the 37
patients received docetaxel-type chemotherapy in addition to
We recruited 37 patients with a minimum age of 57 hormone therapy. This chemotherapy was instituted before
years and a maximum age of 88 years with a median age of radiotherapy, it concerned patients who had pain but also
70 years. The majority of patients were brown-skinned, those who had a high PSA level. Chemotherapy was done
76%. Thirty of the 37 patients had no comorbidities. A with docetaxel on 21 days. Among the 13 patients who had
family history of prostate cancer was found in 3 patients. chemotherapy, 3 needed a second line before radiotherapy,
The majority of patients had a good general condition at the including 2 patients with carboplatin and 1 with etoposide +
first consultation, i.e. 19%, 78% and 3% respectively for a cisplatin. The total number of cures was 9 in 1 patient, 8 in 1
WHO performans status (PS) of 0; 1 and 2. The initial PSA patient also, 7 in 04 patients and 6 in 07 patients. Only one
was greater than 20 ng/ml in 84% of cases. None of the patient benefited from a laminectomy. All 37 patients
patients had a PSA lower than 10 ng/ml. The extreme values underwent radiotherapy of the prostate, 28 of which were
of the initial PSA were 11 ng/ml and 1635 ng/ml with an intensity modulated (Table1). Analgesic radiotherapy on the
average of 160 ng/ml. There was already bone symptoms in bone metastasis was performed in 4 patients before local
16% of cases at the time of diagnosis. In terms of extension radiotherapy on the prostate. The majority of patients (76%)
assessment, all the patients had performed the thoraco- were irradiated at the same time on the prostate and the
abdomino-pelvic CT, only one patient had not performed the pelvic lymph nodes in prophylaxis, with 74 Gray in
scintigraphy at the time of diagnosis. Choline PET was conventional fractionation. In addition to local radiotherapy,
performed in only 16% of patients and those following all patients received hormone therapy, with LHRH analog in
progression or relapse. Prostatic adenocarcinoma was the 20 patients and by pulpectomy in 17 patients. Side effects of
only histological type found. Prostate biopsy was the most treatment were observed in 65% of patients. The
common mode of diagnosis at 84%. We noted 46% of complications found are, among others, acute
Gleason score between 8 and 10; 43% had a Gleason score radiodermatitis grade 2, radiation proctitis, hot flushes,
of 7 and only 11% (04 patients) had a Gleason score of 6. gynecomastia, sexual weakness respectively in 11% of
For the poor prognostic factors, we found the presence of cases, 11%, 24.3%, 14%, 49% of cases (Table 3).
vascular embolism and perineural ensheathing respectively

Table 1 Description of Radiotherapy

n %
TYPE OF RADIOTHERAPY
VMAT 28 75.7
3D 9 24.3
RADIOTHERAPY SITES
Primitive alone 33 89.2
Primitive + metastasis 4 10.8
IRRADIATION VOLUME
Prostate + lymph nodes 28 75.7
Prostate alone 9 24.3
DOSE AND FRACTIONATION
60 Gray in 20 fractions 9 24.3
74 Gray 37 fractions 28 75.7

Table 2 Patients Characteristics

n (%)
GLEASON SCORE
Gleason 6 04 (11%)
Gleason 7 16 (43%)
Gleason 8 09 (24%)
Gleason 9 07 (19%)
Gleason 10 01 (03%)

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BONE SITES OF METASTASIS
Vertebrate 28 (55%)
Pelvic 19 (37%)
Femur 01 (02%)
Scapula 03 (06%)
DISTRIBUTION OF VERTEBRAL METASTASIS
Cervical 01 (03%)
Thoracic 16 (50%)
Lumbar 11 (34%)
sacred 04 (13%)
NUMBER OF METASTASIS
1 15 (42%)
2 18 (50%)
3 03 (08%)

For the response to treatment, 81% remission was noted 3 months after the end of radiotherapy with a total PSA of less than
2 ng/ml. Among the 07 patients who were in progression, 02 were in biological progression and 05 in biological and radiological
progression. Deaths at 3 years of follow-up were 08, including 02 patients who died of coronavirus infection (COVID 19) with
PSA levels remaining undetectable. Overall survival at 24 months and 36 months, respectively, was 92% and 86%. The median
follow-up is 38 months with extremes of 10 months and 60 months. Patients alive and in biological and radiological progression
are 22%. In univariate analysis, there is no statistically significant difference in overall survival or progression-free survival
between patients who received irradiation of the prostate alone and those who received irradiation of the prostate plus the pelvis.
The same was true between those who received radiotherapy of the primary alone and those who received radiotherapy of the
primary plus the bone metastasis. No significant difference was observed in terms of survival between the patients who received
in addition to local radiotherapy and primary palliative chemotherapy and those who received only local radiotherapy (figure 1).

Table 3 Treatment Complications

n %
Grade 2 radiodermatitis 04 10.8
Grade 4 aplasia 01 02.7
Radiation cystitis 01 02.7
Radiation proctitis 04 10.8
Gynecomastia 05 13.5
Hot flush 09 24.3
sexual weakness 18 48.6
Urinary incontinence 01 02.7

Fig 1 Overall Survival Curve According to Chemotherapy

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Fig 2 Curve of Overall Survival According to the Volume of Irradiation

IV. DISCUSSION and their axial or peripheral location represent a major

prognostic factor [13]. In our cohort, 38% of patients had a
The definition of oligometastatic disease remains single bone metastasis and the vertebral location was the
heterogeneous to this day. In the literature, the number of 5 most represented at 55%. No visceral metastasis was found.
maximum bone metastases is the number of secondary We did not note any significant difference in terms of
locations accepted to remain in the oligometastatic [6, 7, 8]. survival according to the number of secondary locations due
In our study, the maximum number of metastatic sites was 3. to the low statistical power of our sample. For a long time,
However, it is recognized that the diagnosis of the metastatic cancers from the outset were unequivocally
oligometastasis stage depends on the capacity of the imaging considered to have an unfavorable prognosis and only
used for the extension assessment [9]. Currently, the systemic treatments were considered [15]. Oligometastatic
standard metastatic assessment recommended by learned disease appeared to be a clinical and prognostic entity in
societies for prostate cancer is scintigraphy and computed which the place of local treatment (of the primary lesion
tomography [10]. However, with advances in molecular and/or metastases) would make it possible to lengthen
imaging techniques, more and more metastases are being overall survival or to delay the progression of the disease
detected. This do that, many patients considered as non- [6]. At the biological level, the local irradiation of the
metastatic in conventional imaging could have an primitive in addition to preventing the formation of
oligometastatic disease, just as an oligometastatic disease cytokines and circulating tumor cells, would interrupt the
could turn out to be polymetastatic with the new imaging process of self-censorship and the formation of metastatic
techniques (PET-choline and PET-PSMA). Positron niches. Radiotherapy would also make it possible to
emission tomography using choline (PET-choline) has a eliminate pro-genitor cells at the origin of resistance to
relatively good specificity of 89.5 to 99.7% and a positive systemic treatments [16]. Lymphocyte activation via pro-
prediction unlike bone scintigraphy which has a specificity inflammatory molecules resulting from radiation-induced
and sensitivity around 65%, which implies that part of the cell death could induce an anti-tumor immune response
metastases is not detected in the standard assessment [8, 11]. [17,18]. This immunomodulatory action of radiotherapy
associated with the abscopal effect described since 1953
The most promising radiotracer in metabolic imaging constitutes a source of enthusiasm in the treatment of cancer
is PSMA (Prostate Specific Membrane Antigen) mainly due to improve overall survival or to delay the progression of the
to increased avidity of the absorption at PSA thresholds disease. As regards oligometastatic prostate cancer, prostatic
below 5 ng/dl [11]. In 15 patients with localized prostate irradiation could limit the capacity of the primary tumor to
cancer considered high risk on scintigraphy and CT, potentiate the metastatic process [6]. To date, there is no
Sterzing et al. using PSMA PET in a staging, noted that 09 international consensus on the local treatment of metastatic
of the 15 patients in the study had synchronous metastatic prostate cancer. In patients with locally advanced or
lesions [12]. In our cohort PET with choline was performed metastatic prostate cancer, the meta-analysis by Cameron et
in only 16% of patients and those following progression or al. analyzed nine retrospective studies dealing with
relapse. Bone is the most frequent site of metastatic symptomatic palliative pelvic irradiation. The symptom
invasion, and often even the only one in prostate cancer response rate was 75% (73% for haematuria, 80% for pain,
[13]. They represent 70% of metastases and occur mainly in 63% for bladder obstruction, 78% for rectal symptoms, 62%
the axial skeleton [14]. These bone metastases, which may for ureteral obstruction). This publication did not allow a
initially be asymptomatic, unfortunately frequently evolve useful conclusion on total dose, fractionation pattern, dose–
into multiple complications such as pain, fractures, spinal response effect or duration of response. The toxicity report
cord or radicular compression, symptomatic hypercalcemia was not systematic and only one study used a validated scale
or spinal cord insufficiency. The number of bone metastases [19]. In our cohort, only one patient was not completely

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relieved of his symptoms and retained the urinary of metastases and overall survival (HR; 1.47, 95% CI 1, 11–
incontinence he had at the time of diagnosis. Prostatic 1.94, p=0.007). The overall survival probability was
radiotherapy is therefore an effective symptomatic treatment improved by 7% at 3 years of follow-up in patients with
even in a metastatic situation. In the literature, we find oligometastatic cancer. The ST0P-CAP meta-analysis [31]
retrospective and prospective studies that testify to the which combined the two randomized trials (HORRAD and
interest of irradiating the prostate in situations of STAMPEDE) confirmed the interaction between the number
oligometastasis, but without significant statistical value for of metastases and overall survival (HR; 1.47, 95% CI 1, 11–
these studies. There are 08 retrospective series suggesting 1.94, p=0.007). The overall survival probability was
the contribution of the treatment of the primary tumor in improved by 7% at 3 years of follow-up in patients with
improving the overall survival of prostate cancer at the oligometastatic cancer. The ST0P-CAP meta-analysis [31]
metastatic stage. These series are taken from the SEER which combined the two randomized trials (HORRAD and
(Surveillance, Epidemiology and End Results database) and STAMPEDE) confirmed the interaction between the number
the NCDB (National Cancer Data Base) [20 - 26] with an of metastases and overall survival (HR; 1.47, 95% CI 1, 11–
Asian series [27]. 1.94, p=0.007). The overall survival probability was
improved by 7% at 3 years of follow-up in patients with
Culp et al. studied 8185 metastatic patients in the oligometastatic cancer. To date, we can therefore say that
SEER database. The probability of overall survival at 5 radiotherapy of the prostate has its place in the management
years was significantly improved in patients treated locally of oligometastatic prostate cancer (less than 5 bone
with brachytherapy or radical prostatectomy compared to metastases or low volume according to CHAARTED). What
those who received no treatment (67.4% and 52.6% versus remains to be demonstrated by clinical trials is the
22.5%). Local treatment was associated with a reduction in fractionation and the volumes to be irradiated. Although in
the relative risk of specific mortality in multifactorial the STAMPEDE trial the hypofractionated regimen on the
analysis (32% for brachytherapy (HR: 0.38, 95% CI: 0.27– prostate alone showed longer failure-free survival (HR:
0.53, p < 0.001) and 62% for surgery (HR: 0.62, 95% CI: 0.69, 95% CI: 0.59–0.80, p < 0.0001) compared to the
0.49–0.93, p = 0.018)) [20]. Löppenberg et al. identified weekly schedule, it is necessary to have a “be to be”
15,501 patients with metastatic cancers from NCDB, comparison in a randomized trial. The low statistical power
including 1,470 treated locally (77% of them by irradiation). of our sample did not allow us to obtain a significant
Compared to patients who did not receive local treatment, difference between patients irradiated in hypofractionated
the probability of overall survival at 3 years was higher (69 and those irradiated in conventional fractionation.
versus 54%, p < 0.001). Age and the absence of local
treatment were found to be predictors of mortality in Taking into account the low alpha/beta ratio of
multifactorial analysis [21]. In our cohort, all patients prostate cancer [32], a hypofractionated regimen could be
received radiotherapy to the prostate. Overall survival at 03 adapted to the metastatic form in order to reduce the
years was 86% (02 deaths are caused by COVID 19 duration of treatment [8]. There are many trials which are in
infection) with relapse-free survival at 81%. Two progress and which will make it possible to further clarify
prospective studies and a meta-analysis also demonstrated the place of local radiotherapy in metastatic prostate cancer.
the benefit of prostate radiotherapy in prostate cancer in the We have among others the French phase III multicenter trial
oligometastatic subgroup. The phase III HORRAD trial [28] PEACE 1 which is in the process of analysis, randomized in
compared androgen suppression alone with androgen 4 arms which compares the combination of androgen
suppression associated with prostate irradiation. No suppression with chemotherapy by docetaxel with or
difference was observed in this trial in overall survival or in without prostatic irradiation (of 74 Gy in 37 fractions) with
survival without biological failure. Better overall survival or without abiraterone acetate and prednisone [33]. The
was found only in patients with less than 5 bone metastases phase III study NCT03678025 from the South-west
(HR: 0.68; 95% CI: 0.42–1.10, p = 0.063). The criticism Oncology Group (SWOG) compares the association of
made of the HORRAD trial is that it contained 60% of surgery or irradiation of the prostate with systemic treatment
patients with high metastatic volume. The prospective phase [34]. The phase II randomized Canadian trial PLATON,
III STAMPEDE trial [29] recently compared 2062 patients which is in the process of being recruited, will compare
assigned to androgen suppression alone versus androgen standard treatment with or without ablative treatment
suppression plus radiotherapy. There were respectively 40% (radiotherapy or surgery) for all the locations of the disease
and 54% of patients with low and high metastatic load [35]. A Croatian phase II study (NCT02913859) aims to
according to the CHARTED criteria [30]. The STAMPEDE determine the impact of radiotherapy in combination with
results showed no significant improvement in overall androgen suppression on progression-free survival [36]. The
survival over the entire cohort (HR: 0.92; 95% CI: 0.8–1.06; IP2-ATLANTA trial is a phase II trial that compares
p = 0.27) on the other hand, failure-free survival a was minimally invasive surgery (cryotherapy or high-intensity
significantly prolonged in the radiotherapy arm (HR: 0.76, focused ultrasound treatment) in 3 arms to standard
95% CI; 0.68–0.84; p < 0.0001). Patients with a low number treatment as well as radiotherapy treatment (60 Gy in 20
of metastases had significantly longer overall survival as fractions or 74 Gy) or radical prostatectomy [37]. For people
well as failure-free survival (HR: 0.68; 95% CI: 0.52–0.90; with early oligometastatic prostate cancer, with longer life
p=0.007). The ST0P-CAP meta-analysis [31] which expectancy and minimal comorbidities, for whom treatment
combined the two randomized trials (HORRAD and remains a prudent consideration, further research is needed
STAMPEDE) confirmed the interaction between the number to identify appropriate treatment paradigms. For example, it

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remains unclear whether ablative therapy at the primary site [10]. Mottet N, Bellmunt J, Bolla M, Briers E,
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