ORIGINAL

Brachytherapy in localized prostate cancer

Abascal Junquera JM*,Hevia Suarez M, *Abascal García JM*, Abascal García R*, Gonzalez Suárez H**, Alonso A**, Juan Rijo G**, Prada PJ**.

*Servicio Urología. **Servicio Radioterapia. Hospital Universitario Central de Asturias. Spain

Actas Urol Esp. 2007;31(6):617-626

ABSTRACT

Brachytherapy in localized prostate cancer

INTRODUCTION AND OBJECTIVES: There are currently minimally invasive techniques that compete with classic surgery, taken into account the high frequency of localized prostate cancer. One of them is the low dose rate brachytherapy with permanent I-125 seed implants.

The aim of this present study is to report our experience from 1998 when we performed the first treatment until today. Results and morbidity of patients with 7.5 years follow up are analyzed.

Material and Methods: A total of 800 patients were treated with Low Rate Dose with a mean age of 68 years, range 48-83. In all patients I125 seeds were used with Rapid-Strand with peripheral load technique and by intraoperative planning.

Results: The urinary complications rate was of 3% Acute urinary retention (AUR) and 0,2% of urinary incontinence. The morbidity on the gastro-intestinal system was of 12% intermittent bleeding, 2% proctitis, and 0,3% rectal fistulas.

Key Words: Brachytherapy. Localized Prostate Cancer.

It is known that prostate carcinoma is the second cause of cancer death in men, and its incidence is increasing, whether by the aging of the population, greater precision in the screening or the increase in the systematic number of prostate biopsies.

The result of all these factors is a great increase in the diagnosis of cancer localized inside the gland, and therefore susceptible to a curative treatment, and also increasingly seen in younger people.

The possibilities of treatment in these selected cases range from monitoring and surveillance to radical prostatectomy, with its variants of laparoscopic surgery, with or without robot, and less invasive techniques such as brachytherapy, cryotherapy or conformed radiotherapy.

Small changes in long-term results irrespective of the technique used, and lower morbidity of the latter is what prompted their development, and introduced in the range of therapeutic possibilities in the treatment of localized prostate carcinoma¹.

Techniques increasingly evolved, tend to minimize the surgical aggression, comparing, often when carcinoma is more localized and better differentiated, the survival to the open radical prostatectomy and laparoscopic surgery.

The technical evolution of the old axioms, improving the incision, bleeding, time of hospital stay, and complications. So the open surgery is matched by results with the laparoscopic, robotic laparoscopic and improved in the areas commented before.

Also in radiation occurs in a similar manner, and since the beginning of the last century, Young 1910, Pasteau 1914² used radio by intraurethral via, Barringer³ later implemented the transperineal route; Flocks via retropubic initiated treatment by colloidal Aurum, and then Whitmore⁴ with I125 in New York.

Hans Holm at the University of Copenhague⁵ in 1980 was the first to use the transperineal via to implant radioactive seeds, and Blasko and Haakon Radge at Northwest Hospital Seattle⁶ who finally normalized the use of the graduate rack, and computer programs that enabled the method reproduction, and a controlled and uniform radiation distribution.

Brachy comes from the Greek word "brachys", which means short, hence brachytherapy is the treatment by encapsulated radioactive sources applied within walking distance of tissue to be treated.

We will refer to interstitial brachytherapy that is the one by which some hollow needles are used to be implemented inside the tissues. There are two types of interstitial brachytherapy with temporary and with permanent implant. In the temporary we place the needle directed by ultrasound, via transperineal, in the prostate; the needles are hollow and a unique irradation dose is administered, in a few minutes, and through a machine of automated deferred load.

The radioactive element that provides that irradiation is the iridium 192 (high dose rate). Once treatment is finished the implant is removed and treatment is repeated at 15 days, and then supplemented with external radiotherapy. (Protocol HDR in Phase II).

In the case of low dose rate permanent implant the same technique applies, but using I125 or Palladium radioactive seeds, which remain within the prostate, and are evenly distributed to achieve a complete gland irradiation.

The first implant to be practiced in our country, interstitial type with Au198, approaching the gland via retropubic (Pfannestield), was performed at the Hospital General de Asturias in 1981⁷.

It was then about twenty patients, later supplemented with external beam radiation. The technique was abandoned because of the need for anesthesia, surgical approach, seeds placement by hand, high morbidity and as a result, the uneven distribution of the implants and an uncontrolled dosage.

The development of imaging techniques, especially ultrasound with rectal transducter and the implementation of programs for measuring and planning dosimetry, give a major impulse to the technique.

In 1983, as already mentioned, Holm was the first to use, guided by transrectal ultrasonography, the perineal route for seed implant. Later in 1984, Blasko and Radge in Seattle were the major impellers of this technique with I125, joining the Palladium in 1986, and that today is rarely used.

On the other hand in 1987 in Germany takes place the first application of High Rate (HDR), systematized and reported in USA by Alvaro Martines, who guided the first High Rate in Spain, performed at the General Hospital of Asturias in 1998.

The first treatment with I125 seeds was conducted for the first time in Spain in 1999, at the General Hospital of Asturias. Since then we have been using both Upper and Lowe rate techniques for the treatment of localized prostate cancer.

At March 1, 2007, Asturias had 800 patients treated with I125, and 330 HDR with Iridium.

The brachytherapy, bearing in mind that prostate cancer is dose dependent, allows the application of higher radiation doses, with up to 14,500 cGy Low rate as a single dose, and getting a comparable biological dose of approximate 15,500 when linked with external radiation.

With the High Rate biological dose of cGy 12,000 to 13,000 cGy can be achieved, while with external radiation we cannot exceed 7,500 cGy, and with conformed the maximum dose is also 8.000cGy^9,10.

It also has as advantages that the dose fall outside the gland is fast, therefore periprostatic tissues do not suffer radiation or to a very limited extent, and being needles fixed at the time of implant it is not influenced by gland movements. It is an ambulatory treatment, minimally invasive, with spinal anesthesia and discharge without catheter in 6-8 hours.

On the contrary and as objections, the most important is the lack of surgical staging, which also causes urinary discomfort in one third of patients, and finally the PSA follow up, which has a behavior sometimes capricious, and that till reaching Nadir in the first five years it can present peaks creating uncertainty.

On the other hand, being a surgical technique, training is needed, and today in our country is often necessary to have a multidisciplinary team for its implementation. There is the possibility of obtaining the title of radioactive isotopes operator-supervisor, for the urologist to have the autonomy to perform the implant with the help of a physicist.

Indications

The indication of brachytherapy treatment following the major American and European Societies, is in all patients with organ confined cancer T1-T2, classified into three risk groups, using as predictive parameters PSA dosage and Gleason degree; low risk of disease recurrence, moderate or high risk^11,12.

Contraindications

We have anesthetic problems, life expectancy of less than 5 years and metastatic disease as formal technique contraindication, and other, which are not technically unfeasible, but they have a high rate of complications as in the prior radiotherapy pelvic or prostate surgery.

In all patients we performed a previous flowmetry, and in those who have obstructive pattern, either by medium lobe neck disectasia or urethral obstruction, a RTU, or previous urethrotomy is made, and in 12 weeks brachytherapy.

In case of prostates larger than 60cc an implant can be done, provided that such growth is not associated with an obstructive process, taking care to make a lithotomy forced position to avoid the pubic arch. All this without avoiding the hormonal blockade pretreatment and the previous ascertainment of size reduction¹³.

In addition to this contraindications section it is necessary to reflect on a chapter that in our opinion is very important, and that there is not sufficient attention in the literature, despite its relevance. We refer to the prior or concurrent rectal pathology. It is advisable to take into account the existence of recent inguinal hernias, changes in the intestinal transit, that can be satellite signs of tumor pathology at colon or rectum level. Similarly attention must be paid to cirrhosis profile, portal hypertension, prostate-haemorrhoidal syndrome, or simple haemorrhoidal pathology. In these cases surgery is the preferable solution 12 weeks prior to seeds implantation.

The pathology that we rule out previous to brachytherapy is:

- Familial Polyposis

- Hairy Adenomas

- Ulcerative colitis

- Pathologies associated with rectal area as: Internal or external, cryptitis, fissures...

As a warning is necessary to settle all previous rectal pathology, and the rectal area cannot be involved, with limits on the rectum-sygmoid junction till 12 months after brachytherapy.

The implant procedure

Once patient documented with PSA, ultrasound, histological studies, flowmetry, history, and accepted for implant a preoperative study is performed and seeds are requested.

Established by ultrasound prostate size, applying the ellipsoid formula, following Wu nomogram depending on the prostate size, the activity per seed is established. For prostates under 30cc would be between 0.38 and 0.41 mCi, between 30 and 50cc (0.48 to 0.52 mCi) and above 50cc 0.58 mCi¹⁴.

The implants can be placed by preplanning technique, consisting in performing a simulation of seeds situation two weeks in advance, and the day of the implant trying to reproduce in the operating room the prior conformation.

The other system is the one we utilize in real time, being able to make corrections during surgery. In principal it appears that the attempt to reproduce the same anatomic position according to preplanning technique, involves small errors, which are avoided with intraoperative. Also with the latter agility and time are earned. There are few studies that establish the comparative advantages and disadvantages of each, but we believe from the experience of having used the two, that latter at least is faster, and allow the adjustment of doses in overdosage or undosage areas¹³.

The prevalence of peripheral implant device on our center, makes that 70-80% of the seeds will be deposited in the periphery, with an average of 12 to 15 needles, and only 3 or 4 at the central level.

The size is not a disadvantage for the implant, being in our casuistry 9% of patients with a volume greater than 50cc and 3% exceeded 60cc. The largest volume implanted was 94cc, with 169 seeds, which served not to repeat the experience in similar cases, due we had problems of urinary retention and urinary catheter for 6 weeks.

In lithotomy position under spinal anesthesia, sometimes supplemented with sedation. The surgical field asepsis is performed, rejecting the scrotal bag to better expose the perineum. A bladder catheter is placed (Foley No 14) (Fig. 1).

FIGURE 1

The rectal transducer placed in the rack (Accuseed stepper) is introduced (Fig 2), which immobilizes and allows an antero posterior movement, and on top of it the template o graduate rack; ultrasound cuts are given each 5 mm, since the apex to the base, identifying the urethra and rectum. These cuts are transferred to a planner to calculate the proper seed distribution.

FIGURE 2

The software used for the distribution of dose calculation provided by seeds is specific from Varian Medycal Systems, Variseed V7.1^15,16.

At present the dosimetric criteria are of receving 98-100% at least 100% of the prescribed dose, 75% of prostate volume 150%.

With the implant situation in the planner, we initiate the needles placement in the patient, readjusting their position in the software in real time, and performing a flexible cystoscopy to verify that there are nor needles in the bladder,neither in the urethra.

Subsequently the seeds are charged in the needles and placed in the prostate tissue. We use seeds in Rapid-Strand format, tied by a thread of reasorbable material. This system has the advantage of diminishing the probability of seeds migration rather than the loose implant method which is more frequent¹⁷ (Fig. 3).

FIGURE 3. Seed.

Once the seeds are deposited, they are located in its actual position and then the calculation of dosage distribtuion can be made based on that position. This allows some changes at the time to complete the implant if required¹⁸.

Effects of radiation

The photons produced by the radioactive source has a direct action on the DNA, RNA, enzymes, proteins and any cellular macromolecule causing cell death, and indirectly has the same effect with the action of toxic substances, radical, coming from the dissociation of water molecules absorbing radiation¹⁹.

The implanted seeds with Iodine 125 remain with the highest radioactivity for 60 days, decreasing gradually until they disappear approximately a year after.

Postimplant

In our series of more than 800 patients there has been no intraoperative complications in the immediate postoperative³².

A simple X-ray of the abdomen helps us to verify the proper seeds alignment. The catheter removal is carried out 4 hors after, and in 12 hours the patient is discharged, prescribing anti-inflammatory, alpha blockers, low molecular weight heparin, and a urinary antiseptic (Fig. 4).

FIGURE 4

Patients are given a manual with precautions and conduct to follow from the placement of the implant, but given the low doses of implant radiation, patients can afford to bear a normal social relationship³¹.

Follow up of patients is with a PSA dosage, every three months the first two years, and every six months the following five years.

The biological recurrence is considered according to ASTRO, when there is an elevation above Nadir in three consecutive measurements, or if following Phoenix method o Phoenix, with Abramowitz when it rises 2 ng / ml above Nadir, the latter seems to have more predictive value than the ASTRO criteria^20,21.

RESULTS

We will describe the most common complication affecting the urinary tract, the diggestive system and the sexual sphere of the 800 Iodine 125 implants perform by our group. The average age of our series is 68 years range from 49 to 83.

Urinary Complications

Irritative type urinary symptons are very frequent, having them until two thirds of patients; they are generally well tolerated with medical treatment (alpha blockers and anti inflammatory), its intensity is in the slight-moderated during first months relaxing over time, emphasizing that in the majority of patients these symptons completely dissapear after a year (Table 1).

Table 1

Incidence of urinary complications comparative table

	Medical Literature Data
	Stock	Wallner	Beyer	Blasko	Own
					Experience
Retention	4%	14%	4%	7%	3%
Incontinence	0%	0%	0,6%	0%	0,2%

In 14 patients we performed previous TUR, medium Lobe (5), disectasia neck (4), prostate TUR (5), and in 1 case an internal Urethrotomy due urethral stricture. The waiting time for the implant was 12 weeks.

This forecast may indeed have influence on the little clinical obstructive our patients presented , with the exception of one case with 94 cc prostate, which forced 6 weeks permanent catheter.

Regarding incontinence is minimal, with a 0.2% in our serie²². Radic lesions altering the sphincter area healing can be the ones determining incontinence cases.

Rectal Complications

The most often complications presented are rectitys, and alterations in the bowel transit with diarrhea, which are of short duration. Also the intermittent and autolimited rectorrhagias are present in up to 12%^23-25.

But the greater concern in these patients with rectal clinic is to prevent progression to recto-prostatic fistula avoiding maneuvers (biopsies, cauterizes or surgery before one year after implant), as these manipulations can seriously compromise the vitality of these tissues under radiation. The improvement is achieved very often with corticoids enema²⁶ (Table 2).

Table 2

Rectal disease incidence comparative table

	Published Series
	Stock	Wallner	Blasko	Beyer	Own experience
Proctitis	1,7%	2%	2%	1%	2%
Rectorrhagias			4%-11%		12%
Rectal ulcer/fistula			0,4-0,7%		0,3%

Sexual Disorders

Most studies, as it happens with radical prostatectomy, reflected a variable complications incidence, ranging from 14 to 50%, probably influenced by the time of collecting the data, as impotence increases with time, it takes between one and five years to show up and sometimes confusing aging physiological cases with secondary to brachytherapy. In our series, the percentage is 65% average on preserving sexual function over these 7.5 years. (Fig. 5).

FIGURE 5. Sexual function maintenance over time.

During the first year of treatment it is commom to have minor ejaculation disorders, decrease or liquefaction of same. The treatment with phosphodiesterase inhibitors are effective in 80% of cases^27,28.

In any case it must be emphasized that is significantly lower than with radical prostatectomy of external radiotherapy.

Biological Outcomes

The biological control of the disease it is performed with PSA dosage, the first three months after, followed by quarterly analysis in the first two years, and thereafter twice a year till fifth year and then annually.

The lowest figure PSA (nadir) can take up to two years to be achieved, being a different figure for each individual. It is not abnormal that PSA figures give small pick ups in the PSA in the first 5 years, which in principle do not have any significance, and that are associated with inflammatory processes.

DISCUSSION

PSA evolution in a group of 112 patients with a follow up of 7.5 years is expressed in Fig. 6, where it is shown the standard deviation of mean PSA; coinciding in essence with the published series, and although the a 7.5 years follow-up is large, since recurrences in this type of cancer are long-term, further studies are needed to confirm the good progress of biological recurrence -free survival, which is 80%, as expressed in Fig. 7, with rates of 93 and 83% respectively for T1 and T2.

FIGURE 6. PSA Evolution in low rate dose (n = 112).

FIGURE 7. Results at 7.5 years.

Also overall survival is 95%. It should be emphasized, as shown in Figure 8, the highest percentage of T1 to 70%, compared with 27% of T2a, and only 3% of cases that go beyond T2a.

FIGURE 8. Distribution by stage (n = 112).

The distribution in Gleason terms, shown in Figure 9, with a marked predominance of the group <7, 96%, compared to 4%> 7.

FIGURE 9. Distribution by Gleason.

PSA distribution by ranges by demonstrates (see Fig. 10), how there is a strong patients selection with 64% of them with less than 10 ng / ml.

FIGURE 10. PSA (ng/ml) distribution according to ranges.

With reference to obstructive type acute urinary complications after implant, in our series are very few (3%), when comparing with other authors^6,10,16,29, (Table 1) we believe because of prior multiples precautions , flowmetry, previous middle lobes or of cervical obstructive TUR, and the type of peripheral implant, which produces less urethra acute inflammation. The procedure in presence of prostates larger than 60cc, is the universal treatment with androgen blockade, associated with or without to 5-a-reductase inhibitors for a minimum period of four months prior to implant.

With regard to incontinence, the authors like Stock, Blasko, Wallner^{6,15,22,30,33} do not include it among its complications; in our series, even minimal occupies a 0.2%. Radic lesions altering the sphincter area healing can be the ones determining incontinence cases. (Table 1).

Regarding rectal morbidity caused by the implant, as shown in Table 2, slight ones like proctitis, occasional rectorrhagias, are not uncommon, responding well to local treatment with ointments or corticoids enema⁴².

The most feared complication is the rectal fistula, although in many cases, is preceded by a pre handling of rectum, before one year after implant, on other occasions without any antecedent appears even 12 months after brachyteraphy^26,39-41,43. The problem is difficult to solve due the tissue alteration tissue which commits any reconstructive surgery.

Our group performed for some time a technique to protect the rectum, with hyaluronic acid injection in the virtual space prostate rectal once needles are placed and before loading the radioactive seeds. The high perirectal radiation absorption, minimizes local complications. The treatment results with Restylene^® injection are accepted for publication in the International Journal of Radiation Oncology (Fig. 11).

FIGURE 11. MRI infiltration with Restylene^®.

Referring to erectile dysfunction as it can be seen in Fig. 5, our experience is discordant with the other series, and since then, we see that as urinary discomfort improve over time and mostly disappear within one year, erectile dysfunction progressively worsens in the first 5 years^31,35,42.

CONCLUSIONS

Our experience over these seven years, with a wide casuistry, allow us to affirm that with a good selection of candidates patients, the results are satisfactory, both in biological control, as in overall survival. Furthermore, the undeniable brachyterapy toxicity as in any type of radiation is minimized and greatly relieved with precautions that even if they seem to be obvious are not always taken into account; we refer to the prior functional study, the non-rectal manipulation within a recommended period, and the use of hyaluronic acid gel, among other measures that are effective.

Furthermore, the flexible cystoscopy to verify the correct placement of the needle before implant seems to us to be essential.

The technique is very sophisticated, and we believe that with planning in real time and the peripheral implant on the low risk stages, the result is equivalent to surgery, but more years of follow-up will be needed to confirm these impressions.

Although as we say, the technological improvement is quite remarkable, probably in the lower rate case has reached its ceiling and probably the future and development will probably come with temporary high dose implants that together with new protocols, low costs for the iridium power source, are directed to a treatment with four high rate doses, obviating the additional external.

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