clinical aspects and applications of high dose-rate brachytherapy

Radiotherapy: Special Techniques

Mª Teresa Muñoz Migueláñez

Clinical Aspects and Applications of High-Dose-Rate Brachytherapy

INDEX Introduction: Definition, History and Types. HDR vs LDR. Clinical applications. Prostate Cancer:

Introduction. Implant Procedure. Uses: Boost, Monotherapy or salvage treatment.

Conclusions. Bibliography.

INTRODUCTIONDefinition, History and Types

Definition Brachytherapy (BT), from the Greek language, means “ therapy at a short

distance”. It involves the precise placement of radiation sources near the site of the

cancer cells. Because the absorbed dose falls off rapidly with increasing distance from the sources, high doses may be delivered safely to a localized target region over a short time. (1)

Compared to external beam radiotherapy (EBRT), brachytherapy has the advantage of delivering a high dose to the tumor while sparing the surrounding normal tissues. (1)

History It was increasingly used in the treatment of

malignant tumors shortly after the discovery of radium – 226 (226Ra) by Marie Curie in 1898. (2)

Sustained a rapid growth with the development of afterloading devices (treatment with radioactive sources controlled from a distance)

and the introduction of artificial radionuclides. (2)

Types (3)

Source placement Interstitial Intracavitary (e Intraluminal) Superficial (surface applicators)

Duration of dose delivery Temporary Permanent

Dose rate Low-dose rate (LDR): rate of up to 2 Gy/h. (Iodine 125 (125I) or Palladium 103 (103Pd))

Medium-dose rate (MDR): rate between 2 Gy/h to 12 Gy/h High-dose rate (HDR): rate > 12 Gy/h. Iridium-192 (192Ir):

Is the most commonly used isotope for HDR. Has an average energy of 380 KeV, a half-life of 73,8 days and a half value layer of 2,5 mm of lead.

HDR VS LDR

While LDR BT has been examinated and assesed the most and become a standard treatment option, HDR brachytherapy has recently gained momentum as an alternative.

Advantages DisadvantagesRadiation protection.•HDR eliminates radiation exposure hazard for care givers and visitors.•HDR eliminates source preparation and transportation.•Since there is only one source, there is minimal risk of losing a radioactive source.

Radiobiological.•The short treatment times do not allow for the repair of sublethal damage in normal tissue or the redistribution of cells within the cell cycle or reoxygenation of the tumor cells; hence, multiple treatments are required.

Allows shorter treatments times.•There is less patient disconfort since prolonged rest is eliminated.•It is posible to treat patients who may not tolerate long periods of isolation and those who are at high risk for pulmonary embolism due to prolonged bed rest.•There is less risk of applicator movement during therapy.•There are reduced hospitalization costs since outpatient therapy is posible.•HDR may allow greater displacement of nearby normal tissues (by packing or retraction) which could potentially reduce morbidity.•It is posible to treat a larger number of patients in instutions that have a high volumen of BT patients but insufficient inpatient facilities.•Allow intraoperative treatments, wich are completed while patient is still in the operating room.

Limited experience.•Few centers in the United States have long-term (>20 years) experience.•Until recently, standarized treatment guidelines were not available; however, the American Brachytherapy Society (ABS) has recently provide guidelines for HDR at various sites (http://www.americanbrachytherapy.org/guidelines/)

HDR sources are of smaller diameter than the cesium sources that are used for intracavitary LDR.•This reduces the need of dilatation of the cervix and therefore reduces the need for heavy sedation or general anesthesia.•High-risk patients who are unable to tolerate general anesthesia can be more safely treated.•HDR allows for intesrtitial, intraluminal, and percutaneus insertions.

The economic disadvantage•The use of HDR BT as compared to manual afterloading techniques requiers a large initial capital expenditure since the remote afterloaders cost about $ 300000.•There are aditional cost for a shielded toom and personnel cost are higher as the procedures are more labor intensive

HDR makes treatment dose distribution optimization possible.•Variations of the dwell times of a single stepping source allow an almost infinite variation of the effective source strengths, and the source position allows for greater control of the dose distribution and potenctially less morbidity

Greater potential risks•Since a high activity source is used, there is greater potential harm if the machine malfunctions or if ther is a calcualtion error. The short treatment times, compared to LDR, allow muchs less time to dectect and correct errors(1) Halperin, Edward C; Brady, Luther W; Perez, Carlos A; Wazer, David E (2013) Perez & Brady's Principles and Practice of Radiation Oncology (6th ed)

http://www.americanbrachytherapy.org/guidelines/

http://www.americanbrachytherapy.org/guidelines/

CLINICAL APPLICATIONSHDR BT has been used in almost every site in the body, generally as a component of multimodality treatment (4)

1. Cervical cancer 2. Endometrial cancer3. Prostate4. Breast5. Skin6. Bronchus/Trachea7. Bile duct8. Esophagus9. Head and neck

10. Soft tissue sarcoma11. Pediatric tumors12. Intraoperative brachytherapy13. Anorectal14. Other indications:

Penis BladderUrethraOcularBlood vessels (coronary and peripheral arteries)…

PROSTATE CANCER

Introduction Multiple treatment options are available for clinically localized prostate cancer:

Radical prostatectomy, EBRT, BT, EBRT + BT….

BT can deliver a highly localized radiation dose to the tumor. While LDR BT has been examined and assessed the most, and become a standard

treatment option (permanent implantation 125I or 103Pd (1)), HDR BT has recently gained momentum as an alternative (5-6): Most commonly as a dose escalating boost delivered in combination with EBRT. There is also increasing experience in HDR BT used alone to deliver a radical dose radiation and as a

salvage treatment to local recurrence. Recomendations on temporary transperineal prostate BT, were first published on

behalf of GEC/ESTRO-EAU Prostate Brachytherapy Group (PROBATE) in 2005 (7)

Advantages Disadvantages

It is possible to individualise the source positions over the full lenght of the prostate based on a defined planning target volume and organs at risk. Dose distribution optimisation by inverse planning enables highly conformal dose delivery.

Use of a fractionated schedule results in more work load per patient and logistic issues related to quality assurance across several radiation exposures

The use of image guide catheter or needle placement enables accurate implantation which can be extended to include extracapsular disease and seminal vesicles.

The treatments must be executed carefully because the short treatment times do not allow any time for correction errors, and mistakes can result in harm to patients

The fixation of the prostate by the implant and rapid radiation delivery minimises the problems of target and OAR movement.

During multifractionated HDR treatment, catheter migration could cause degradation of dosimetry.

The use of high dose per fraction has a biological dose advantage for tumors with a low alpha beta ratio of which prostate is a common example.

Temporary BT using a stepping source does not need any source preparation time and there is good radiation protection for personnel.

The use of a single source for all patients using a multipurpose facility makes HDRBT highly cost effective.

(6)(5-6)

IMPLANT PROCEDURE (6-9)

Equipment Operating room or brachytherapy suite suitable for sterile procedures and access to anaesthetic support. HDR afterloader. TRUS unit with template, the ultrasound should be capable of both transaxial an sagital image acquisition. TRUS fixation and stepping unit. Intestitial implant catheters of a suitable design compatible with the TRUS based template; They should

also be CT or MR compatible if this imaging method is to be used. Rigid steel or flexible catheters can be used for the implant procedure. The advantage of flexible catheters is that the may be seen to bend around the pubic arch and then regain their plane in the more anterior aspects of the prostate gland.

Appropiate software to enable importation of post implant TRUS or CT or MR imaging with image fusion. A planning system which can achieve accurate implant reconstruction and 3D dosimetry. A brachytherapy suite with adequate shielding to perform the HDR treatment, according to national

radiation protection rules. Access to appropriate imaging post implant with either TRUS, CT or MR.

General Considerations Brachytherapy is done under spinal anesthesia. The patient is placed in the lithotomy position and a

urinary catheter is placed into the urinary bladder. The skin is prepared and full sterile theater precautions

should be used.

TRUS is now the standard means of guiding applicators. Setting up of the TRUS prior to implantation is very important.

The position of the patient and the template position are critical before implantation is commenced: The urethra should be identified and positioned along the central row of

the template (usually row D) The inferior row of applicator positions must reflect the lowest part of the

gland to be implanted and if seminal vesicles are to be included in the PTV it is essential these are also considered in the set up.

Catheter insertion

The applicators are inserted transperineally under direct US control.

When homogenous cover of the gland is required then catheters should be placed with no greater tan 1 cm intervals between applicators.

Peripheral coverage is most important so it is vital to have a ring of catheters around the edge of the peripheral zones, with a distance of about 3 mm from the prostate CTV border. It is advantageous start to implant with the anterior catheters.

Imaging for dosimetryTRUS

Obtained whilst the patient remains in the lithotomy position under anaesthetic or sedation. The whole prostate should be covered and in addition at least 5 mm cranially and caudally outside the gland.

CT or MRI Obtained following recovery from anaesthetic

and transfer to the imaging deparment: CT acquisition should be at no more tan 3 mm intervals T2 will provided optimal anatomical definition but T1 will

provide more accurate catheter reconstruction. Image fusion may be used to maximise information. Fiducial

markers are placed in the prostate to compare catheter localited prior to each treatment.

Volumes for treament plannig CTV is defined by:

The prostate capsule. Plus any macroscopic extracapsular

disease or seminal vesicle involvement identified on diagnostic images expanded by 3 mm. (Usually constrained posteriorly to the anterior rectal wall and superiorly to the bladder base.)

Organs at risk (OAR): Rectum. Urethra: Should extend from bladder

base to 5 – 50 mm bellow the prostatic apex.

OAR dose constraints

Urethra: Dmax ≤ 120%Rectum: V70 < 1cc

Planning aim and dose prescription

Once satisfactory dose distribution has been obtained, this will be transfered into the HDR control program as a series of dwell times for each catheter.

Typical treatment times are very short, most catheters having total treatment times for the implant being of the order of 10 – 15 min, depending upon the total number of catheters.

Complications and toxicity This technique is well tolerated. Perineal presure after catheter removal will minimize the risks of

hematoma formation. Antibiotics, steroid medications and α blockers can be prescribed.

Genitourinary: Acute urinary irritative symptoms (urgency, frequency…) are common and usually resolve with time. Urinary retention occurs in < 5% of cases and can be managed with catheterization. Urinary strictures are reported in up to 15% of patients (most commonly in bulbomembranous urethra). TURP

should be avoided after HDR prostate BT, but there is no absolute contraindication to a properly performed procedure.

Prolonged urinary incontinencee is extremely rare, < 2%.

Complications and toxicity Gastrointestinal:

Rectal irritation causing rectal urgency or frequency is more likely when HDR is use in conjunction with EBRT.

Late rectal bleeding may occur and is usually not clinically significant. Serius complications, such as a rectal fistula, are extremely rare, and seen in < 1%.

Sexual dysfunction: Erectile dysfunction has been reported in up to 40% of men who were fully potent at

baseline but approximately 80% respond to pharmacologic agents . 5 – year probability of impotence 49% LDR and 21% HDR (p = 0,006) (2)

USES OF HDRBT IN PROSTATE CANCERBoost with EBRT, Monotherapy or Salvage treatment to local recurrence

BOOST with EBRT

HDRBT as a boost with EBRT is now estabilished as an effective means of dose escalation in the radical treatment of prostate cancer supported by level 1 evidence from one randomised trial (10) and a large body of published series.Represents a succesful treatment of choice and results in excellent bNED, local control and survival rates.

Patient Selection Criteria Stages T1b to T3b prostate cancers, any Gleason

Score and any PSA level are candidates for HDR as a boost to EBRT

Relative Contraindications:

Large glande size (>60cc) Significant urinary obstructive symptons Recent TURP within the last 6 months Large TURP defects Pubic arch interference Rectum-prostate distance on TRUS of < 5 mm

Absolute Contraindications: (9)

Preexisting rectal fistula. Lithotomy position or anesthesia not possible No proof of malignancy

GEC-ESTRO/EAU 2005

GEC/ESTRO 2013

Treatment Schedules It is not possible to make a firm recommendation on plannig aim dose EBRT:

45 Gy in 25 fx, 46 Gy in 23 fx; 35,7 Gy in 13 fx; 37,5 Gy in 15 fx… Before currently with or after HDRBT. Minimum volumen treated should include the entire prostate and vesicles with

margin +/- pelvic lymph nodes.

HDR: Is given in multiple fractions, generally twice a day with a minimum of 6 h between

fractions, in 1 – 3 implant procedures. 15 Gy in 3 fx; 11 – 22 Gy in 2 fx; 12 – 15 Gy in 1 fx… A single dose of 15 Gy is gaining

increasing acceptance (11)

GEC/ESTRO 2013 (6)

A single dose of 15 Gy

1. HDR Brachytherapy 2. EBRT (IMRT)

Pelvic lymph nodes: 45 GyProstate + vesicles: 54 Gy

MONOTHERAPY

First proposed by Yoshioka et al, almost 2 decades ago (12).

Radiobiological considerations, which asume a low α/β for prostate cancer, predict a significant advantage for HDRBT alone delivered in a small number of very large fractions in terms of total biologically effective dose over EBRT and LDRBT.

Advantages relating to dosimetry and radioprotection. Demands higher degree of technical and planning expertise than boost.

Patient Selection Criteria

Hot debate (5): Reported by several institutions, largely for low-risk, but also for low-to-

intermediate-risk patients. For high-risk patients should be considered investigational. However,

recently published reports revealed excellent biochemical control rates, even for intermediate- and high-risk patients (13-15)

As yet, no guidelines or recommendations have been established .

Treatment Schedules

Long term date are not yet available.

34 Gy in 4 fx (1 implant)

36-48 Gy in 4 fx (1 implant)

38 Gy in 4 fx (2 implants)

34,5Gy in 3 fx (3 implants)

31,5 Gy in 3 fx (1 implant)



Gunderson (2)

SALVAGE TREATMENT TO LR Locally recurrent prostate cancer following RT represent a clinical challenge (16).

Surgery, cryotherapy and BT are among the most frequently used salvage treatment options (17)

Several aspects unique to HDR BT make it ideally suite or use as a salvage procedure (18): Delivers high dose radiation directly to the target tissue. Results in very little treatment related uncertainty. Is well suited to hypofractionated treatment schedules. EBRT is not able to achieve either the high doses to the prostate or the dose sparing effect on normal

tissues that HDR BT is able to achieve (19)

Patient Selection Criteria Have a biospy-proven recurrence after definitive EBRT, with no evidence

of disease elsewhere.

Treatment schedules36 Gy in 6 fx (20)

21 Gy in 3 fx (21)

30 Gy in 2 fx after 30 – 40 Gy EBRT (post prostatectomy) (22)

There is limited experience and this is no recommended outside a formal prospective study. OAR constraints are critical in this setting (6)

HDRBT 36 Gy in 6 fx (2 implants, 1 week apart)

Mediam followup 18,7m: bNED 89% with 14% G3-4 toxicity. (20)

Mediam followup 60m: bNED 51% with 4% G3-4 toxicity. Suggestig that, with further time, G3 complicantions trend to improve. (23)

CONCLUSIONS

HDRBT is a vehicle for dose escalation that has resulted in high tumor control and low toxicity rates.

With proper selection and delivery technique, HDRBT has great promise and convenience because of avoidance of radiation exposure, short treatment times, and outpatient therapy.

The development of well-controlled randomized trials addressing issues of efficacy, toxicity, quality of life and costs versus benefits will ultimate define the role of HDR BT in the therapeutic armamentarium.

With excellent tumor control and a favorable side-effect profile, HDR BT is now an established and important treatment for prostate cancer.

BIBLIOGRAPHY

1. Halperin, Edward C; Brady, Luther W; Perez, Carlos A; Wazer, David E (2013). Perez & Brady's Principles and Practice of Radiation Oncology (6th ed) . Philadelphia: Lippincott Williams & Wilkins.

2. Gunderson ,Leonard L; Tepper, Joel E (2012). Clinical Radiation Oncology (3rd ed). Philadelphia: Elsevier Saunders.3. Guinot, JL; Lanzós, E; Muñoz, V; Polo, A; Ramos, A (2008). Guía de Braquiterapia. Madrid: SEOR.4. Erickson BA, Demanes DJ, Ibbott GS, et al. American Society for Radiation Oncology (ASTRO) and American College of Radiology (ACR)

practice guideline for the performance of high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 2011 ;79: 641 – 649.5. Yoshioka Y, Suzuki O, Otani Y, et al. High-dose-rate brachytherapy as monotherapy for prostate cancer: technique, rationale and

perspective. J Contemp Brachytherapy 2014; 6: 91 – 98. 6. Hoskin PJ, Colombo A, Henry A et al. GEC/ESTRO recomendations on high dose rate afterloading brachytherapy for localised prostate

cancer: an update. Radiother Oncol 2013; 107: 325 – 332.7. Kovacs G, Potter R, Loch T, et al. GEC-ESTRO EAU recommendations on temporary brachytherapy using stepping sources for localized

prostate cancer. Radiother Oncol 2005; 74: 137 – 148.8. Joslin, C.A.F; Hall, E; Flynn, A (2001); Principles and Practice of Brachytherapy: Using Afterloading Systems. London: Arnold.9. Yamada Y, Rogers L, Demanes DJ, et al. American Brachytherapy Society consensus guidelines for high-dose-rate prostate

brachytherapy. Brachytherapy 2012; 11: 20 – 32.10. Hoskin PJ, Rojas AM, Bownes PJ, Lowe GJ, Ostler PJ, Bryant L. Randomised trial of external beam radiotherapy alone or combined with

high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103: 217 – 222.11. Morton G, Loblaw A, Cheung P, et al. Is single fraction 15 Gy the preferred high-dose-rate brachytherapy boost dose for prostate

cancer?. Radiother Oncol 2011; 100: 463 – 467.12. Hoskin P, Rojas A, Ostler P, Hughes R, et al. High-dose-rate brachytherapy alone given as two or one fraction to patients for locally

advanced prostate cancer: Acute toxicity. Radiother Oncol 2014; 110: 268 – 271.

13. Rogers CL, Alder SC, Rogers RL et al. High dose brachytherapy as monotherapy for ingermediate risk prostate cancer. J Urol 2012; 187: 109 – 116.

14. Hoskin P, Rojas A, Lowe G et al. High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence. Int J Radiat Oncol Biol Phys 2012; 82: 1376 – 1384.

15. Zamboglou N, Tselis N, Baltas D, et al. High-Dose-Rate Interstitial Brachytherapy as Monotherapy for Clinically Localized Prostate Cancer: Treatment Evolution and Mature Results. Int J Radiat Oncol Biol Phys 2013. 85: 672 – 678.

16. Hsu IC, Yamada Y, Assimos DG, et al. ACR Appropriateness Criteria high-dose-rate brachytherapy for prostate cancer. Brachytherapy 2014; 13: 27 – 31.

17. Henríquez I, Sancho G, Hervás A, Guix B, et al. Salvage brachytherapy in prostate local recurrence after radiation therapy: predicting factors for control and toxicity. Radiat Oncol 2014; 9: 102.

18. Yamada Y, Kollmeier M.A, Pei X, et al. A Phase II study of salvage high-dose-rate brachytherapu for the treatment of locally recurrent prostate cancer after definitive external beam radiotherapy. Brachytherapy 2014. 13: 111 – 116.

19. Spratt DE, Scala LM, Folkert M, et al. A comparative dosimetric analysis of virtual stereotactic body radiotherapy to high-dose-rate monotherapy for intermediate-risk prostate cancer. Brachytherapy 2013. 12: 428 – 433.

20. Lee B, Shinohara K, Weinberg V, et al. Feasibility of high dose rate brachytherapy salvage for local prostate cacner recurrence afteer radiotherapy: the University of San Francisco experience. Int J Radiat Oncol Biol Phys 2007. 67: 1106 – 1112.

21. Tharp M, Hardacre M, Bennett R, et al. Prostate high dose rate brachytherapy as salvage treatment of local failure after previous external or permanent seed irradiation for prostate cancer. Brachytherapy 2008; 7: 231 – 236.

22. Niehoff P, Loch T, Nurnber N, et al. Feasibility and preliminary outcome of salvage combined brachytherapy and external beam radiotherapy for local recurrences after radical prostatectomy. Brachytherapy 2005; 4: 141 – 145.

23. Chen CP, Weinberg V, Shinohara K, et al. Salvage HDR brachytherapy for recurrent prostate cancer after previous definitive radiation therapy: 5 – Year otcomes. Int J Radiat Oncol Biol Phys 2013. 86: 324 – 329.

”Life is not easy for any of us. But what of that? We must have perseverance and above all confidence in ourselves. We must believe that we are gifted for something and that this thing must be attained.”

Marie Curie

clinical aspects and applications of high dose-rate brachytherapy

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