22 Penis cancer

First page 1 Next page Last page

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE 22 Penis cancer Juanita Crook, Cyrus Chargari

Editors Bradley Pieters Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

22 Penis cancer

Juanita Crook and Cyrus Chargari

1. Summary 2. Introduction 3. Anatomy 4. Pathology

3 3 3 3 4 5 5 5

9. Treatment planning

9 9

10. Dose, dose rate and fractionation

11. Monitoring

12 12 12 13 14

12. Results

5. Work up

13. Adverse side effects 14. Key messages

6. Indications, contra-indications 7. Tumour and target volume

15. References

8. Technique

1. SUMMARY

Penile cancer remains uncommon in western societies but over recent years, an etiologic path through Human Papilloma Virus (HPV) has altered demographics to implicate younger individuals. This has spurred motivation to turn away from traditional surgical management with penectomy or partial penectomy towards penile conserving approaches. Radiation, either in the form of external beam radiotherapy or brachytherapy, provides an effective means of penile sparing. Brachytherapy can be delivered as either interstitial or surface mold techniques, using either traditional low dose rate (LDR), pulsed dose rate (PDR) or high dose rate (HDR) approaches. Brachytherapy generally provides local control and penile sparing of 70-85% and cause-specific survival of 85-95% at 5 years. Penile amputation is reserved for treatment failures. We will review patient selection and the specialized techniques for various brachytherapy approaches.

2. INTRODUCTION

3. ANATOMY

There is considerable geographic variation in the incidence of penile cancer worldwide. The incidence in less developed nations such as India, China, Brazil and Uganda is up to 10 times that seen in developed nations [1][2]. The low incidence of penile cancer in western countries (approximately 1/100,000) has impeded clinical study of optimal management. The traditional risk factors of advanced age, smoking, lack of circumcision, phimosis, poor hygiene and lack of access to health care[1][2][3] are being superseded by HPV exposure which is now implicated in 45-50%of cases[4]. Sexual practices contribute to the increased prevalence of HPV in society but there is hope that widespread penetration of HPVmultivalent vaccination for both girls and boys will flatten that curve[5]. The increased responsiveness to radiation and chemoradiotherapy demonstrated by other HPV-positive squamous cancers such as oropharynx, cervix, vulva and anal canal, has promoted interest in these alternative forms of treatment. As the psychologic impact of penile amputation is considerable [6][7], penile-sparing approaches, both surgical and radiation, are encouraged.

The penis is comprised of two anatomical parts that are distinct in terms of topographic and functional aspects: the penile root, which is immobile and embedded in the superficial perineum, and the penile body, which is visible and mobile and is comprised of 3 erectile bodies. There are two cylindrical dorsolateral corpora cavernosa and one medio-ventral corpus spongiosum surrounding the urethra. The penile glans is the distal part of the corpus spongiosum, covered by the prepuce.The balano-prepucial sulcus, also known as the coronal sulcus, is the boundary between the penile glans and the penile body (Figure 1).

4. PATHOLOGY

Although other histologic types have been reported, including basal cell, lymphoma, melanoma and sarcoma, 95% of primary penile cancers are squamous cell (SCC). Overall HPVpositivity is reported in 40-50% but varies geographically, and with histologic subtype.

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

5 5

Figure 1: MRI of the penis, axial and sagital view (T2 weighted. 1. Corpora cavernosa 2. Ventral corpus spongiosum 3. Glans penis

4. Bulbous spongiosum 5. Cavernosal arteries

Of the various SCC subtypes, verrucous has the best prognosis, despite the fact that only 25% are reported to be associated with HPV. The basaloid type is most frequently associated with HPV positivity, reported in up to 2/3 of cases, while the classic SCC (not-otherwise-specified (NOS)), sarcomatoid and adenosquamous are HPV positive less often[8]. The most common HPV type is HPV 16[8]. HPV DNA is highly prevalent in penile dysplasia and penile intraepithelial neoplasia (PeIN) [9]. P16 status can be evaluated by immunohistochemistry (IHC) and is considered representative of HPV infection [10]. There is an association with better disease specific survival for those positive for HPV by either PCR (polymerase chain reaction) or IHC [11]. Similar to vulvar cancer, there are 2 epidemiologic pathways for SCC of the penis, an HPV-related pathway and the traditional chronic inflammation pathway seen more frequently in older individuals and in association with conditions such as lichen sclerosis. Recent work has demonstrated the potential for biologic therapy aimed at mutations like PDL1. PDL1 is more prevalent in locally advanced (> 4 cm diameter) and node positive cases (69% PDL1 positive). PDL1 positivity has been reported to be 100% in high grade cancers [12]. A Swedish series reported 31%PDL1 positivity in 222 patients and found it associated with reduced cause specific survival (CSS)[13].

urethral infiltration, or extension to cutaneous structures. Palpation of the groins should also look for regional node involvement. As depth of infiltration can be difficult to assess clinically, clinical examination is completed with a radiological assessment that should include magnetic resonance imaging (MRI) withmedically- induced erection. PGE1 alprostadil injection accentuates the boundary between the tunica albuginea and the corpus cavernosa on T2 weighted images, which is important in local staging. In addition, MRI can assess the degree of infiltration of the corpus spongiosum. Historically, patients with clinical infiltration of the corpora cavernosa would not be offered brachytherapy [14] but it is uncertain whether early subclinical infiltration detected on MRI should also exclude brachytherapy as an option. In the case of contra-indications to MRI, an ultrasound performed by an expert radiologist may be useful to assess tumour infiltration. In addition to local staging, MRI provides adequate cross-sectional imaging to assess for potential inguinal or pelvic lymph node involvement, which is the main prognostic factor. For patients with disease confined to the penile glans by clinical and radiological assessment, more invasive lymph node staging may be indicated according to the grade and depth of infiltration of the primary tumour. Patients with Ta-T1 grade 1 tumours on biopsy have a low risk of occult lymph node involvement and therefore surveillance of the groins is usually recommended. Patients with pT1 Grade2 tumours are considered intermediate risk, while pT1G3 and pT2-3 Grade 1-3 tumours are at high risk of lymph node metastases. In patients with intermediate to high- risk tumours, a bilateral inguinal sentinel lymph node sampling is associated with less lymphedema than bilateral modified inguinal lymph node dissection. In experienced centres, sentinel lymph node sampling is therefore recommended to complete lymph node staging with minimal morbidity. For patients with clinical or radiological inguinal involvement, a fine needle aspiration should be performed to confirm pathology, followed by radical inguinal dissection on the involved side. The contralateral side may be managed with a modified inguinal lymph node dissection.

5. WORK UP

Primary workup should look for any potential contra-indications to brachytherapy. Clinical examination of the penis is important to determine suitability for brachytherapy as well as to decide the most suitable geometry for the implant. It should report the tumour topography, the size (dimensions) of the tumour, whether it is ulcerated or infiltrating, the presence of multifocal disease,

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

For patients with either suspicion or histological evidence of inguinal lymph node extension, a 18-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18-FDG PET/ CT) is recommended to assess for possible metastases to pelvic lymph nodes or distantly.

carcinoma) often treated with surface applicators, a 5 mmmargin at a depth is sufficient. For deeply infiltrating tumours, the whole glans should be included in the clinical target volume as there is no anatomical barrier in the penile glans, and it is difficult to assess accurately the extent of tumour invasion. The organs at risk during penile brachytherapy are the urethra and the testes. For intact tumours, the penile glans mucosa is part of the target volume as tumours usually develop from the surface of the penile glans. For postoperative indications, the mucosa may be considered as an organ at risk when the margin is not at the glans surface.

6. INDICATIONS, CONTRA-INDICATIONS

Discussion will focus on SCC although other pathologies can be considered for brachytherapy on an individual basis if technically suitable, even including oligometastatic disease to the penis from other primary cancers [15]. Generally, SCC under 4 cm confined to the glans or with limited involvement of the coronal sulcus would be considered suitable, provided coverage can be obtained with one plane of needles in addition to those required for treatment of tumour in the glans[16]. Larger tumours are associated with higher rates of necrosis, but still offer a reasonable chance of penile sparing. Circumcision is essential prior to undertaking any type of brachytherapy in order to fully expose the lesion and debulk that portion of the tumour which straddles the foreskin and the glans. In addition, if not removed, the foreskin is liable to both painful necrosis after brachytherapy, and phimosis which makes subsequent follow up difficult. Brachytherapy can be planned two weeks after the circumcision. In cases where the urethral meatus is involved, the interstitial needles should not be placed too close to the meatus as this risks subsequent meatal stenosis. Penile cancers on the shaft are much less common but still can be approached with brachytherapy, provided that “in transit” skipmetastases froma penile glans tumour are excluded, in which case total penectomy would be indicated. Superficial, and thus very low volume tumours, even if larger than 4cm in extent, may be suitable for surface mold brachytherapy. An interstitial implant in these cases is less desirable because it would involve treating the full thickness of the organ in order to cover a superficial rind of involved tissue. Lymph node status is the most important prognostic factor and lymph node management must be included in the initial treatment plan. Patients with a small volume primary and limited nodal involvement can still do well with a penile sparing approach. For patients with bulky nodal involvement, neoadjuvant treatment with chemotherapy or chemo-radiation is generally the preferred initial approach, as currently being investigated by the international InPACT trial (https://clinicaltrials.gov/ct2/show/NCT02305654). The role of brachytherapy can however be discussed according to tumour response, in order to avoid severe local symptoms from local progression.

8. TECHNIQUE

LDR template approach (also PDR) This is an in-patient technique performed under general or local anaesthesia (penile block) and requiring on average 5 days of hospitalization for treatment delivery at a classic low dose rate of 50-55 cGy/hour. Following induction of anaesthesia, the patient is catheterized with an in-dwelling Foley urinary catheter which will remain until treatment is completed. The tumour is then carefully examined and palpated to determine the number and spacing of needles and planes, and their orientation. This is facilitated by having various lucite templates available that are predrilled with needle spacings ranging from 12-15 mm. Generally, 2-4 planes of needles, and a total of 4-12 needles are required. The transparent templates are constructed to be 5 mm thick and can be placed over the tumour to more easily visualize the appropriate spacing and placement. 17-gauge steel needles are used for PDR after-loading, while 19.5 gauge needles were used for manually loaded Iridum-192 wire.The needles can be oriented either left-right (Figure 2), or from anterior to posterior (Figure 3), either unilaterally or bracketing the urethra, which can easily be palpated due to the presence of the urinary catheter. An exterior plane of needles that does not traverse tissue can be placed adjacent to the tumour, separated from it by tissue-equivalent bolus material such as superflab. This allows the superficial plane to be deep enough in tissue to avoid linear scarring or necrosis, while avoiding underdosing the surface of the tumour. A tumour that is primarily located on the dorsal or ventral surface of the glans will be preferentially approached with a left-right needle orientation. Reference 17 provides an illustrative summary of various implant approaches. We recommend beginning the needle insertion with the most distal, paracentral needles closest to the meatus. Once these are positioned through the chosen template, thematching exit template is placed, and the remaining needles are easily inserted. The templates are then snugged up against the penis and are adjusted to be parallel. The needles are adjusted so that the distance from the template to each needle hub is the same and the locking nuts are tightened. A Styrofoam or sponge collar is placed around the shaft of the penis proximal to the implant to distance the treated area from normal tissues. The implant procedure generally takes about 30-45 minutes. As the implant structure is rigid, and the geometry very stable over the duration of treatment, dose calculation can be done from measurements (Figure 4), or from a CT simulation. The penis should be oriented so that the CT is performed as transverse slices at right angles to the implant needles. Dilute contrast is placed in the urinary catheter to aid

7. TUMOUR AND TARGET VOLUME

The gross tumour volume (GTV) is defined clinically and radiologically. Clinical target volume (CTV) is defined as the gross tumour volume plus an anatomical margin of 1 cm in all directions. For very superficial tumours, without infiltration of corpus spongiosum (in situ tumours or non-invasive verrucous

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

Figure 1: PDR Implant for ventral tumor. 2-plane implant with single plane of 3 needles within tissue plus a second exterior plane with bolus between the needles and the tumor.

Figure 2: PDR Implant for ventral tumor. 2-plane implant with single plane of 3 needles within tissue plus a second exterior plane with bolus between the needles and the tumor.

Figure 1: PDR Implant for ventral tumor. 2-plane implant with single a second exterior plane with bolus between the needles and the tum

Figure 3: 2-plane, 6-needle implant showing Paris System calculations. With the Basal Dose Rate being the point of dose rate minimum between the planes, the 85% Reference Isodose (shown) covers the volume. The same approach can be applied to the geometry of a PDR implant. Permission obtained Reference 16) Figure 4: 2-plane, 6-needle implant showing Paris System calculations. With the Basal Dose Rate being the point of dose rate minimum between the planes, the 85% Reference Isodose (shown) covers the volume. The same approach can be applied to the geometry of a PDR implant. Permission obtained Reference 16).

Figure 2: 4-needle, 2-plane implant for PDR brachytherapy, showing Basal Dose Rate and 85% Reference Isodose (permission obtained reference 17) Figure 3: 4-needle, 2-plane implant for PDR brachytherapy, showing Basal Dose Rate and 85% Reference Isodose (permission obtained reference 17)

Figure 5: Dose distribution 3-plane LDR implant

Figure 4: Dose distribution 3-plane LDR implant

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

c c

d c dddddd dddddd

Figure 6: HDR brachytherapy a) Tumor at presentation

b) Implant in process: shows entrance and exit templates with fixation “nuts” on the entrance side to screw into the template and lock the needles in place c) Implant stabilized and ready for treatment. The urinary catheter is in place, and the needles locked into the template to prevent displacement. In the 4 corners of the template, needles that will not be used for treatment delivery have been positioned and locked into both templates to prevent the spacing of the templates from changing d) Dose distribution: 100% red, 125% blue, 150% orange. 5 mm of bolus wrapping penis, with 7 needles exterior to penis e) Appearance of penis 2 months after treatment f) Another patient 6 years post treatment

Figure 5: HDR brachytherapy

urethral visualization for planning (Figure 5). a) tumor at presentation b) Implant in process: shows entrance and exit templates with fixatio “nuts” on the entrance side to screw into the template and lock the needles in place c) Implant stabilized and ready for treatment. The urinary catheter is in place, and the needles locked into the template to prevent displacement. In the 4 corners of the template, needles that will not be used for treatment delivery have been positioned and locked into both templates to prevent the spacing of the templates from changing d) Dose distribution: 100% red, 125% blue, 150% range. 5 mm of b lus wrapping penis, with 7 needles exterior to penis e) Appearance of penis 2 months after treatment f) Another pa ient 6 years post treat ent HDR template procedure This is very similar to the above described LDR procedure. The important difference is that the spacing of the needles and planes for HDR should generally be closer than for LDR, in the range of 9-12 mm. For both HDR and PDR, since dose optimization is readily accomplished by adjusting dwell times, the needles and planes do not necessarily need to be equidistant as in a manually- loaded LDR procedure. In our experience, one pair of 5cm x 5cm templates is sufficient, with holes drilled every 3-4mm. 17-gauge steel needles are employed with both entrance and exit template guidance. For HDR, the wider spacing (12 mm) would be chosen for needles that bracket the urethra. Needles are inserted as required to cover the tumour, again beginning with the one consideredmost critical with respect to the urethra. Exterior needles adjacent to the tumor but not penetrating penile tissue can also be used as described in the LDR scenario (Figure 6). Bolus such as superflab should be placed between these needles and penile tissue to ensure adequate dose build-up. For HDR brachytherapy planning, CT simulation is essential for dose calculation and can be performed immediately following the procedure. Slices should be nomore than 1.2mm thick and should be oriented perpendicular to the implant needles. We recommend urethral catheter contrast. HDR surface mold Surface mold treatment should be restricted to superficial tumours (Tis or T1a) not more than 3mm thick. Published experience with HDR surface mold treatment for penile cancer is very limited. Treatment can be delivered with either a custom-made

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

c Figure 6: Cylindrical applicator for surface HDR brachytherapy. Figure 7: Cylindrical applicator for surface HDR brachytherapy. a) Penis positioned and visible within applicator. 5 mm of superflab bolus was placed on the dorsal surface to ensure snug fit. The lucite cork with a concave end has been placed in the distal end of the applicator, in contact with the glans to ensure tissue equivalent bolus. A snug constriction ring can be seen at the base of the penis (under the edge of the superflab) to keep redundant penile skin from sliding into the treatment volume. b) Dose distribution: Imbedding the treatment catheters 5 mm within the applicator prevents overdose of the skin surface through direct contact. CTV is in light blue, skin dark blue, 40 Gy isodose in green and 36 Gy (yellow) centrally. c) Dose volume histogram: CTV orange, skin blue d) Clinical result 4 years later a) Penis positioned and visible within applicator. 5 mm of superflab bolus was placed on the surface to ensure a snug fit. The lucite cork with a concave end has been placed in the dis of the applicator, in contact with the glans to ensure tissue equivalent bolus. A snug const ring can be seen at the base of the penis (under the edge of the superflab) to keep redund penile skin from sliding into the treatment volume.

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

3D printed applicator[18] or a bivalved lucite cylinder (diameter range 3 - 4.5 cm)[19]. The penis should fit snugly in the cylinder. To avoid excessive dose to the penile skin/mucosa, longitudinal source channels should be embedded 5mm from the inner surface which is in contact with the penis, and should be close enough to provide optimum homogeneity and minimize hyperdose sleeves around each source track. CT simulation is performed with the penis placed in the posterior half of the cylinder, supported and positioned to be horizontal. The GTV (or CTV if no GTV due to prior excision) is marked with wire based on pathology and prior clinical photos. The anterior half of the cylinder is then positioned and attached. The transparent material allows easy verification of penile position. A lucite “cork” with a convex end is advanced into the open end of the cylinder until it touches the glans. Any redundant skin on the shaft of the penis should be retracted out of the way using a penile constriction ring so it does not slide down into the treated volume while treatment is ongoing (Figure 7). Although the patient can be catheterized for the CT simulation, even without a catheter the urethra can generally be identified on the CT images from themeatus through the length of the applicator, located between and ventral to the corpora cavernosa. The GTV/ CTV is contoured. For the surface mold technique, because of some potential variability in positioning from day to day, a 5 mm PTV margin is recommended along the longitudinal axis of the penis. Treatment is accomplished as an outpatient, twice daily, 6 hours apart, over 5 days. LDR interstitial The majority of the interstitial penile brachytherapy experience over the decades (Table 1) has been obtained following the Paris System recommendations for geometry and dose prescription (Figure 4). Needles are inserted parallel and equidistant in parallel planes.The dose rate minimumbetween the planes is known as the Basal Dose Rate. The prescription dose (60-65Gy) is delivered to the Reference Isodose which is 85% of the Basal Dose Rate (Figure 3). From the needle spacing, the lateral clearance margins can be calculated. This algorithm ensured that the hyperdose sleeves around each source would not be excessive and generally <20%. HDR and PDR interstitial After CT simulation (slices at 1.2mm), the GTV is contoured based on prior clinical examination and imaging. A minimum 5 mm margin is added to define the CTV. Homogeneity constraints are important to minimize the risk of necrosis, especially with HDR. For PDR, dose may be prescribed to the 85% isodose following Paris System rules as for an LDR implant [20]. However, manual isodose optimization can be performed to improve target coverage andminimize hyperdose sleeves close to the urethra and/or mucosa. As described before, critical structures are the urethra and the penile mucosa though the treatment volume. As can be appreciated from Table 2, there is no agreed prescription for HDR penile brachytherapy. We recommend limiting the dose to the urethra and penile mucosa to less than 125% of the prescription dose, though there is no firmdata to confirm this recommendation. See Table 3 for the EQD2 and BED of various fractionation schemes. 9. TREATMENT PLANNING

With this recommendation, the dose limit to the organs at risk will depend on the prescription and can be seen to range from 45-52.5 Gy with EQD2 ranging from 59-70 Gy. It is preferable to report urethral dose as EQD2 per volume of urethra in cm 3 . This is less ambiguous than reporting the dose to a percentage of total contoured volume, as there are no accepted guidelines as to what constitutes the appropriate contoured volume. In an unpublished study based on PDR data, the risk of meatal stenosis correlated with distal urethra D 0.1cm 3 and D 0.2cm 3 , with a threshold of 82 Gy (HR=0.12, 95%CI = 0.04-0.38) for D 0.1cm 3 and 78 Gy (HR=0.19, 95%CI = 0.06-0.56) for D 0.2cm 3 [21]. Similar data for HDR will be of great benefit. Table 4 suggests minimal reporting requirements for HDR interstitial penile brachytherapy. Suggested homogeneity constraints for HDR include V 125% < 40% of the treated volume, V 150% < 20% and V 200% < 5%. With the V 125% < 40% of the treated volume, it should be possible to keep the urethra and skin under 125%but the dose distribution needs to be carefully evaluated and optimized as necessary to protect these critical structures. For PDR treatments, slightly higher inhomogeneity can be accepted, provided the Dose Non-uniformity Ratio V150/ V100 is maintained < 25%. GTV should receive 100% of prescription (GTV D 98% ≥ 100%) and CTV 90% (CTV D 98% ≥ 90%). Wherever external needles have been placed, bolus material is required between the surface and the external needles, generally 5 mm superflab. HDR surface mold In our experience 40 Gy/10 fractions/5 days, is prescribed at 100% to the GTV/CTV. A PTV margin is advisable because of some uncertainty of set up, especially along the longitudinal axis, but is not required at a depth. With skin contoured as the outermost 2 mm of the penile structure, skin D 0.1cm 3 should be < EQD2 70Gy (125% of a prescription dose of 40Gy (19)). Since this is a surface prescription with a maximum 3 mm thickness, urethral dose is not a concern and will be much less than prescription. A tighter skin constraint of D 0.1cm 3 EQD2 58.8 Gy for the same prescription (skin dose limited to 105% of 40 Gy/10/5days) has been associated with a higher toll of local recurrence (18). LDR and PDR interstitial Decades of experience with LDR interstitial penile brachytherapy employed manually afterloaded Ir-192 wire. Recommended activity was 1-1.5 mCi/cm (37-55 MBq/cm) but variable length and spacing of sources per individual implant resulted in a range of dose rates generally from 40-70 cGy/hr. Prescribed dose was 60-65 Gy, delivered over 4-5 days. The use of PDR permits prescription at a classic average low dose rate of 42-55 cGy/hr through brief hourly HDR pulses [22] without the need for a correction for Radiobiologic Effect (RBE) with respect to classic LDR. The largest brachytherapy series for penile glans tumours, including 205 patients treated over 45 years at Institut Gustave Roussy, has shown that a dose ≥ 62 Gy correlated with better local control than lower doses in node negative patients (p=0.038). The risk of complications correlated with the prescribed dose at the 85% 10. DOSE, DOSE RATE, FRACTIONATION

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

TABLE 1 SELECTED RESULTS FOR LDR AND PDR INTERSTITIAL PENILE BRACHYTHERAPY Author/year n LDR vs. PDR Dose (Gy) F/up (mo) LC:5y (10y)

CSS 5y

complications Penis intact

Achkari 2020[21]

20% necrosis 21% stenosis 0 necrosis 2/23 stenosis 12% necrosis 9% stenosis 23% necrosis 45% stenosis 21% necrosis 25% stenosis 8% necrosis 44% stenosis 3 necrosis 19% stenosis 4% necrosis 43% stenosis 21% necrosis 5% stenosis ns

PDR

37(3-120)

85% (3y)

Chaudhary 1999[27] Crook 2008[28] Delannes 1992[29] Delaunay 2013[30] Escande 2017(14) Kiltie 2000[31] Mazeron 1984[32] Pimenta 2015[33] Rozan 1995[34] Soria 1997[35]

LDR

21 (4-117)

70%

70% (8y)

LDR 26 PDR 41

87%(5y) 72(10y)

84% (10 y)

88% (5y) 67%(10y)

48 (4-194)

LDR

50-65

65 (12-144)

86% crude

85%

75%

LDR

80(13-190)

81%

87%

60%

LDR 166 PDR 35

201

128

82%

85%

LDR

63.5

61.5

81%

85%

75%

LDR

60-70

36-96

78% crude

74%

LDR 14 PDR 10

110

96%

91%

86%

184

LDR

139

86%

88%

78%

102

LDR

61-70

111

77%

72% (6y)

F/up(mo): Followup (months), LC 5y(10y): Local Control at 5 years (10 year results in brackets), CSS 5y: Cause specific survival at 5 years

TABLE 2 SELECTED RESULTS FOR HDR INTERSTITIAL PENILE BRACHYTHERAPY

Daily dose (GyX2/day)

Penile preserv n

Author (year) n

F/up months Total dose Gray

CSS 5-year

Toxicity

Pohankova 2019 [24]

77% (83% 5y)

Necrosis 4% (amputation)

85 (7-200)

3 X 2

100%

73%

Sharma 2014[23] Rouscoff 2014[26]

G2 fibrosis 29% Hyperpig 14% 93%

22 (6-40)

42-45

3 X 2

12/14

83% (3 yr)

Necrosis 9% Telangiect 33% G2 fibrosis 9% Necrosis 3% Stenosis 1% Hyperpig 35%

4- 4.34 X 2

27(5-83)

36-39

92%

100%

92%

Kellas-Slekza 2019 (25)

3-3.5 X 2

76 (7-204)

49(30-54)

73%

85%

70%

Necrosis 43% Stenosis 43% Telangiectasia 67%

Marban 2020(19)

3.12-3.75 X 2

90 (11-106)

38.4-53

86%

100%

86%

Martz 2021[36]

72 (3-174)

35-39

3.89-4.33

82%

88%

Necrosis 10% 79%

F/up: Followup, LC: Local Control, CSS: Cause specific survival, preservn: preservation, Hyperpig: hyperpigmentation, telangiect: telangiectasia

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

TABLE 3 EQD2 FOR VARIOUS HDR FRACTIONATION SCHEMES USING α/β-RATIO = 3GY FOR COMPLICATIONS AND 10 GY FOR TUMOUR. THE CALCULATED EQD2 IS ALSO SHOWN FOR THE 125% ISODOSE FOR VARIOUS PRESCRIPTIONS Prescription Dose (100%) 125% Isodose Dose per fraction (Gy) Total Dose (Gy) EQD2 (Gy) α/β-ratio = 3Gy EQD2 (Gy) α/β-ratio = 10Gy Total dose (Gy) EQD2 (Gy) α/β-ratio = 3Gy 3 (23) 42 50.4 45.5 52.5 63

3.12 (19)

38.4

58.8

3.3 (36)

43.2

48.8

61.5

3.9 (36)

40.5

43.8

60.4

4 (26)

50.4

4 (19)

46.7

TABLE 4 RECOMMENDATIONS FOR REPORTING HDR PENILE BRACHYTHERAPY INCLUDE:

GTV (cm 3 ) and CTV (cm 3 ) Number of needles and spacing Prescription total dose, number of fractions, fraction size

GTV D 98% , D 90% , V 125% , V 150% , V 200% CTV D 98% , D 90% , V 125% , V 150% , V 200% Urethra D 0.1cm 3 and D 0.2 cm 3 Skin D 0.1cm 3 and D 0.2 cm 3

HDR interstitial As this technique is still evolving, a range of doses have been reported (Table 2). Treatment fractions are given twice daily, 6 hours apart. Although very low volume residual disease can be treated with 38.4 Gy/12 fractions, the most commonly used prescription would be 42-45 Gy/12-14 fractions of 3.1-3.2 Gy per fraction (19). Table 2 shows reported fractionation schedules ranging from 3 Gy daily fractions, through 3-3.5 Gy and up to 4-4.3 Gy[23][24][25] [26]. Table 3 shows the corresponding EQD2. General consensus would suggest fraction sizes of 3-3.5 Gy and total dose depending on bulk of disease in the range of 38 Gy to 45 Gy (EQD2 42-45 Gy for α/β-ratio=10 Gy). Dose homogeneity is an important factor to reduce late sequelae, as are dose constraints to urethra and skin. Unfortunately, inconsistent reporting and limited experience have not allowed these to be clearly defined. We recommend reporting absolute volume of urethra receiving at least 115%of the prescribed dose(19)), and limiting urethral dose such that D 0.1cm 3 < 125% (~EQD2 60 Gy). In practice, confluent areas with dose of 125% at the skin surface should also be as limited as much as possible.

reference isodose according to the Paris system (20). Doses > 60 Gy correlated with stenoses, and doses > 65 Gy were associated with painful ulcerations. Complications were higher with larger treated volume (> 25 cm 3 ), more needle planes (>2) and higher dose rate (14). HDR surface mold The most frequently reported dose is 40 Gy/10 fractions delivered bid 6 hours apart over 5 days. Skin D 0.1cm 3 of 125% (50 Gy: EQD2 70 Gy) appears to be tolerated while skin D 0.1cm 3 105% (EQD2 58.8 Gy) was associated with more local failures. This may be a result of the lower surface dose being associated with less dose at a depth. The number of patients reported is very small and more data is required. All data is from HDR afterloading systems with an Ir-192 source.

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

a manually afterloaded LDR technique. This may reduce toxicity in the future. HDR experience is a relatively recent development with smaller numbers reported but appears comparable and is certainly more widely available in modern radiotherapy departments. (Table 2)

13. ADVERSE SIDE EFFECTS

Acute adverse events are frequent, observed inmost patients treated with brachytherapy andmainly represented by acute radiomucositis/ epidermatitis and urethritis. Acute symptoms should be treatedwith symptomatic local and systemic treatments, including analgesics and antibiotics if necessary. With long-term follow-up, painful ulcerations and necroses may be observed, associated with higher volumes, higher dose rate, and higher total dose (14). Biopsies should be avoided. Painful necroses will respond well to a course of hyperbaric oxygen (40 dives breathing 100% oxygen at 2-2.5 atmospheres) and may eventually heal [37] (Figure 8) Distal urethral stenoses are also frequently seen, with a higher probability among patients having tumour infiltration of the distal meatus or with pre-existing symptoms. These rarely need surgical management, though urethral dilatations and, in severe cases, a meatotomy can be considered. In the largest series, 23% of patients required surgery for local relapse or toxicity, including 25 (12.4%) partial glansectomy, 14 (7.0%) total glansectomy, and 7 (3.5%) total penectomies (14). Early urethral adhesions should be separated by passing a catheter or urethral dilator and can be prevented by teaching the patient to self-dilate as required. Erectile dysfunction is another possible consequence but a survey has shown than 70% of men with baseline potency continued to be sexually active with only mild erectile dysfunction. Patient- assessed quality of life was considered good with a median score of 80/100 (IQR = 65-90) and was only impacted by pain. Overall, 57% and 39% declared having no or moderate pain or discomfort, respectively [38].

Figure 7: Radionecrosis after LDR brachytherapy for T3 SCC in a 48 year old man. Managed with Hyperbaric Oxygen. Figure 8: Radionecrosis after LDR brachytherapy for T3 SCC in a 48 year old man. Managed with Hyperbaric Oxygen. a) After first series of 40 dives b) After second series of 40 dives c) Long-term result at 8 years

a) After first series of 40 dives b) After second series of 40 dives c) Longterm result at 8 years

11. MONITORING

After treatment, follow-up is based on a consultation with clinical examination. The patients should be seen every 3-6 months for 2 years, then every 6 months for 3 years, then annually for life, given the risk of delayed local recurrence and late complications (> 10 years follow-up). This surveillance aims to detect isolated local relapses suitable for salvage penectomy, and also to monitor and treat delayed complications. For patients who did not undergo lymph node surgical staging despite risk factors for nodal relapse (e.g. high grade or deep infiltration), ultrasound of the bilateral groins is recommended every 6 months. Although data is lacking on when this could safely be discontinued, a minimumof 3 years is advisable. Other radiological examinations are ordered as necessary for symptoms. A chest/abdomen/pelvis computed tomography should be considered in patients with lymph node involvement.

12. RESULTS

Experience with LDR penile brachytherapy extends over four decades during which time staging systems and techniques have evolved. In general, penile preservation rate is approximately 85% at 5 years and 70% at 10 years (Table 1). The more recent reports show the evolution from classic LDR with manual afterloading to PDR.The results of these 2 techniques are combined in Table 1, but centres that include both techniques are indicated. Complications like meatal stenosis and ulceration/necrosis are seen consistently through the decades. PDR, however, allows the practitioner to address and modify issues such as meatal dose prior to treatment through dose optimization, something that was not possible with

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

14. KEYMESSAGES

• Penile brachytherapy is an effective penile sparing option for curative treatment of SCC of the glans penis under 4 cm in size, stage T1, and selected T2 and T3. • Although the classic LDR approach is used less frequently, the same techniques apply to PDR implants and similar results can be expected. HDR experience is increasing and although the dose and fractionation are still evolving, results are very promising.

• Penile preservation can be expected in 85% of men at 5 years and 70% by 10 years.

• Protracted follow up is recommended as late local recurrences can be effectively managed surgically.

• Lymph node status remains the most important prognostic factor and close collaboration with urologists is recommended for appropriate lymph node surgical staging in higher risk tumours

Penis cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 15/07/2022

15. REFERENCES

1. Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ. Penile cancer: epidemiology, pathogenesis and prevention. World J Urol 2009 Apr;27(2):141-150. 2. Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl 2000(205):189-93. 3. Maden C, Sherman KJ, Beckmann AM, Hislop TG, Teh CZ, Ashley RL, et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst 1993 Jan 6;85(1):19-24. 4. Kidd LC, Chaing S, Chipollini J, Giuliano AR, Spiess PE, Sharma P. Relationship between human papillomavirus and penile cancer-implications for prevention and treatment. Transl Androl Urol 2017 Oct;6(5):791-802. 5. Anic GM, Giuliano AR. Genital HPV infection and related lesions inmen. Prev Med 2011 Oct;53 Suppl 1:S36-41. 6. Opjordsmoen S, Fossa SD. Quality of life in patients treated for penile cancer. A follow-up study. Br J Urol 1994 Nov;74(5):652-7. 7. Opjordsmoen S, Waehre H, Aass N, Fossa SD. Sexuality in patients treated for penile cancer: patients' experience and doctors' judgement. Br J Urol 1994 May;73(5):554-60. 8. Djajadiningrat RS, Jordanova ES, Kroon BK, vanWerkhoven E, de Jong J, Pronk DT, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol 2015 Feb;193(2):526-531. 9. Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla AL, Quint WG, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol 2001 Oct;159(4):1211-8. 10. Cubilla AL, Velazquez EF, Amin MB, Epstein J, Berney DM, Corbishley CM, et al. The World Health Organisation 2016 classification of penile carcinomas: a review and update from the International Society of Urological Pathology expert-driven recommendations. Histopathology 2018 May;72(6):893-904. 11. Sand FL, Rasmussen CL, FrederiksenMH, Andersen KK, Kjaer SK. Prognostic Significance of HPV and p16 Status in Men Diagnosed with Penile Cancer: A Systematic Review andMeta-analysis. Cancer Epidemiol Biomarkers Prev 2018 Oct;27(10):1123-1132. 12. De BaccoMW, Carvalhal GF, MacGregor B, Marcal JMB, Wagner MB, Sonpavde GP, et al. PD-L1 and p16 Expression in Penile Squamous Cell Carcinoma From an Endemic Region. Clin Genitourin Cancer 2020 Jun;18(3):e254-e259. 13. Davidsson S, Carlsson J, Giunchi F, Harlow A, Kirrander P, Rider J, et al. PD- L1 Expression in Men with Penile Cancer and its Association with Clinical Outcomes. Eur Urol Oncol 2019 Mar;2(2):214-221. 14. Escande A, Haie-Meder C, Mazeron R, Maroun P, Cavalcanti A, de Crevoisier R, et al. Brachytherapy for Conservative Treatment of Invasive Penile Carcinoma: Prognostic Factors and Long-Term Analysis of Outcome. Int J Radiat Oncol Biol Phys 2017 Nov 1;99(3):563-570. 15. Martz N, Benziane-Ouaritini N, Gautier M, Brenot-Rossi I, Montagne L, Salem N, et al. Brachytherapy for oligometastatic prostate cancer to the penis. J Contemp Brachytherapy 2021 Oct;13(5):593-597. 16. Crook JM, Haie-Meder C, Demanes DJ, Mazeron JJ, Martinez AA, Rivard MJ. American Brachytherapy Society- (ABS-GEC-ESTRO) consensus statement for penile brachytherapy. Brachytherapy 2013 May-Jun;12(3):191-198. 17. Crook J, Jezioranski J, Cygler JE. Penile brachytherapy: technical aspects and postimplant issues. Brachytherapy 2010 Apr-Jun;9(2):151-158. 18. D'Alimonte L, Ravi A, Helou J, MorrisonD, Mendez LC, EastonH, et al. Optimized penile surface mold brachytherapy using latest stereolithography techniques: A single-institution experience. Brachytherapy 2019 May - Jun;18(3):348-352. 19. Marban M, Crook J, Keyes M, Dubash R, Batchelar D. High-dose-rate brachytherapy for localized penile cancer: Evolution of a technique. Brachytherapy 2020 Mar - Apr;19(2):201-209. 20. Pierquin B, Chassagne D, Wilson F. Modern Brachytherapy. NY: Masoom Pub; 1987. 21. Achkari S, Bourdais R, Sun R, Kumar T, K,M., Felefly T, et al. Dose-volume predictors of distal urethral toxicity after PDR brachytehrapy for penile cancer. Radiother Oncol 2020(https://www.estro.org/Congresses/ESTRO-2020/462/ clinicaltrack-urology-non-prostate/1367/). 22. Crook JM, Jezioranski J, Grimard L, Esche B, Pond G. Penile Brachytherapy: Results for 49 patients. Int J Radiat Oncol Biol Phys 2005 Jun 1;62(2):460-467. 23. Sharma DN, Joshi NP, Gandhi AK, Haresh KP, Gupta S, Julka PK, et al. High- dose-rate interstitial brachytherapy for T1-T2-stage penile carcinoma: short-term results. Brachytherapy 2014 Sep-Oct;13(5):481-487.

24. Pohankova D, Sirak I, Kasaova L, Grepl J, Paluska P, Louda M, et al. High-Dose Rate Brachyther-apy in the Treatment of Early Stages of Penile Carcinoma. Klin Onkol Winter 2019;32(1):52-57. 25. Kellas-Sleczka S, Bialas B, Fijalkowski M, Wojcieszek P, SzlagM, Cholewka A, et al. Nineteen-year single-center experience in 76 patients with penile cancer treated with high-dose-rate brachytherapy. Brachytherapy 2019 Jul - Aug;18(4):493-502. 26. Rouscoff Y, Falk AT, Durand M, Gal J, Chand ME, Gautier M, et al. High-dose rate brachytherapy in localized penile cancer: short-term clinical outcome analysis. Radiat Oncol 2014 Jun 19;9:142-717X-9-142. 27. Chaudhary AJ, Ghosh S, Bhalavat RL, Kulkarni JN, Sequeira BV. Interstitial brachytherapy in carcinoma of the penis. Strahlenther Onkol 1999 Jan;175(1):17- 20. 28. Crook J, Ma C, Grimard L. Radiation therapy in the management of the primary penile tumor: an update. World J Urol 2009;27(2):189. 29. Delannes M, Malavaud B, Douchez J, Bonnet J, Daly NJ. Iridium-192 interstitial therapy for squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 1992;24(3):479-83. 30. Delaunay B, Soh PN, Delannes M, Riou O, Malavaud B, Moreno F, et al. Brachytherapy for penile cancer: Efficacy and impact on sexual function. Brachytherapy 2013 Jul 26. 31. Kiltie AE, Elwell C, Close HJ, Ash DV. Iridium-192 implantation for node- negative carcinoma of the penis: the Cookridge Hospital experience. Clin Oncol (R Coll Radiol) 2000;12(1):25-31. 32. Mazeron JJ, Langlois D, Lobo PA, Huart JA, Calitchi E, Lusinchi A, et al. Interstitial radiation therapy for carcinoma of the penis using iridium 192 wires: the Henri Mondor experience (1970-1979). Int J Radiat Oncol Biol Phys 1984 Oct;10(10):1891-5. 33. Pimenta A, Gutierrez C, Mosquera D, Pera J, Martinez E, Londres B, et al. Penile brachytherapy-Retrospective review of a single institution. Brachytherapy 2015 Jul-Aug;14(4):525-530. 34. Rozan R, Albuisson E, Giraud B, Donnarieix D, Delannes M, Pigneux J, et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol 1995 Aug;36(2):83-93. 35. Soria JC, Fizazi K, Piron D, Kramar A, Gerbaulet A, Haie-Meder C, et al. Squamous cell carcinoma of the penis: multivariate analysis of prognostic factors and natural history in monocentric study with a conservative policy. Ann Oncol 1997 Nov;8(11):1089-98. 36. Martz N, Bodokh Y, Gautier M, Thamphya B, Schiappa R, Lam Cham Kee D, et al. High-dose rate brachytherapy in localized penile cancer: 5-Year clinical outcome analysis. Clin Transl Radiat Oncol 2021 Jan 17;27:89-95. 37. Gomez-Iturriaga A, Crook J, EvansW, Saibishkumar EP, Jezioranski J.The efficacy of hyperbaric oxygen therapy in the treatment of medically refractory soft tissue necrosis after penile brachytherapy. Brachytherapy 2011 Nov;10(6):491-497. 38. Gambachidze D, Lebacle C, Maroun P, Escande A, Bossi A, Blanchard P, et al. Long-term evaluation of urinary, sexual, and quality of life outcomes after brachytherapy for penile carcinoma. Brachytherapy 2018 Jan - Feb;17(1):221-226.

ACKNOWLEDGEMENTS The authors of this chapter are much indebted to Alain Gerbaulet, author of the original version of the chapter on Penis Cancer in the first edition of the GEC-ESTRO Handbook of Brachytherapy 2002.

AUTHORS

Juanita Crook MD FRCPC Professor of Radiation Oncology University of British Columbia, BC Cancer Kelowna Canada Cyrus Chargari MD PhD Professor of medicine - Radiation Oncology Gustave Roussy Cancer Campus France

Page 2 Page 3 Page 4 Page 5 Page 6 Page 7 Page 8 Page 9 Page 10 Page 11 Page 12 Page 13 Page 14

Made with FlippingBook flipbook maker