22 Penis Cancer

22 Penis Cancer Alain Gerbaulet .

1 Introduction Penile carcinoma is relatively uncommon in Western Countries, representing approximately 1% of male cancers. (10) Carcinoma of the penis is virtually unknown in Jews, who practice infant circumcision, and it is seen only occasionally in Moslems, who delay circumcision until the ages of 3- 13. These tumours occur almost exclusively in uncircumcised men, usually after the age of 50, and are often associated with phimosis (Fig 21.1) and subsequent poor hygiene. (10) The main aetiological factor is chronic irritation due to smegma and secretion associated with HPV, (29,15) and this is exacerbated by phimosis, which is present in 20 - 30% of the population with penile cancer. (1,4)

Fig 21.1: Partial phimosis with a tumour of the glans. Symptoms are in decreasing order: mass lesions, pain, itching, bleeding, groin nodes, urinary symptoms. Secondary infections are very common. (10,11) Inguinal lymph node status is the most important prognostic factor, as demonstrated in a large multicentric retrospective study (35): with negative nodes the 5 year survival was 66%; with positive nodes it was only 27% (35). In a univariate analysis performed at the IGR of 102 patients treated with brachytherapy (33), the following prognostic factors were found, given in decreasing order of importance: nodal status, tumour size, corpus involvement, age, verrucous histologic type. Surgical management is effective in treating penile cancer, but surgery of the penis usually means partial or total amputation with subsequent functional disability and psychosexual morbidity (25). Radiotherapy has therefore been used for many years in several institutions, to preserve penile function (28). The conservative approach using radiation alone is the treatment of choice if the rate of local control is comparable to surgery. Penile carcinoma can be cured by radiation : however, the local cure rate and the frequency of treatment complications vary significantly according to the type of radiotherapy procedure used. LDR interstitial brachytherapy plays a major role in the conservative radiotherapeutic management of limited local disease (11,27).

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2 Anatomical Topography The penis is divided into three portions: the root, the body (or shaft) and the glans. The root is embedded into the superficial perineum; the body consists of erectile bodies (corpora cavernosa, corpus spongiosum) and overlying tissues; the glans constitutes the distal part of the corpus spongiosum covered by the prepuce. (10) The arbitrary limit between glans and body is the coronal sulcus or balanopreputial area. (11,18) Critical organs are the distal penile urethra and the testis. (10,11) Pathology Premalignant lesions are present before or associated with invasive lesions in 20 to 30% of cancers. Bowen’s disease, balanitis xerotica obliterans, erythroplasia of Queyrat, Buschke-Lowenstein disease, Kaposi’s sarcoma and leucoplakia are the most frequent. (3) Three kinds of macroscopic lesions are described: infiltrative-ulcerative tumours, serpiginous forms and exophytic papillary tumours (Fig 21.2): the two latter types have a better prognosis. (21) 3

Fig 21.2: Macroscopic appearance of a tumour limited to the glans with involvement of urethral meatus. The primary tumour is mainly localized in the glans (83%), prepuce (55%) and shaft (7%) (30). In 80% of the cases, the tumour starts at the level of the balano-preputial sulcus. While inguinal nodes are palpable in one third of patients, only half of them are related to secondary nodal metastasis; 15 to 20% of patients without palpable nodes have occult metastases. (2) Squamous-cell carcinoma represents more than 90% of invasive cancers of the glans; other histopathological primary tumour types are: malignant melanoma, basal cell carcinoma, sarcoma. (21) Work Up After general history and physical examination, under general anaesthesia if necessary, the following investigations are needed: (10) 4

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− for the primary tumour: biopsy, urethrocystoscopy; in case of difficulty in evaluating tumour infiltration, ultrasound and/or CT and/or MRI can be performed; (36,17) − for the nodes (groin, pelvic and paraaortic areas): ultrasound and/or CT and/or MRI; whenever possible percutaneous needle aspiration or biopsy of suspicious nodes; (36,4) − for distant dissemination: chest radiograph, bone scan, liver CT, ultrasonography, as clinically indicated. General laboratory systematic studies: blood count and chemistry profile, urinary analysis. Different staging systems are used: the TNM classification (32) (see appendix 1) is the most common; many results are presented according to this classification, but for the indications of brachytherapy, Jackson’s staging is more appropriate (Table 21.1). Using the Jackson staging system, (18) in practice brachytherapy is indicated only for stage I tumours. Indications, Contra-indications Indications for brachytherapy alone are, in principle, all tumours, up to 4 cm, strictly limited to the glans and not extending beyond the balano-preputial sulcus. (10,11) The true problem is to detect extension in the corpus spongiosum towards the shaft. The balano- preputial sulcus is only an outer arbitrary and virtual limit between the glans and the shaft and does not represent a real anatomical barrier. (1,5,11,12,13,27) Moreover, the prepuce, particularly in cases of phimosis, often makes it difficult to evaluate the exact tumour extension. (5,10) Surgery is indicated for large tumours (e.g. >4 - 5 cm) exceeding beyond the glans, with partial or total amputation of the penis according to the infiltrating tumour size. (25,26,31) If there is any contraindication to brachytherapy and/or surgery, patients may also be treated by external beam radiotherapy. (23,25,28) In case of large tumours in which brachytherapy alone is not indicated, some patients do not accept any surgical removal of the penis. In these cases, a combination of external beam irradiation plus a brachytherapy boost may be indicated. (10,23,30) Treating lymph nodes by external beam therapy should follow certain principles. First of all, nodal involvement should be confirmed histologically. Inguinal nodal excision can be performed at the same time as circumcision: one involved node without capsular extension needs no further treatment. If there are several involved nodes or capsular extension, adjuvant treatment by external beam irradiation to the groin area ± the iliac nodes is indicated. (11,23) Target Volume The target volume (CTV) encompasses the tumour volume (GTV) plus a safety margin of 5 -10 mm. Since superinfection is very often associated with cancer of the penis, it is difficult to delineate the exact target volume. (11,12,13) The first step of treatment is to perform a wide circumcision, regardless of subsequent surgery or irradiation. This circumcision has two aims: first to allow optimal tumour assessment, and 5 6

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consequently better determination of the target volume; secondly to decrease side effects of brachytherapy or external beam radiotherapy. (10) The target volume must also be defined taking into account the different tumour types (see Fig 21.2): − superficial tumours : thickness, peripheral limits, − exophytic tumours : accurate knowledge of the tumour and its basis (depth of implantation), − infiltrating (± ulcerating) tumours : exact topography of the infiltration, depth of the ulceration. The anatomical position of the penile urethra should be marked with a Foley catheter. (12) Some authors consider it is necessary to include the whole glans in the target volume; we prefer a selected PTV, which is possible with a well adapted technique and a good knowledge of the GTV. 7.1 Plesiobrachytherapy Plesiobrachytherapy is indicated for very superficial lesions (no more than 5mm thick) with well defined limits. (1,24) Essentially two types of surface applicators can be used: a personalized one, made for each patient, or a standard one, less individualised but perhaps easier to use. The first consists of a mould containing catheters placed according to the tumour topography afterloaded with an iridium source for HDR (Fig 21.3) or LDR brachytherapy. When LDR brachytherapy is applied, the mould must be fixed to the surface of the penis, because of the risk of displacement during irradiation. 7 Technique

Fig 21.3: Personalized plastic applicator (courtesy of JC Horiot and S Naudy)

The second is more often used; it is made of two plastic cylinders, the inner one worn over the penis, the outer one containing iridium sources. This kind of LDR brachytherapy requires close compliance from the patient, who usually has to place the applicator around the penis himself and also record the exact duration of each treatment.

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7.2

Interstitial brachytherapy

7.2.1 Classical method After many decades of radium-needle implants, the first modern technique was described by the IGR group of Pierquin and Chassagne during the sixties. (5,10,14,27) This classical procedure is based on the use of hypodermic needles manually afterloaded with iridium wires. After healing of the previous circumcision, the implant is performed under general or spinal anaesthesia. A Foley catheter is inserted to determine the exact position of the urethra to avoid implantation of the urethra by the needles. The urinary catheter stays in place during the whole irradiation. After precise evaluation of the target volume, hypodermic needles are implanted through the glans, perpendicularly to the axis of the penis. The lengths of the needles and the distance in between are adapted to the target volume respecting the rules of the Paris System. During the placement of the needles, two lucite plaques are prepared in the operating room itself. These handmade templates are adapted to each implant. Size, shape and distance of perforations in the template are pre-determined according to the position of the needles. The needles are introduced into the corresponding holes of the plaques (Fig 21.4). In order to maintain these two templates in parallel to each other, plaster strips are inserted around them between the needles.

Fig 21.4 : Pierquin-Chassagne applicator. Finally, a sponge, which is perforated to slide over the penis, is fastened in place in the prepubic area to immobilize the penis and to keep the radioactive material away from the testis. This interstitial technique using hypodermic needles has become classical. Its merits have been proven by the good results obtained from hundreds of patients treated with this method. Nevertheless, this is a protracted and detailed technique, not always easy to administer and it involves risks of sepsis. The preparation of the plates of plexiglas and the application of the plaster strips are potential sources of infection. Strict parallelism of the needles is not always possible and is difficult to maintain throughout treatment. Distortion of the apparatus can occur, resulting in loss of parallelism of the radioactive lines. Such

distortion can also cause discomfort and pain. An improved system was therefore developed.

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7.2.2 Gerbaulet’s glans applicator (GAG) (11,12) This system consists of 2 square plates of transparent plastic, 50mm wide and 2mm thick. These two identical plates are perforated by holes of 1mm in diameter, to allow the passage of hypodermic needles; these perforations are located at 5mm intervals from each other, forming a regular equilateral/ triangular-shaped arrangement which is ideal for a homogeneous distribution of dose according to the Paris System rules. (27) At the 4 angles of each plate, there is one hole of 3mm in diameter, which allows the passage of 4 threaded screws 2.8mm in diameter and 65mm in length, made of stainless steel or brass. These threaded screws ensure that the apparatus is held in parallel position, both at the moment of application and during irradiation. To secure the whole apparatus of screws and plates, there is a set of 16 small 5mm-exterior-diameter hexagonal nuts. Each nut is placed on the rod on each side of the plate, and tightened with a flat mini spanner. Since the four rods are in fact a kind of screw without any end, the distance between the plate, and thus between the nuts, is variable and can be adapted to the length of the hypodermic needles, which are themselves dependent on the size of the penis and the dimensions of the tumour. The whole system, with its 4 corner rods and 16 nuts, weighs 15g, and is sterilised before implant. There are also rectangular plates, 50 x 60mm, whose perforations are set at 5mm intervals and arranged in staggered rows. The first steps are strictly identical to those of the classic implant: the indications for interstitial brachytherapy are not modified by the use of this new system. The system of “plate-screw-nut” is taken apart after the urinary catheter is inserted. Plate A is placed according to the lesion to be implanted and to the projection of the tumour, which will be visible through the transparent plate, and which is drawn on the first plate (Fig 21.5).

Fig 21.5: Transfer of the tumour topography onto the template of the GAG. Fig 21.6: Transfer of the GTV on the second template of the GAG, delimitation of the PTV

Fig 21.7: Implantation of hypodermic needles into the target volume.

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Plates A and B are superimposed, with plate B opposite plate A, so that the projection of the tumour can be reproduced on this second plate (Fig 21.6). The apparatus for implantation is chosen according to this precise plan. The holes to be used are selected and marked on plate A, then on plate B. These holes for the passage of needles should, of course, be strictly identical on both plates, and are marked by a coloured dot (Fig 21.7). It has to be stressed that all these procedures can be carried out before the actual implantation, at the consultation following circumcision: accurate provisional dosimetry can be calculated: the duration of the implant is thus predetermined, allowing choice for the start and end of the procedure. The risks of infection linked to the manual preparation of the plates, which are custom-made at the moment of application, can thus be eliminated. The parallelism of the plates and needles is thus ensured, and is maintained throughout the treatment. The use of this new technique of implant significantly saves time and improves logistics. The patient’s tolerance is greatly increased as the risk of infections is reduced and problems of secondary distortion are eliminated. The whole apparatus is lightweight. Finally, a better quality implant is achieved allowing an increase in local control. In this system, hypodermic needles may be replaced by plastic tubes to make PDR therapy possible, but so far no data have been reported.

Fig 21.8: The penis is maintained with a perforated adapted sponge, the radioactive material is pushed away from the testis.

Fig 21.9: Loading of Iridium 192 wire inside the needles

Fig 21.10: Radiograph as a basis for computerized dosimetry.

486 Penis Cancer

The dose to the testis should be as low as possible. Some authors use lead shielding, but it is poorly tolerated. Therefore, we recommend to use a sponge to keep the radioactive sources away from the penis. This maintains the organ in a semierect position and maximizes the distance between the testis and the sources (Fig 21.8) At the end of the implant, the hypodermic needles are loaded with Iridium wires (Fig 21.9) and radiographs are taken (Fig 21.10).

8

Dosimetry

8.1 For plesiobrachytherapy the reference isodose must be chosen according to the tumour volume (GTV). Two parameters are considered : thickness and external boundaries of the rumour. The CTV includes the thickness of the tumour plus a safety margin of 5mm, and its boundaries plus a safety margin of 10mm, taking into account the position of the urethra. 8.2 For interstitial brachytherapy the classical rules of the Paris System can be used without difficulty, since the two templates are perfectly parallel and the position of the needles going through the selected perforations are perfectly parallel and equidistant (see Fig 21.10). (27) In the Paris System, the recommended spacing between the radioactive lines is 8 to 22mm. For carcinoma of the penis, we recommend a distance between 15 and 18mm, allowing 2 - 8 needles to be implanted (mean ≈ 5 (11,30)). Sometimes, to encompass the target volume (PTV) adequately, some peripheral needles will be in air (Fig 21.11). These needles are implanted through the templates and the dose distribution in the air is comparable to the dose distribution in the glans tissue. (12)

Fig 21.11: Interstitial brachytherapy combined with plesiobrachytherapy (two needles are in the air) to adapt PTV to GTV.

9 Dose, Dose Rate, Fractionation • For LDR plesiobrachytherapy as well as for LDR interstitial brachytherapy the minimal target dose (PTV) is usually 65 Gy delivered in 6 - 7 days at a dose-rate of 40cGy per hour. The mean central dose is 75Gy. The treated volume is dependent on the target volume, mean 50 cm 3 . 18,19 Some

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authors (12,13,15) prefer to deliver brachytherapy at a higher dose rate, so for Akimoto (1) using a silicone mould, the dose of brachytherapy ranged from 32 to 74 Gy (with or without electron boost), with a median dose rate of 2 Gy/h. • For HDR brachytherapy no data have been published so far. Two schedules have been orally presented and must be considered only as proposals: 36 Gy/ 12 fr/ 30 days with a boost of 15 Gy/ 5 fr/ 11 days one month later, or 54 Gy/ 27 fr/ 42 days (Fig 21.12). This irradiation was given with a personalized surface applicator (presented in Fig 21.3). • As far as critical organs are concerned, the dose to the urethra should be restricted as much as possible. In any case, direct implantation of the urethra must be avoided. (10,30) Dose to the urethra and to the testis is calculated routinely.

Fig 21.12: HDR plesiobrachytherapy (surface applicator) : computerized dosimetry (courtesy of JC Horiot and S Naudy)

10 Monitoring (5,11,13) − For plesiobrachytherapy, complications from infection seem to be rare. However, it is useful to prescribe an antiseptic local treatment. (1,24) − For interstitial implants the risk of local infection is higher. If there is local superinfection, fever or urinary infection, appropriate antibiotic therapy is given. (5,11) − Routine urine analysis is indicated in all cases during irradiation with appropriate treatment as necessary. To prevent urinary infection, which is increased by having the catheter in place during the whole treatment, some recommend prophylactic antibiotics in certain clinical situations. (11,12) − Analgesic treatment must be individualized, but usually these implants are well tolerated. Anti- inflammatory treatment may be clinically indicated (e.g. severe shaft oedema).(5)

11 Results When comparing the results of brachytherapy with surgery and external beam therapy, patient and disease-related prognostic factors must be kept in mind.

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11.1 Results of surgery In the last few decades, there have been two literature reviews, the first by Paymaster et al concerning 1022 patients, with a 5-year survival rate of 42%; (26) and a second by Gerbaulet et al (10) of 633 patients showing a 5-year survival rate of 54%. A cooperative study (31) led by the urologic group of the French National Federation of Cancer Centres has included 506 patients; the 5-year cancer specific survival and the local control were 75 and 84% respectively. 11.2 Results of external beam irradiation One of the latest series including 276 patients was reported by Ravi et al. (28). Local control of the primary tumour was achieved in 65% of patients with EBRT alone and in another 33% in combination with salvage surgery. For McLean et al, (23) EBRT was applied in the management of 26 patients. The 5 year overall actuarial survival and the cause specific survival were 62% and 69% respectively with a local control of 61.5 %. A retrospective study by Naeve et al (24) concerned 44 patients divided in two groups: the first was treated with iridium moulds (79% complete response), the second with EBRT (53% of complete response), but the stage distribution was more favourable in the brachytherapy group. Clifford and Perez (7) reported tumour control of 51% and preservation of the penis in 80% of a population of 156 patients.

11.3 Results of brachytherapy 11.3.1 Local control and survival

Recently a large review by Gerbaulet (14) compared results obtained by different therapeutic strategies. Subsequent publications are summarized in Table 2. More than 500 patients are included. 80% presented at the time of diagnosis with a primary T1 or T2 tumour. LDR interstitial brachytherapy was the main treatment with a 5 yr overall survival of 70 to 75%, a local control of 80 to 85% and a complication rate of 20 to 30% (details see below) The penis was conserved in 75 to 80%.

11.3.2 Adverse Side Effects a) Acute side effects

For plesiobrachytherapy the tolerance during treatment is quite acceptable, since the lesions are superficial and usually not infected. (1,24) For interstitial implants, antibiotic therapy, anti-inflammatory and analgesic treatments should be prescribed. Because of the risk of radioepidermitis and radiomucositis (Fig 21.13), sometimes complicated by dysuria or urinary infection, it is often necessary to continue this treatment for some weeks following the implant. (5,9,10,14)

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21.13: Radio-epithelitis two weeks after the end of brachytherapy, delineating the PTV.

b) Late side effects In assessing the importance of late sequelae, it must to be remembered that with this brachytherapy approach -in contrast to any form of amputation- the organ itself can be spared in 70 - 75% of cases, which avoids a major psychological impairment in body representation. (11,14,25,31) Overall, the complication rate is proportional to the total dose, the dose distribution, and the treated volume. Telangiectasia and/or sclerosis are frequent but do not impact on quality of life. In contrast, urethral stenosis and/or necrosis are less frequent but may have a significant impact on quality of life. (5,11,13,14,30)

Fig 21.14 : Dilatation of urethral stenosis Fig 21.15 : Superficial necrosis of balano-preputial sulcus

Table 21.2: Penis Carcinoma: Results of Brachytherapy

Authors

Pts N.

TNM stage

Treatments

Brachytherapy Survival % Local control %

Complications %

Akimoto (1) Chaudary (6) Delannes (9)

15 23 51

T1 8; T2 5; T3 2 T1 7; T2 7; Rec 9 T1 15; T2 28; T3 6 N0 43

BT ± EBRT BT alone BT S ± EBRT/N S ± EBRT/N BT ± EBRT BT alone S±EBRT/N BT alone 25; S+BT 6 BT alone 37

LDR mould interstitial LDR

DFS 74

80 78 86

PC 73 US 9

interstitial LDR AS 72

US 33; NC 18; PC 67

Gerbaulet (11,13) 109 T1 28; T2 54; T3 22; T4 11; Rec 4 – N0 89 BT

interstitial LDR DFS 74

82

US 15; NC 13; PC 82

Guedea (16) Kanfir (19)

16

T1 16; T2 5; T3 2

interstitial LDR DFS 79 interstitial LDR OS 55 CSS 85 interstitial LDR OS 69

87 84

Cpl 25; PC 87

145 T1 107; T2 18; T3 11; Tx 9 pN+ 17

US 24; NC 14; PC 80

Kiltre (20)

31

St I 27; St II4 N0 3

81

US 35; PC 81

Mazeron (22)

50

T1 9; T2 27; T3 14 N0 45

interstitial LDR DFS 74

78

US 16; NC 6; PC 14

Rozan (30)

259 T1 112; T2 97; T3 25 N0 191

BT alone 184 (A) EBRT±S+BT 75 (B) S±EBRT/N

interstitial LDR OS 66 CSS 88 DFS 78

85

LSE 53 PC: A 78; B 64

Suchaud (24)

53

T1 7; T2 32; T3 15 N0 37

BT alone 48 EBRT+BT 5

interstitial LDR

79

Cpl 28

ƒ Stage :

Rec : recurrence PN+ : pathological positive nodes BT : Brachytherapy EBRT : External Beam Radiotherapy Surgery

ƒ Treatments :

ƒ Complications :

US : urethral stenosis NC : necrosis PC : penis conservation Cpl : complications

ƒ Results :

AS : Actuarial survival

DFS : Disease Free Survival OS : Overall survival CSS : Cause specific survival

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In case of urethral stenosis (10 - 20%), dilatation may allow successful symptom relief in up to 90% of cases. This dilatation is started by the urologist (Fig 21.14) and later performed regularly by the patient. (5,11) The most important complication is necrosis (10 - 15%), firstly because of severe pain which can last several months; secondly because of the difficult differential diagnosis between “pure” necrosis (Fig 21.15) and necrosis associated with local recurrence. Local antiseptic therapy associated with antibiotic therapy should be prescribed. If response is poor and tumour recurrence or residual tumour suspected, a limited, careful biopsy should be taken to establish the diagnosis. (7,14,31) Slow decrease in the size of the penis may occur after more than 2 years, due to progressive fibrosis. This can be complicated by a neoprepuce, constituting a handicap for sexual life. (5,14) 12 References 1. Akimoto T, Mitsuhashi, Takahashi I, et al. Brachytherapy for penile cancer using silicon mould. Oncology 1997; 54 : 23-7. 2. Ayyappan K, Anamthakrishnan N, Sankaran V. Can regional lymph node involvement be predicted in patients with carcinoma of the penis? Br J Urol 1994; 73 : 549-53. 3. Barton Crossman H. Premalignant and early carcinoma of the penis and scrotum. In: Crawford DE, Das S. (eds) Penile, urethral, and scrotal cancer. The Urologic Clinics of North America . Philadelphia: W.B. Saunders 1992; 221-6. 4. Bouchot O, Bouvier S, Bocherau G, Jeddi M. Cancer of the penis: the value of systematic biopsy of the surgical inguinal lymph nodes in clinical N0 stage patients. Progr Urol 1993; 3 : 228-33. 5. Chassagne D, Wibault P, Court B. Tumeur de la verge. Encycl Med Chir (Rein) . Paris 1978; 11 : 18375 A10. 6. Chaudhary AJ, Ghosh S, Bhalavat RL, et al. Interstitial brachytherapy in carcinoma of the penis. Strahlenth Oncol 1999; 175 : 17-20. 7. Clifford Chao KD, Perez CA. Penis and male urethra. In: Perez CA, Brady LW (eds.): Principles and practice of radiation oncology (3 rd edition). Philadelphia: Saunders-Lippincott-Raven 1997; 1717-31. 8. Clifford and Perez. Results from external beam therapy 9. Delannes M, Malavaud V, Douchez J, et al. Iridium-192 interstitial radiation therapy for squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 1984; 10 : 1891-5. 10. Gerbaulet A. Cancers de la verge. In: Steg A, Eschwege F. (ed.) Cancers uro-genitaux . Paris: Flammarion Medecine Science 1991; 406-24. 11. Gerbaulet A, Lambin P. Radiation therapy of cancer of the penis: indications, advantages and pitfalls. In: Crawford DE, Das S. (eds) Penile, urethral, and scrotal cancer . The Urologic Clinics of North America . Philadelphia: W.B. Saunders 1992; 325-32. 12. Gerbaulet A, Delapierre M, Haie-Meder C, Lambin P, et al. La curiethérapie du cancer de la verge. A propos d` un nouveau…GAG (gland applicateur de Gerbaulet) . Bull Cancer Radiother 1992; 79 : 95-100. 13. Gerbaulet A, Lambin P, Haie-Meder C, et al. Brachytherapy in penile cancer. Ann Urol 1994; 28 : 306-11. 14. Gerbaulet A. Tumours of the penis. In: Souhami RL, Tannock I, Hohenberger P, Horiot JC (eds) Oxford textbook of Oncology (2 nd edition). Oxford University Press-Oxford, New York 2002; 2047- 56 15. Gregoire L, Cubilla AL, Reuter VE, et al.. Preferential association of human papilloma virus with high-grade histologic variants of penile-invasive squamous-cell carcinoma. J Natl Cancer Inst 1995; 87 : 1705-9.

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16. Guedea F, Craven-Bartle J, Caeles J, et al. Interstitial radiotherapy using iridium 192 wires for carcinoma of the penis. Bull Cancer Radiother 1991; 78 : 141-47. 17. Hornblas S, Kroger R, Gallee MP, et al. Ultrasound in squamous cell carcinoma of the penis; a useful addition to clinical staging? A comparison of ultrasound and histopathology. Urology 1994; 43 : 702-7. 18. Jackson SM. The treatment of carcinoma of the penis. Br J Surg 1966; 53 : 33-5. 19. Kanfir K, Haie-Meder C, Albano M, et al. Outcome of patients treated with exclusive brachytherapy for carcinoma of the penis: the IGR experience. Radiother Oncol 2000; 55 (suppl 1) : 25 (abstract 36). 20. Kiltie AE, Elwell C, Close HJ, Ash DV. Iridium-192 implantation for node-negative carcinoma of the penis: the Cookridge Hospital experience. Clin Oncol 2000; 12 : 25-31. 21. Lucia MS, Miller GJ. Histopathology of malignant lesions of the penis. In: Crawford DE, Das S. (eds) Penile, urethral, and scrotal cancer. The Urologic Clinics of North America . Philadelphia: W.B. Saunders 1992; 227-46. 22. Mazeron JJ, Langlois D, Lobo PA, et al. Interstitial radiation therapy for carcinoma of the penis using iridium 192 wires: the Henri Mondor expierience (1970-1979). Int J Radiat Oncol Biol Phys 1984; 10 : 1891-5. 23. McLean M, Aki AM, Warde P, et al. The results of primary radiation therapy in the management of squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 1993; 25 : 623-8. 24. Neave F, Neal AJ, Hoskin PJ, Hope-Stone HF. Carcinoma of the penis: a retrospective review of treatment with iridium mould and external beam irradiation. Clin Oncol 1993; 5 : 207-10. 25. Ornellas AA, Correia AL, Marota A, et al. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994; 151 : 1244-9. 26. Paymaster JC, Gangadhara P. Cancer of the penis in India. J Urol 1967; 97 : 110-3. 27. Pierquin B, Bunescu U, Chassagne D, Jomain J. La radiotherapie des cancers de la verge par l`iridium 192. J Urol Nephrol 1970; 76 : 1-8. 28. Ravi R, Chaturvedi HK, Sastry DVLN. Role of radiation therapy of carcinoma of the penis. Br J Urol 1994; 74 : 646-51. 29. Reddy DJ, Baruah IKSM. Carcinogenic action of human smega. Arch Pathol 1986; 75 : 414-20. 30. Rozan R, Albuisson E, Giraud B, et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol 1995; 36 : 83-93. 31. Rozan R, Albuisson E, Giraud B, et al. Epitheliomas de la verge traité par chirurgie. Progr Urol 1996; 6 : 926-35. 32. Sobin LH, Wittckind Ch (ed.). UICC/TNM classification of malignant tumours (5 th edn). New York: Wiley-Liss 1997; 167-69. 33. Soria JC, Fizazi K, Piron D, et al. Squamous cell carcinoma of the penis: multivariate analysis of prognostic factors and natural history in a monocentric study with a conservative policy. Ann Oncol 1987; 98 : 1089-98. 34. Suchaud JP, Kantor G, Richaud P, et al. Brachytherapy of the cancer of the penis. Analysis of a series of 53 cases . J Urol 1989; 95 : 27-31. 35. Sufrin G, Huben R. Benign and malignant lesions of the penis. In Gillewater JY (ed.) Adult and Pediatric Urology , Chicago Medical Publisher 1991; 1643-62. 36. Vapnek JM, Hricak H, Carroll PR. Recent advances in imaging studies for staging of penile and urethral carcinoma. In: Crawford DE, Das S. (eds) Penile, urethral, and scrotal cancer. The Urologic Clinics of North America . Philadelphia: W.B. Saunders 1992; 257-66.