Radiation Oncology/Penis

Epidemiology US - 1500 cases annually, <2% of GU cancers Incidence is dramatically higher in the developing world US - 0.2 / 100,000 Bombay - 1.8 / 100,000 (10-fold increase) Sao Paolo - 28 / 100,000 (another 15-fold increase) Uganda - most common male malignancy Risk factors Phimosis - narrowed opening of the prepuce resulting in non-retractile foreskin. Odds ratio 10 Smegma Circumcision - in Uganda, circumcised tribes 0.5 vs. uncircumcised tribes 2.9 / 100,000 HPV - primarily 16, prevalence 30-70% Age - meadian age at diagnosis in US is 60 Tobacco Premalignant lesions HPV16 Amsterdam; 2007 17925550 -- "Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma." (Heideman DA, J Clin Oncol. 2007 Oct 10;25(29):4550-6.) Molecular and serologic analysis of HPV on 83 penile SCC vs. age-matched controls Outcome: HPV DNA in 55% samples - HPV16 75%. HPV18 and HPV6 seropositivity associated, but not by molecular findings Conclusion: HPV16 is the main HPV type associated with penile SCC Histology Squamous cell (95%) Papillary Basaloid Warty Sarcomatoid Verrucous (up to 25%) Melanoma Lymphoma Basal cell Urethral Grading Differentiation grading systems for SCC Broder's grading system I - well differentiated with keratinization, prominent intercellular bridges, and keratin pearls II to III - greater nuclear atypia, increased mitotic activity, and decreased keratin pearls IV - deeply invasive, marked nuclear pleomorphism, nuclear mitoses, necrosis, lymphatic and perineural invasion, and no keratin pearls Maiche’s system score currently seems to be the most suitable staging system Staging AJCC Current Staging AJCC 7th Edition (2009) Primary Tumor: Tis - carcinoma in situ Ta - non-invasive verrucous carcinoma T1 T1a - invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated (i.e. tumor is grade 1-2 of 4) T1b - invades subepithelial connective tissue with lymphovascular invasion or is poorly differentiated (i.e. tumor is grade 3-4 of 4) T2 - invades corpus spongiosum or cavernosum T3 - invades urethra T4 - invades other adjuacent structures (including prostate) Regional Lymph Nodes: include superficial and deep inguinal, internal and external iliac, pelvic lymph nodes Clinical assessment (based on palpation or imaging): cN0 - none cN1 - palpable mobile unilateral inguinal LN cN2 - palpable mobile multiple or bilateral inguinal LN cN3 - fixed inguinal nodal mass or pelvic lymphadenopathy Regional Lymph Nodes (pathologic assessment): pN0 - none pN1 - metastasis in single inguinal LN pN2 - multiple or bilateral inguinal lymph nodes pN3 - extranodal extension or pelvic lymph node involvement Distant Metastases: M0 - no M1 - yes Stage Grouping: 0 - Tis or Ta I - T1a N0 II - T1b-T3 N0 IIIA - T1-3 N1 IIIB - T1-3 N2 IV - T4, N3, M1 Changes from 6th Edition: T1 subdivided into T1a and T1b based on LVI and grade Prostate invasion moved from T3 to T4. T3 limited to urethral invasion Added new schemes for clinical vs pathologic lymph node assessment T1b (new subdivision) becomes Stage II and T1a remains Stage I Any LN+ is now at least Stage III. Divided into IIIA and IIIB. Older staging systems AJCC 6th Edition (2002) Primary Tumor: Tis - carcinoma in situ Ta - non-invasive verrucous carcinoma T1 - invades subepithelial connective tissue T2 - invades corpus spongiosum or cavernosum T3 - invades urethra or prostate T4 - invades other adjuacent structures Regional Lymph Nodes: N0 - none N1 - single superficial inguinal lymph node N2 - multiple or bilateral superficial inguinal lymph nodes N3 - deep inguinal or pelvic lymph nodes (unilateral or bilateral) Distant Metastases: M0 - no M1 - yes Stage Grouping: I - T1 N0 II - T1 N1, T2 N0-1 III - T1-2 N2, T3 N0-2 IV - T4, N3, M1 Other staging systems Jackson's Staging Stage I (A) - tumor is confined to glans, prepuce or both Stage II (B) - tumor extends onto shaft of penis; no nodal or distant metastases Stage III (C) - tumor has inguinal nodal metastases that are operable Stage IV (D) - tumor involves adjacent structures and is associated with inoperable inguinal metastasis or distant metastasis Spread Lymph Nodes Drainage to superficial inguinal -> deep inguinal -> external iliac At presentation 50% clinically enlarged 50% disease 50% reactive - so should treat first with a course of ABX 50% clinically negative 20% occult disease Decision on who should undergo inguinal dissection one of the hardest in penile CA management. Sentinel LN reasonable option Highly correlates with T-stage and grade (11342906) T1 11%, T2 63%, T3 63% G1 15%, G2 67%, G3 75% + Risk Group Stage & Grade LN (+)Low T1 G1 0%Intermediate T1 G2-3, T2 G1 33%High T2 G2-3, T3 G1-3 83% LN+ correlates with 5-year survival: N0 - 80-90% N1 - 70% N2-3 inguinal - 35% N3 pelvic - 20% Overall N+ 40-50% Mets <10% M+ at presentation Sentinel Lymph Node Netherlands Cancer Institute; 2009 19414668 -- "Two-center evaluation of dynamic sentinel node biopsy for squamous cell carcinoma of the penis." (Leijte JA, J Clin Oncol. 2009 Jul 10;27(20):3325-9. Epub 2009 May 4.) Prospective. 323 patients (from 611 cN0 patients). Outcome: Technical success rate 97%. LN+ in 24%. Inguinal recurrences (false-negative SLNB) 7% Toxicity: 5% (mostly seroma/lymphocele and infections) Conclusion: SLNB suitable procedure to stage clinically N0 penile cancer Treatment Guidelines NCI Guidelines are driven by TNM staging + NCI Guidelines Stage TNM Recommendation Stage 0 Tis Ta Mohs surgery Laser, cryosurgery Iquimod, topical 5-FU Stage 1 T1 N0Foreskin: wide local excision Penile amputation Mohs surgery RT Stage 2T1 N1 T2 N0-1Penile amputation EBRT/BT Stage 3T1-2 N2 T3 N-2Penile amputation, with LN dissection if clinically LN+ Penile amputation, with nodal RT if clinically LN+ and not surgical candidate Stage 4T4 Any T N3 M1Palliative surgery Palliative RT European Association of Urologists guidelines are driven by TNM and by lesion grade + EAU Guidelines Group Stage Recommendation Low RiskTa-1 G1Penis conservation (Mohs or RT) Penile amputation (partial or total) in patients with poor follow-up All OthersT1 G3 >=T2Penile amputation (partial or total) Penis conservation (Mohs or RT) in carefully selected patients Neoadjuvant chemotherapy followed by penis conservation is investigational Surgery vs. RT Lausanne, 2006 (Switzerland) 16949770 -- "Treatment of penile carcinoma: To cut or not to cut?" (Ozsahin M, Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):674-9.) Retrospective. 60 patients, 5 surgery, 22 surgery + adjuvant RT, 29 primary RT. Mean F/U 62 months 5-year OS: surgery 53% vs. RT 56% (NS). RT failures underwent surgical salvage Local failure: Median time to LR failure 14 months; Surgery (+/- RT) 13% vs. RT 56% (SS) Patients treated with RT: penis preservation 52%. 5-year probability of intact penis 43% Conclusion: Surgery better LR rate, RT better penile preservation, OS same Brachytherapy Princess Margaret, 2005 (Canada) 1989-2003 15890588 -- "Penile brachytherapy: results for 49 patients." (Crook JM, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):460-7.) Retrospective. 49 patients. T1 51%, T2 33%. G1 31%, G2 45%. RT treated 23 with PDR BT, 22 Iridium BT, 4 seeds BT to 60 Gy. Medium F/U 2.7 years 5-year OS: 78%, CSS 90% Local failure: 15%, all salvaged by surgery. Regional failure 20%. Distant failure 10% 5-year penile preservation: 86% Side effects: soft tissue necrosis 16%, urethral stenosis 12%