Next-generation sequencing of primary testicular lymphoma and relapse in the glans penis after prophylactic radiation therapy: a rare case report.

BACKGROUND: Primary testicular lymphoma (PTL) is relatively rare. The contralateral testis is a common site of PTL relapse; therefore, once complete remission is achieved, radiation therapy (RT) is administered to the contralateral testis to prevent relapse. CASE PRESENTATION: A 76-year-old man was diagnosed with PTL and received RT as described above. However, despite achieving and maintaining complete remission, a mass diagnosed as diffuse large B-cell lymphoma by tissue biopsy developed in the glans penis 6.5 years after prophylactic RT. We investigated whether the glans penile lymphoma was PTL relapse or a new malignancy by genomic analysis using next-generation sequencing of DNA extracted from two histopathological specimens. CONCLUSIONS: We found the same variant allele fraction in four somatic genes (MYD88, IL7R, BLNK, and FLT3) at similar frequencies, indicating that the glans penile lymphoma had the same origin as the PTL. To the best of our knowledge, this is the first case report of PTL relapse in the glans penis.

A Technique to Deliver Conformal External Beam Radiation for Squamous Carcinoma of the Penile Glans and Urethra.

This study presents an approach to external beam radiation therapy for treating penile cancer using a small water bath. This modified technique involves the use of an acrylic, cuboid-shaped water bath with dimensions 6 × 6 × 8 cm3. The water bath is filled with readily available saline solution maintained at room temperature. The patient is positioned in the prone position, and the penis is placed within the water bath. The isocenter is set at the center of the water bath, and bilateral beams are positioned at 89.1° and 270.9°. The proposed technique was evaluated based on dose calculations, demonstrating a clinical target volume dose with a Dmax of 103.5% and a Dmin of 100.0% of the prescribed dose. Additionally, the method showed a low organs-at-risk dose, with a Dmean of only 1% for the testicles. The treatment zone inside the water bath also showed a uniform dose distribution. This technique not only offers high treatment efficiency and more accurate dose distribution to the targeted area but also provides additional benefits, including reduced toxicity to organs at risk and increased device utilization efficiency. In conclusion, the proposed modified external beam radiation therapy method presents a promising alternative for patients with penile cancer, enhancing treatment precision and safety.

Organ sparing treatment for penile cancer using a 3D-printed high-dose-rate brachytherapy applicator.

PURPOSE: We present a case study of the treatment of localized squamous cell carcinoma on the glans penis with a custom-fabricated high-dose-rate (HDR) brachytherapy applicator. METHODS AND MATERIALS: A cylindrically shaped applicator was fabricated with eight embedded channels suitable for standard plastic brachytherapy catheters. An additional custom silicone bolus/sleeve was designed to be used with the 3D-printed applicator to provide an additional offset from the source to skin to reduce the surface dose and for patient comfort. RESULTS: The patient (recurrent cT1a penile cancer) underwent CT simulation, and the brachytherapy plan was created with a nominal prescription dose of 40 Gy in 10 fractions given bidaily to the surface, and 35 Gy at 5 mm depth. Dose coverage to the clinical target volume was 94% (D90). Most fractions were treated with only 5-10 min of setup time. Follow up visits up to 1 year showed no evidence of disease with no significant changes in urinary and sexual function and limited cosmetic detriment to the patient. CONCLUSIONS: Patient-specific organ-sparing HDR plesiotherapy using 3D printing technology can provide reliable and reproducible patient setup and may be effective in achieving disease control for superficial penile cancer, although preserving patient quality of life.

Atezolizumab With or Without Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (The PERICLES Study): A Phase II Trial.

PURPOSE: Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT). PATIENTS AND METHODS: A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens. RESULTS: Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)-positive tumors (P = .003) and those with high infiltration of intratumoral CD3+CD8+ T cells (P = .037). CONCLUSION: Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3+CD8+ T-cell infiltration, may help to better select responders.

Optimizing Target Volume for Adjuvant Radiation Therapy in Penile Cancer.

PURPOSE: Recent studies have reported improved outcomes with adjuvant radiation therapy in penile cancer. However, the appropriate target volumes to be irradiated in this group of patients for optimal outcomes are still unclear. This study aims to report the patterns of failure and define target volumes to be irradiated in patients with pN3 penile cancer. METHODS AND MATERIALS: Patients with pT1-T4, pN3, cM0, and squamous cell carcinoma of the penis who received adjuvant radiation therapy (involved field or extended field), with or without concurrent chemotherapy were included in the study. Complete information on disease characteristics, radiation therapy target details, and patterns of failure were available for 75 patients. Disease-free (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and log-rank test was used to compare survival outcomes between the involved field and extended field radiation therapy groups. Multivariate analysis was performed using the Cox proportional hazards model to analyze factors correlating with survival outcomes. RESULTS: At a median follow-up of 39 months, 38.6% (29/75) of patients had relapsed either locally, regionally, or at distant sites. Of the 24 patients who received extended field radiation therapy (EFRT), only 1 (4%) patient experienced relapse. Twenty-eight (55%) patients experienced relapse after involved-field radiation therapy (IFRT), of which 28.5% were regional-only relapses and 64% relapses were associated with a regional component. The 2-year DFS and OS of the entire cohort were 62.2% and 70.8%, respectively. The 2-year DFS was 67.9% in patients who received IFRT and 94.1% in those who received EFRT (P = .002), and the 2-year OS was 62.4% with IFRT and 91.1% with EFRT (P = .014). Extended field radiation therapy was associated with an improved DFS (hazard ratio, 12.2; 95% confidence interval, 1.5-97.4; P = .02) and OS (hazard ratio, 4.6; 95% confidence interval, 1-21.5; P = .05) on multivariate analysis. CONCLUSIONS: Extended field radiation therapy significantly improves clinical outcomes compared with involved-field radiation in patients with pN3 penile cancer.

Novel portable apparatus for outpatient high-dose-rate (HDR) brachytherapy in penile cancer.

BACKGROUND: Penile squamous cell carcinoma (PSC) is traditionally treated with surgical resection with significant morbidity. Penile sparing approaches, such as brachytherapy, require expertise, prolonged inpatient stays, poor patient convenience, and heterogenous plans with variable long-term toxicity. In this study, we describe the protocol for novel portable apparatus created for PSC, allowing outpatient hybrid interstitial/surface brachytherapy, improving homogeneity and patient convenience. METHODS: A portable brachytherapy apparatus was developed utilizing a foley catheter, prostate template, 6F interstitial catheters, 5 mm bolus, and a jock strap. The apparatus allowed for internal and external catheter placement housed in a jock strap to allow mobility and defecation without affecting the implant. High-dose-rate brachytherapy was performed as an outpatient. RESULTS: The apparatus was then used on a 62-year-old male with cT2pN0M0 (stage IIA) PSC with bilateral glans and urethral meatus involvement, who elected for definitive brachytherapy (4000cGy in 10 fractions over 5-days). Given external dwell positions, heterogeneity correction of the template was calculated (AAPM TG186) with <2% variation. Patient had minimal impact on his active lifestyle during treatment and had complete clinical response at 3-months. Grade 2 skin desquamation resolved at 2-months, with no necrosis. At 6-months, he was able to resume sexual intercourse, and at 12-months, he remained disease-free with sexual and urinary function intact. CONCLUSIONS: Novel portable implant allows for improved patient convenience, reduced inpatient stay, capable of optimizing dosimetry with hybrid brachytherapy. This outpatient treatment allows the opportunity to increase fractionation, offering high local-control and lower toxicity. Future studies utilizing this apparatus for more fractionated regimens with further lower dose-per-fraction (∼3 Gy/fraction) is recommended.

Organ preserving radiation strategies for penile cancer.

INTRODUCTION: The majorities of penile cancers are of squamous cell origin and thus are amenable to treatment and cure by radiation. Despite the move toward penile sparing strategies, radiation remains an under-utilized and often neglected option. This paper will review the various radio-therapeutic approaches for penile cancer and the literature supporting their use. English, French and Spanish literature on penile cancer was reviewed for the past 5 decades and classified according to modality: external beam radiotherapy, interstitial brachytherapy and surface mold brachytherapy. Many series span several decades and include a wide range of stages, especially for external beam radiotherapy. Penile preservation obviously will depend on dose prescription and stage at treatment. Nonetheless, in general, penile sparing with external beam ranges from 36% to 66% at 5 years. For the selected patients appropriate for interstitial brachytherapy penile sparing is 77% to 87% at 5 years, decreasing to 70% at 10 years. Mold therapy is selected for those with very superficial disease and penile sparing is consequently higher. CONCLUSIONS: The development of centers of excellence for the management of this uncommon disease is encouraged. The required surgical and radiotherapy skill sets cannot be expected to be available in all centers. A multidisciplinary evaluation of each patient will facilitate selection of optimal management from the outset.

Radiotherapy for penile cancers.

Penile cancers are uncommon and should be treated in expert center. Radiotherapy indications are mainly limited to exclusive brachytherapy for early stage penile glans cancer. Brachytherapy yields to excellent outcome for disease control and organ and function preservation. Only scarce data are available for external beam radiation therapy. It could be considered as palliative setting for irradiation of the primary tumor. For lymph node irradiation, external beam radiation therapy (with or without chemotherapy) could be discussed either as neoadjuvant approach prior to surgery for massive inguinal lymph node invasion or as adjuvant approach in case of high-risk of relapse. However, these cases should be discussed on an individual basis, as the level of evidence is poor. We present the recommendations of the French Society of Oncological Radiotherapy on the indications and techniques for external beam radiotherapy and brachytherapy for penile glans cancer.

Recommendations and Clinical Validation of Inguinal Clinical Target Volume Delineation in Penile Cancer.

PURPOSE: This study determined the patterns of distribution of inguinal nodes and the optimal margin needed around the femoral vessels to propose guidelines for inguinal clinical target volume (CTV) delineation in penile cancer. METHODS AND MATERIALS: Patients with biopsy-proven penile squamous cell carcinoma with inguinal node metastases were identified on a computed tomography scan. Distribution of nodes and distance of nodes to the nearest femoral vessel and inferior edge of pubic symphysis (IPS) were obtained. A 3-dimensional CTV margin to cover 95% of the nodes was estimated to evolve contouring guidelines. A comprehensive contouring guide with a visual atlas for inguinal CTV delineation was created. The proposed CTV was prospectively validated in 14 consecutive patients with penile squamous cell carcinoma treated with post-operative radiation therapy to the inguino-femoral region. RESULTS: Of the 222 inguinal lymph nodes analyzed in 33 patients, 99% were located anterior (81% antero-medial, 18% antero-lateral) to femoral vessels. A majority (95%) of the antero-laterally located nodes were superior to IPS. Margin around the femoral vessels to cover 95% of the nodes for supra-IPS region in anterior, medial, and lateral directions was 29, 23, and 21 mm, respectively, and for infra-IPS region in anterior and medial directions was 21 and 23 mm, respectively. Cranial and caudal extent of CTV delineation with respect to IPS was at 48 and 50 mm, respectively for 95% nodal coverage. On prospective validation, after a median follow-up of 24 months (range, 5-31), none of the patients developed marginal recurrences. Grade 1 and grade 2 lymphedema was seen in 6 (42.8%) and 4 (28.5%) patients, respectively. CONCLUSIONS: This study analyzed pattern of distribution of inguinal nodes and proposes guidelines for inguinal CTV delineation in penile cancer. The proposed guidelines were validated prospectively in a small cohort of patients and found to be implementable and safe.

High-dose-rate brachytherapy with surface applicator in penile cancer.

PURPOSE: An alternative to surgery for penile cancer is radiation therapy which is administered with external beam techniques and/or brachytherapy (BT) either interstitial or using a surface applicator. Here we report our experience in penile cancer patients treated with high-dose-rate (HDR)-BT with the surface technique, analyzing dosimetric parameters and clinical outcomes. METHODS AND MATERIALS: Between June 2016 and December 2019, 7 patients with squamous cell carcinoma of the penis received HDR-BT by means of customized applicators that were constructed using a 3D printer or thermoplastic mask. The total dose was 57 Gy in 19 fractions. RESULTS: Median clinical target volume percentage receiving 95%, 125%, and 150% of the prescribed dose were 93.1% (range 92.2-98.5), 12% (range 7.4-32.2), and 0.24% (range 0-10.8), respectively. Median urethral volumes receiving 90% and 115% of the prescribed dose were 40.2% (range 21.0-83.8) and 0% (range 0-1), respectively. All patients achieved complete remission. No patient developed G3 or G4 acute or late toxicities. No patient experienced urethral stenosis. CONCLUSIONS: Surface HDR-BT in penile cancer is feasible and is associated with a high tolerance profile and good outcomes.

Radiotherapy is effective in the management of rare penile metastases: Two case reports.

Penile metastasization is an uncommon condition, mostly derived from primitive advanced abdominal cancers, with disabling symptoms. Palliative treatment, in reason of poor prognosis patients, is frequently surgical with destructive management. We report two cases of penile metastasis, from primitive prostatic adenocarcinoma and primitive urothelial carcinoma, effectively managed with radiation treatment at our institution. A three-dimensional conformal radiation therapy with 42Gy to the planning target volume in 14 fractions was delivered. Radiation treatment was safely delivered, with low toxicity profile and achieved adequate symptoms control without compromising genitourinary functions. Radiation therapy should be considered in management of rare penile metastases.

Long-term multicentre experience of adjuvant radiotherapy for pN3 squamous cell carcinoma of the penis.

OBJECTIVE: To present the long-term adjuvant radiotherapy outcomes of patients with pN3 squamous cell carcinoma of the penis (SCCp) treated at two UK centres. PATIENTS AND METHODS: We conducted a retrospective audit of all pN3 SCCp patients, deemed suitable for adjuvant therapy by a specialist multidisciplinary team at St George's and Leeds Hospitals, who received adjuvant radiotherapy. Primary outcomes were recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Secondary outcomes were time to adjuvant treatment, frequency of in-field recurrence, site and side of recurrence, and dose and schedule of radiotherapy. RESULTS: A total of 146 patients were included: 121 completed radiotherapy, 4 did not complete radiotherapy and 21 did not start it. The median (interquartile range [IQR]) age was 59 (54-70)years. The 5-year RFS was 51%, CSS was 51% and OS was 44%. Adjuvant radiotherapy was started at a median (IQR) of 75 (48-106) days. A dose of 45 Gy in 20 fractions was most commonly used. Of the 125 patients who started adjuvant treatment, 55 relapsed. Of these relapses, 30 occurred in an inguinal or pelvic nodal station and 26 of the 30 were in a radiation field. Relapses in 18 of the 55 cases were in visceral sites only and seven were in both nodal (non-irradiated sites) and visceral sites. Doses of <50 Gy were used more commonly before 2013 and higher doses (>50 Gy) were more commonly used after 2013. CONCLUSIONS: Application of a standard radiotherapy protocol within a centralized supra-network setting has achieved survival outcomes that would appear better than those previously documented for either radiotherapy or chemotherapy in a cohort with solely pN3 disease. The addition of adjuvant chemotherapy may improve these outcomes further. These data suggest that adjuvant radiotherapy has a role to play in the management of men with pN3 SCCp.

Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma.

BACKGROUND: Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node-involved penile squamous-cell carcinoma (PSCC) are lacking. OBJECTIVE: To analyze the benefit from perioperative radiotherapy (RT) for PSCC according to HPV infection status. DESIGN, SETTING, AND PARTICIPANTS: In an international multicenter database of 1254 patients with PSCC who received inguinal lymph node dissection (ILND), 507 had suitable clinical information. INTERVENTION: ILND, with or without chemotherapy or RT for involved lymph nodes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier and restricted mean survival time (RMST) analyses for overall survival (OS) were performed for all patients and after propensity score-matching (PSM; n = 136), for which patient age, histology, type of penile surgical procedure, pathological tumor and nodal stage, ILND laterality, pelvic LND, and perioperative treatment were taken into account when assessing differences between HPV+ and HPV- patients. Finally, we looked at genomic alterations in PSCC using data from the Foundation Medicine database (n = 199) to characterize HPV+ PSCC. RESULTS AND LIMITATIONS: Patients with HPV+ PSCC (n = 86; 17%) had lower clinical N stage (p < 0.001) and inguinal lymph node metastasis density (p < 0.001). Perioperative RT was delivered in 49 patients (9.7%), with the vast majority receiving adjuvant RT (n = 40). HPV+ patients had similar median OS (p = 0.1) but longer RMST than HPV- patients at different time points. Nevertheless, HPV+ patients treated with perioperative RT exhibited longer median OS (p = 0.015) and longer RMST compared to HPV- patients. In the PSM cohorts, HPV+ status remained significantly associated with longer OS after RT. The HPV- PSCC group had a higher frequency of TP53 mutations compared to HPV+ PSCC (75% vs 15%; p < 0.001). The results are limited by the retrospective nature of the data. CONCLUSIONS: Perioperative RT was more effective in the HPV+ PSCC subgroup. Reasons for the enhanced radiosensitivity may be related to the lack of TP53 mutations. PATIENT SUMMARY: We analyzed data from a large multicenter database for patients with penile cancer who had received inguinal lymph node dissection, with or without chemotherapy or radiotherapy. We found that for tumors positive for human papillomavirus (HPV), use of radiotherapy resulted in prolonged survival compared to HPV-negative tumors. On the basis of these results we are inspired to design studies on the use of radiotherapy in HPV-selected patients.

Adjuvant radiation compares favorably to chemotherapy in patients with carcinoma penis and nodal positivity restricted to groin.

OBJECTIVES: To compare overall survival (OS) between adjuvant radiation, chemotherapy and chemoradiation (CCRT) postsurgery for node-positive patients with carcinoma penis. METHODS: Prospectively maintained registry for 45 patients receiving adjuvant treatment following lymph node dissection from 2011 to 2017, having minimum 6 months follow-up and more than 2 positive inguinal nodes was analyzed. Patients without pelvic nodal positivity (n= 32) were treated by radiotherapy (RT) (n = 25) or chemotherapy (n = 7); CCRT (n = 6) or chemotherapy (n = 7) was used in patients with positive pelvic nodes (n = 13). Data was collected for age, comorbidities, body mass index, tobacco exposure, treatment modality, tumor grade, pathological T and N stage, and extra-nodal extension. OS was compared between different treatment modalities stratifying patients with and without pelvic nodal positivity. Multivariate cox proportional hazard analysis was used to narrow down remaining variables and Inverse Probability Treatment Weights modeling was used to determine average treatment effect. RESULTS: About 12 of 14 patients in the chemotherapy group received both cisplatin and paclitaxel. Pathological T stage, N stage and extra-nodal extension had significant association with OS on multivariate analysis. Among patients with nodal positivity restricted to groin the estimated average OS when all patients received adjuvant RT was 1,438 days (95% confidence interval [CI] 1,256-1,619 days, Pvalue <0.0001). The estimated average OS if all patients received chemotherapy was lower by 1,007 days (95% CI 810-1,202 days, P value <0.0001). Among patients with positive pelvic nodes the estimated average OS when all patients received adjuvant CCRT was 467 days (95% CI 368-566 days, P value <0.0001). The estimated average OS difference if all patients received chemotherapy was 17 days (95% CI -144 to 178 days, Pvalue 0.21). CONCLUSION: In patients with nodal positivity limited to groin, adjuvant RT proved superior to chemotherapy. Among patients with pelvic nodal positivity, CCRT offers no significant OS advantage over combination chemotherapy.

PSMA-PET/CT-avid metastatic prostate cancer to the penis.

Penile metastases from prostate cancer (PC) are rarely reported in the literature. Most commonly diagnosed due to presentation with malignant priapism and other urinary symptoms or from findings on clinical examination, prognosis has been reported to be poor. The authors outline a case of penile metastasis from advanced PC. Initially treated with neoadjuvant androgen deprivation therapy for locally advanced PC, this patient displayed upfront castrate resistance, and subsequent prostate-specific membrane antigen positron emission tomography revealed penile metastatic deposits. The patient was treated with external beam radiotherapy, and worsening urethral stricture disease resulted in the placement of a suprapubic catheter.

High-dose-rate brachytherapy for localized penile cancer: Evolution of a technique.

PURPOSE: High-dose-rate (HDR) brachytherapy is a convenient treatment option for selected patients with T1-T2 penile squamous cell carcinoma (SCC), providing high rates of penile preservation and tumor control. We present the results of penile SCC treated with HDR brachytherapy either interstitially or via a surface mold. METHODS AND MATERIALS: Between November 2009 and April 2019, seven patients (2 T1a and 5 T2) were treated with interstitial HDR and 8 (1 Tis, six T1a, and one T1b) with surface mold. Prescribed dose for interstitial patients ranged from 38.4 Gy in 6 days (3.2 Gy × 12) to 53 Gy in 9 days (3.12 × 17), BID. All patients treated with mold brachytherapy received 40 Gy in 10 fractions BID. Toxicity and oncological results were assessed for both groups, and their relation with dosimetry is described. RESULTS: Median follow up was 90 months for interstitial and 27 months for those treated with surface mold. Fourteen of 15 patients are alive and disease-free; one surface mold patient died of non-small-cell lung cancer. There was one relapse in each group, each treated with salvage penectomy. The potency was preserved in 82%. For interstitial, G2 necrosis occurred in 43%, G2 meatal stenosis in 29% and G3 stenosis in 14%. CONCLUSIONS: Both techniques have excellent rates of tumor control and organ preservation. Implant geometry and homogeneity constraints must be carefully designed to minimize toxicity in interstitial brachytherapy. Urethral contouring and reporting of dosimetric parameters should be defined.