SUO 2023: Advances in Radiotherapy for Penile Cancer

(UroToday.com) The 2023 SUO annual meeting included a session on penile cancer, featuring a presentation by Dr. Juanita Crook discussing advances in radiotherapy for penile cancer. Dr. Crook emphasized that the reason to consider radiation is that the majority of squamous cell carcinomas, including cervical, vulva, and head and neck cancer are highly radio-curable.

Furthermore, penile cancer has a similar bimodal etiology as vulvar squamous cell carcinoma: HPV infection and chronic inflammation. Other additional reasons for considering primary radiotherapy for penile squamous cell carcinoma are as follows:

Primary organ preservation
The potential for surgical salvage, if required
Radiation of the primary in conjunction with surgical nodal staging
Consideration of post-operative radiation when multiple nodes are involved or if there is extracapsular disease
Multidisciplinary collaboration with urologists

With regards to radiation to the primary, the two radiation modalities are external beam and brachytherapy. External beam radiotherapy is given with or without concurrent chemotherapy, including cisplatin 40 mg/m²/week or 5-FU/mitomycin or capecitabine. For brachytherapy, the majority of the experience is with low dose rate (LDR), with iridium 192 manually after loaded. Pulse dose rate (PDR) is equivalent from a radiobiologic standpoint if the hourly pulses are ~50 cGy. Additionally, high dose rate (HDR) brachytherapy is widely available after loaders, with the published experience of HDR increasing over recent years.

The ideal patient for brachytherapy has a tumor confined to the glans penis, <= 4 cm in size, and is circumcised. Dr. Crook notes that lymphovascular invasion and grade are not contraindications to brachytherapy. Microscopic disease and palpable disease are predictors of regional failure, thus lymph nodes should be addressed in the initial management in collaboration with a urologist. Brachytherapy is performed under local or general anesthesia, usually taking 30-45 minutes, with the patient catheterized during implantation. If the patient is having inpatient treatment, the penis is supported in a styrofoam collar to minimize dose to the neighboring tissue:

Moreover, the patient should be on prophylactic low-dose heparin or low molecular heparin and should wear anti-embolic stockings.

For LDR and PDR, there should be 2-3 planes, 4-9 needles spaced at 12-18 mm, at a dose of 60-65 Gy (LDR) or 50-65 cGy/hr (PDR) for 4-5 days:
penile cancer Brachytherapy diagram
The local control rate at 5 years for LDR/PDR ranges from 70-96%, with a penile conservation rate of ~70% at 10 years. As follows is a summary of the literature for LDR/PDR: LDR HDR table
For HDR brachytherapy, treatment parameters are as follows:

Needle spacing: 9-12 mm
Recommended fraction size: 3-4.3 Gy BID
Total dose range: 38-53 Gy (depending on tumor volume)
Homogeneity guideline: V150 < 20%, V125 < 40%
Urethral dose should be limited to 115%
Post implant CT for planning: define the tumor volume with a wire
Margin for microscopic spread (CTV): 0.5 – 1.0 cm
Margin for uncertainty of set-up (PTV): not required

The following figure highlights the penile brachytherapy template: penile cancer Brachytherapy image 2
The HDR literature reports a local control rate of 73-92% and penile conservation rate of 70-93%, with the following summary of the literature:
penile cancer dose table Dr. Crook then presented a case of a 72 year old male who had HPV positive for penile squamous cell carcinoma. After multiple local excisions, he had refused penectomy and was subsequently treated with 44/14/7 days (3.2 Gy/fraction) brachytherapy with the following pre- and post-treatment images:

Dr. Crook notes that most desquamation heals in about 3 months with expected sterile urethritis. However, urethral adhesions in the healing phase should be separated and sexual activity should be withheld until 3-8 weeks post-treatment. Late effects of brachytherapy include meatal stenosis in 8%-25% of cases, thus care must be taken with needle placement (meatal self-dilation reduces risk of stenosis to approximately 10%). Additionally, late soft tissue ulceration/necrosis can occur in up to 20% of cases, especially in larger or more deeply invasive tumors where more needles may be required. Most will heal with conservative measures, but hyperbaric oxygen may be useful in severe cases.

Even in complex cases, perhaps penectomy is not the only option. Dr. Crook presented another case of a 49 year old with T2cN2 penile squamous cell carcinoma who subsequently received 55.8 Gy to the primary and 45 Gy to the positive nodes, in addition to 6 cycles of concurrent cisplatin (40 mg/m²) weekly. He has been without evidence of disease for 7 years with the following pre-treatment and 9 month post treatment images:¹

Another case is of a 54 year old with T1bN3 penile squamous cell carcinoma who subsequently received 55.8 Gy to the primary and 45 Gy to the positive nodes with 2 cycles of 5-FU + mitomycin C. He has been without evidence of disease for 7 years with the following pre-treatment and 9 month post treatment images [1]:¹
External beam radiotherapy has a local control rate of 44%-70% and a penile sparing rate of 36%-66%, with the following table summarizing the reported literature: External beam radiotherapy table squamous cell penile cancer
Dr. Crook summarized her portion of the presentation discussing radiation to the primary with the following thoughts:

Interstitial brachytherapy (whether LDR/PDR or HDR) has a penile preservation rate at 5 years of approximately 85% and roughly 70% at 10 years
External beam radiotherapy +/- concurrent chemotherapy is best suited for younger patients who can tolerate treatment and want to keep their penis

The second part of Dr. Crook’s presentation focused on management of radiation to the lymph nodes. We know that N-stage is crucial in determining survival for these patients: the 5 year cancer specific survival for patients with pN1 disease is ~70%, whereas for pN3 is 20%-30%. Chemo-radiotherapy is an option for patients with nodal disease. Dr. Crook then presented a case of a 67 year old male who had nodal recurrence 1 year after excisional biopsy of the primary lesion. He was subsequently treated with 67 Gy to the mass, 45 Gy to the pelvic lymph nodes and started on concurrent weekly platinum-based chemotherapy: pelvic lymph node images
Three months post completion of chemo-radiation his groin lesion PET/CT SUV max was 3.2, and 7 years later he was doing well with no leg edema:
edema images
As a cautionary note, Dr. Crook emphasized that HPV + squamous cell carcinoma responds better to chemo-radiation, with 50 Gy in 25 fractions typically sufficient to control micrometastatic disease in >90% of cases for breast and head and neck cancers. Generally, the radiation sensitivity index indicates that squamous cell carcinoma of the penis is less sensitive overall to radiotherapy than other squamous cell carcinomas, such as cervical and head and neck cancer:²
Yuan et al. assessed the genomic-adjusted radiation dose (GARD) profiles of 25 patients, noting that penile squamous cell carcinoma GARD ranged from 9.56 to 38.39 (median 18.25), suggesting variable therapeutic effects from post-operative radiation therapy.² Additionally, therapeutic benefit was only achieved in 52% of lesions with post-operative radiation therapy of 50 Gy, in contrast to 84% benefit from GARD-modeled post-operative radiation therapy of 66 Gy.

When it comes to penile, vulvar, and anal squamous cell cancer, the NCCN guidelines are quite divergent in terms of optimal treatment paradigms, with penile squamous cell carcinoma favoring a surgical approach and vulvar/anal squamous cell carcinoma favoring a chemo-radiation approach: cancer type table
Dr. Crook emphasized that adjuvant pelvic radiotherapy after a positive pelvic lymph none dissection for penile squamous cell carcinoma increases overall survival. In a multi-institutional study, Tang and colleagues assessed 92 patients with available adjuvant pelvic radiation status and positive pelvic lymph nodes [3], noting that 43% received adjuvant radiation after positive pelvic lymph node dissection. Over a median follow-up of 9.3 months patients receiving adjuvant pelvic radiation had a median disease specific survival of 14.4 months vs. 8 months in the non-radiation group, respectively (p = 0.023). Patients without adjuvant pelvic radiation were associated with worse overall survival (HR 1.7, 95% CI 1.01-2.92) and disease specific survival (HR 1.9, 95% CI 1.09-3.36) on multivariable analysis:
pelvic radiation overall survival

pelvic radiation disease specific survival
Median time to recurrence was 7.7 months vs. 5.3 months in the radiation and non-radiation arm, respectively (p = 0.042).

For locally advanced penile squamous cell carcinoma, neoadjuvant chemotherapy followed by surgery is typically standard of care, but with a 1 year survival probability of ~50%. To assess the role of chemo-radiotherapy in the locally advanced setting, Ottenhof et al. [4] performed a prospective, single-center, assessment of 49.5 Gy (33 × 1.5 Gy) on the affected inguinal and pelvic areas combined with intravenous mitomycin C on day 1 and capecitabine on radiation days. Primary tumors and PET/CT-positive deposits received a boost of 59.4 Gy (33 × 1.8 Gy). Among 33 patients (n = 29 stage IV), 32 completed chemo-radiotherapy. Over a median follow-up of 41 months, 24 patients (73%) responded, including 13 (39%) complete responses. There were 9 patients (27%) that underwent salvage surgery, and an additional 8 patients underwent later surgery (52% overall). The 1- and 2-year PFS rates were 34% and 31%, respectively, and the 1- and 2-year overall survival rates were 73% and 46%, respectively: pelvic radiation progression free survival
The International Penile Advanced Cancer Trial (InPACT) is investigating the roles and optimal sequencing of surgery, chemotherapy, and chemo-radiotherapy for men presenting with nodal disease. Several key questions from the InPACT trial include:

What is the role of neoadjuvant treatment for men presenting with nodal disease?
Which is preferable? Chemotherapy or chemo-radiotherapy?
Can pelvic chemo-radiotherapy lead to equivalent outcomes to pelvic lymph node dissection for men at high risk of pelvic nodes after inguinal lymph node dissection?

With a target accrual of 200 patients and a primary endpoint of overall survival, Dr. Crook notes that the trial has accrued over 50% of the expected enrolment.

To conclude her presentation discussing radiotherapy for penile squamous cell carcinoma, Dr. Crook noted that the EAU/ASCO collaborative penile cancer guidelines were updated in 2023.⁵

Presented by: Juanita Crook, MD, FRCPC, BC Cancer, Kelowna, British Columbia, Canada

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023.

References:

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