ASCO GU 2019: Penile Carcinoma Regional Lymph Node Involvement: Radiation Versus Surgery – Radiation Oncology Perspective

San Francisco, CA ( In this talk, the first of two talks on the topic, Dr. Hoffmann provided the radiation oncologist perspective for penile cancer regional lymph node management. As a reminder, squamous cell carcinoma of the penis, or penile cancer, has an established drainage pathway through the superficial inguinal nodes, deep inguinal nodes and then to the pelvic lymph nodes. To reflect this, the staging for penile cancer has stratified nodal staging into 4 substages – pN0 – N3, based on the presence of lymph nodes, number of lymph nodes, laterality, and mobility.
PeCa squamous cell carcinoma has similar management and natural history as vulvar SCC in female patients. As such, Dr. Hoffmann utilizes literature from the vulvar cancer field often in her talk to demonstrate the potential use in the management of PeCa nodal disease.

She jumped right into the overview of her talk – and the current role of radiation therapy in the management of PeCa nodal disease. There are 3 primary areas for radiation therapy:
  • Neoadjuvant therapy – to downsize unresectable disease and to reduce risk of recurrence
  • Adjuvant therapy – To reduce risk of recurrence after resection
  • Definitive treatment – in lieu of lymph node dissection
Neoadjuvant therapy

In the vulvar SCC literature, in a phase II trial of 42 women with the unresectable disease, radiation of inguinal, femoral and pelvic lymph nodes with concurrent 5-FU/cisplatin chemotherapy converted ~90% to resectable disease. Indeed, 40% of those patients had pN0 disease and therapy was well tolerated – primarily Grade 2 complications (wound breakdowns).

A study by Ravi et al. (BJU 1994), pre-operative inguinal radiation in men with PeCa SCC improved resectability – this was a retrospective review of patients between 1959-1988, so it was also an older radiation therapy modality. Importantly, they noted that besides increasing respectability, there was also an associated complete response rate to RT alone and improved DFS with subsequent ILND. This data begins to hint at benefit beyond just increasing resectability.

She briefly touched upon morbidity of combined chemoradiation therapy – especially in the era of IMRT. In a study of 18 women treated with chemo-IMRT, there were moderate adverse events. Primarily, there are acute skin effects during treatment, but in the perioperative setting (ILND completed 6-8 weeks after chemoradiation), it was associated with prolonged wound healing (21%) and measurable lymphedema (33%). Therefore, it is not benign.

Ultimately, her conclusions about neoadjuvant radiation:

  • Can convert unresectable disease to resectable disease
  • May decrease the risk of nodal recurrence
  • Should be delivered with concurrent chemotherapy as a radiosensitizer
  • Additional data is needed to understand how it compares to chemotherapy alone and its impact on survival
Adjuvant radiation

Nodal recurrence is associated with very poor survival outcomes – so any effort to reduce local recurrence following node dissection may help shift patient natural history. Adjuvant radiotherapy may be one such modality that can be used in the perioperative setting.

Reddy et al. (IJROBP 2015) identified risks of nodal recurrence – specifically having > 3 positive lymph nodes and having extranodal extension were the strongest predictors of local recurrence.

Again referring back to the vulvar SCC literature, a randomized trial by Kunos et al (Ob Gyn 2009) compared PLND against RT to the inguinal and pelvic LN. They found that cancer-related deaths were lower and recurrence rates were improved in women treated with RT – and the greatest benefit was in women with clinically suspicious nodes or more than one groin node. The adverse event profile was similar between the two groups as well, without any significant differences.

Unfortunately, most of PeCa adjuvant therapy literature is retrospective and significantly flawed by selection bias. Additionally, many of the retrospective studies looked at older RT modalities.

Tang et al. (Urol Onc 2017) looked at 92 patients from 4 institutions with positive lymph nodes on ILND. Of these patients, 45% received adjuvant radiation. They found that pelvic RT was associated with improved cancer-specific and overall survival – but it too was compromised by selection bias and immortal time bias. Only patients that did well and made it past ILND received adjuvant XRT.

Winters et al. (Urol Onc 2018) also looked at 589 men in NCDB who underwent ILND for stage III penile cancer. 23% received adjuvant RT. On multivariable analysis, adjuvant RT was associated with improved 3 and 5-year OS.

Her take-home points for adjuvant RT:
  • Pathologic features can help identify appropriate patients at high risk of local recurrence (+ENE, > 3 lymph nodes, > 3 cm in size)
  • Adjuvant chemoradiation may reduce the risk of recurrence and improve survival
  • Additional data is needed to understand if it can replace PLND and its impact on treatment toxicity
Definitive chemoradiation to address nodal disease

At this time, this is recommended for patients who cannot tolerate surgery or are not surgical candidates. There are some patients that refuse surgery and this may be an option in those patients as well.

Importantly, there is evidence that chemoradiation can be used as definitive therapy for squamous cell carcinomas of other disease sites: head and neck cancer, anal cancer, cervical cancer. It has also been demonstrated in primary penile cancer as well.

However, there is little data in this disease space and primarily small series and anecdotal experience. 

Presented by: Karen E. Hoffman, MD, MPH - The University of Texas MD Anderson Cancer Center

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

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