HOLLYWOOD, Fla.—New treatment guidelines for penile cancer from the National Comprehensive Cancer Network (NCCN) suggest that conservative treatment should be considered for this rare cancer, according to the report released here at the organization's National Conference.
“The bottom line in this new treatment guideline is that penile preservation therapy is feasible,” said Philippe E. Spiess, MD, Associate Member of the Department of Genitourinary Oncology at Moffitt Cancer Center and a member of the NCCN Bladder/Penile Cancers Panel.
Although a relatively rare cancer (about 1,200 new cases a year), the disease can be deadly. One man dies from the disease in the United States almost every day, Spiess noted in presenting the guidelines on behalf of the 27-member writing panel. He said that the incidence of penile cancer is more extensive in South America and in parts of Africa, compared with that in the U.S.
Treatment of the disease varies from institution to institution, and hence calls for a standardized treatment algorithm, he said. “Penile cancer is a spectrum. We know there are some dysplastic conditions that increase the likelihood, and there is also a strong association with human papillomavirus as there is with head and neck tumors.” He said, however, that the path from a dysplastic lesion to cancer can fluctuate dramatically from man to man.
When a patient presents with a suspicious penile lesion, the characteristics should be noted, and a punch, excisional, or incisional biopsy should be performed to determine the stage and grade. “In terms of superficial tumors, there is a wide spectrum of options,” Spiess said.
The options for Tis and Ta tumors include topical imiquimod five percent or fluorouracil cream; a wide local incision that can include circumcision; laser therapy or complete glansectomy. However, he noted that because lasers have not been closely studied in this context, the guideline committee gave the use of the devices a category 2b recommendation—consensus among the guideline writers. All the other recommendations are category 2a, meaning uniform consensus despite low levels of evidence.
Spiess explained that the gold standard for treatment of penile tumors is complete excision of the tumor with wide negative margins—“but there are increasing reports and acceptance of consideration of less or non-invasive management of primary penile tumors following the principles of wide excision, which may improve quality of life and overall functioning for patients,” he said.
For patients with carcinoma in situ or superficial Ta tumors, “fluorouracil or imiquimod can give excellent outcomes with response rates of 60 to 70 percent after five years,” he said. Laser required retreatment is about 26 percent of patients at 32 months.
Spiess noted that European doctors have reported good results with use of topical agents. The topical agents—fluorouracil as first line and imiquimod as second line—were applied to the lesion for 12 hours every 48 hours for 28 days. Complete responses were achieved in 25 of 44 patients (57%) and partial responses were observed in another 14 percent of patients. After a mean follow-up of 34 months, none of these patients had a recurrence or tumor progression.
He also cited a study from Massachusetts General Hospital that followed 60 patients who had undergone penile-sparing surgery there since 1995. Of the evaluable patients, about 21 percent had a recurrence (equal rates among the 28 men with Tis tumors and the 28 with pT1 tumors). “What's important here is to note that these recurrences can occur fairly late, which means patients should be followed for at least 10 years,” he said. None of the Tis patients had recurrence, and five of the T1 patients developed metastases.
Even for T1 and T2 tumors, the guidelines suggest that penile sparing is possible, he said. The lead option for Grade 1-2, T1 tumor is wide local excision, with complete excision of skin assuring a wide negative margin. Skin grafting using split-thickness skin grafts or full thickness skin grafts can be employed as needed. Laser therapy or radiotherapy (both category 2B) are also considered options.
Radiotherapy using brachytherapy techniques had good results, he noted, citing a French study reported in 2009. In that trial, 144 men with squamous cell carcinoma of the penis were treated at two centers with a follow-up of 5.7 years. The 10-year penile recurrence rate was 20 percent, and the 10-year inguinal recurrence rate was 11 percent.
Few Centers of Excellence for Penile Brachytherapy
“However,” he said, “the centers of excellence for penile brachytherapy are few and far between, which is why when these guidelines were put together by our group, we were somewhat cautious about making this recommendation.” The recurrence rate among men undergoing brachytherapy for penile cancer approaches 40 percent, “so you have to be very vigilant. We teach our residents and trainees that if you see any area that is not healing well, it has to be biopsied.”
For patients with grade 3-4 T1 tumors, wide local excision remains an option, but calls for intraoperative frozen sections to assure that negative margins are achieved; glansectomy can be performed if the tumor is confined to the glans. Other options can be partial or complete penectomy. Radiotherapy with chemotherapy is a category 3 recommendation, meaning there is no consensus. “There really is not a lot of evidence to support that treatment,” Spiess said.
The guidelines state that when it is necessary to dissect into the corpora cavernosum to achieve a negative margin, a partial or total penectomy is performed: “Partial penectomy should be considered the standard for high-grade primary penile tumors, provided a functional penile stump can be preserved and negative margins are obtained.”
For T2 or greater tumors, partial penectomy or total penectomy are the category 2a recommendations, although radiotherapy or radiation plus concurrent chemotherapy may be considered as an option (category 2b). “There is scant information in the medical literature to support that option,” Spiess said.
Although mentioned as an option in the footnotes of the guidelines, the use of Mohs microsurgery in penile cancer did not have good long-term success, he said.
In dealing with nonpalpable inguinal lymph nodes treatment, the guidelines recommend that if the primary lesion is considered low-risk, surveillance is suggested for follow-up for patients with stages Tis, Ta, or T1G1 tumors. For higher grade tumors, inguinal lymph node dissection is considered an option, as is dynamic sentinel node biopsy.
With patients with palpable lymph nodes, the guidelines suggest use of fine needle aspiration biopsy with inguinal lymph node dissection if the biopsy is positive.
Sentinel node biopsy procedures for penile cancer have “relatively high false-negative rate,” he said, although combining the treatment with ultrasound can reduce the false-negative rate to around 11 percent. “Patients with lymphovascular invasion or who have high-grade tumors should be considered for the gold standard of treatment—i.e., inguinal lymph node dissection,” he said.
Surveillance of patients with penile cancer following initial definitive treatment includes physical examination, including examination of the penis and groin, every three months for the first two years; and then every six months for years three to five, and then annually though year 10. That schedule should be followed for patients who had penile-sparing procedures such as the use of topical agents or wide incision surgery of the primary lesion.
Men who underwent partial or total penectomy should be seen every six months for two years after the procedure and then every year through five years, the guidelines state.
As with all NCCN guidelines, the organization suggests that “the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.”