Squamous cell cancer of the penis is a radiocurable malignancy all too often managed solely by partial or total penectomy. Effective management of the primary tumor while preserving penile morphology and function is a priority. External radiotherapy and brachytherapy have a role to play in the definitive management of the primary tumor. Surgical nodal staging remains a cornerstone of management because it is the strongest predictor of survival, and inguinal status determines pelvic management. Postoperative radiotherapy of the regional nodes for high-risk pathology is indicated. Chemoradiotherapy should be considered as neoadjuvant treatment for unresectable nodes or as definitive management.
Key points
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Squamous cell cancer of the penis is a radiocurable malignancy all too often managed by partial or total penectomy.
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External radiotherapy and brachytherapy have a role to play in the definitive management of the primary tumor, with 5-year penile preservation rates reported at 60% and 85%, respectively.
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Nodal staging remains a cornerstone of management because it is the strongest predictor of survival and inguinal status determines pelvic management.
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Postoperative radiotherapy of the regional nodes for high-risk pathology is indicated.
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Chemoradiotherapy should be considered as neoadjuvant treatment for unresectable nodes or as definitive management.
Introduction
The vast majority of penile cancers are squamous cell carcinoma (SCC), a radiosensitive and radio curable malignancy. There is consistent evidence across other SCC sites, including head and neck, cervix, vulva, and anal canal, that radiotherapy and the combination of sensitizing chemotherapy and radiotherapy are effective treatment. Furthermore, all these sites share a common pathway in human papillomavirus causation in a significant percentage of cases. Human papillomavirus positivity is associated with a better outcome and higher response rates to chemoradiation, and in penile cancer has been associated with improved 5-year survival.
Largely owing to the relative rarity of penile cancer in Western societies, there is a paucity of level 1 evidence to guide treatment. The incidence of approximately 1 per 100,000 in North America and the developed countries of Western Europe is an obstacle to completion of randomized studies to compare surgery with radiotherapy or radiation to chemoradiation.
The traditional surgical approach to penile cancer has been partial or total penectomy. Because of the impact on sexual function, quality of life, and mental health, recent advances in surgery toward maximizing penile preservation, such as glansectomy and glans resurfacing, have attempted to address these issues but are not widely adopted. There are obvious quality of life advantages to organ preservation that can be provided by nonsurgical alternatives.
In localized disease, various forms of radiotherapy, including external beam, interstitial brachytherapy, and surface mold brachytherapy, offer a high chance of cure with organ preservation, reserving surgery for local recurrence. When there is a significant risk of regional node involvement by virtue of the stage or grade of the primary tumor, management with radiation can be combined with surgical staging of the nodes. The indications for postoperative adjuvant radiation to regional lymphatics following nodal staging are well-established from other anogenital SCC sites and include:
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Multiple node involvement,
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Extracapsular/extranodal extension, and
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Positive surgical margins.
For men presenting with locally and/or regionally advanced disease, chemoradiotherapy may render the disease resectable or can be instituted as a definitive treatment.
Introduction
The vast majority of penile cancers are squamous cell carcinoma (SCC), a radiosensitive and radio curable malignancy. There is consistent evidence across other SCC sites, including head and neck, cervix, vulva, and anal canal, that radiotherapy and the combination of sensitizing chemotherapy and radiotherapy are effective treatment. Furthermore, all these sites share a common pathway in human papillomavirus causation in a significant percentage of cases. Human papillomavirus positivity is associated with a better outcome and higher response rates to chemoradiation, and in penile cancer has been associated with improved 5-year survival.
Largely owing to the relative rarity of penile cancer in Western societies, there is a paucity of level 1 evidence to guide treatment. The incidence of approximately 1 per 100,000 in North America and the developed countries of Western Europe is an obstacle to completion of randomized studies to compare surgery with radiotherapy or radiation to chemoradiation.
The traditional surgical approach to penile cancer has been partial or total penectomy. Because of the impact on sexual function, quality of life, and mental health, recent advances in surgery toward maximizing penile preservation, such as glansectomy and glans resurfacing, have attempted to address these issues but are not widely adopted. There are obvious quality of life advantages to organ preservation that can be provided by nonsurgical alternatives.
In localized disease, various forms of radiotherapy, including external beam, interstitial brachytherapy, and surface mold brachytherapy, offer a high chance of cure with organ preservation, reserving surgery for local recurrence. When there is a significant risk of regional node involvement by virtue of the stage or grade of the primary tumor, management with radiation can be combined with surgical staging of the nodes. The indications for postoperative adjuvant radiation to regional lymphatics following nodal staging are well-established from other anogenital SCC sites and include:
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Multiple node involvement,
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Extracapsular/extranodal extension, and
- •
Positive surgical margins.
For men presenting with locally and/or regionally advanced disease, chemoradiotherapy may render the disease resectable or can be instituted as a definitive treatment.
Radiotherapy for the primary tumor
Penile preservation should always be considered for the primary tumor. Although not always possible, especially in more locally advanced T3 to T4 disease, quality of life advantages include maintenance of erectile and sexual function and preserved sense of manliness. Delaunay and colleagues published results of a self-reported questionnaire administered to 21 men at an average of 80 months after penile brachytherapy. Seventeen of 18 men potent before brachytherapy reported maintenance of erections and 10 were still in an active sexual relationship. Although the capacity for erection and ejaculation can be maintained after partial penectomy, the lack of a glans and small penile size are cited as reasons for cessation of sexual activity. Emotional and mood disorders, anxiety, depression, and even suicide or attempted suicide are reported. Radiation therapy is associated with better global sexual scores than partial penectomy or local excision. An analysis of 128 patients from 6 studies of surgical management of penile carcinoma reported impaired well-being in up to 40%, with psychiatric symptoms in approximately 50%. Additionally, up to 75% of patients report a reduction in sexual function after surgery.
Carcinoma in situ
SCC in situ may be adequately treated with circumcision if confined to the foreskin. Topical therapies such as 5-flouro-uracil cream or imiquoid provide excellent cosmetic results but careful follow-up is mandatory as recurrence is not uncommon. Other penile-sparing options include laser ablation, preferably Nd-YAG lasers, which penetrate up to 6 mm, have shown good tumor control (7% local failure [LF] at 4 years) with satisfactory function and cosmesis; 75% of men resume sexual activity. Mohs micrographic surgery or surgical excision with frozen section for intraoperative margin verification may permit local excision, but local recurrence remains a risk after any penile-sparing procedure, reported in up to one-third of patients. External beam radiation therapy may be used with a report of 100% local control for in situ disease, but the preferred radiation may be mold plesiotherapy ( Box 1 ).
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Circumcision (if confined to foreskin)
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Topical 5-flouro-uracil/imiquoid
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Nd-YAG laser ablation
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Local excision with margin verification
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External beam radiotherapy
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Surface mold plesiotherapy
Invasive cancer
Curative radiotherapy of the primary tumor can be delivered either through external beam radiation, interstitial brachytherapy, or surface mold plesiotherapy. For external beam radiotherapy, the 5-year local control and penile preservation rates are about 60%. For low dose rate (LDR) interstitial brachytherapy both local control and penile preservation are about 85% at 5 years and 70% at 10 years. Local recurrence is salvageable by surgery and does not affect disease-specific mortality. Each of these modalities is considered in turn.
External Beam Radiotherapy
External beam radiotherapy for early stage localized T1 to T2 SCC of the penis presents challenges with supporting and isolating the organ from adjacent normal structures while positioning it for treatment. Full bolus must be applied to eliminate the skin-sparing characteristics of modern megavoltage beams. With the patient supine, the penis is supported vertically in a split block of tissue-equivalent material with a central chamber to encase the penis ( Fig. 1 ). Initially, wax blocks were used for this purpose but being opaque, do not allow verification of penile position for setup before each treatment. Alternatively, if Plexiglas or Lucite chambers are used, the chambers can be sterilized and reused, and setup can be visually checked daily. A range of diameters of the central chamber should be available to accommodate penile change over the course of treatment, owing to either swelling or tumor response. With either type of block, it is important to plug the open end with same material to eliminate the air gap distally. Erythema, desquamation, and edema are expected during treatment and take 2 to 4 weeks to heal.
The clinical target volume is the visible/palpable disease with a 1-cm margin. The planned target volume should be a minimum of 2 cm beyond visible/palpable disease to allow for minor setup variation and penumbra. The treated volume includes the full thickness of the penis.
Although dose and fractionation have varied over the decades, currently 66 to 70 Gy over 6.5 to 7 weeks is accepted. Fraction sizes of less than 2 Gy, treatment courses longer than 45 days, and total dose of less than 60 Gy are associated with an increase in local failure. The 5-year local control and penile preservation rates range from 41% to 70% with a weighted average of about 61%. Most local failures are salvaged surgically with either partial or total penectomy. Results from selected series are presented in Table 1 .
| Author | n | Follow-up (mo) | Dose(Gray)/# fractions | CSS (%) | DFS | LC (%) | Complications | Penile Preservation (%) |
|---|---|---|---|---|---|---|---|---|
| Neave et al, 1993 | 20 | 36+ | 50–55/20–22 | 58 | — | 70 | 10% stenosis | — |
| McLean et al, 1993 | 26 | 116 | 35/10–60/25 | 69 | 15/26 | 62 | 27% unspecified | 100 |
| Ravi et al, 1994 | 128 | 83 | 50–60 | — | 84% | 65 | 6% necrosis 24% stenosis | — |
| Sarin et al, 1997 | 59 | 62 | 50–60 | 66 | — | 59 | 3% necrosis 14% stenosis | 55 |
| Gotsadze et akl, 2000 | 155 | 40 | 40–60 | 88 | — | 65 | 1% necrosis 7% stenosis | 65 |
| Zouhair et al, 2001 | 23 | 70 | 45–74 @ 1.8–2 Gy | — | — | 57 | 10% stenosis | 36 |
| Ozsahin et al, 2006 | 33 | 62 | 52 | 53 at 10 y | — | 44 | 10% stenosis | 52 |
| Azrif et al, 2006 | 41 | 54 | 50–52/16 | 96 | 51% | 62 | 8% necrosis 29% stenosis | 62 |
| Mistry et al, 2007 | 18 | 62 | 50/20–55/16 | 85 | 63% | 63 | 2 necrosis 1 stenosis | 66 |
External beam radiotherapy is most frequently considered in elderly or debilitated patients or those presenting with locoregionally advanced disease where the primary would be treated in contiguity with the nodal regions, including both groins and the pelvis. This topic is addressed further under Regional Radiotherapy.
Interstitial Low-Dose Rate Brachytherapy
LDR interstitial brachytherapy has been successfully used for decades and can deliver the required dose to the target without excessive treatment of the penile shaft, sparing the contralateral glans in lateralized lesions, and without concerns about daily setup.
LDR interstitial brachytherapy is a 1-hour procedure performed using sterile technique under general anesthesia or penile block. The patient is admitted afterward for 4 to 6 days for treatment delivery. After creation of a sterile field, the visible/palpable lesion is delineated with a sterile pen and appropriate margins chosen. An in-dwelling Foley catheter is inserted and remains for the duration the brachytherapy treatment. The position and spacing of the interstitial needles is chosen to avoid the urethra, and to have the superficial needles within 3 mm of the treated surface. If they are too shallow, skin ulceration and scarring result. A minimum of a 2-plane implant is required ( Fig. 2 ). If necessary, a plesiotherapy plane can be added externally on the side of the cancer with the air gap filled with appropriate bolus material ( Fig. 3 ). A guide template is recommended to ensure parallelism and equal spacing, ideally 12 to 18 mm, with the needles and planes being equidistant. Pairs of templates can be predrilled at a range of needle spacings, but a “universal template” with holes drilled every 3 mm allows more flexibility ( Fig. 4 ). Once positioned, the needles must be locked in place individually. Historically, dosimetry was calculated based on measurements of spacing and treated lengths, but the current standard depends on a computed tomography scan for reconstruction of the needles, delineation of the target volume, and dose calculation.
The basic rules of geometry of the Paris system of dosimetry should be appreciated to place the needles optimally. In a classic LDR treatment with iridium wire, the length of the treated volume along the axis of the needles is 0.75 of the active length of the wire sources owing to in-drawing of the isodoses distally between the wires. Similarly, the spacing between the needles determines the lateral margin treated beyond the wires (0.27 × spacing; ie, 4 mm for 15 mm spacing). If a stepping source is used from an automated afterloader, such as in pulse dose rate brachytherapy, then dose optimization is possible ( Fig. 5 ). The prescribing rules of the Paris system give guidance as to desirable homogeneity, such that dose rate minima between the sources are approximately 115% of the prescription isodose.
Classic continuous LDR brachytherapy aims for a dose rate of 50 to 60 cGy per hour. Pulse dose rate brachytherapy is radiobiologically equivalent if hourly fractions of 0.5 to 0.6 Gy are delivered, 24 hours per day. The total dose recommended is 60 to 65 Gy over 5 days. Minimal analgesia is required, but as many patients are relatively immobile, antithrombotic measures are advised. Needle removal occurs at the bedside after premedication with a narcotic analgesic. Bleeding is usually minimal and the patient can be discharged the same day.
Selected results from the literature are shown in Table 2 . Five-year local control ranges from 70% to 96% and 10-year from 70% to 80%, with penile preservation at 10 years being 70%. Local failures are salvaged surgically and but may occur late, with 20% occurring up to 8 to 10 years after treatment. Continued surveillance and patient awareness are essential.
| Author, year | HDR/LDR | n | Follow-up, mo (Range) | Dose, Gray | CSS | DFS | LC | Complications | Penile Preservation |
|---|---|---|---|---|---|---|---|---|---|
| Mazeron et al, 1984 | LDR | 50 | 36–96 | 60–70 | 79% | 63% | 78% | 3% necrosis 16% stenosis | 74% |
| Delannes et al, 1992 | LDR | 51 | 65 (12–144) | 50–65 | 85% | — | 86% | 23% necrosis 45% stenosis | 75% |
| Rozan et al, 1995 | LDR | 184 | 139 | 59 | 88% at 5 y; 88 at 10% y | 78% at 5 y; 67% at 10 y | 85% | 21% necrosis 45% stenosis | 76% |
| Soria et al, 1997 | LDR | 102 | 111 | 61–70 | 72% at 5 y; 66% at 10 y | 56% at 5 y; 42% at 10 y | 89% | 1 necrosis 1 stenosis | 68% |
| Chaudhery et al, 1999 | LDR | 23 | 24 (4–117) | 50 (40–60) | — | — | 70% | 0 necrosis 2/23 stenosis | 70% |
| Kiltie et al, 2000 | LDR | 31 | 61.5 | 63.5 | 85% | 85% | 81% | 8% necrosis 44% stenosis | 75% |
| de Crevoi sier et al, 2009 | LDR | 144 | 68 (6–348) | 65 | 92% at 10 y | 78% at 10 y | 80% at 10 y | 26% necrosis 29% stenosis | 72% at 10 y |
| Crook et al, 2009 | LDR | 67 | 48 (44–194) | 60 | 84% | 71% at 5 y | 87% at 5 y; 72% at 10 y | 12% necrosis 9% stenosis | 88% at 5 y 67% at 10 y |
| Pimenta et al, 2015 | LDR | 25 | 110 (0–228) | 60–65 Gy | 91% | 92% at 5 y crude | 1 LF at 4 mo | 8% necrosis 43% stenosis | 86% at 5 y |
| Kamsu-Kom et al, 2015 | PDR | 27 | 33 (6–64) | 60–70 | NS | 85% | 88% at 3 y | 9% necrosis 22% stenosis | 85% |
| Petera et al, 2011 | HDR | 10 | 20 | 3 Gy bid = 42–45 | 100% | NS | 100% | 0 necrosis 0 stenosis | 100% |
| Sharm et al, 2014 | HDR | 14 | 22 (6–40) | 3 Gy bid = 51 Gy | 83% at 3 y | NS | 12/14 | 0 necrosis 0 stenosis | 93% |
| Rouscoff et al, 2014 | HDR | 12 | 27 (5–83) | 36/9–39/9 bid | 100% | 83% | 11/12 | 1/12 necrosis 1/12 stenosis | 11/12 |
| Kellas et al, 2015 | HDR | 55 | 55 (8–154) | 3–3.5 bid = 30–54 | NS | NS | 73% | 0 necrosis 0 stenosis | 80% |
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