Curr Probl Cancer ] (2015) ]]]–]]]
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
The role of radiotherapy in the management of penile cancer Juanita Crook, MD
Introduction Just as for squamous cell carcinoma (SCC) in other body sites such as head and neck, cervix, and vulva, radiotherapy plays an important role in the management of SCC of the penis. In localized presentations, curative treatment with the important secondary endpoint of organ preservation can be offered. For localized tumors with a high risk of nodal involvement, management of the primary with radiation can be combined with surgical staging of the lymph nodes. In locoregionally advanced cases, combined radiation and chemotherapy can be used either as definitive treatment or in a preoperative scenario to be followed by surgery when resectability is achieved. The indications for postoperative radiotherapy following a primary surgical approach are the same as for other genital SCC such as vulva: close margins, multiple lymph node involvement, or extracapsular spread. The rarity of this disease in developed nations results in a severe lack of Level 1 evidence on which to base recommendations. Published single-center experience, often spanning decades, and randomized trials from other tumor sites with similar pathology, etiology, and natural history must thus be relied upon to form the basis of such recommendations.
Localized disease The most common malignant pathology diagnosed on the penis is SCC. Similar to SCC in other organ sites,1-3 penile SCC is a radiosensitive tumor. Specialized techniques have been developed to administer radiotherapy safely and effectively to this organ site. Either external beam or brachytherapy can be used, depending on the experience and skill sets of the department. The most common localization on the penis is the glans or prepuce, with the shaft involved much less frequently, usually by direct extension, rarely de novo. All patients should be circumcised prior to the start of radiotherapy. This serves several purposes, including removal of the portion of the cancer involving the prepuce, exposure of the full extent of the lesion in those men with phimosis, and prevents subsequent contraction or painful necrosis of the irradiated foreskin (Fig 1). http://dx.doi.org/10.1016/j.currproblcancer.2015.03.007 0147-0272/& 2015 Published by Elsevier Inc.
2
J. Crook / Curr Probl Cancer ] (2015) ]]]–]]]
Fig. 1. Uncircumcised male with tumor clinically involving both the glans and foreskin. Much of the bulk of tumor will be removed at the time of circumcision, making subsequent radiotherapy technically easier and avoiding posttreatment complications of a fibrotic or necrotic and unretractable foreskin. (Color version of figure is available online.)
External beam As SCC originates on the skin surface, external beam techniques need to be employed that avoid skin sparing and deliver full dose to the skin surface with sufficient penetration to treat the invasive disease, generally full thickness of the penis. This involves encasing the penis in tissueequivalent material that also supports the penis to distance it from nearby uninvolved tissues such as the suprapubic region, and the scrotum. Originally a wax block was used for this purpose, bivalved for easy placement around the penis, with a central cylindrical chamber custom-made to the correct size and shape to house the penis. A wax plug was placed in the open end to ensure full dose to the entire glans. The most common beam arrangement to be used in conjunction with this device is a parallel-opposed pair of beams, originally from a Co-60 unit but in recent years often employing low-energy photons from a linear accelerator such as 6 MV.4 It is not often necessary to treat the entire shaft, provided the setup is consistent and can be verified on a daily basis. Care should be taken to ensure that the clinical target volume includes a 2-cm margin around the clinically evident gross tumor volume. More recently, clear plastic such as Lucite or Plexiglas can be used in place of wax, with a similar applicator design. This material has the advantage of being transparent so that the position of the penis within the block can be checked visually. A series of blocks can be constructed with a range of sizes of the central chamber so that in case of organ edema during treatment, an applicator with a slightly larger central chamber can be chosen without requiring replanning and without any delay or interruption of treatment for modification of the device such as would be required when wax is used. The patient is positioned supine, with the block placed comfortably in the suprapubic region to contain the penis. An alternative technique has been described involving prone positioning with the penis suspended in a water bath. The patient lies on Styrofoam blocks with the water bath positioned between the block for the patient's body and the one for his legs.5 Dose and fractionation schemes are similar to those for SCC in other body sites, generally 6-7 weeks of treatment at 1.8-2 Gy per day for a total dose of 65-70 Gy. The local skin reaction will be evident by the second to third week and take 3-6 weeks to resolve after completion of treatment. Brachytherapy The penis lends itself well to interstitial brachytherapy which has been used successfully for decades, with published literature from Canada, France, India, and the United Kingdom.6-9 Most
J. Crook / Curr Probl Cancer ] (2015) ]]]–]]]
3
of the series employed low-dose-rate (LDR) brachytherapy most frequently using Iridium 192 wires and a classic continuous LDR delivery of 40-75 cGy/h for a total dose of 60 Gy. Pulse dose rate brachytherapy using an afterloading high-activity Iridium 192 source and hourly fractions designed radiobiologically to imitate LDR by delivering 50-60 cGy/h have been employed in some centers with the same total prescribed dose. Tumors that are of clinical stage T1b or T2, less than 4 cm in diameter, and confined to the glans are most suitable for brachytherapy. Many tumors will involve both the glans and prepuce, placing the coronal sulcus at risk following circumcision (Fig 1). Extension to, or slightly beyond, the coronal sulcus is acceptable provided it can be encompassed with a single additional plane of needles. Penile brachytherapy can be performed under either local or general anesthetic and in experienced hands takes 45 minutes to 1 hour. Once anesthesia is achieved, the patient is catheterized with an indwelling Foley catheter that will remain for the duration of treatment. This also helps localize the urethra by palpation during needle placement to avoid transfixing the urethra with 1 of the needles. The important first step is to map out the tumor and desired margin on the penis and then determine the number of needles, their spacing, and the orientation of the planes. Single-plane implants are not recommended owing to uncertainty concerning the depth of penetration of the tumor. Generally, 2-3 parallel planes will be fashioned, with needles bracketing the urethra. Ideal spacing for an LDR implant is 15 mm (range: 12-18 mm). For a detailed discussion of techniques, see Crook et al.10 The needles and planes of needles should be equidistant. Templates designed for the purpose, made of predrilled Lucite, should be available with a range of hole spacing (12-18 mm) in order to fit the clinical scenario. In the case of an asymmetric tumor, or if there is a concern that the most superficial needles may be a little too deep, an external plane can be added, with tissue-equivalent bolus material such as superflab placed between the penis and the external needles (Fig 2). The needles are secured in position with lock nuts on the needle shaft snugly tightened against the template surface. As the entire construct is rigid and geometrically invariable for the duration of the implant, planning can be performed, if desired, without the use of computed tomographic imaging but based on physical measurement of the needle positions, spacing, and desired treated lengths.
Fig. 2. Interstitial implant showing the templates and needles in place. A layer of tissue-equivalent bolus material is seen on the left side of the photograph (patient's right) with an overlying plane of needles, to ensure that full dose is delivered to the skin surface. (Color version of figure is available online.)
J. Crook / Curr Probl Cancer ] (2015) ]]]–]]]
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The usual prescribed dose is 60 Gy in approximately 5 days (50 cGy/h). The patient remains hospitalized during this time. A sponge or Styrofoam collar supports the penis to distance it from surrounding normal tissues. In younger patients, if future fertility is an issue, a thin layer of lead can be added to the supporting collar to reduce testicular dose. During the course of treatment, analgesia should be available as required but in most cases discomfort is surprisingly minimal and pain requirements can be met with acetaminophen with or without additional codeine. Antiembolic stockings and prophylaxis against deep vein thrombosis are recommended. Removal of the implant can take place at the bedside following premedication with a single dose of meperidine or morphine. Bleeding is minimal and the patient can be discharged home the same day with instructions for daily soaks using baking soda and water. Neither prophylactic antibiotics nor prescription analgesia is required. The local reaction will peak in approximately 3 weeks and then resolve over the subsequent 2-3 months. Healing takes longer in patients with diabetes mellitus. The depth of invasion of the tumor can often be well appreciated 3-4 weeks after the procedure when the tumor resolution leaves a shallow crater at the site. In addition to local hygiene, topical Vitamin E, cortisone, or antibiotic ointments may be beneficial. Intercourse can be resumed when the patient is comfortable, generally at least 6 weeks after the procedure, but additional water-based lubricant is recommended to minimize trauma to the healing epithelium. Results for both external beam radiotherapy and brachytherapy are summarized in the Table. Penile preservation rates are higher at 5-10 years with brachytherapy, approximately 70% at 10 years, although these patients are generally more carefully selected to have tumors under 4 cm in maximum diameter, with no or minimal involvement of the shaft. It should be noted that, as with other penile-preserving modalities, long-term follow-up is important as late local recurrences are not uncommon. Crook et al6 reported 5-year local control and penile preservation of 87% and 88%, but decreasing by 10 years to 72% and 67% respectively. There were 8 local failures in 67 patients, 5 of which were before 2 years and the remaining 3 occurred at 4.5, 7 and 8 years following treatment. Similarly, de Crevoisier et al7 reported that 20% of local failures occurred after 8 years. If detected promptly, these late failures tend to be purely local and amenable to successful surgical salvage such that 10-year cause-specific survival is maintained at 84% and 92% in these 2 series.6,7 External beam series often include less-favorable presentations, a fact that contributes to the higher incidence of local recurrence and greater use of salvage penectomy. Nonetheless, penile preservation rates up to 50% at 5 years are reported.19 Table Selected references on LDR brachytherapy, HDR brachytherapy and external beam radiotherapy References
n
Low-dose-rate brachytherapy Chaudhery et al8 23 Crook and Mac6 67 De Crevoisier et al7 144 47 Delaunay et al19 Kiltie et al9 21
Follow-up (mo) Med (range)
Dose (Gy)
Local control
5-y CSS
Penile preservation
21 (4-117) 48 (6-194) 68 (6-348) 80 (13-190) 61.5 (med)
50 60 70 60 60
70 (8 y) 72 (10 y) 80 (10 y) 60% 81%
– 83.6% 92% (10 y) 87.6% 85.4%
70% (8 y) 67% (10 y) 72% (10 y) 60% 60%
100%
100%
100%
12/14
83% (3 y)
93%
55% 41%
66% –
50% 36%
High-dose-rate brachytherapy 10 20 Petera11 Sharma et al12
14
22 (6-40)
51 Gy administered 3 Gy twice daily 42-45 Gy administered 3 Gy twice daily
External beam Sarin20 Zouhair21
59 23
62 (2-269) 12 (5-139)
60/30 45-74 Gy in 25-37#
CSS, Cage Specific Survival. #, fractions.
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Fig. 3. 3D printing can be used to make a custom mold fitted with catheters for delivery of the high-dose-rate (HDR) source. This device would be applied twice per day for 5 days and is used to treat superficial cancers where no more than 5-mm depth of treatment is required. 3D, 3-dimensional. (Photo courtesy of Dr Gerard Morton, Department of Radiation Oncology, Odette Cancer Center, University of Toronto.) (Color version of figure is available online.)
Because of the prevalence today of high-dose-rate (HDR) brachytherapy equipment in radiation departments, there is growing interest in HDR brachytherapy for penile SCC. Published results are limited.11,12 The reported fractionation schemes include 42-51 Gy with twice-daily fractions over 7 to 9 days. Neither series reported any incidence of late toxicity in the form of necrosis. Superficial SCC of the glans can be quite extensive, involving 450% of the surface area of the glans. In these cases, interstitial techniques are not optimal as they necessitate irradiating the full thickness of the glans. Mold applications using LDR sources have been described in the past.13 Recently, 3-dimensional printing has been used to create custom molds used in conjunction with HDR treatment that enables treatment of the entire circumference of the glans to the required depth (eg, 5 mm), sparing the urethra and central erectile tissue (Fig 3). At this time, HDR brachytherapy for penile cancer has to be considered to be in evolution. Fractionation schemes, late toxicity, and efficacy are not yet well established. Toxicity of brachytherapy Penile cosmesis after brachytherapy is generally very good. A pale scar is often visible at the site of the original tumor and may be accompanied by changes in pigmentation (hypo or hyper) and telangiectasia (Fig 4). The 2 most common late effects are meatal stenosis (9%-44%) and nonhealing soft tissue ulceration (0%-23%). The incidence varies with dose, fractionation, and technique. Routine use of a meatal dilator in the healing phase and for a few months beyond can decrease the frequency of meatal stenosis to less than 10%. Soft tissue ulceration is more frequent in larger and more deeply invasive cancers but will usually heal with conservative measures such as attention to hygiene, topical antibiotics, or steroid creams (Fig 5). More severe cases may respond well to a course of hyperbaric oxygen.14 Assessment and management of regional lymph nodes The EORTC Guidelines on penile cancer published by Solsona et al15 provide risk groupings for management of regional nodes. In cases with nonpalpable inguinal nodes, patients with pTis, pTaG1-2, or pT1G1 are at low risk of nodal metastases and surveillance is appropriate. In patients
6
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Fig. 4. Appearance 3 years after High Dose Rate brachytherapy for a 40-year-old man treated with circumcision and local excision for a T1 SCC. Brachytherapy for positive margins. (Color version of figure is available online.)
with intermediate risk factors such as T1G2 or evidence of lymphovascular invasion, surgical staging using either dynamic sentinel node biopsy or a modified lymphadenectomy is recommended. Patients at high risk of nodal spread are considered to be those with G3 tumors or ZT2 and require surgical staging of the inguinal lymph nodes. As nodal status is such an important prognostic factor, surgical staging is preferred over primary radiotherapy to the nodal regions in those patients at high risk but with unknown nodal status. The requirement for surgical staging does not preclude the use of organ-sparing radiotherapy in management of the primary tumor. Locoregionally advanced Clinically, node-positive cases will often be managed surgically if the patient's general condition permits and the disease is resectable. If the patient is not well enough or refuses
Fig. 5. (A) Deep ulceration 8 months following brachytherapy in a 49-year-old male treated for a T3 cancer. (B) Treated successfully with hyperbaric oxygen. Appearance at 7-year follow-up. Potency retained. (Color version of figure is available online.)
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surgery, definitive radiation to the primary and nodes should be undertaken. In these cases the status of the pelvic nodes may well be uncertain and they should thus be included in the clinical target volume to a dose of 4500 cGy if imaging is negative. Positron emission tomography/ computed tomography (PET-CT) can be very useful for identification of involved nodes, as it is in SCC of the cervix, and a boost to involved nodes can be delivered to a dose appropriate for the volume of disease. The same considerations are important regarding the technical aspects of irradiation of the primary tumor as for external beam for localized disease. The possibility of intransit metastases between the primary and the groins should not be ignored or forgotten. The addition of radiosensitizing chemotherapy, such as weekly cisplatinum as per the standard of care for cervical cancer, should be considered.1 In situations where the patient is well enough for surgery but the tumor is unresectable, preoperative chemoradiation may permit subsequent surgery. A dose of at least 4500 cGy is required to obtain sufficient response; higher doses than this may be associated with increased perioperative morbidity. Although the only neoadjuvant trials performed for penile cancer have involved neoadjuvant chemotherapy alone without radiation,16 there is ample evidence from other tumor sites where chemoradiation has become the standard of care for SCC, as either neoadjuvant or definitive treatment, that the combination is better.21,3 Weekly cisplatinum as per a cervical or vulvar carcinoma regimen is well tolerated in conjunction with radiotherapy at 1.8 Gy per day for 5 weeks to a prescribed dose of 45 Gy. If a definitive approach is intended then sites of gross disease can be boosted to an appropriate dose. Postoperative Following surgical management of the primary and nodes, postoperative radiotherapy is indicated to the primary site for close margins, and to the regional nodes when there is multiple nodal involvement or extracapsular nodal spread, such as is the standard of care in vulvar cancer.17 In a review of the SEER database of 490 women with node-positive vulvar cancer, a 5-year disease-specific survival advantage was found for postoperative radiotherapy for women with a single positive node who had a less extensive node resection with fewer than 12 lymph nodes removed.18 If the inguinal nodes are involved and the pelvic nodes have not been surgically staged, then the treated volume should include at least the pelvic nodes ipsilateral to the involved groin. For microscopic disease, 4500 cGy/25 fractions over 5 weeks is an adequate dose. In the case of extracapsular disease in the groin, an additional local boost to a total dose of 50.4 Gy up to 54.8 Gy may be indicated. If the pelvic nodes are known to be negative, treatment can be limited to the involved groin and delivered with an appropriate energy of electrons. Palliative A short course of palliative radiotherapy is indicated for painful metastases using a fractionation scheme of 20 Gy/5 fractions over 1 week or 30 Gy/10 fractions in 2 weeks. A short course is unlikely to have much effect on advanced locoregional disease. If the patient's general condition permits, a more prolonged fractionation, especially with the addition of radiosensitizing chemotherapy such as low dose weekly cisplatinum will produce longer lasting benefit.
Conclusion SCC of the penis is a radiosensitive and radiocurable malignancy. Radiotherapy in the form of either external beam radiation or brachytherapy is an organ-sparing approach that can be applied exclusively or in conjunction with surgical node staging as required. For locoregionally advanced disease, the combination of chemotherapy and radiation is effective as either definitive or preoperative management. Postoperatively, adjuvant radiotherapy to the groins or pelvis is indicated in cases with multiple involved nodes or extracapsular spread.
8
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References 1. Viswanathan AN, Beriwal S, De Los Santos JF, et al. American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy. Brachytherapy 2012;11(1):47–52. 2. Expert Panel on Radiation Oncology-Gynecology, Kidd E, Moore D, et al. ACR Appropriateness Criterias management of locoregionally advanced squamous cell carcinoma of the vulva. Am J Clin Oncol 2013;36(4):415–422. 3. NCCN guideline version 2.2014 head and neck cancer. http://www.nccn.org/professionals/physician_gls/PDF/ head-and-neck.pdf. 4. McLean M, Akl AM, Warde P, Bissett R, Panzarella T, Gospodarowicz M. The results of primary radiation therapy in the management of squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 1993;25(4):623–628. 5. Vujovic Olga, Grant John B, Davis Stewart. Carcinoma of the penis: a treatment technique with external beam radiation. Ann RCPSC 2001;34(8):495–497. 6. Crook J, Ma C, Grimard L. Radiation therapy in the management of the primary penile tumor: an update. World J Urol 2009;27(2):189. 7. de Crevoisier R, Slimane K, Sanfilippo N, et al. Long-term results of brachytherapy for carcinoma of the penis confined to the glans (N- or NX). Int J Radiat Oncol Biol Phys 2009;74(4):1150–1156. 8. Chaudhary AJ, Ghosh S, Bhalavat RL, Kulkarni JN, Sequeira BV. Interstitial brachytherapy in carcinoma of the penis. Strahlenther Onkol 1999;175(1):17–20. 9. Kiltie AE, Elwell C, Close HJ, Ash DV. Iridium-192 implantation for node-negative carcinoma of the penis: the Cookridge Hospital experience. Clin Oncol (R Coll Radiol) 2000;12(1):25–31. 10. Crook J, Jezioranski J, Cygler JE. Penile brachytherapy: technical aspects and postimplant issues. Brachytherapy 2010; 9(2):151–158. 11. Petera J, Sirak I, Kasaova L, et al. High-dose rate brachytherapy in the treatment of penile carcinoma—first experience. Brachytherapy 2011;10(2):136–140. 12. Sharma DN, Joshi NP, Gandhi AK, et al. High-dose-rate interstitial brachytherapy for T1-T2-stage penile carcinoma: short-term results. Brachytherapy 2014;13(5):481–487. 13. Neave F, Neal AJ, Hoskin PJ, Hope-Stone HF. Carcinoma of the penis: a retrospective review of treatment with iridium mould and external beam irradiation. Clin Oncol (R Coll Radiol) 1993;5(4):207–210. 14. Gomez-Iturriaga A, Crook J, Evans W, Saibishkumar EP, Jezioranski J. The efficacy of hyperbaric oxygen therapy in the treatment of medically refractory soft tissue necrosis after penile brachytherapy. Brachytherapy 2011;10(6):491–497. 15. Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T, European Association of Urology. EAU guidelines on penile cancer. Eur Urol 2004;46(1):1–8. 16. Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol 2010;28(2):3851–3857. 17. de Hullu JA, van der Zee AG. Surgery and radiotherapy in vulvar cancer. Crit Rev Oncol Hematol 2006;60(1):38–58. 18. Parthasarathy A, Cheung MK, Osann K, et al. The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma. Gynecol Oncol 2006;103(3):1095–1099. 19. Delaunay B, Soh PN, Delannes M, et al. Brachytherapy for penile cancer: efficacy and impact on sexual function. Brachytherapy 2013;4:380–387. 20. Sarin R, Norman AR, Steel GG, Horwich A. Treatment results and prognostic factors in 101 men treated for squamous carcinoma of the penis. Int J Radiat Oncol Biol Phys 1997;38:713–722. 21. Zouhair A, Coucke PA, Jeanneret W, et al. Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis? Eur J Cancer 2001;37(2):198–203.
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
The role of radiotherapy in the management of penile cancer Juanita Crook, MD
Introduction Just as for squamous cell carcinoma (SCC) in other body sites such as head and neck, cervix, and vulva, radiotherapy plays an important role in the management of SCC of the penis. In localized presentations, curative treatment with the important secondary endpoint of organ preservation can be offered. For localized tumors with a high risk of nodal involvement, management of the primary with radiation can be combined with surgical staging of the lymph nodes. In locoregionally advanced cases, combined radiation and chemotherapy can be used either as definitive treatment or in a preoperative scenario to be followed by surgery when resectability is achieved. The indications for postoperative radiotherapy following a primary surgical approach are the same as for other genital SCC such as vulva: close margins, multiple lymph node involvement, or extracapsular spread. The rarity of this disease in developed nations results in a severe lack of Level 1 evidence on which to base recommendations. Published single-center experience, often spanning decades, and randomized trials from other tumor sites with similar pathology, etiology, and natural history must thus be relied upon to form the basis of such recommendations.
Localized disease The most common malignant pathology diagnosed on the penis is SCC. Similar to SCC in other organ sites,1-3 penile SCC is a radiosensitive tumor. Specialized techniques have been developed to administer radiotherapy safely and effectively to this organ site. Either external beam or brachytherapy can be used, depending on the experience and skill sets of the department. The most common localization on the penis is the glans or prepuce, with the shaft involved much less frequently, usually by direct extension, rarely de novo. All patients should be circumcised prior to the start of radiotherapy. This serves several purposes, including removal of the portion of the cancer involving the prepuce, exposure of the full extent of the lesion in those men with phimosis, and prevents subsequent contraction or painful necrosis of the irradiated foreskin (Fig 1). http://dx.doi.org/10.1016/j.currproblcancer.2015.03.007 0147-0272/& 2015 Published by Elsevier Inc.
2
J. Crook / Curr Probl Cancer ] (2015) ]]]–]]]
Fig. 1. Uncircumcised male with tumor clinically involving both the glans and foreskin. Much of the bulk of tumor will be removed at the time of circumcision, making subsequent radiotherapy technically easier and avoiding posttreatment complications of a fibrotic or necrotic and unretractable foreskin. (Color version of figure is available online.)
External beam As SCC originates on the skin surface, external beam techniques need to be employed that avoid skin sparing and deliver full dose to the skin surface with sufficient penetration to treat the invasive disease, generally full thickness of the penis. This involves encasing the penis in tissueequivalent material that also supports the penis to distance it from nearby uninvolved tissues such as the suprapubic region, and the scrotum. Originally a wax block was used for this purpose, bivalved for easy placement around the penis, with a central cylindrical chamber custom-made to the correct size and shape to house the penis. A wax plug was placed in the open end to ensure full dose to the entire glans. The most common beam arrangement to be used in conjunction with this device is a parallel-opposed pair of beams, originally from a Co-60 unit but in recent years often employing low-energy photons from a linear accelerator such as 6 MV.4 It is not often necessary to treat the entire shaft, provided the setup is consistent and can be verified on a daily basis. Care should be taken to ensure that the clinical target volume includes a 2-cm margin around the clinically evident gross tumor volume. More recently, clear plastic such as Lucite or Plexiglas can be used in place of wax, with a similar applicator design. This material has the advantage of being transparent so that the position of the penis within the block can be checked visually. A series of blocks can be constructed with a range of sizes of the central chamber so that in case of organ edema during treatment, an applicator with a slightly larger central chamber can be chosen without requiring replanning and without any delay or interruption of treatment for modification of the device such as would be required when wax is used. The patient is positioned supine, with the block placed comfortably in the suprapubic region to contain the penis. An alternative technique has been described involving prone positioning with the penis suspended in a water bath. The patient lies on Styrofoam blocks with the water bath positioned between the block for the patient's body and the one for his legs.5 Dose and fractionation schemes are similar to those for SCC in other body sites, generally 6-7 weeks of treatment at 1.8-2 Gy per day for a total dose of 65-70 Gy. The local skin reaction will be evident by the second to third week and take 3-6 weeks to resolve after completion of treatment. Brachytherapy The penis lends itself well to interstitial brachytherapy which has been used successfully for decades, with published literature from Canada, France, India, and the United Kingdom.6-9 Most
J. Crook / Curr Probl Cancer ] (2015) ]]]–]]]
3
of the series employed low-dose-rate (LDR) brachytherapy most frequently using Iridium 192 wires and a classic continuous LDR delivery of 40-75 cGy/h for a total dose of 60 Gy. Pulse dose rate brachytherapy using an afterloading high-activity Iridium 192 source and hourly fractions designed radiobiologically to imitate LDR by delivering 50-60 cGy/h have been employed in some centers with the same total prescribed dose. Tumors that are of clinical stage T1b or T2, less than 4 cm in diameter, and confined to the glans are most suitable for brachytherapy. Many tumors will involve both the glans and prepuce, placing the coronal sulcus at risk following circumcision (Fig 1). Extension to, or slightly beyond, the coronal sulcus is acceptable provided it can be encompassed with a single additional plane of needles. Penile brachytherapy can be performed under either local or general anesthetic and in experienced hands takes 45 minutes to 1 hour. Once anesthesia is achieved, the patient is catheterized with an indwelling Foley catheter that will remain for the duration of treatment. This also helps localize the urethra by palpation during needle placement to avoid transfixing the urethra with 1 of the needles. The important first step is to map out the tumor and desired margin on the penis and then determine the number of needles, their spacing, and the orientation of the planes. Single-plane implants are not recommended owing to uncertainty concerning the depth of penetration of the tumor. Generally, 2-3 parallel planes will be fashioned, with needles bracketing the urethra. Ideal spacing for an LDR implant is 15 mm (range: 12-18 mm). For a detailed discussion of techniques, see Crook et al.10 The needles and planes of needles should be equidistant. Templates designed for the purpose, made of predrilled Lucite, should be available with a range of hole spacing (12-18 mm) in order to fit the clinical scenario. In the case of an asymmetric tumor, or if there is a concern that the most superficial needles may be a little too deep, an external plane can be added, with tissue-equivalent bolus material such as superflab placed between the penis and the external needles (Fig 2). The needles are secured in position with lock nuts on the needle shaft snugly tightened against the template surface. As the entire construct is rigid and geometrically invariable for the duration of the implant, planning can be performed, if desired, without the use of computed tomographic imaging but based on physical measurement of the needle positions, spacing, and desired treated lengths.
Fig. 2. Interstitial implant showing the templates and needles in place. A layer of tissue-equivalent bolus material is seen on the left side of the photograph (patient's right) with an overlying plane of needles, to ensure that full dose is delivered to the skin surface. (Color version of figure is available online.)
J. Crook / Curr Probl Cancer ] (2015) ]]]–]]]
4
The usual prescribed dose is 60 Gy in approximately 5 days (50 cGy/h). The patient remains hospitalized during this time. A sponge or Styrofoam collar supports the penis to distance it from surrounding normal tissues. In younger patients, if future fertility is an issue, a thin layer of lead can be added to the supporting collar to reduce testicular dose. During the course of treatment, analgesia should be available as required but in most cases discomfort is surprisingly minimal and pain requirements can be met with acetaminophen with or without additional codeine. Antiembolic stockings and prophylaxis against deep vein thrombosis are recommended. Removal of the implant can take place at the bedside following premedication with a single dose of meperidine or morphine. Bleeding is minimal and the patient can be discharged home the same day with instructions for daily soaks using baking soda and water. Neither prophylactic antibiotics nor prescription analgesia is required. The local reaction will peak in approximately 3 weeks and then resolve over the subsequent 2-3 months. Healing takes longer in patients with diabetes mellitus. The depth of invasion of the tumor can often be well appreciated 3-4 weeks after the procedure when the tumor resolution leaves a shallow crater at the site. In addition to local hygiene, topical Vitamin E, cortisone, or antibiotic ointments may be beneficial. Intercourse can be resumed when the patient is comfortable, generally at least 6 weeks after the procedure, but additional water-based lubricant is recommended to minimize trauma to the healing epithelium. Results for both external beam radiotherapy and brachytherapy are summarized in the Table. Penile preservation rates are higher at 5-10 years with brachytherapy, approximately 70% at 10 years, although these patients are generally more carefully selected to have tumors under 4 cm in maximum diameter, with no or minimal involvement of the shaft. It should be noted that, as with other penile-preserving modalities, long-term follow-up is important as late local recurrences are not uncommon. Crook et al6 reported 5-year local control and penile preservation of 87% and 88%, but decreasing by 10 years to 72% and 67% respectively. There were 8 local failures in 67 patients, 5 of which were before 2 years and the remaining 3 occurred at 4.5, 7 and 8 years following treatment. Similarly, de Crevoisier et al7 reported that 20% of local failures occurred after 8 years. If detected promptly, these late failures tend to be purely local and amenable to successful surgical salvage such that 10-year cause-specific survival is maintained at 84% and 92% in these 2 series.6,7 External beam series often include less-favorable presentations, a fact that contributes to the higher incidence of local recurrence and greater use of salvage penectomy. Nonetheless, penile preservation rates up to 50% at 5 years are reported.19 Table Selected references on LDR brachytherapy, HDR brachytherapy and external beam radiotherapy References
n
Low-dose-rate brachytherapy Chaudhery et al8 23 Crook and Mac6 67 De Crevoisier et al7 144 47 Delaunay et al19 Kiltie et al9 21
Follow-up (mo) Med (range)
Dose (Gy)
Local control
5-y CSS
Penile preservation
21 (4-117) 48 (6-194) 68 (6-348) 80 (13-190) 61.5 (med)
50 60 70 60 60
70 (8 y) 72 (10 y) 80 (10 y) 60% 81%
– 83.6% 92% (10 y) 87.6% 85.4%
70% (8 y) 67% (10 y) 72% (10 y) 60% 60%
100%
100%
100%
12/14
83% (3 y)
93%
55% 41%
66% –
50% 36%
High-dose-rate brachytherapy 10 20 Petera11 Sharma et al12
14
22 (6-40)
51 Gy administered 3 Gy twice daily 42-45 Gy administered 3 Gy twice daily
External beam Sarin20 Zouhair21
59 23
62 (2-269) 12 (5-139)
60/30 45-74 Gy in 25-37#
CSS, Cage Specific Survival. #, fractions.
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Fig. 3. 3D printing can be used to make a custom mold fitted with catheters for delivery of the high-dose-rate (HDR) source. This device would be applied twice per day for 5 days and is used to treat superficial cancers where no more than 5-mm depth of treatment is required. 3D, 3-dimensional. (Photo courtesy of Dr Gerard Morton, Department of Radiation Oncology, Odette Cancer Center, University of Toronto.) (Color version of figure is available online.)
Because of the prevalence today of high-dose-rate (HDR) brachytherapy equipment in radiation departments, there is growing interest in HDR brachytherapy for penile SCC. Published results are limited.11,12 The reported fractionation schemes include 42-51 Gy with twice-daily fractions over 7 to 9 days. Neither series reported any incidence of late toxicity in the form of necrosis. Superficial SCC of the glans can be quite extensive, involving 450% of the surface area of the glans. In these cases, interstitial techniques are not optimal as they necessitate irradiating the full thickness of the glans. Mold applications using LDR sources have been described in the past.13 Recently, 3-dimensional printing has been used to create custom molds used in conjunction with HDR treatment that enables treatment of the entire circumference of the glans to the required depth (eg, 5 mm), sparing the urethra and central erectile tissue (Fig 3). At this time, HDR brachytherapy for penile cancer has to be considered to be in evolution. Fractionation schemes, late toxicity, and efficacy are not yet well established. Toxicity of brachytherapy Penile cosmesis after brachytherapy is generally very good. A pale scar is often visible at the site of the original tumor and may be accompanied by changes in pigmentation (hypo or hyper) and telangiectasia (Fig 4). The 2 most common late effects are meatal stenosis (9%-44%) and nonhealing soft tissue ulceration (0%-23%). The incidence varies with dose, fractionation, and technique. Routine use of a meatal dilator in the healing phase and for a few months beyond can decrease the frequency of meatal stenosis to less than 10%. Soft tissue ulceration is more frequent in larger and more deeply invasive cancers but will usually heal with conservative measures such as attention to hygiene, topical antibiotics, or steroid creams (Fig 5). More severe cases may respond well to a course of hyperbaric oxygen.14 Assessment and management of regional lymph nodes The EORTC Guidelines on penile cancer published by Solsona et al15 provide risk groupings for management of regional nodes. In cases with nonpalpable inguinal nodes, patients with pTis, pTaG1-2, or pT1G1 are at low risk of nodal metastases and surveillance is appropriate. In patients
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Fig. 4. Appearance 3 years after High Dose Rate brachytherapy for a 40-year-old man treated with circumcision and local excision for a T1 SCC. Brachytherapy for positive margins. (Color version of figure is available online.)
with intermediate risk factors such as T1G2 or evidence of lymphovascular invasion, surgical staging using either dynamic sentinel node biopsy or a modified lymphadenectomy is recommended. Patients at high risk of nodal spread are considered to be those with G3 tumors or ZT2 and require surgical staging of the inguinal lymph nodes. As nodal status is such an important prognostic factor, surgical staging is preferred over primary radiotherapy to the nodal regions in those patients at high risk but with unknown nodal status. The requirement for surgical staging does not preclude the use of organ-sparing radiotherapy in management of the primary tumor. Locoregionally advanced Clinically, node-positive cases will often be managed surgically if the patient's general condition permits and the disease is resectable. If the patient is not well enough or refuses
Fig. 5. (A) Deep ulceration 8 months following brachytherapy in a 49-year-old male treated for a T3 cancer. (B) Treated successfully with hyperbaric oxygen. Appearance at 7-year follow-up. Potency retained. (Color version of figure is available online.)
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surgery, definitive radiation to the primary and nodes should be undertaken. In these cases the status of the pelvic nodes may well be uncertain and they should thus be included in the clinical target volume to a dose of 4500 cGy if imaging is negative. Positron emission tomography/ computed tomography (PET-CT) can be very useful for identification of involved nodes, as it is in SCC of the cervix, and a boost to involved nodes can be delivered to a dose appropriate for the volume of disease. The same considerations are important regarding the technical aspects of irradiation of the primary tumor as for external beam for localized disease. The possibility of intransit metastases between the primary and the groins should not be ignored or forgotten. The addition of radiosensitizing chemotherapy, such as weekly cisplatinum as per the standard of care for cervical cancer, should be considered.1 In situations where the patient is well enough for surgery but the tumor is unresectable, preoperative chemoradiation may permit subsequent surgery. A dose of at least 4500 cGy is required to obtain sufficient response; higher doses than this may be associated with increased perioperative morbidity. Although the only neoadjuvant trials performed for penile cancer have involved neoadjuvant chemotherapy alone without radiation,16 there is ample evidence from other tumor sites where chemoradiation has become the standard of care for SCC, as either neoadjuvant or definitive treatment, that the combination is better.21,3 Weekly cisplatinum as per a cervical or vulvar carcinoma regimen is well tolerated in conjunction with radiotherapy at 1.8 Gy per day for 5 weeks to a prescribed dose of 45 Gy. If a definitive approach is intended then sites of gross disease can be boosted to an appropriate dose. Postoperative Following surgical management of the primary and nodes, postoperative radiotherapy is indicated to the primary site for close margins, and to the regional nodes when there is multiple nodal involvement or extracapsular nodal spread, such as is the standard of care in vulvar cancer.17 In a review of the SEER database of 490 women with node-positive vulvar cancer, a 5-year disease-specific survival advantage was found for postoperative radiotherapy for women with a single positive node who had a less extensive node resection with fewer than 12 lymph nodes removed.18 If the inguinal nodes are involved and the pelvic nodes have not been surgically staged, then the treated volume should include at least the pelvic nodes ipsilateral to the involved groin. For microscopic disease, 4500 cGy/25 fractions over 5 weeks is an adequate dose. In the case of extracapsular disease in the groin, an additional local boost to a total dose of 50.4 Gy up to 54.8 Gy may be indicated. If the pelvic nodes are known to be negative, treatment can be limited to the involved groin and delivered with an appropriate energy of electrons. Palliative A short course of palliative radiotherapy is indicated for painful metastases using a fractionation scheme of 20 Gy/5 fractions over 1 week or 30 Gy/10 fractions in 2 weeks. A short course is unlikely to have much effect on advanced locoregional disease. If the patient's general condition permits, a more prolonged fractionation, especially with the addition of radiosensitizing chemotherapy such as low dose weekly cisplatinum will produce longer lasting benefit.
Conclusion SCC of the penis is a radiosensitive and radiocurable malignancy. Radiotherapy in the form of either external beam radiation or brachytherapy is an organ-sparing approach that can be applied exclusively or in conjunction with surgical node staging as required. For locoregionally advanced disease, the combination of chemotherapy and radiation is effective as either definitive or preoperative management. Postoperatively, adjuvant radiotherapy to the groins or pelvis is indicated in cases with multiple involved nodes or extracapsular spread.
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