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| Updates in the use of radiotherapy in the management of primary and locally-advanced penile cancer |
Akshar Patela,Arash O. Naghavib,Peter A. Johnstoneb,Philippe E. Spiessc,G. Daniel Grassb,*( )
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aUniversity of South Florida Morsani College of Medicine, Tampa, FL, USA
bDepartment of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
cDepartment of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA |
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Abstract Objective: Penile cancer is a rare malignancy in most developed countries, but may represent a significant oncologic challenge in certain African, Asian, and South American regions. Various treatment approaches have been described in penile cancer, including radiotherapy. This review aimed to provide a synopsis of radiotherapy use in penile cancer management and the associated toxicities. In addition, we aimed to discuss palliative radiation for metastases to the penis and provide a brief overview of how tumor biology may assist with treatment decision-making. Methods: Peer-reviewed manuscripts related to the treatment of penile cancer with radiotherapy were evaluated by a PubMed search (1960-2021) in order to assess its role in the definitive and adjuvant settings. Selected manuscripts were also evaluated for descriptions of radiation-related toxicity. Results: Though surgical resection of the primary is an excellent option for tumor control, select patients may be treated with organ-sparing radiotherapy by either external beam radiation or brachytherapy. Data from randomized controlled trials comparing radiotherapy and surgery are lacking, and thus management is frequently determined by institutional practice patterns and available expertise. Similarly, this lack of clinical trial data leads to divergence in opinion regarding lymph node management. This is further complicated in that many cited studies evaluating lymph node radiotherapy used non-modern radiotherapy delivery techniques. Groin toxicity from either surgery or radiotherapy remains a challenging problem and further risk assessment is needed to guide intensification with multi-modal therapy. Intrinsic differences in tumor biology, based on human papillomavirus infection, may help aid future prognostic and predictive models in patient risk stratification or treatment approach. Conclusion: Penile cancer is a rare disease with limited clinical trial data driving the majority of treatment decisions. As a result, the goal of management is to effectively treat the disease while balancing the importance of quality of life through integrated multidisciplinary discussions. More international collaborations and interrogations of penile cancer biology are needed to better understand this disease and improve patient outcomes.
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Received: 12 November 2021
Available online: 20 October 2022
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Corresponding Authors:
G. Daniel Grass
E-mail: daniel.grass@moffitt.org
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| Study | Pts, n | RT dose, Gy | Median follow-up, month | 5-year LC, % | 5-year CSS, % | 5-year penile preservation, % | Stenosis or necrosis rate | Tumor characteristic | Tumor location | | McLean et al., 1993 [22] | 26 | 35 Gy/10 fx;
60 Gy/25 fx | 116 | 61 | 69 | 66 | ?
NR (seven Pts with late complications) | ?
73.1% T1; 15.3% T2; 7.7% T3; 3.9% T4 | ?
65% glans or prepuce; 4% shaft; 31% multiple sites | | Sarin et al., 1997 [29] | 59 | 60 Gy/30 fx | 62 | 55 | 66 | 50 | ?
3% necrosis; 14% stenosis | ?
86.4% T1; 8.5% T2; 1.7% T3; 3.4% T4 | ?
In 101 Pts, 78% were confined to glans; only 59 received EBRT | | Gotsadze et al., 2000 [25] | 155 | 40-60 Gy | 40 | 65 | 86 | 65 | ?
1% necrosis; 7% stenosis | ?
36.8% T1; 55.5% T2; 7.7% T3; | ?
NR | | Zouhair et al., 2001 [27] | 23 | 45-74 Gy/25-37 fx | 12 | 41 | NR | 36 | ?
10% stenosis | ?
29% T1; 59% T2; 10% T3; 2% Tx | ?
In 41 Pts: 41% glans; 22% prepuce; 20% shaft; 10% corona; 5% prepuce or glans; 2% prepuce or shaft | | Azrif et al., 2006 [24] | 41 | 50.0-52.5 Gy/16 fx | 41 | 62 | 96 | 62 | ?
8% necrosis; 29% stenosis | ?
90.2% T1; 9.8% T2 | ?
98% glans/prepuce | | Ozsahin et al., 2006 [23] | 21 | 52 Gy | 62 | 49 | NR | 52 | ?
10% stenosis | ?
37% T1; 53% T2; 8% T3; 2% Tx | ?
In 60 Pts: 40% glans; 26% prepuce; 22% shaft; 7% corona;
3% prepuce/glans; 1% prepuce/shaft | | Mistry et al., 2007 [26] | 18 | 55 Gy/16 fx?50 Gy/20fx | 62 | 63 | NR | 62 | ? 10% necrosis;
5% stenosis | ?
23.5% Tx; 17.6% in situ; 35.3% T1; 17.6% T2; 6% T3 | ?
In 65 Pts: 76% were on glans/prepuce; 5% on shaft |
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Use of EBRT in definitive management of primary penile squamous cell carcinoma.
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| Study | Brachytherapy type | Patient, n | RT dose, median (range), Gy | Follow-up, median (range), month | 5-year LC, % | 5-year CSS, % | 5-year penile preservation, % | Stenosis or necrosis rate | Tumor characteristic | | Crook et al., 2005 [38] | Pulsed dose rate | 49 | 60 (NR) | 33.4 (4.0-140.0) | 85.3 | 90 | 86.5 | ?
16% necrosis; 12% stenosis | ?
51% T1; 33% T2; 8% T3; 4% Tx; 4% in situ | | Crook et al., 2009 [28] | Pulsed dose rate/low dose rate | 67 | 60 | 48.0 (2.4-194.4) | 87.3 | 83.6 | 88.0 | ?
16% necrosis; 12% stenosis | ?
56% T1; 33% T2; 8% T3; 3% Tx | | de Crevoisier et al., 2009 [41] | Low dose rate | 144 | 65 (37-75) | 68.4 (6.0-348.0) | 80.0 (at 10 years) | 92.0 (at 10 years) | 7.0 (at 10 years) | ?
26% necrosis; 29% stenosis | ?
Confined to glans, N0 | | Pimenta et al., 2015 [42] | Low dose rate | 25 | 60 (50-65) | 110.4 (0.0-228.0) | NR | 91.3 (at 5 years and 10 years) | 86.1 | ?
0% necrosis; 43% stenosis | ?
T1-T2 | | Cordoba et al., 2016 [40] | Low dose rate | 73 | 60 (40-70) | 51.0 (33.4-68.7) | NR | 91.4 | 87.6 | ?
6.8% necrosis; 6.6% stenosis | ?
91.8% of lesions on glans | ?
75.3% T1 lesions; 15% T2; 1.3% Tx | | Kellas-Sleczka et al., 2019 [44] | High dose rate | 76 | 28?54.8a (median EQD2);47.4?55.1b (median EQD2) | 76.0 (7.0-204.0) | 65.6 | 85.0 | 69.5 | ?
2.6% necrosis; 1.3% stenosis | ?
11.8% in situ; 46.1% T1; 21.1% T2; 9.2% T3; 11.8% Tx | | Martz et al., 2021 [10] | High dose rate | 29 | 36 (31-39) | 72.4 (3-174) | 82.0 | 88.0 | 79.3 | ?
10.3% necrosis; 17% telangiectasia | ?
T1-T2, N0-N2, M0 |
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Use of brachytherapy in management of primary penile squamous cell carcinoma.
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High dose rate interstitial penile brachytherapy. (A) Example of a mobile hybrid implantation with interstitial catheters, bolus with external catheters to supplement superficial dose and aid in homogeneity, along with a foley in place during the duration of the implant; (B-D) Treatment planning of a bilateral glans tumor. (B) Axial; (C) Sagittal; (D) Coronal. Note the catheter spacing and dosing, limiting the V150 (blue) and V200 (green) volume to mitigate stenosis/necrosis risk. Note the catheter spacing from the urethra/meatus and supplementing dose from outside of the bolus, allowing a homogenous plan and limiting urethral toxicity. Note the supplemental dose from outside the template contributing to the target volume.
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| Study | Treatment years | Patient, n | LND, n | EBRT, n | Age, median (IQR), year | Median follow-up, month | Chemotherapy, n or % | Adjuvant EBRT target | | Demkow, 1999 [75] | 1989-1994 | 64 | 35 | 12 | 64 (21-86) | 33.0 | NACT: 2;
CCRT: 3 | NR | | Zouhair et al., 2001 [27] | 1962-1994 | 41 | 5 | 14 | 59 (35-75) | 70.0 | No | ILN | | Chen et al., 2004 [108] | 1989-2000 | 45 | 19 | 9 | 64 (29-87) | 37.0 | CT: 1 | Primary/bilateral ILN and lower iliac LN | | Langsenlehner et al., 2008 [52] | 1987-2006 | 24 | 8 | Penis/surgical stump (n=14); ILN (n=8) | 62.7 (35.5-90.4) | 58.4 | No | Penis/stump/ILN & iliac nodes | | Franks et al., 2011 [77] | 2002-2008 | 23 | 14 | 14 | 58 (40-81) | 27.0 | No | Bilateral ILN and PLN | | Graafland et al., 2011 [73] | 1988-2007 | 161 | 161 | 67 | 64 (33-91) | 60.0 | NACT: 4 | Ipsilateral ILN ± PLN | | Tang et al., 2017 [84] | 1980-2013 | 92 | 92 | 40 | 65.3 (53-70) | 9.3 | Perioperative CT: 27 | Bilateral PLN | | Winters et al., 2018 [68] | 1998-2012 | 589 | 589 | 136 | 61.8 (NR) | NR | Perioperative CT: 169 | ILN + PLN | | Johnstone et al., 2019 [85] | Multi-institutional (NR) | 93 | 93 | 58 | 65.3 (36-90) | 9.4 | Perioperative CT: 46 | ILN ± PLN (ipsilateral if involved) | | Ager et al., 2021 [87] | 2002-2017 | 146 | 146 | 121 | 59 (54-70) | 10.6 | CCRT: 41% | Ipsilateral ILN ± pelvic LN | | Choo et al., 2020 [89] | 1995-2015 | 23 | 23 | 11 | 57 (43-68) | 15.8 | CCRT: 11 | Bilateral ILN & PLN | | Li et al., 2021 [91] | 2003-2015 | 93 | 93 | 32 | 49 (NR) | 8.8 | CCRT: 34% | NR | | Jaipuria et al., 2020 [90] | 2011-2017 | 45 | 45 | 31 | 56 (45-67) | 12.5 | CCRT: 6 | Bilateral ILN and PLN + suprapubic region | | Yuan et al., 2020 [123] | 1999-2016 | 51 | 47 | 19 | 61 (37-91) | 36.6 | CCRT: 17;
CT alone: 20 | PLN (n=15);
ILN (n=13) | | Mittal et al., 2021 [78] | 2014-2017 | 14 | 14 | 14 | NR | 24.0 | CT: 14 | Bilateral ILN ± PLN | | Khurud et al., 2022 [88] | 2010-2018 | 128 | 128 | 78 | 57 (50-65) | 22.0 | CT alone: 19%;
CCRT: 13%;
CT into EBRT: 24%;
CT into CCRT: 12% | Variable: involved ILN and PLN (68%); involved & uninvolved ILN + PLN (32%) | | Demkow, 1999 [75] | ≥2 ILNs or ENE | NR | NR | NR | NR (3-yr: 76%) | NR | NR | LR: 11% (entire cohort) | | Zouhair et al., 2001 [27] | (+) surgical margins or lymph node involvement | Parallel opposed AP/PA fields (18 MV); e-field boost for positive nodes | 36-66 Gy/20-36 fx | NR | 57% | 48% | NR | pN2: 7%; pN3: 1% | | Chen et al., 2004 [108] | pN+ | Parallel opposed AP/PA field | 40-70 Gy/20-35 fx | NR | 54.30% | NR (3-yr: 89% [AIRT group]) | Grade 3 lymphedema: 22% (AIRT); radionecrosis of inguinal region: 11% (AIRT group) | pN+ (n=17) | | Langsenlehner et al., 2008 [52] | (+) surgical margins and pN+ | Parallel opposed AP/PA fields; e-field boost for positive nodes | 45-60 Gy/25-60 fx | 84.30% | 56.60% | 100% with AIRT | 10% with persistent lymphedema | Of 12 patients with cN+, definitive EBRT to ILN resulted in 5-yr regional control of 92% | | Franks et al., 2011 [77] | pN2/3 or ENE | Parallel opposed AP/PA fields; e-field boost for positive nodes | Phase I: 45 Gy/20 fx;Phase II: 12 Gy/5 fx (boost if needed) | NR | NR (3-yr: 66%) | NR (3-yr: 56%) | Scrotal/penile/lower leg lymphedema: 6 | Locoregional relapse-free survival: 56% | | Graafland et al., 2011 [73] | ≥2 ILNs or ENE | NR | 50 Gy/25 fx | NR | NR | NR | NR | 5-yr ILN recurrence: 16% | | Tang et al., 2017 [84] | pN3 | NR | 50 Gy/25 fx (n=27);<40 Gy (n=4);>50 Gy (n=5) | 14.4 months | 12.2 months | Adjuvant EBRT with better median time to recurrence (7.7 vs. 5.3 months) | NR | Median PLN+ (n=2);ENE+ in PLN (n=39) | | Winters et al., 2018 [68] | NR | NR | 75% received ≥45 Gy | NR | 64% | NR | NR | pN2 (n=433) | | Johnstone et al., 2019 [85] | ≥2 ILNs or ENE | NR | 50 Gy in 25 fx | NR | Median OS: 10.6 months | NR | NR | Median ILN+ (n=4), 72% ENE; median PLN+ (n=2), 49% ENE; median DSS: 11 months | | Ager et al., 2021 [87] | pN3 | NR | Variable:
45 Gy/20 fx;
54 Gy/27 fx;
50-54 Gy/25-27 fx | 51% | 44% | 56% | NR | ENE: 99% (ILN: 74%; PLN: 25%);
5-yr RFS: 51%; in-field recurrence: 47% | | Choo et al., 2020 [89] | Regional LN+ | NR | 45 Gy/25 fx (uninvolved LN);
56 Gy/28 fx (involved LN) | NR (2-yr: 49.3%) | NR (2-yr: 25%) | NR (2-yr: 27%) | Lymphedema: 46%; necrosis: 9% | pN3: 43% | | Li et al., 2021 [91] | pN3 | Parallel opposed AP/PA fields (equally weighted) | 30-68 Gy/15-34 fx | NR (3-yr CSS: 28.5% [CCRT] vs. 16.2% [CT]) | NR | NR | NR | 21% CCRT underwent salvage surgery | | Jaipuria et al., 2020 [90] | ≥2 ILNs ± PLN ± ENE | IMRT/VMAT | 45 Gy/25 fx (pelvis);
54 Gy (ENE+ region);
57-60 Gy (gross residual) | NR | Mean OS: 3.9 yr (RT);
mean OS: 2.8 yr (Chemo);
median OS not met in PLN-cohort | NR | 39% of RT group with persistent lymphedema; no RT-related necrosis | Pelvic LN+ (n=13);
ENE: 78% | | Yuan et al., 2020 [123] | NR | NR | 39.6-54 Gy/22-30 fx (PLN);
42.5-64.8 Gy (ILN) | NR | NR | 2-yr: 54% | G2 skin: 18% (acute);
G2 GI; 12% (acute);
G1 lymphedema: 18% (late) | N2/3 (n=23);
ENE+: 12% | | Mittal et al., 2021 [78] | pN3 | IMRT | 50 Gy/25 fx | NR | NR (2-yr: 79%) | NR (2-yr: 79%) | G2 lymphedema: 29%;
G3 lymphedema: 0% | 93% received adjuvant and CCRT | | Khurud et al., 2022 [88] | pN3 | Conventional (54%);
3DCRT (26%);
IMRT (20%); | 45 Gy/25 fx;
50.4 Gy/28 fx;
50 Gy/25 fx | NR | NR (2-yr: 62%) | NR (2-yr: 83% [multi-modal]) | 45% of AIRT group with lymphedema | 2-yr DFS: 55% |
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Select studies evaluating adjuvant EBRT ± chemotherapy to the groin or pelvis.
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Adjuvant EBRT to prepubic fat and bilateral ILNs and PLNs. Case of a 55-year-old male with hrHPV? pT3 N3 M0 poorly differentiated PSCC of the glans status post partial penectomy with mons panniculectomy requiring reconstruction with split thickness graft. Approximately 2 months later he underwent bilateral superficial and deep ILN dissection with pathology demonstrating negative margins at the primary site and 3/15 ILNs involved with malignancy with evidence of bilateral ENE. (A and B) Axial slices showing the prepubic space (green), bilateral ILNs (blue), and bilateral PLNs (pink) clinical target volumes; (C) Sagittal view demonstrating prepubic space and PLN coverage; (D) Coronal view showing prepubic space and ILN interface. Other organs at risk include bladder (yellow) and rectum (brown). The patient was treated with 52 Gy to the prepubic fat and bilateral PLNs and 62.4 Gy to the bilateral ILNs over 26 fractions with concurrent weekly cisplatin. EBRT, external beam radiotherapy; ILN, lymph node; PLN, pelvic lymph node; hrHPV, high-risk HPV; PSCC, penile squamous cell carcinoma; ENE, extranodal extension; R, rectum.
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