Combined Laser Treatment for Penile Carcinoma: Results After Long-Term Followup

0022-5347/03/1696-2118/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 169, 2118 –2121, June 2003 Printed in U.S.A.

DOI: 10.1097/01.ju.0000067361.81295.a2

COMBINED LASER TREATMENT FOR PENILE CARCINOMA: RESULTS AFTER LONG-TERM FOLLOWUP TORGNY WINDAHL

AND

SWEN-OLOF ANDERSSON

¨ rebro University Hospital, O ¨ rebro, Sweden From the Department of Urology, O

ABSTRACT

Purpose: We evaluated local disease control, side effects and cause specific survival of penile carcinoma treated with laser therapy. Materials and Methods: In a prospective study from 1986 to 2002 we included 67 men with a mean age of 60 years with newly diagnosed penile carcinoma. No patient was lost to followup. Results: At a median followup of 42 months (range 12 to 186) 59 patients were alive and 8 had died of penile carcinoma (2) and concurrent disease (6). Of the 13 patients (19%) with local recurrence during the study period 10 underwent repeat laser treatment successfully. Side effects were few but 5 patients (7%) had postoperative bleeding. Overall cosmetic and functional results were highly satisfactory. Conclusions: The results of this study show that treating penile carcinoma with the combination of carbon dioxide and neodymium:YAG lasers can safely be done with highly satisfactory cosmetic results as well as good local tumor control. KEY WORDS: penis; penile neoplasms; lasers; carcinoma, squamous cell

Conventional treatment for localized penile carcinoma with partial or total amputation provides excellent local tumor control but the cosmetic and functional results have often heavily affected psychosexual function. External radiotherapy sometimes combined with chemotherapy has been tried successfully, although it is often followed by chronic edema, meatal stenosis and decreased sexual function.1–3 Interstitial brachytherapy has also been used in small series, especially in Europe, with acceptable local control but with a risk of meatal stenosis and atrophy of the glans.4, 5 Another conservative treatment for low stage disease that was presented in a small series is Mohs micrographic surgery with an overall 5-year cure rate of 74%.6 Laser treatment with a carbon dioxide and/or neodymium:YAG laser has been shown to control local disease to the same extent as conventional therapies but with superior cosmetic and functional results and without compromising cure.7, 8 In this study we update our previous study,7 focusing on local disease control, side effects and cause specific survival of the combined laser treatment. We also assessed current clinical staging procedures. MATERIALS AND METHODS

Study population. In a prospective study from July 1986 to January 2002 we included 67 men with newly diagnosed squamous cell carcinoma of the penis. Mean patient age at diagnosis was 60 years (range 26 to 87). Of these men 24 had previously been treated with local excision elsewhere in Sweden but they were referred to our institution for further therapy due to residual tumor or local recurrence. A total of 48 men (72%) had undergone circumcision as adults due to phimosis or had phimosis at diagnosis. Furthermore, 11 men had a history of concomitant lichen sclerosus or it was detected in the penile specimen. The 1997 TNM classification and the WHO grading system were used for tumor categorization.9 All histopathological specimens were reviewed by 2 pathologists at our institution.

Table 1 shows the distribution of tumor grade in relation to pathological classification. In general, patients with Tis to T2 N0, M0 tumors with a low or intermediate grade of differentiation (grades 1 and 2) and with a tumor of less than 3 cm. were considered appropriate candidates for laser surgery. However, 6 patients with more advanced tumor stages who refused penile amputation were also included in the study. All tumors were located on the glans, sulcus or foreskin and none was on the penile shaft. Tumor ulceration was not a contraindication to treatment. Table 2 shows the distribution of clinical and pathological classifications. In patients with penile carcinoma nodal status is based on physical examination and imaging investigations, that is ultrasound or computerized tomography (CT). In the absence of imaging the tumor was considered NX in accordance with the TNM classification. The patient was considered a candidate for radical or modified lymphadenectomy when tumor stage was greater than T1 and/or the WHO grade of differentiation was grade 2 or greater even without palpable lymph nodes or normal imaging. If no imaging, such as ultrasound, CT, chest x-ray or magnetic resonance imaging, was done, the tumor was classified as MX. Only those with normal findings on imaging were considered M0. Operative method. The aim of combined treatment with the carbon dioxide/neodymium:YAG laser was first to excise all macroscopically visible lesion using the carbon dioxide laser with a margin of 3 to 5 mm. We used a laser with an output of 20 W. and a focused beam. We did not obtain frozen sections from the margins and we never used knife excision. When the tumor was excised, the neodymium:YAG laser with its deep penetrating wavelength of 3 to 5 mm. was then applied to coagulate the tumor bed. We used an output of 40 to 60 W. for coagulation. In general, the tissue defect was left open for spontaneous healing by re-epithelialization from the normal margins, which was usually completed in 8 to 10 weeks. Treatment was mostly performed using local anesthesia and usually as an outpatient procedure. If excision involved or was close to the distal urethra, the patient received an indwelling catheter for 1 week postoperatively. During the first 2 years of the study period we only had

Accepted for publication January 31, 2003. Supported by grants from Maud och Birger Gustavssons Foundation and the Research Foundation at the Urological Department, ¨ Orebro University Hospital. 2118

2119

LASER TREATMENT FOR PENILE CARCINOMA TABLE 1. Distribution of tumor grade and pT stage in 67 patients with penile carcinoma pT Stage pTIS pTa pT1 pT2 pT3 Totals

No. TiS

No. GI

No. GII

No. GIII

21 2 18 6 21

26

3 9 2

2 4

14

6

Total No. 21 2 23 19 2 67

access to a carbon dioxide laser and, therefore, 13 patients were treated with a carbon dioxide laser alone. Furthermore, 1 patient was treated only with the neodymium:YAG laser due to carbon dioxide laser failure. The remaining 53 patients were treated with the combined laser method. Generally we performed modified inguinal lymphadenectomy, as described in 1988 by Catalona.10 If metastasis was noted on frozen section, we continued with radical lymph node dissection, including the pelvic lymph nodes on the ipsilateral side. A total of 22 patients underwent lymphadenectomy. Followup. The patients were followed every 3 months by clinical examination and groin evaluation, for the subsequent 2 years and every 6 months thereafter until 5 years. However, some patients referred from elsewhere have not followed this schedule strictly. All cases were assessable for local recurrence, progression and survival by the end of 2001. End points and statistical procedure. Primary study end points were death from penile cancer or intercurrent disease and local recurrence. The medical records of all deceased patients were reviewed. All macroscopic lesions suspicious for local recurrence were verified histopathologically. Plots of local recurrences and cause specific survival were calculated by the Kaplan-Meier estimate.

FIG. 1. Disease specific (DS) and observed (OS) survival in 67 laser treated patients with penile carcinoma.

TABLE 3. Distribution of stage and grade in 13 patients with local recurrence after laser treatment for penile carcinoma Primary Tumor

Local Recurrence 1

Ca in situ Ca in situ Ca in situ* Ca in situ Ca in situ Ca in situ ⫹ pT1G1 pT1G1 pT1G1 pT1G1 pT1G1 pT1G1 pTaG1 pT1G1 Ca in situ pT1G2 Ca in situ pT1G2 Ca in situ pT2G2 pT2G1 pT2G2 pT2G2 pT2G2† pT3G2 pT3G2 pT2G3 * Immunosuppression, pT3G3 third recurrence. † Metastatic disease, death from penile cancer.

Local Recurrence 2 Ca in situ

pTaG1

RESULTS

Survival. At a mean followup of 60 months 59 patients were alive. No patient was lost to followup. Figure 1 shows disease specific and observed survival. Eight patients died, including 2 of penile carcinoma and 6 of concurrent disease. At diagnosis 1 patient who died of penile carcinoma already had a pT2, G3, N3, M0 tumor with fixed, inoperable deep pelvic metastases. The other patient who died of penile carcinoma was diagnosed with a pT2, G3, NX, MX tumor. This patient was advised to undergo lymphadenectomy but he refused. Six months after laser treatment he was referred with multiple metastases and treated with radiotherapy and chemotherapy. However, he died of rapidly progressive disease 10 months after initial treatment. There was no sign of local recurrence at the site of laser treatment. Six patients died of intercurrent disease, including myocardial infarction in 2, and lung cancer, prostatic carcinoma, a cerebrovascular lesion and pulmonary emboli in 1 each. None showed any evidence of local or generalized penile carcinoma. Local recurrences. A total of 13 patients (19%) had local recurrences during the study period. Table 3 shows the disTABLE 2. Distribution of clinical and pathological stage in 67 patients with penile carcinoma pT Stage Ca in situ pTa pT1 pT2 pT3

No. Clinical Stage Ca In Situ

T1

T2

Total No.

16

3 2 14 3 1

2 8 16 1

21 2 23 19 2

23

27

67

1

Totals 17 No clinical stage Ta or T3 tumors.

tribution of histopathological examinations of tumor recurrence. Two patients had more than 1 recurrence. The stage or grade of the recurrence compared with the primary tumor was worse in 3 patients, including 1 treated with immunosuppression due to concomitant collagenous disease. His first local recurrence was carcinoma in situ, as was the primary tumor and he was re-treated with the laser. Unfortunately followup was delayed and a second recurrence 11⁄2 years later was histopathologically shown to be a pT3, G3 tumor. He was treated elsewhere with partial amputation. The other patient with two recurrences was re-treated twice with the laser. A patient treated primarily for a pT3, G2 tumor had recurrence 67 months later and underwent partial amputation. A patient with metastases at primary laser treatment had a recurrence on the penis but was not re-treated with the laser. The remaining 10 patients with local recurrence were successfully re-treated with laser therapy and are currently without evidence of cancer. After carbon dioxide resection the margins were negative in 43 patients, positive in 10 and ambiguous in 14. Eight of the 13 recurrences had positive or ambiguous margins and 7 (almost 50%) appeared within 2 years after primary treatment. The remaining 6 recurrences appeared after more than 5 years of followup and in 1 patient after 14 years (fig. 2). Further statistical analyses to explore the impact of different variables on the risk of local recurrence did not provide any meaningful information due to the small number of local recurrences. Tumor classification. The primary tumor was clinically classified correctly in 46 patients (69%), over staged in 16 (24%) and under staged in 5 (7%) (table 2). According to N status 21, 5, 0 and 3 cases were N0 to N3, respectively, while 39 were classified as NX. Lymphadenectomy was performed

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LASER TREATMENT FOR PENILE CARCINOMA

FIG. 2. Actuarial local failure-free survival in 67 patients with penile carcinoma.

in 22 patients, including 17, 1, 3 and 1 with pN0 to pN3 disease, while 40 and 27 were classified with MX and M0 tumors, respectively. Cosmetic results and function. The cosmetic result and erectile function were evaluated separately using structured interviews. Overall the cosmetic results were satisfying/very satisfying for 78% of the men and 72% reported unaltered erectile function postoperatively (data not shown). Although the cosmetic result after laser therapy was highly satisfactory (fig. 3), the healing process of the laser treated area required 8 to 10 weeks. The side effects were few. Five patients (7%) had minor postoperative bleeding without any specific sequelae. In 2 cases bleeding occurred 2 to 3 weeks after laser treatment, probably due to involuntary nightly erections. Despite the unpleasant appearance of the wound postoperatively during the first weeks few patients complained about pain in the treated area. The healing process was completed without scar formation in all treated patients. No sign of impaired voiding was noted. If we had to remove the distal part of urethra with the tumor, the urinary stream deviated postoperatively. However, there were no cases of postoperative meatal stenosis requiring dilation. DISCUSSION

The results of this study show that treatment of localized penile carcinoma with a combination of carbon dioxide and neodymium:YAG lasers can be safely done with good local tumor control and highly satisfactory cosmesis. Of the 67

patients 13 (19%) had local recurrence, of whom 10 were successfully re-treated with the laser without further recurrence during a mean followup of 60 months. Two patients (3%) died of penile carcinoma during followup, including 1 who already had metastases at diagnosis. In 7 of 13 patients local recurrence appeared within the first 2 years of followup, while the remaining recurrences in 6 appeared after 6 years and in 2 after more than 10 years following primary treatment. It is reasonable to assume that the early recurrences were due to inadequate primary treatment. Indeed, as mentioned, 8 of the 13 patients with local recurrence had positive or ambiguous margins. The advantage of the laser method that we used (carbon dioxide and neodymium:YAG laser) is the combined excellent cutting ability of the carbon dioxide laser and the deep penetrating neodymium:YAG laser. The use of either laser technology alone has drawbacks. The carbon dioxide laser with its minimal penetration depth only removes visible tumor tissue and the safe margin is limited. On the other hand, it is easy for the pathologist to identify tumor margins. The neodymium:YAG laser removes little tissue and is not a good cutting tool but on the other hand it has a deeper penetrating wavelength that makes it excellent for tumor bed coagulation after removal of the tumor by the carbon dioxide laser. The main advantage of laser treatment is the good cosmetic and functional results, which contrast markedly with those of conventional penile amputation. There are few published studies of laser treatment for localized penile carcinoma. In a study from the Mayo Clinic there was an overall recurrence rate of 11.4%.11 However, tumor stages were lower and 40% of the treated lesions were premalignant. Three lasers (carbon dioxide, neodymium:YAG and KTP/532) were used and in some patients a combination carbon dioxide and neodymium:YAG laser was applied. In a laser study from The Netherlands recurrence was reported in 26% of the patients treated for carcinoma in situ.8 A total of 12 patients were treated with the carbon dioxide laser and 7 were treated with the neodymium:YAG laser. Four of the 5 patients with recurrence were treated only with the carbon dioxide laser. In the study of Horenblas et al of 110 patients the risk of local recurrence in stage T1 tumors was 10% and for stage T2 tumors it was 32% but only 17 patients were treated with a laser.12 In our study we noted recurrence in 3 of 21 patients (14%) with carcinoma in situ, in 6 of 24 (25%) with pT1 tumors, in 4 of 19 (21%) with pT2 tumors and in 1 of 2 with a pT3 tumor. The 2 patients in our study who died of metastatic disease during the study period also had primary pT2 tumors. We have no explanation for the high frequency of recurrence associated with pT1 tumors. Nevertheless, all 6 patients were successfully retreated with the laser. An alternative treatment option for localized penile cancer is interstitial brachytherapy. Local failure rates of 11% to

FIG. 3. Penile squamous cell carcinoma (pT1, G1) before (A) and after (B) laser treatment

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LASER TREATMENT FOR PENILE CARCINOMA

50% have been reported in different series for interstitial brachytherapy depending on tumor size.13 In a study from Ottawa 30 patients with T1–T3 tumors were treated.5 During a medium followup of 34 months 4 recurrences were reported. Although a shorter followup was reported, these values correspond well with the results of our study. A drawback regarding brachytherapy is that it could only be used as primary treatment, which means that local recurrence must be treated with partial or total penectomy. Moreover, side effects such as meatal stenosis are relatively frequent with brachytherapy. There were no such side effects in our series. The healing process after brachytherapy is completed in 2 to 3 months, which is comparable with the healing process after laser therapy.5, 13, 14 The Mohs’ micrographic surgery method has a high cure rate for low stage tumors but the results are highly variable and technique dependent. Complications are disfigurement of the glans and meatal stenosis.1, 6 Clinical staging of penile carcinoma is undoubtedly problematic. Neither clinical investigation nor imaging are sufficiently reliable. In our study tumors were incorrectly classified in 30% of the patients, including 24% that were over and 6% that were under staged (table 2). This finding is in agreement with those of others.1, 15, 16 Lymph node involvement should be assessed by physical examination and imaging but the value of lymphangiography and CT has been questioned because lymph nodes escaping clinical detection are rarely revealed by available imaging methods.17 Consequently CT was performed only when palpable nodes or primary tumors at high risk for metastases were present. The accuracy of the classic sentinel node biopsy has been questioned and this method was not used in our study.18, 19 However, the dynamic sentinel node procedure seems to be a more reliable method and we are now performing a study comparing dynamic sentinel node biopsy with the modified inguinal lymphadenectomy described by Catalona.10 In our current study only 6 patients had had lymph node metastases, which was probably due to relatively low stage disease with 24% carcinoma in situ. Advanced disease was an exclusion criterion in this study. From an ethical point of view it is difficult to perform a randomized study comparing laser treatment with partial amputation of localized tumors. However, it is important to remember that in the absence of inguinal metastasis adequate partial amputation provides 70% to 80% long-term survival. On the other hand, conservative treatment with local excision has a significant risk of local recurrence of up to 50% with a worsening prognosis.1 In our study 35% of the patients who were referred to our hospital for treatment had previously undergone local excision and they were sent to our institution for further therapy due to residual tumor or local recurrence. Despite this fact survival was excellent and local recurrences were manageable. CONCLUSIONS

The results of this study show that treating penile carcinoma with the combination of carbon dioxide and neodymium:YAG lasers can safely be done in a subset of patients with Tis-T2, GI-II tumors that are less than 3 cm. with highly satisfactory cosmetic results as well as good local tumor

control. Local recurrences do not seem to be the focus for regional metastases.

REFERENCES

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