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    -  Radhakrishnan V
    -  Raja A
    -  Ganesan TS
    -  Dhanushkodi M
    -  Sagar TG

 
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ORIGINAL ARTICLE
Ahead of print publication
 

Outcomes with chemotherapy in carcinoma penis: Experience from a tertiary cancer center


1 Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu; Department of Medical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
3 Department of Surgical Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India

Date of Submission01-Apr-2020
Date of Decision22-Sep-2020
Date of Acceptance30-Dec-2020
Date of Web Publication02-Aug-2022

Correspondence Address:
Venkatraman Radhakrishnan,
Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_266_20

  Abstract 


Background: Carcinoma penis is more common in India compared to the West. The role of chemotherapy in carcinoma penis is ambiguous. We analyzed the profile and outcomes of patients with carcinoma penis treated with chemotherapy.
Methods: We analyzed the details of all patients with carcinoma penis treated at our institute between 2012 and 2015. We collected particulars regarding demography, clinical presentation, treatment details, toxicities, and outcomes of these patients. Event-free and overall (OS) survival were calculated from the time of diagnosis until documentation of disease relapse/progression or death for the patients with advanced carcinoma penis who were eligible for chemotherapy.
Results: There were 171 patients with carcinoma penis treated at our institute during the study period including 54 (31.6%) patients with stage I, 49 (28.7%) patients with stage II, 24 (14.0%) patients with stage III, 25 (14.6%) patients with stage IV, and 19 (11.1%) patients with recurrent disease at presentation. The present study included 68 patients with advanced carcinoma penis (stages III and IV) who were eligible for chemotherapy, with a median age of 55 years (range: 27–79 years). Sixteen patients received paclitaxel and carboplatin (PC) and 26 patients cisplatin and 5-FluoroUracil (CF). Neoadjuvant chemotherapy (NACT) was given to four patients with stage III and nine patients with stage IV disease. Of the 13 patients given NACT, we observed a partial response in five (38.5%), stable disease in two (15.4%), and progressive disease in five (38.5%) evaluable patients. Six (46%) patients underwent surgery after NACT. Only 28/54 (52%) patients received adjuvant chemotherapy. After a median follow-up of 17.2 months, the 2-year OS rates were 95.8, 89, 62.7, 51.9, and 28.6% for stages I, II, III, IV, and recurrent disease, respectively. The 2-year OS of patients who were given chemotherapy versus those who were not given chemotherapy were 52.7 and 63.2%, respectively (P = 0.762).
Conclusions: We report the real-world outcomes of two chemotherapeutic regimens used in consecutive patients with advanced carcinoma penis. Both PC and CF seemed effective and safe. However, approximately half of patients with advanced carcinoma penis do not receive the planned/indicated chemotherapy. We need further prospective trials regarding the sequencing, protocols and indications of chemotherapy in this malignancy.


Keywords: Carcinoma penis, chemotherapy



How to cite this URL:
Mailankody S, Radhakrishnan V, Raja A, Ganesan TS, Dhanushkodi M, Sagar TG. Outcomes with chemotherapy in carcinoma penis: Experience from a tertiary cancer center. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=353185





  Introduction Top


Squamous cell carcinoma of the penis is a rare tumor that is more prevalent in India compared to the West.[1] The role of chemotherapy in the management of carcinoma penis is not clearly defined. The current practice offers neoadjuvant chemotherapy (NACT) to patients with inoperable bulky disease at presentation.[2] This recommendation is based on studies using a combination of paclitaxel, ifosfamide, and cisplatin in the neoadjuvant setting.[3],[4],[5] There is also a paucity of randomized evidence for adjuvant chemotherapy (ACT) in carcinoma penis. After definitive surgery, ACT is recommended in patients with high histological grade, regional lymph node positivity, and perinodal spread.[2] The ideal chemotherapy schedule is not known as the few studies on NACT and ACT have used different protocols, mostly platinum-based.[6] Older studies have used vincristine, methotrexate, and bleomycin,[7],[8],[9],[10] while newer studies have described varying protocols like 5FU and cisplatin (CF); paclitaxel ifosfamide and cisplatin (TIP); paclitaxel, 5FU and cisplatin (TPF); and irinotecan and cisplatin.[11],[12],[13],[14],[15],[16],[17] We undertook this study to analyze the chemotherapy profile and efficacy in patients with carcinoma penis treated at our hospital, with two chemotherapy regimens.


  Materials and Methods Top


The case records of patients treated for squamous cell carcinoma of the penis from January 2012 to December 2015 were retrieved and analyzed. We included the patients who had advanced disease (stages III and IV) who were eligible for chemotherapy. We collected the details regarding the clinical features, chemotherapeutic regimens, toxicity, and outcomes of these patients. The study was approved by the hospital ethics committee. All patients were started on treatment after obtaining written informed consent.

The diagnosis was confirmed by biopsy and histopathological examination of the penile lesion. HPV analysis was not done in our institute during the study period (2012–2015), as the prognostic role of HPV was not yet established.[18] Computed tomographic scans with contrast of the chest, abdomen, and pelvis were performed for staging. Fine needle aspiration cytology of inguinal lymph node was performed in patients with clinical or radiological suspicion of nodal involvement with disease. NACT was given in patients with bulky (inoperable) inguinal nodes at presentation. Patients with operable disease at presentation underwent partial penectomy with or without sentinel lymph node biopsy based on the inguinal node status. Patients with positive inguinal lymph nodes underwent ilioinguinal block dissection. A multispecialty tumor board decided on the adjuvant therapy. ACT was given in patients with high-risk features (node positivity and perinodal invasion).[2] The chemotherapeutic regimens used at our institute were CF [5 FU at 325 mg/m2 IV bolus from day 1–3, cisplatin at 70 mg/m2 on day 1 (every three weekly)] till 2013 and PC [(Paclitaxel 175 mg/m2 infusion over 3 hours) and carboplatin [five times the area under the curve] every 3 weeks, after January 2014. Six cycles of ACT were prescribed. Toxicities were noted from the case records and graded as per the Common Terminology Criteria for Adverse Events, National Cancer Institute, version 4.0. The response to NACT was assessed clinically and if needed radiological confirmation was performed. All patients who had a reduction in the size of the tumor were considered as having a partial response (PR) while documented increases were considered as progressive disease (PD). All other patients were considered as having stable disease (SD).

Descriptive statistics were used to summarize the data. Event-free survival (EFS) was calculated from the date of the start of treatment until the date of relapse or progression of the disease or death. Overall survival (OS) was calculated from the start date of treatment till death due to any cause. Follow-up data was censored on April 1, 2017. The actuarial probability of survival was estimated using the Kaplan–Meier method, and parameters affecting OS were compared using the log-rank test using SPSS statistical software version 13.0 (IBM Inc.).


  Results Top


During the study period, 171 patients with carcinoma penis were treated at Cancer Institute (W.I.A), Chennai, India. There were 54 (31.6%) patients with stage I, 49 (28.7%) with stage II, 24 (14.0%) with stage III, 25 (14.6%) with stage IV, and 19 (11.1%) with recurrent disease at presentation. The present study included only 68 patients with advanced/recurrent carcinoma penis (stages III and IV) who were eligible for chemotherapy.

The median age of the 68 patients was 55 years (range: 27–79 years). Twenty-six patients (38.2%) were over the age of 60 years. The histology was squamous cell in all patients; however, the data on further histopathological subtyping was not available. One patient had a concurrent HIV infection. [Table 1] summarizes the other baseline characteristics.
Table 1: Baseline characteristics of patients diagnosed with carcinoma penis (n=171)

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Treatment details

We used NACT in 13 patients with bulky inoperable disease or recurrent inguinal node at presentation to our institute; PC in seven and CF in six patients. The median number of NACT cycles was three (range 1–4). One patient was lost to follow-up, so the response was not assessed. [Table 2] shows the comparison of toxicity and outcomes of the two different regimens used. We observed PR in five (38.5%), SD in two (15.4%), and PD in five (38.5%) patients. There was an ORR of 40 and 71% to CF and PC, respectively (p = 0.276). One patient did not follow up after three cycles of chemotherapy and hence did not undergo surgery. Six (46.1%) patients who had PR/SD underwent definitive surgery after NACT and three of them received ACT (median 2, range 2–4). Of the six patients who underwent surgery, two patients defaulted and, therefore, were not given adjuvant therapy. One patient had no residual tumor during surgery (after four cycles of NACT) and was kept on follow-up.
Table 2: Comparison of the two chemotherapy regimens used

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Palliative chemotherapy (paclitaxel/carboplatin) was given in one patient with lung metastasis, who initially had stage II disease.

After excluding 13 patients who were given NACT and one patient who was given palliative chemotherapy, postoperative chemotherapy was indicated in 54 patients who underwent surgery [Table 3]. However, ACT could be delivered only in 28 patients. Only 22 (52.3%) of the patients could complete the planned course of NACT and ACT. PC was used in 8 patients and CF in 20 patients [Table 3]. The median number of cycles was 4 (1–6).
Table 3: Summary of chemotherapy in advanced carcinoma penis

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The reasons for not giving postoperative chemotherapy (n = 26) were poor general condition in ten (38.5%), physician decisions in seven (26.9%), treatment abandonment in four (15.4%), patient refusal in three (11.5%), and disease progression in two (7.7%) patients.

Eleven patients were given radiotherapy. Only one patient received adjuvant radiotherapy; the other patients were given radiotherapy (to the inguinal nodal mass) in the palliative setting at recurrence.

Toxicities of chemotherapy

Only 28.6% (12/42) of all the patients who received chemotherapy developed toxicities. Grade 3 or 4 toxicities were observed in eight (19%) of the patients [Table 2]. There was no chemotherapy-associated death.

Outcomes

The median duration of follow up was 17.2 months. There were 26 events among patients with advanced disease. The 2-year EFS and OS rates for the 68 study patients were 51.8 and 56.6%, respectively [Figure 1]a and [Figure 1]b. The 2-year EFS rates of the patients who were given chemotherapy and the patients who were not given chemotherapy were 47.9 and 58.8%, respectively (P = 0.623). Likewise, the 2-year OS rates of patients who were given chemotherapy versus those who were not given chemotherapy were 52.7 and 63.2%, respectively (P = 0.762), as demonstrated in [Table 4] and [Figure 2]a and [Figure 2]b. Forty-three (63.2%) of 68 patients were alive at the end of the study period. The stage of the disease was found to be associated significantly with OS. We could not find a significant correlation between circumcision, the grade of the tumor, and perinodal spread with OS. The 2-year OS rates were 95.8, 89, 62.7, 51.9, and 28.6% for stages I, II, III, IV, and metastatic disease, respectively [Figure 3].
Figure 1: Kaplan Meier survival curves (a) 2-year EFS; (b) 2-year OS. EFS – Event free survival, OS – Overall survival

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Figure 2: EFS (a) and OS (b) based on chemotherapy delivery. EFS – Event free survival, OS – Overall survival

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Figure 3: Stage-wise OS. EFS – Event free survival, OS – Overall survival

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Table 4: The outcomes of treatment

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  Discussion Top


The present study describes the outcomes of 68 patients with advanced carcinoma penis treated at our institute. Chemotherapy was used in the neoadjuvant setting (n = 13) with overall response rates of 38.5%, the postoperative setting (n = 28), and the palliative setting (n = 1). The 2-year EFS and OS rates of patients given chemotherapy were 47.9 and 52.7%, respectively. We found that we could not provide chemotherapy in 48% of patients with advanced carcinoma penis in this dataset. Poor performance status after surgery was one of the common reasons (38.5%); the other grounds were physician decision, treatment abandonment, patient unwillingness, and disease progression. This represents the only report of the real-world outcomes of the treatment of advanced carcinoma penis in a consecutive series of patients to the best of our knowledge. We also report a summary of the use of two different treatment protocols in penile carcinoma. Patients tolerated the chemotherapy regimens (CF and PC) well, with grade 3–4 toxicities in only 19% of the patients.

Our institute used CF chemotherapy until 2013. However, the dosing of 5FU was suboptimal compared to the other studies that have used higher doses.[4],[11] This dose was adopted because of anticipated significant toxicity with higher doses and the need for a central line. However, the patients developed toxicity with the modified dosage also. A study on patients with inoperable carcinoma penis reported ORR of 72% to CF therapy, whereas ORR in our study was only 40%, albeit in a smaller subset.[11] Another study prospectively evaluated the outcomes of a combination of cisplatin, methotrexate, and bleomycin in patients with advanced carcinoma penis.[7] Though the response rates were 32.5%, the high toxicity rates led to the elimination of bleomycin from the later studies. Studies have also demonstrated good outcomes with Paclitaxel, Ifosfamide and Cisplatin (TIP) protocol with responses in 50% of patients and operability in 73% of the patients, while we observed lower rates (ORR 38.5% and 46% operability).[3],[5] The addition of another active agent to the chemotherapy protocol may account for the higher responses than our analysis. TIP is a toxic protocol with three drugs and infusional treatment, requiring admission.[3],[5],[12] This leads to a higher cost of treatment and morbidity due to toxicities. Also, there is evidence for the effectiveness of the more straightforward, less toxic regimen of paclitaxel/platinum doublet in carcinoma penis from India.[13],[16] As randomized data comparing different regimens is not available, given the disease's rarity in industrialized countries, we changed our protocol to PC for NACT and ACT in our institute from 2013.

As a multidisciplinary board discussion with case-to-case analysis has decided the adjuvant treatment, clinicians likely gave chemotherapy to patients with more aggressive disease biology or higher relapse risk. This choice of patients may have led to an intrinsic bias in the retrospective analysis masking the benefit of ACT. Hence, the OS rates seemed higher in the subset of chemotherapy naïve patients (63.2% versus 52.7%, P = 0.762). Another study of 84 patients with positive pelvic lymph nodes following lymph node dissection reported better OS in patients who received chemotherapy. Like in our data, only less than half of the patients with the advanced disease received chemotherapy in the above study, again causing a bias in the choice of fitter patients for chemotherapy, leading to improved survival.[14]

Indian studies have reported the use of platinum taxane doublet (paclitaxel with cisplatin or carboplatin) in the adjuvant setting (n = 19) and the palliative setting (n = 18).[13],[16] The indications for adjuvant therapy in the above-mentioned trial were a perinodal extension, bilateral lymph node involvement, pelvic lymph node involvement, and R1 resection. The median disease-free survival was 16.2 months, similar to our results. The significant reported toxicities were vomiting (73.7%), myalgia (57.9%), loose stools (10.5%), and one treatment-related death. Similar to our findings, only 63% of patients could complete the prescribed course of chemotherapy cycles. Our study included all patients eligible for chemotherapy, while this study included only patients who received chemotherapy.

In this study, we also looked into the reasons for not delivering chemotherapy postoperatively. More than one-fourth of the patients were not keen on further therapy. This figure suggests that interventions to improve patient compliance may help to improve outcomes in this aggressive disease. Ours is the first study to report the reasons for nondelivery of chemotherapy in indicated patients; there may be similar issues in other low-middle-income countries.

NACT is indicated in unresectable carcinoma penis. Nearly half of the patients with high-risk features cannot receive chemotherapy after surgery, mainly due to surgical morbidities. Hence, sequencing of treatment, with chemotherapy delivery before surgery in patients with known advanced disease, merits exploration. We also noted disease progression in nearly half of the patients during or immediately after NACT, which may also factor during treatment planning. One of the study's drawback is that the number of patients who received NACT were only 13, making meaningful analysis difficult. Nevertheless, given the rarity of the disease and limited indications for NACT, it may be challenging to recruit a sufficient number of patients for a randomized trial to establish the ideal sequencing of surgery and chemotherapy in this aggressive disease. In our study, radiotherapy was not frequently used in the adjuvant setting due to the expected associated morbidities after surgery. The use of concurrent chemoradiotherapy after surgery also needs to be analyzed in further studies.


  Conclusions Top


This retrospective study reports the outcomes of 68 consecutive patients with advanced carcinoma penis treated at our center. The combinations of cisplatin/5FU and paclitaxel/carboplatin were found well tolerated. Nearly half of patients with high-risk disease did not receive ACT due to multiple factors. We need to focus on population-specific issues to improve the outcomes of treatment in our country. Our study also emphasizes the need for randomized trials studying a change in the conventional treatment paradigm, to delineate the exact role, indications, and sequencing of chemotherapy in squamous cell carcinoma of the penis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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GLOBOCAN 2018. Available from: http://gco.iarc.fr/today/data/factsheets/cancers/26-Penis-fact-sheet.pd. [Last accessed on 2020 Feb 01].  Back to cited text no. 1
    
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Van Poppel, H, Watkin, NA, Osanto, S, Moonen L, Horwich A, Kataja V, et al. ESMO Guidelines Working Group. Penile cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24:vi115–24.  Back to cited text no. 2
    
3.
Pagliaro LC, Williams DL, Daliani D, Williams MB, Osai W, Kincaid M, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: A phase II study. J Clin Oncol 2010;28:3851–7.  Back to cited text no. 3
    
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Leijte JA, Kerst JM, Bais E, Antonini N, Horenblas S. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol 2007;52:488-94.  Back to cited text no. 4
    
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Bermejo C, Busby JE, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol 2007;177:1335-8.  Back to cited text no. 5
    
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Sonpavde G, Pagliaro LC, Buonerba C, Dorff TB, Lee RJ, Di Lorenzo G. Penile cancer: Current therapy and future directions. Ann Oncol 2013;24:1179-89.  Back to cited text no. 6
    
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Haas GP, Blumenstein BA, Gagliano RG, Russell CA, Rivkin SE, Culkin DJ, et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: A Southwest Oncology Group study. J Urol 1999;161:1823–5.  Back to cited text no. 7
    
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Dexeus FH, Logothetis CJ, Sella A, Amato R, Kilbourn R, Fitz K, et al. Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol 1991;146:1284-7.  Back to cited text no. 8
    
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Pizzocaro G, Piva L. Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol 1988;27:823-4.  Back to cited text no. 9
    
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Hakenberg OW, Nippgen JB, Froehner M, Zastrow S, Wirth MP. Cisplatin, methotrexate and bleomycin for treating advanced penile carcinoma. BJU Int 2006;98:1225-7.  Back to cited text no. 10
    
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Di Lorenzo G, Buonerba C, Federico P, Perdonà S, Aieta M, Rescigno P, et al. Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis. BJU Int 2012;110:E661-6.  Back to cited text no. 11
    
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Pizzocaro G, Nicolai N, Milani A. Taxanes in combination with cisplatin and fluorouracil for advanced penile cancer: Preliminary results. Eur Urol 2009;55:546-51.  Back to cited text no. 12
    
13.
Noronha V, Patil V, Ostwal V, Tongaonkar H, Bakshi G, Prabhash K. Role of paclitaxel and platinum-based adjuvant chemotherapy in high-risk penile cancer. Urol Ann 2012;4:150–3.  Back to cited text no. 13
[PUBMED]  [Full text]  
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Sharma P, Djajadiningrat R, Zargar-Shoshtari K, Catanzaro M, Zhu Y, Nicolai N, et al. Adjuvant chemotherapy is associated with improved overall survival in pelvic node-positive penile cancer after lymph node dissection: A multi-institutional study. Urol Oncol 2015;33:496.e17-23.  Back to cited text no. 14
    
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Theodore C, Skoneczna I, Bodrogi I, Leahy M, Kerst JM, Collette L, et al. A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992). Ann Oncol 2008;19:1304-7.  Back to cited text no. 15
    
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Patil VM, Noronha V, Joshi A, Muddu V, Bhosale B, Bakshi G, et al. Palliative chemotherapy in carcinoma penis: Does platinum and taxane combination hold a promise? Urol Ann 2014;6:18–22.  Back to cited text no. 16
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Pettaway CA, Pagliaro L, Theodore C, Haas G. Treatment of visceral, unresectable, or bulky/unresectable regional metastases of penile cancer. Urology 2010;76:S58-65.  Back to cited text no. 17
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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