RCT compares platinum/5-FU, platinum/paclitaxel in high-risk penile cancer

A randomized controlled trial (CTRI/2016/12/007567) evaluating adjuvant platinum-based chemotherapy plus 5-Fluorouracil (5-FU) vs adjuvant platinum-based chemotherapy plus paclitaxel yielded “numerically higher” median progression-free survival (PFS) and overall survival (OS) in patients with high-risk penile cancer, according to data presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.¹

Aditya Dhanawat, MBBS, MD, DM

“Globally, penile cancer is rare. However, countries like India have a higher incidence of penile cancer. Presence of more than 1 inguinal node, pelvic lymph node, perinodal extension, or bulky lymph nodes confers poor prognosis.^2,3 There is no randomized evidence to guide the choice of neoadjuvant or adjuvant chemotherapy in this setting. There is a clear evidence gap. The aim of our study was to compare the safety and efficacy of adjuvant platinum plus 5-FU to platinum-paclitaxel in high-risk penile cancer,” explained presenting author Aditya Dhanawat, MBBS, MD, DM, medical oncologist at Tata Memorial Centre in Mumbai, India.

The study was a prospective, open label, phase 3 randomized controlled trial conducted at Tata Memorial Centre in Mumbai, India between March 2017 and October 2024. High-risk features were classified as more than 1 inguinal node, bulky lymph node (at least 4 cm), pelvic lymph node, or peri-nodal extension. Men were included if they were between 18 and 70 years of age, had an ECOG Performance Status of 0-2, had squamous cell carcinoma, had undergone curative resection with nodal dissection, and had at least 1 high-risk feature. Patient were excluded if they had received R2 resection of the groin or pelvic regional nodes; had an unhealthy wound, significant local infection, or discharging sinuses; had a prior invasive malignancy in remission for less than 3 years; had peripheral neuropathy greater than grade 2; had a history of severe hypersensitivity to paclitaxel, carboplatin, or cisplatin and 5-FU; had uncontrolled co-morbidities, distant metastatic disease, or had a high expectancy of less than 6 months.

Patients were randomly assigned 1:1 to cisplatin 75 mg/m² on day 1 plus 5-FU 1000 mg/m² for days 1-4 every 3 weeks for 4 cycles or to cisplatin 75 mg/m² on day 1 plus paclitaxel 175 mg/m² on day 1 every 3 weeks for 4 cycles. The study’s primary end point was PFS. Secondary end points included OS, loco-regional control, adverse events, and quality of life (QoL). The investigators had estimated a sample size of 150 patients, but the study was prematurely closed due to slow accrual.

“We assessed 124 patients for eligibility, of which 49 patients were randomized, 25 in the 5-FU arm and 24 in the paclitaxel arm. We included all patients in intention-to-treat and quality of life analysis,” Dhanawat. The baseline characteristics were well balanced between the 2 arms. Seventeen (68%) patients in the 5-FU arm underwent partial penectomy compared with 16 (66.6%) of patients in the paclitaxel arm, and 21 (84%) patients in the 5-FU arm had pathological N stage of N3 at surgery compared with 20 (83.3%) patients in the paclitaxel arm. Presence of lymphovascular invasion or perineural invasion was seen 11 (44%) patients in the 5-FU arm vs 9 (37.5%) patients in the paclitaxel arm.

A total of 12 (48%) in the 5-FU arm completed 4 cycles of adjuvant chemotherapy vs 20 (83.3%) patients in the paclitaxel arm (P = .009). Dose reductions occurred in 7 (31.8%) patients in the 5-FU arm vs 1 (4.3%) patient in the paclitaxel arm (P = .016), and dose discontinuation occurred in 10 (45.5%) patients in the 5-FU arm vs 4 (17.4%) patients in the paclitaxel arm (P = .092).

“The most common reason for discontinuation was disease progression in both the groups,” Dhanawat said.

Regarding safety, there was a 54.5% incidence of grade 3-4 toxicities in the 5-FU arm vs 39.1% in the paclitaxel arm (P = .300). Higher incidences of grade 3-4 gastrointestinal and hematological toxicities were also seen in the 5-FU arm of 31.8% for each type vs 4.3% and 13%, respectively in the paclitaxel arm (P = .016 and P = .130, respectively). Hospitalization rate was higher in the 5-FU arm at 40.9% vs 17.4% in the paclitaxel arm (P =.082). Elevated liver enzymes and sensory neuropathy occurred more frequently in the paclitaxel arm.

In terms of efficacy, “On the intention-to-treat efficacy analysis, with a median follow-up of 60[.1] months, the median PFS was numerically higher for the paclitaxel arm; that is, 36 months, as compared to 12 months for the 5-FU arm. The 5-year PFS was 36% [in the 5-FU arm and 38% [in the paclitaxel arm], respectively,” Dhanawat reported.

Median OS was 21.6 months in the 5-FU arm vs 37.2 months in the paclitaxel arm (HR=1.28); Dhanawat said this was not statistically significant.

In patients who completed 4 cycles of adjuvant chemotherapy (n=32), median PFS was not reached in the 5-FU group vs 35.9 months in the paclitaxel arm (P = .66). Five-year PFS was 51.6% in the 5-FU arm vs 40.2% in the paclitaxel arm. Also in patients who completed 4 cycles of adjuvant chemotherapy, median OS was not reached in the 5-FU arm vs 45.5 months in the paclitaxel arm (HR=0.59). Five-year OS was 78.6% in the 5-FU arm vs 43.4% in the paclitaxel arm.

Rates of distant metastases in the 5-FU and paclitaxel arms were 28% and 33%, respectively; these occurred in the lungs (18.4%), skin (6.1%), and bones (6.1%). Subsequent treatment consisted of palliative chemotherapy in 28.6% and best supportive care in 18.4%.

In terms of QoL, Dhanawat reported no significant difference between the arms in the measures used.

Dhanawat cited the open-label design and small sample as limitations of the study.

“The key takeaways are numerically higher median PFS and median OS with the paclitaxel group, higher GI toxicities and hematological toxicities with the 5-FU arm, more neuropathy and liver dysfunction with paclitaxel, similar results in EORTC and Male Sexual Health Questionnaire between the 2 groups,” Dhanawat concluded.

REFERENCES

1. Dhanawat A, Noronha V, Menon N, et al. An open label randomized non-inferiority trial comparing adjuvant platinum plus paclitaxel to platinum plus 5-FU after curative resection in high-risk penile carcinoma. J Clin Oncol. 2025;43(suppl 17):LBA5012. doi:10.1200/JCO.2025.43.17_suppl.LBA5012

2. Liu J-Y, Li Y-H, Zhang Z-L, et al. The risk factors for the presence of pelvic lymph node metastasis in penile squamous cell carcinoma patients with inguinal lymph node dissection. World J Urol. 2013;31(6):1519-1524. doi:10.1007/s00345-013-1024-4

3. Reddy JP, Pettaway CA, Levy LB, et al. Factors associated with regional recurrence after lymph node dissection for penile squamous cell carcinoma. BJU Int. 2017;119(4):591-597. doi:10.1111/bju.13686