Neoadjuvant docetaxel, cisplatin and ifosfamide (ITP) combination chemotherapy for treating penile squamous cell carcinoma patients with terminal lymph node metastasis

Squamous cell carcinoma (SCC) of the penis is a relatively rare and aggressive disease in the developed countries, but higher incidences have been observed in the developing countries [1, 2]. Perhaps due to benign initial symptoms, embarrassment and insufficient awareness or knowledge, a considerable proportion of patients with penile cancer had a patients’ delay of more than 6 months, which lead 25% of men to present with advanced disease at the time of diagnosis. The lymph node metastasis of penile cancer occurs first in the groin lymph nodes. The greatest prognostic factors in SCC of penis are the presence and extent of lymph node involvement [3]. Whether exist the regional lymph node metastasis, the extent of metastasis and whether can undergo radical resection are the determinant of the survival rate. For patients with fixed inguinal lymph node (LN) metastasis or pelvic lymph node (N3) involvement, upfront operation is not recommended because of the small possibility of cure, short survival time and wide range of operation. Upfront chemotherapy seems to be a more reasonable method [3]. The aim of neoadjuvant chemotherapy is to reduce the size and infiltration of tumors, to improve the effect of resection, to alleviate surrounding injury and to eliminate distant micro-metastasis. According to previous studies, chemotherapy as a neoadjuvant therapy for locally advanced penile cancer may show good results, but the scarcity of samples and the lack of large-scale clinical trials hinder attempt to establish a solid evidence base for its routine use [4] . This should strengthen research and further improve the related chemotherapy regimen.

Neoadjuvant chemotherapy is now commonly used in penile cancer with locally invasive or fixed inguinal lymph nodes as well as in treatment and palliation for advanced or metastatic disease [5]. In the neoadjuvant treatment, up to 69% of the patients who were clinically unresected had an objective response allowing them to be clinically removed [6]. Multiple regimens had been studied and implemented. The BMP regimen (bleomycin, methotrexate and cisplatin) being most commonly used had a 33–63% response rate which had definite therapeutic effect, but a confirmatory study reported that the treatment might be highly toxic and modest effect [7]. In head and neck cancer, neoadjuvant combination regimens containing taxanes produced high-response rates and improved survival outcomes in patients with unresectable disease [8, 9]. The chemotherapy regimens containing taxanes also Showed promising results to Penile cancer. The TPF protocol, including cisplatin (DDP), 5-fluorouracil and paclitaxel, is becoming widely accepted as the first-line treatment option because of good efficacy and low toxicity. However, a new study suggested that neoadjuvant TPF-chemotherapy obtained an imaging-based response in 60% of patients. However, pathologic complete response rate was only 4%. The 2-year PFS and DSS probability were only 12 and 28%, respectively. Toxicity was considerable in every study patient. TPF chemotherapy should be used with caution because of poor tolerance and disappointing survival rates [10]. Bermejo and his colleagues reported that four-fifths of patients receiving ITP neoadjuvant therapy (paclitaxel, cisplatin and ifosfamide) had a complete response, and three of them had a histologically confirmed complete response [11]. A larger sample study in the United States showed that 30 men received ITP treatment, of which 15 (50.0%) had an objective response, 22 (73.3%) underwent surgery and 9 had long-term survival [12].

To further evaluate the efficacy of neoadjuvant chemotherapy for penile cancer, we conducted a retrospective study of a combination of ITP administered before surgery for fixed inguinal lymph node metastasis or involved pelvic LN(N3) in patients with SCC of penis in China.

As previously mentioned, a lot of penile cancer patients had lymph node metastasis when newly diagnosed. The natural course of penile cancer is a progressive violation of the penis and then spread through the lymphatic vessels to the inguinal lymph nodes, ultimately involving the pelvic lymph nodes. The study of penile lymphangiography showed that the lymphatic metastasis of the penile carcinoma was from the inguinal superficial to deep inguinal lymph nodes and finally transferred to the pelvic lymph nodes, but did not find lymphatic jump transfer [15]. If untreated, the lymph node of the inguinal region will further expand and form an ulcer or tumor on the local skin that will invade the adjacent blood vessels and lead to blood and distant metastasis [16]. According to previous studies, whether the transfer of lymph nodes, degree of metastasis and whether the radical resection are the most important factors in determining prognosis [17, 18]. The occurrence of lymph node metastasis of penile cancer patients with the number of positive lymph nodes, unilateral or bilateral inguinal lymph node metastasis and whether there are pelvic lymph node involvement and lymph node invasion determine a different prognosis [19]. Pandey et al. [20] analyzed 102 cases of lymph node metastasis of penile cancer patients, which the results showed that 1 to 3, 4 to 5, 5 or more lymph node metastasis 5-year survival rates were 75. 6%, 8. 4%, 0, respectively. Studies have also shown that patients with inguinal lymph node metastasis had the 5-year survival rate of < 60% and the 5-year survival rate in pelvic lymph node metastasis was < 30% [21]. Therefore, early detection and treatment can lead to better prognosis. But just as previously described, due to benign initial symptoms, shame and insufficient awareness, a lot of the patients postponed treatment. In this study, the average course of disease was 6.6 months (range 40 days–2 years).

Lymph node metastasis is an important prognostic factor in patients with penile cancer, so the treatment of lymph nodes is essential. Fraley et al. [22] found that lymph node-positive patients with lymph node dissection in a 5-year disease-free survival rate of 75%, while the extension of surgery was 8%. Therefore, patients with pathologically confirmed lymph node metastasis, if safely and completely removed, should be immediately treated lymph node dissection to improve the prognosis of patients. Ravi et al. [23] found that up to 57% of patients with more than 3 positive inguinal lymph nodes had pelvic lymph node metastases. Therefore, the patients with ≥2 positive inguinal lymph nodes were recommended to be added pelvic lymph node dissection [3]. The patients with fixed inguinal lymph nodes or limited pelvic lymph node metastasis (N3) were recommended radiotherapy and chemotherapy combined surgery to achieve the basic principle which is to completely remove the lesion as much as possible. All of the studied patients were diagnosed with stage PN3 SSC of the penis. The responsive group (12 cases) were undergone Partial or total penectomy +lymph node dissection + pelvic lymph node dissection after the neoadjuvant chemotherapy, and the incisal margins were negative, which were in line with the principle of treatment. Postoperative pathology showed pelvic lymph node metastasis in 3 cases and the 3 cases all had pelvic lymph node recurrence or metastases later. Followed-up for average 39.6 months, four cases had pelvic lymph node recurrence or metastases in responsive group and then had both regional and systemic metastases, there was only one survivor (26 months) so far. Therefore, whether is meaningful for the pelvic lymph node-positive patients with pelvic lymph node dissection need further study.

Systemic chemotherapy can be used for lymph node metastasis of neoadjuvant therapy and adjuvant therapy. While the former can achieve tumor shrinkage small to achieve the purpose of complete resection of the operation, the latter mainly used for the multiple lymph node metastasis after surgery [24]. As the low incidence of penile cancer there was no large-scale literature published to guide the treatment of chemotherapy. Therefore, there is no standard treatment program so far. Through a variety of chemotherapeutic drugs in the treatment of penile cancer research, cisplatin-based combination of neoadjuvant chemotherapy can control the disease, reduce the lesion and improve the surgical results. In 1991, Dexeus and colleagues [25] reported that cisplatin (20 mg/m2 day 2–6) ,methotrexate (200 mg/m2 day 1 and 15) and bleomycin (10 mg/m2 day 2–6)(BMP) regimen for advanced squamous cell carcinoma achieved a response in 10 of 14 enrolled patients,which adverse effects were moderate. The regimen was soon widely used for penile cancer. But a series of subsequent studies have found that the program had limited efficacy, high toxicity and high treatment-related deaths [7, 26, 27]. Other regimens were tried later. As previously stated, TPF regimen, including cisplatin, 5-fluorouracil and paclitaxel, also had problems as similar as BMP regimen. Recently, the ITP regimen had been reported. As previously described, in a phase II trial involving 30 pN2/pN3 penile cancer patients treated in the neoadjuvant setting, there were able to achieve an objective response in 50% of men using neoadjuvant ITP (docetaxel, cisplatin and ifosfamide), which was accompanied by acceptable side effects. Ten patients (33.03%) were surviving after a median follow-up of 34 months [12]. On the basis of previous cases [12], a follow up study was implemented by Dickstein and colleagues [17] which broaden additional 31 patients and 5 years of follow-up. All patients were clinical or pathological stage T_any and N1–3 penile cancer. Fifty-four patients (88.5%) received ITP chemotherapy and seven received other initial therapy. CRs or PRs were found in 64% of regionally advanced penile cancer patients receiving ITP chemotherapy. OS of patients with objective response to chemotherapy (CR or PR) was 50.1% in 5 years. Despite the optimistic results, there are still many difficulties to overcome in these studies. Despite the optimistic results, there were still many difficulties that need to be overcome in these studies. As the paper said, because of the clinical or pathological stage N1–3, chemotherapy may delay the definitive operation, rendering some unresponsive patients unable to operate. The lack of chemotherapeutic regimen standardization and dose optimization limited the broader application of the ITP regimen. In our study, the recruited patients with histologically proven SCC of the penis were clinically staged TxN3M0, which would have been difficult to resect inguinal and pelvic lymph nodes without objective response for chemotherapy, so that it avoided the possibility that chemotherapy delayed definitive surgery.

Docetaxel and paclitaxel are taxanes. Docetaxel as a new generation of taxane drugs, is a semi-synthetic taxane. Its ability to bind to microtubule proteins is twice that of paclitaxel, which prevents the formation of spindles when cells are mitotic [28]. The accumulation of docetaxel in tumor cells is higher than that of paclitaxel, and the residence time is longer, which is more effective in anti-tumor effect [29]. In vitro tests, docetaxel’s tumor cell reduction rate was three times that of paclitaxel [30]. In the toxic and side effects, docetaxel’s allergic reactions, neurotoxicity and blood toxicity, especially leukopenia are significantly lighter than paclitaxel [31]. In our study, docetaxel replaced paclitaxel. The preoperative regimen consisted of up to 2–4 cycles every 21 days with docetaxel 75 mg/m² on day 1, ifosfamide 1200 mg/m² on days 1 to 3 and cisplatin 25 mg/m² on days 1 to 3. Postoperative patients received adjuvant chemotherapy with the same regimen of preoperative neoadjuvant chemotherapy that included 2–4 cycles. Usually each patient received a total of 6 cycles of chemotherapy, including preoperative and postoperative. Toxicity and side effects were controllable. No deaths which related to the treatment occurred.

In the present study, the overall objective response rate of neoadjuvant chemotherapy was 63% (12/19), similar to that described earlier [17]. Although making use of radiotherapy for non-responsive group, the treatment effect was still poor. The responsive group to chemotherapy had the median OS of 54 months (95% CI 22.035–85.965), while those with non-response had 15 months (95% CI 9.868–20.132). The data for PFS were similar when comparing responders with non-responders. The difference was statistically significant (log-rank test; P < 0.001). The survival number of patients in the responsive group was significantly higher than that of non-responsive group, suggesting that neoadjuvant chemotherapy of ITP in combination with surgery have good therapeutic effects for penile cancer patients with advanced lymph node metastasis.

In conclusion, according to our preliminary study, neoadjuvant docetaxel, cisplatin and ifosfamide chemotherapy gave 63% (12/19) of patients who were diagnosed with stage n3 penile cancer the chance of radical resection of metastases, and their OS and PFS were significantly higher than those who could not be operated on and the therapeutic dose, toxic and side effects are acceptable in the Chinese Han population. Therefore, neoadjuvant ITP chemotherapy in the treatment of stage T3 penile cancer patients may have cheerful prospects in the Chinese Han population. Due to limitations of small sample size further evaluation is necessary. The next study needs to expand the number of specimens and design prospective studies to improve the current research results.