The treatment guidelines for localized CDC align with those for localized RCC. Small tumors are typically managed with partial nephrectomies, while larger tumors often require radical or open nephrectomies. For patients who are not surgical candidates, options such as radiofrequency ablation, stereotactic body radiotherapy (SBRT), microwave ablation, or active surveillance may be considered, particularly for frail individuals with limited life expectancy [7] . However, localized disease of CDC remains an uncommon entity due to the tumor aggressiveness and progression.

Nephrectomy remains the number one treating modality based on the literature with many isolated cases of early disease having a long-term survival reported in the literature [9] - [11] . It is important to note that almost all localized collecting duct tumors are diagnosed based on pathology after nephrectomy. The nephrectomy being diagnostic and therapeutic in these cases. The type of surgery when treating these tumors remains unknown due to limited and insufficient data. However, there is a consensus that given the aggressive nature of this tumor, the most radical technique possible should be always considered (radical nephrectomy plus lymphadenectomy) [12] .

The effectiveness of adjuvant treatment after nephrectomy, for most cases of CDC reported in the literature, remains unsatisfactory. While some patients have undergone adjuvant systemic therapy, the outcomes have demonstrated limited efficacy, with survival times ranging from 4 to 7 months. In fact, Staehler et al. reported Two patients with CDC who underwent an adjuvant regimen of gemcitabine and cisplatin for two cycles following radical nephrectomy and lymphadenectomy. Local recurrence occurred subsequently in both cases. Additionally, sunitinib, used after complete resection of the relapse, failed to produce any clinical benefit [13] .

The ESMO approach of advanced CDC is similar to others non-clear-cell and non-papillary RCC. As consequence, enrolment into clinical trials is strongly recommended for treatment of advanced CDC, since any available evidence is primarily drawn from small prospective studies and subgroup analyses of larger trials. The ESMO recommends four regimens: cisplatin-based chemotherapy, Sunitinib, Pazopanib and Cabozantinib with these degrees of evidence II C, V C, V C and II C respectively [7] .

Data favoring cytoreductive nephrectomy (CN) and systemic therapy over systemic therapy (ST) alone is present in the literature. Panunzio et al. demonstrated that with a median overall survival of 4.0 months for CN alone vs. 5.5 months for ST alone vs. 9.0 months for combination of both CN + ST [14] . Class, dose, and duration of administered systemic therapy were unavailable.

Extrapolated from advanced bladder cancer therapy, the Gemcitabine-Cisplatin (GC) regimen remains nowadays, the first-line systemic treatment in metastatic CDC as no other specific chemotherapeutic agent has demonstrated a beneficial effect. Oudard et al. succeeded in confirming the effectiveness of the GC regimen in treating metastatic CDC. Participants received 21-day cycles of gemcitabine 1250 mg/m² on days 1 and 8, plus cisplatin 70 mg/m² or carboplatin on day 1, depending on renal function. The study showed a 26% (95% CI: 8% - 44%) objective response rate, almost similar to responses seen in urothelial carcinoma. Notably, 87% of patients had undergone nephrectomy before starting chemotherapy. Progression-free survival (PFS) was 7.1 months, and overall survival (OS) was 10.5 months. GC was relatively safe, with only mild-to-moderate toxicities (Grade 1 - 2) reported and no treatment discontinuation due to side effects [15] . In the McMaster series, cytoreductive nephrectomy was performed in 4 out of 6 patients. Among 2 patients who received MVAC therapy (methotrexate, vinblastine, doxorubicin, and cisplatin), no response was observed. While no major therapeutic complications were reported, median survival was 11 months (range: 10 - 33 months) [16] . Case reports have also highlighted responses to paclitaxel [17] , and paclitaxel and carboplatin [11] [18] .

Two old retrospective studies reported limited benefit of immunotherapy in treating metastatic CDC. In a Japanese study by Tokuda et al., 34 patients with CDC received interferon-alpha (IFN-α), interferon-gamma (IFN-γ), or interleukin-2 (IL-2), but no responses were observed. The authors noted only one partial response to gemcitabine-cisplatin after the failure of immunotherapy. Similarly, Motzer et al. reported no response among 15 patients treated with IFN-α or IL-2 for metastatic CDC. Based on these findings, immunotherapy appears to offer no significant benefit in this rare and aggressive cancer [4] [19] .

Concerning the new generation immunotherapy such as immune check-point inhibitors, nivolumab alone or in combination with ipilimumab have been used in several case studies with promising outcome [20] - [22] . Mizutani et al. and Yasuoka S et al. reported two cases that showed efficacy of Nivolumab in metastatic CDC with high PDL1 expression and progression on prior therapies with chemotherapy and targeted therapy [21] [22] . Fuu et al. described a case of CDC with high PD-L1 expression that received ipilimumab and nivolumab after progression. Despite developing interstitial pneumonitis due to treatment and receiving only one dose of it, the patient achieved complete response after three years of follow-up [20] . Watanabe et al. reported a case of CDC with metastases involving the paraaortic and bilateral external iliac lymph nodes on presentation. Cytoreductive open nephrectomy without lymphadenectomy was done and treatment with Ipilimumab and Nivolumab was given. Complete response was achieved at 6 months and lymphadenopathies shrunk to less than 1 cm. No data was given concerning the PD-L1 expression [23] .

The Phase II BONSAI Trial evaluated cabozantinib, a multi-targeted TKI given as 60 mg daily, in 25 patients with metastatic CDC. Among 23 evaluable patients, 3 achieved stable disease, 1 had a confirmed complete response, and 7 showed a partial response, resulting in an objective response rate of 35%. The median progression-free survival was 4 months (95% CI: 3 - 13 months), and the median overall survival was 7 months (95% CI: 3 - 31 months). After 12 months, 10 patients (43%) were still alive, and 5 patients (23%) were continuing treatment. Cabozantinib was generally safe with grade 3 adverse effects being reported such as arterial hypertension, pulmonary thromboembolism, bleeding, and fatigue. There were no permanent discontinuations owing to adverse effects. Four patients required dose reduction to 40 mg, and four a transitory interruption to manage toxic effects [24] .

In a systematic review and meta-analysis on systemic therapy in non-clear cell RCC, sunitinib was reported to be less efficient in this histologic type compared to sunitinib used in clear-cell RCC. Non-clear cell RCC included in this study papillary I/II, chromophobe, collecting duct, renal medullary, mucinous tubular, spindle cell, carcinoma associated with neuroblastoma, Xp11 translocation, and unclassified carcinomas. Sarcomatoid variant was considered a high-grade transformation of different subtypes of RCC. Specific data on collecting duct carcinomas was not recorded. The difference in response between clear cell and non-clear cell patients was not noted with Sorafenib which can be due to low number of treated patients with the agent [25] .

In a cohort of 333 patients including 7 with metastatic CDC, six patients had nephrectomies, while one was diagnosed through a biopsy due to local tumor extension. All 7 patients were treated with targeted therapies: 4 received sorafenib, 1 received sunitinib, and 2 received temsirolimus. After disease progression, 2 patients were given second-line treatment with sunitinib. Two patients showed disease control with their first treatment: one with sorafenib (33 months) and the other with temsirolimus (6 months). After progression, both received sunitinib as second-line therapy, achieving an additional 10 and 9 months of disease control, with overall survival of 49 and 19 months, respectively. The other five patients, who experienced early progression (3 on sorafenib, 1 on sunitinib, and 1 on temsirolimus), had a survival of only 4 months [26] . Zhao et al. reported a case of metastatic CDC treated with nephrectomy followed by GC. After disease progression, sorafenib was initiated, leading to a partial response with over 30% reduction in metastasis size. However, progression was observed 12 months after starting sorafenib [27] . Ansari et al. reported a patient with metastatic CDC showing an excellent clinical and radiological response, with progression-free survival exceeding 13 months with sorafenib therapy [28] .

In a Phase II trial, the combination of oral sorafenib with gemcitabine and cisplatin was evaluated in 26 metastatic CDC patients. Most patients had undergone nephrectomy prior to treatment. After four cycles of combination therapy, patients with complete response, partial response, or stable disease received maintenance sorafenib until disease progression or unacceptable toxicity. The treatment showed promising results, with a median progression-free survival of 8.8 months and a median overall survival of 12.5 months. The therapy was generally safe, with most side effects being mild to moderate and manageable through dose adjustments or supportive care. Myelosuppression and gastrointestinal issues were the most common side effects, and no treatment-related deaths were reported. Grade 3 - 4 toxicities such as leucopenia, thrombocytopenia and anaemia were also recorded [29] .

The combination of chemotherapy and Bevacizumab was also investigated in the setting of metastatic CDC. Despite small studies reporting positive responses when added to the combination of gemcitabine and cisplatin, larger trials have shown limited benefit [30] [31] . In fact, a small study of five patients with metastatic CDC treated with this combination followed by maintenance bevacizumab reported a median progression-free survival of 15.1 months and overall survival of 27.8 months, with manageable toxicities [30] . However, a phase II trial published in 2023, found no significant benefit from adding bevacizumab to chemotherapy in metastatic renal medullary carcinoma and metastatic CDC, with higher than-expected toxicity [32] . As a result, the addition of bevacizumab to GC regimen is not a standard therapeutic option for metastatic CDC patients.