The potential roles of pelvic lymph node dissection in patients with prostate cancer: obtaining deeper understandings based on current clinical evidence

Dear Editor,

With the elevation of mean global living quality and expansion of the aging population, the prevalence of prostate cancer (PCa) is dramatically increasing. Considering the significant impacts on the health of elderly males, it is essential to explore a comprehensive management strategy across the whole stage of PCa progression. PCa is featured with complicated tumor heterogeneity even at the same stage and possesses distinct molecular mechanisms among different subsets of patients in a specific manner. In real-world clinical practice, radical prostatectomy (RP) is widely recommended as a standard intervention for clinically localized PCa, usually accompanied by pelvic lymph node dissection (PLND) in selected patients¹. However, the standard protocol of PLND, which includes standard PLND (sPLND) and extended PLND (ePLND), and the related data regarding the detailed influence on clinical outcomes remain limited.

In the recent issue of the International Journal of Surgery, Ding et al.² conducted a meta-analysis to compare the difference in perioperative complications and biochemical recurrence (BCR) outcome after RP in combination with the sPLND or ePLND protocol. A total of 4962 PCa patients from nine published studies (three randomized clinical trials and six prospective studies) were included in their quantitative analysis. This study demonstrated that there were no obvious disparities presenting in overall perioperative complications or BCR between the sPLND subgroup and the ePLND subgroup. Only partial perioperative complications, such as lymphedema and urinary retention, were found to be more prevalent in the ePLND subgroup. Regarding BCR, they pointed out that ePLND did not bring a more favorable outcome, and no significant difference was observed in the setting of delaying PCa development. However, the authors proposed that patients may benefit from a diagnostic advantage from ePLND due to the elevated detection rate of lymph node metastasis. In view of the inconsistent data and conflicting perspectives on this issue, the results raised great interest for us to try to gain a deeper understanding of the potential roles of PLND in patients with PCa who are eligible to receive RP surgery. Thus, we aim to propose our narrow viewpoints to further explore the implications of PLND in RP protocol after carefully studying the research by Ding et al.

We are conscious that the authors chose to include prospective studies or random clinical trials (RCT) in the final quantity analysis, and only nine studies (including three RCTs) met the selection criteria. Although prospective clinical trials have a stronger level of evidence with reliability and generalizability, retrospective or single-armed data is also worthy of being taken into consideration in the context of limited muticenter prospective studies or scarce breakthroughs³. More importantly, the negative conclusions, unbalanced baseline characteristics, and tiny sample numbers of this study underscore the need to perform a comprehensive evaluation based on current, reliable prospective and retrospective data. Of note, the potential heterogeneities across different study types should be carefully addressed to maximize the scientificity and rationality of data interpretation.

The PCa-specific efficiency or prognostic outcomes are important to be carefully analyzed to draw a conclusion, and only the BCR endpoint was included in this study. As mentioned in the results, no significant differences were presented between the sPLND and ePLND subgroups. However, the detailed process of PCa progression is more complex than we could understand. In addition to BCR, pathologic metastasis can occur even when the level of prostate-specific antigen (PSA) has not changed obviously. Under this circumstance, metastasis confers the completely distinct molecular features onto tumor biology in a subset of patients that are linked to poor long-term survival⁴. Thus, if we can combine metastatic status, overall survival, progression-free survival (including clinical, radiographical, and biochemical), cancer-specific survival, and other endpoints, a more reliable conclusion will be reached to elucidate the PLND-associated tumor prognosis.

The main endpoints of interest in this study were perioperative complications and BCR. The factors impacting these outcomes can be derived from four aspects: surgeon, operative protocol, tumor heterogeneity, and individual differences. To reduce the non-study effects of the potential confounding factors listed above, we can analyze more data to gain an informed conclusion with generalizability. For example, authors can conduct more comparisons on the surgeon’s seniority or experience or study country/region, operative time and modality (open or laparoscopic), tumor features (including size, stage, local invasion, etc.), and patient demographic characteristics if these data were available. Maybe more statistically significant results will be revealed among these detailed subsets of patients between sPLND and ePLND.

Noteworthy, in clinical practice, neoadjuvant hormonal therapy (NAHT) is applied in selected subsets of PCa patients, which may reduce the incidence or probability of pT3, positive surgical margins, and positive lymph nodes⁵. It is unclear whether NAHT could change tumor load and correlate to the different perioperative complications and BCR of subsequent RP surgery. The possible impacts of NAHT on PLND remain unexplored and need to be further confirmed. Likewise, postoperative adjuvant or salvage therapy can be utilized to gain prognostic benefits when positive incisal margin or lymph nodes are detected among high-risk patients. The currently available options mainly consist of hormonal therapy, radiotherapy, and chemotherapy after RP⁶. However, there is no consensus on the optimal management for this dilemma. Collectively, both NHAT and postoperative adjuvant modalities can potentially influence the survival outcomes and surgery-induced adverse events (AEs) of sPLND and ePLND arms. The extent that can be explained by additional interventions is poorly understood, which is also not properly considered as a confounding factor in this study.

In conclusion, the study by Ding and his colleagues provides intensive perspectives in the field of PCa and surgical advances. Based on currently available clinical evidence, it is hard to say which option is the best. In our opinion, given the equivalent effectiveness and safety revealed by recent studies, it is better to choose sPLND or ePLND after comprehensively evaluating the benefits and risks for different patients. For patients who have a relatively long expected lifetime, the decision-making may be more radical with ePLND, which may provide additional information about pathologic staging and reduce the recurrence or metastasis risk. It is not suitable to apply ePLND among all patients without gaining definite evidence that ePLND can improve survival outcomes compared to sPLND. Thus, sPLND is a more secure option for aged or common patients at the current stage. With a more finessed understanding of the roles of PLND in locally confined PCa receiving RP, more research would be needed to further confirm the molecular mechanisms behind current clinical observations and correlations and, consequently, to guide personalized therapy.

Ethical approval

As the data is publicly accessible, institutional review board approval was not required.

Consent

Not applicable.

Source of funding

This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFC3602900), the National Natural Science Foundation of China (Grant No. 82170785, 81974099), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYGD23001), the Science and Technology Innovation Talent Project of Sichuan, China (Grant No. 2023JDRC0023), the Postdoctoral Fellowship Program of CPSF under Grant Number GZB20240491, and the Clinical Research Incubation Project of West China Hospital of Sichuan University (Grant No. 2020HXFH033).

Author contribution

Q.W. and H.D.: conceptualization and methodology; Y.H.: data collection; J.Y., T.P., and H.X.: writing – original draft; Q.W. and H.D.: writing – review and editing, supervision, and funding acquisition.

Conflicts of interest disclosure

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Hongbo Dong.

Data availability statement

Not applicable.

Provenance and peer review

Not commissioned, externally peer-reviewed.