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Ah-Thiane, L.; Rousseau, C.; Aumont, M.; Cailleteau, A.; Doré, M.; Mervoyer, A.; Vaugier, L.; Supiot, S. The Sentinel Lymph Node in Treatment Planning. Encyclopedia. Available online: https://encyclopedia.pub/entry/45436 (accessed on 27 July 2024).
Ah-Thiane L, Rousseau C, Aumont M, Cailleteau A, Doré M, Mervoyer A, et al. The Sentinel Lymph Node in Treatment Planning. Encyclopedia. Available at: https://encyclopedia.pub/entry/45436. Accessed July 27, 2024.
Ah-Thiane, Loic, Caroline Rousseau, Maud Aumont, Axel Cailleteau, Mélanie Doré, Augustin Mervoyer, Loig Vaugier, Stéphane Supiot. "The Sentinel Lymph Node in Treatment Planning" Encyclopedia, https://encyclopedia.pub/entry/45436 (accessed July 27, 2024).
Ah-Thiane, L., Rousseau, C., Aumont, M., Cailleteau, A., Doré, M., Mervoyer, A., Vaugier, L., & Supiot, S. (2023, June 12). The Sentinel Lymph Node in Treatment Planning. In Encyclopedia. https://encyclopedia.pub/entry/45436
Ah-Thiane, Loic, et al. "The Sentinel Lymph Node in Treatment Planning." Encyclopedia. Web. 12 June, 2023.
The Sentinel Lymph Node in Treatment Planning
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15102736

The sentinel lymph node is a surgical technique developed in oncological surgery to identify and analyze fewer lymph nodes than a conventional lymph node dissection in order to limit the morbidity and mortality of such an extensive procedure without compromising the patients’ outcomes. This concept seems to also be useful in radiation oncology that treats lymph node areas. This may help radiation oncologists to treat their patients more precisely by targeting more accurately pathological sites and sparing healthy tissues.

sentinel lymph node lymphatic drainage radiation therapy lymph flow guided radiotherapy

1. Introduction

The lymphatic vasculature is a system draining the organs through vessels and lymph nodes that act as filters. Its complexity stems from the numerous anatomical variants described in studies during cadaver dissections or surgical explorations, but knowledge of these variations is becoming increasingly available [1]. The metastatic spreading of cancer was described in some models to start with the invasion of the first draining loco-regional nodes, which then became known as sentinel lymph nodes (SLNs) [2]. The idea of using these SLNs thus emerged, based on a sentinel lymph node mapping (SLNM) using colorimetric, fluorescent or radioisotope tracers to identify the area of drainage of an anatomical territory, followed by sentinel lymph node biopsies (SLNBs) to assess whether a node is pathological (pSLN) or not (nSLN) [3]. The concept of SLNs was a major breakthrough for surgeons, allowing for a decrease in the number of morbid extensive lymph node dissections (ELND). SLNB is a minimally invasive technique, used routinely in penile cancer, breast cancer and melanoma thanks to its reliable performance and proven safety, and plays a key role in cancer staging and treatment decisions [4][5].

2. Breast Cancer

2.1. Axillary Lymph Node Dissection (ALND) Can Be Avoided Thanks to SLNB

In patients with nSLN, ALND can be avoided, as no difference was observed in overall and disease-free survival, or in axillary failure, which was low and reported in 0.7–0.8% of patients [6][7].
In patients with pSLN presenting a tumor smaller than 5 cm and no palpable adenopathy (cT1-T2 cN0), ALND could be avoided in patients with micrometastasis (<2 mm), since the IBCSG 23-01 trial showed no inferiority in disease-free survival after 10 years [8], as well as in patients with up to two macrometastasis but no capsular effraction, since the ACOSOG Z0011 (Alliance) trial showed no inferiority in overall survival after 10 years [9]. ALND was also proposed to be replaced by axillary radiotherapy, since the AMAROS and OTOASOR trials showed no difference in overall and disease-free survival between ALND and axillary radiotherapy [10][11]. A retrospective study compared 260 patients who received axillary radiotherapy versus those who did not and found no significant difference: 5-year overall survival was 93.4% versus 96.8% (p = 0.19), respectively, and 5-year disease-free survival was 92.3% versus 100% (p = 1.06), respectively [12].
A systematic review highlighted that ALND induced significantly more lymphedemas and shoulder dysfunctions in comparison with observation or axillary radiotherapy [13]. For most patients with nSLN or with pSLN (up to two metastasis) and cT1-T2 cN0 tumors, ALND should be avoided to decrease morbidity. Axillary radiotherapy is worth discussing in case of risk factors.

2.2. SLNM/SLNB Indicates Nodal Irradiation

Regional nodal irradiation, in addition to breast/chest wall irradiation, is currently indicated in case of clinical or pathological node involvement but deserves to be challenged. In fact, two phase III trials demonstrated that nodal irradiation (including axillary, infra/supraclavicular, internal mammary nodes) reduced breast cancer recurrence and specific mortality but did not significantly improve overall survival [14][15]. Moreover, a recent trial randomized 735 patients who received nodal irradiation, both including and excluding the internal mammary nodes, and found no benefit to irradiating this area, with the exception of a subgroup of patients with medial/central tumors [16], explained by their pattern of lymphatic drainage. Some authors suggested performing SLNM with the acquisition of SPECT/CT images to identify the drainage of each tumor, knowing that up to 50% of patients can present drainage in both axillary and internal mammary nodes, depending on the tumor’s location [17]. Figure 1 shows two examples of drainage in internal mammary nodes. However, in practice, only axillary nodes are noticed because they matter in surgery. Given recent findings, knowing the specific drainage of the cancer would help radiation oncologists delineate lymphatic areas, notably the internal mammary nodes, for relevant prophylactic irradiation [18].
Cancers 15 02736 g001
Figure 1. Examples of breast cancer drainage in the internal mammary nodes visualized in SPECT-CT. (A) A 36-year-old woman was diagnosed with two malignant nodules in the right breast, localized in the inner quadrants. The sentinel lymph node mapping revealed drainage in both the axillary (green line) and the internal mammary nodes (red arrow). (B) A 40-year-old woman was diagnosed with a malignant nodule in the left breast, localized in the upper-inner quadrant. The sentinel lymph node mapping revealed drainage in the internal mammary nodes (red arrow).
While SLNM identifies lymphatic drainage of the breast tumor after peritumoral tracer injection, axillary reverse mapping (ARM) identifies drainage of the upper limb after arm injection. ARM was initially developed for surgeons to preserve the main nodes draining the arm and not the tumor during ALND 6, but ARM seemed to be applicable for axillary irradiation too [19]. A dosimetric evaluation pointed out that all the nodes identified by ARM received the prescribed dose during standard axillary radiotherapy, explaining the rate of arm lymphedema [20]. A pilot study showed the feasibility of combining SLNM and ARM to preserve the main nodes, draining the arm while conserving the good coverage of the SLN sites in 5/6 of the patients. In the remaining patient, it was not possible to preserve these nodes because the SLNM and ARM overlapped [21]. The next step is to conduct trials to evaluate the oncological outcomes and their impact on lymphedema when reducing axillary irradiation volumes.

2.3. The Role of SLNB Needs to Be Redefined in a Neoadjuvant Setting

In cN0 patients, SLNB after neoadjuvant chemotherapy demonstrated a comparable performance to SLNB in upfront surgery and reduced the need to perform an ALND [22].
In patients with nodes confirmed by histology, the SN FNAC trial validated SLNB after neoadjuvant chemotherapy [23]. In case of residual nodal disease (ypN+), the guidelines recommend treating the axillary nodes [24]. For these patients, the ongoing ALLIANCE A011202 trial aims to determine the optimal treatment by comparing ALND and axillary radiotherapy with axillary radiotherapy alone (ClinicalTrials.gov number: NCT01901094). In case of complete nodal response (ypNO), the need for adjuvant nodal treatment is more debatable; hence, the ongoing NSAPB B-51 trial compares nodal irradiation with observation (ClinicalTrials.gov number: NCT01872975).
In conclusion, there is a clear decrease in ALND in breast cancer thanks to SLNB, in cases of nSLN but also in selected cases of pSLN. The results of SLNB indicate nodal irradiation, but SLNM may also provide some information on specific tumor drainage (especially internal mammary drainage) to help define which volumes should be targeted in radiotherapy. Moreover, ARM identifies the lymphatic nodes that drain the arm instead of the tumor and is worth exploring to reduce radiation-induced lymphedema. LFGRT is thus appealing as an effective method of irradiation with lower toxicity.

3. Gynecologic Cancers

3.1. SLNB Is a Well-Documented Technique in Vulvar Cancers

Locally advanced vulvar carcinomas are usually treated conservatively thanks to chemoradiation, whereas early-stage treatment consists of radical resection with nodal assessment and can be followed by adjuvant radiotherapy. Lymph node staging is a major prognostic factor in vulvar cancers [25]. For FIGO IB to II and lateral lesions (≥2 cm from vulvar midline) with clinically/radiologically node negative tumors, SLNB is recommended, since nSLN is associated with low morbidity, groin recurrence and disease-specific mortality, while being more cost-effective than extensive lymphadenectomy [26].
In case of pSLN, the management of ipsilateral groin with lymphadenectomy and radiotherapy should be discussed [27]. The GROINSS-V-II trial studied 322 patients with pSLN to evaluate whether groin dissection could be replaced by inguinofemoral radiotherapy. Due to high groin recurrence, the protocol had to be amended to allow for patients with SLN > 2 mm (macrometastasis) to undergo lymphadenectomy as the standard of care, but patients with SLN ≤ 2 mm (micrometastasis) could continue to receive radiotherapy. The 2-year groin recurrence rate was low for patients with micrometastasis (1.6%), but high for patients with macrometastasis when treated by radiotherapy (22%) compared to those treated by lymphadenectomy (6.9%). Ipsilateral inguinofemoral irradiation appears to be a low-morbidity option for patients with micrometastasis but should not be the first intention in case of macrometastasis [28].
How to manage contralateral groin remains unclear. Two retrospective monocentric studies suggested not treating contralateral groin, since they found very low rates of contralateral involvement: 0% (0/28) patients and 5.3% (1/19) patients, respectively [29][30]. However, a recent study reported a higher rate of contralateral involvement, at 22.2% (4/18) of patients, after an initial diagnosis of unilateral metastasis, supporting current guidelines in favor of contralateral prophylactic treatment by either lymphadenectomy or radiotherapy [31].
For larger tumors (greater than 4 cm), the negative predictive value deteriorates, so there is no strong evidence to recommend using the SLN technique [30].

3.2. SLNB Is Not the Standard Reference for Node Staging in Cervical Cancers at Present

Lymph node status leads the indication for radiotherapy in cervical cancers. The treatment is exclusively chemoradiation if metastatic lymph nodes are detected before radical surgery, or adjuvant chemoradiation if detected after resection. SLNB is currently employed in addition to pelvic node dissection but not alone, despite some interesting performances [32]. Indeed, questions have been raised about the ability to detect micrometastasis, reliability in intraoperative detection and the limited evidence obtained from prospective studies [33]. The SENTIX trial evaluated intraoperative SLN frozen section and SLNB without pelvic node dissection in 395 patients: SLN pathological examinations achieved high detection for node staging, but the intraoperative SLN frozen section failed to detect about 50% of pathological nodes [34]. Ongoing SENTICOL III and PHENIX trials are enrolling patients with early-stage cervical cancer. The SENTICOL III trial follows the SENTICOL II trial, which showed the decreased morbidity of SLNB alone [35] and randomizes patients between SLNB alone (experimental arm) and SLNB plus pelvic node dissection (reference arm). In the PHENIX trial, all patients undergo SLNB and are allocated into either the PHENIX-I (if nSLN) or PHENIX-II (if pSLN) cohorts. Patients in each cohort are randomized after the SLNB between observation (experimental arm) and pelvic node dissection (reference arm). The primary outcome of these two trials is disease-free survival to demonstrate non-inferiority, and results are expected in 2026 [36][37].
For more advanced cervical cancers, higher than FIGO 2018 stage Ib3, the involvement of para-aortic nodes needs to be assessed to guide irradiation volumes. This assessment is based on FDG PET-CT and para-aortic lymphadenectomy. The role played by SLNB is little documented and thus cannot be recommended [38][39].

4. Urologic Cancers

4.1. Penile Cancers Represent a Leading Indication of SLNB

In penile cancers, SLNB is a highly recommended procedure for the management of clinically node-negative patients based on the European Association of Urology guidelines [40]. Systematic reviews have confirmed the relevance of SLNB in this cancer, which has a very stereotyped echelon-based pattern of lymphatic drainage [41][42]. SLNs are detected during surgery with a high sensitivity and specificity of about 77% and 100%, respectively [43], especially when using blue dye and radiotracer in combination [44]. Performances appear even better when acquiring 3D-imaging in SPECT/CT before surgical detection, to increase the detection rate [45] and decrease the rate of false-positive nodes [46].
However, no studies investigated the use of SLNM and SLNB in radiation oncology, mainly because the benefits of nodal irradiation have not been demonstrated. In the absence of nodal involvement, prophylactic inguinal irradiation at 50 Gy showed no decrease in recurrences compared to surveillance [47]. If lymph nodes are involved, inguinal dissection is performed, and adjuvant radiotherapy might be offered in case of bad prognosis factors. The use of adjuvant radiotherapy is under debate since a systematic review showed no benefits, and thus a standard recommendation cannot be made [48].

4.2. SLNB Is Non-Mature in Bladder, Testicular, and Renal Cancers

SLNB has been described in bladder cancers for more than 20 years, but still presents non-negligible rates of false-negative lymph nodes, thus requiring further investigation, notably regarding radiotracers and detection techniques [49][50].
In testicular cancers, SLNB appears safe in prospective studies, but its value for guiding adjuvant treatment remains to be demonstrated [51][52].
In renal cancers, SLNM is not an easy technique to reproduce because it can be non-contributory in 30% of cases due to a lack of drainage of the radiotracer through lymphatic vessels [53]. Aside from these technical difficulties, its ability to detect and then treat lymph nodes is debated since it does not seem to change overall survival according to a recent meta-analysis [54].

5. Anal Cancer

5.1. SLNB Shows Better Performances Than FDG PET-CT for Detecting Metastases in Inguinal Nodes

The standard treatment of anal cancers is based on radiotherapy for T1 N0 tumors or concurrent radiochemotherapy (most often with 5FU and mitomycine C) for the others. Irradiation concerns the gross tumor, pelvic nodes, and inguinal nodes. Cancer staging currently relies on FDG PET-CT due to its high sensitivity. For instance, a study showed the perfect sensitivity of PET-CT, which did not miss any metastatic inguinal nodes, but reported a significant number of false-positive images, leading to a poor positive predictive value of only 43% [55]. Another study evaluated the SLNB of inguinal nodes and found this technique to be superior to FDG PET-CT, with fewer false-positive and false-negative patients [56]. In addition to better accuracy, a study revealed that pSLN was associated with oncological outcomes and a much better prognosis factor than positive inguinal uptake in FDG PET-CT. In fact, inguinal pSLN was significantly associated with a decrease in disease-free (21 vs. 56 months; p = 0.046) and overall (28 vs. 59 months; p = 0.028) survival [57]. Inguinal SLNB should be used more [58], as several literature reviews have reported good reproducibility and performance and acceptable rates of complications, but its deployment is limited by a lack of trials with a large population, notably because anal cancer is a rather rare cancer [59][60].

5.2. SLNB Could Spare Groin Irradiation and Its Toxicities

The selection of patients for groin irradiation currently depends on tumor size: T1 tumors are not a systematic indication, while groin irradiation is generally indicated for T2 or higher tumors. These rules present two problems: first, some T1 tumors may have occult inguinal metastasis whereas some T2 tumors may not, and second, groin irradiation can be poorly tolerated. The idea of adjusting radiation fields based on SLNB is not new in anal cancers [61]. A pilot study tested the feasibility of performing inguinal SLNB on patients with T1 or T2 anal tumors and irradiating the groin only in cases of pSLN [62]. The results of SLNB changed management in half (10/20) of their patients: 4 patients with a T1 tumor and pSLN received groin irradiation that was not initially indicated, and 6 patients with a T2 tumor and nSLN avoided groin irradiation that was initially indicated. Nevertheless, treatment de-escalation requires caution because a prospective study agreed with the feasibility of SLNB but also reported the cases of 2 out of 14 patients with nSLN who were spared groin irradiation, and who then developed inguinal metastasis at one year and two years, respectively [63]. Another study combined the use of FDG PET-CT and SLNB for inguinal staging, and patients presenting no sign of inguinal involvement in both exams avoided groin irradiation, and then presented significantly less inguinal dermatitis, especially severe dermatitis (grades 1–2: 12% vs. 50% and grades 3–4: 0% vs. 17%; p < 0.05) [64]. A retrospective study confirmed the difference between patients with nSLN and pSLN in terms of prognosis for disease-free and overall survival, and showed that it seemed safe not to target inguinal nodes in cases of nSLN, as none of their patients presented inguinal recurrence after a mean follow-up of 43 months [65].
In conclusion, disease staging in anal cancers is currently based on FDG PET-CT, which has shown good performances for pelvic nodes or visceral metastasis. However, FDG PET-CT has its limits for inguinal status, with a high rate of false positives. Inguinal SLNB can be seen as a more reliable alternative to inguinal staging, as well as to “LFGRT” where radiation fields are tailored to each patient. As anal cancers are uncommon, data on oncologic outcomes are lacking and comparative trials are needed.

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Subjects: Radiology, Nuclear Medicine & Medical Imaging
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Loic Ah-Thiane
,
Caroline Rousseau
,
Maud Aumont
,
Axel Cailleteau
,
Mélanie Doré
,
Augustin Mervoyer
,
Loig Vaugier
,
Stéphane Supiot
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Update Date: 13 Jun 2023
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