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Abstract
Para-aortic lymph node status at initial assessment is the most important prognostic factor and a key point for the therapeutic strategy in patients with locally advanced cervical cancer. Undiagnosed lymph node metastasis is a major clinical problem as the finding of positive para-aortic lymph nodes leads to treatment modification, with a possible impact on disease free survival. When aortic lymph node disease is discovered, radiotherapy is extended to the para-aortic area, and other treatment modalities may be considered. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is the most accurate imaging examination to assess para-aortic extension in patients with locally advanced cervical cancer. The gold standard to identify para-aortic extension remains histologic evaluation of the lymph nodes. Indeed, PET/CT fails to detect approximately 10–15% of patients with negative PET/CT aortic nodes who have lymph node metastasis on pathologic staging. Patients with positive pelvic lymph nodes have para-aortic extension in 25–30% of cases, and surgical staging will lead to treatment modification and probably to improved para-aortic and distant control. Surgical staging also avoids unnecessary toxicity associated with extended field radiation in approximately 75% of patients with pelvic lymph node metastasis. The best modality to identify para-aortic extension is histological evaluation of the lymph nodes, but the survival benefit of surgical staging remains controversial. On the other hand, current studies include a majority of patients without pelvic lymph node spread, who are likely to be those who will benefit the least from surgical staging.
- cervical cancer
- surgical procedures, operative
- lymph nodes
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Introduction
Worldwide, cervical cancer is one of the most common malignancies, and remains one of the most common causes of death among women.1 Although cervical cancer is often curable if detected early, unfortunately more than one-third of patients present with a locally advanced cervical cancer at diagnosis, even in developed countries.2 Locally advanced cervical cancer corresponds to an invasive carcinoma of more than 4 cm in greatest dimension and/or to a tumor that extends beyond the uterus.3 Para-aortic lymph node status is the most important prognostic factor in patients with locally advanced cervical cancer, with a mortality rate of about 30–50%.4 Based on the results of five phase III randomized trials, the American National Cancer Institute recommends concurrent platinum based chemotherapy to treat patients with locally advanced cervical cancer.5 6 According to the 2016 American Cancer Society data, the 5 year survival rate per stage is approximately 63% for stage IIA, 58% for stage IIB, 35% for stage IIIA, 30% for stage IIIB, and about 16% for stage IVA.7 Lymph node involvement and para-aortic location are the most important prognostic factors, along with age, race, performance status, stage, tumor volume, depth of cervical stromal invasion, histological type, grade, lymphovascular space invasion, locoregional extension, and response to concurrent chemoradiotherapy.8 Survival of patients with para-aortic lymph node involvement remains poor, with the majority of patients experiencing distant failures.9 10
The recent International Federation of Gynecology and Obstetrics (FIGO) classification of cervical cancer has integrated lymph node involvement.3 Patients are assigned to stage IIIC1 or IIIC2 when pelvic or aortic lymph nodes are involved on radiological or pathology examination, irrespective of the extent of the cervical tumor.3 In a systematic review article including 22 articles, para-aortic lymph node metastasis was found in 11% of stage IB2 patients, 13% of stage IIA patients, 16% of stage IIB patients, 29% of stage III patients, and 36% of stage IVA patients.11 Isolated para-aortic lymph node metastasis was present in 25% of patients (range 0–70%), and para-aortic lymph node and pelvic lymph node metastasis in 75% of patients (range 30–100%).11
In addition, aortic involvement guides treatment planning. Aortic lymph node involvement requires extension of the irradiation field and possibly additional adjuvant chemotherapy.12 13 The use of imaging techniques, such as magnetic resonance imaging (MRI) or computed tomography (CT) is limited by the high false negative rate. The use of positron emission tomography/computed tomography (PET/CT) has a lower false negative rate but surgical staging is the only strategy to achieve maximum sensitivity in the assessment of lymph node status in patients with locally advanced cervical cancer. However, the survival benefit of surgical staging compared with radiological staging remains controversial,14–18 particularly when using PET/CT, and national and international guidelines differ in staging modalities in assessing para-aortic lymph node status.19–22
Para-aortic Lymph Node Imaging Assessment
Assessment of aortic lymph node involvement has been performed using different imaging modalities. Choi et al performed a meta-analysis to evaluate the diagnostic performance of different imaging modalities to detect lymph node involvement in patients with cervical cancer.23 Analysis from 41 studies showed an overall higher diagnostic accuracy for PET/CT, in a per patient and region or node based analysis. Sensitivity was 82%, 50%, and 56%, and specificity was 95%, 90%, and 91% for PET/CT, CT, and MRI, respectively. In node based data analysis, sensitivities for CT (52%), and PET or PET/CT (54%) were higher than MRI (38%).23 The false negative rate for para-aortic lymph node on preoperative imaging was 9–35% for CT scan and/or MRI, 4–11% for PET, and 6–15% for PET/CT in a review article including 22 studies.11 PET/CT is consequently used as the reference imaging examination for the non-invasive staging of locally advanced cervical cancer to assess lymph node involvement and distant sites of metastatic disease.20 Of note, a recent meta-analysis including 10 studies found a higher diagnostic performance of PET/CT in a populations of patients with a risk of para-aortic lymph node metastasis higher than 15%, with 73% sensitivity and 93% specificity. In contrast, the authors reported a false positive rates of 35% when prevalence decreased to 15%.24
The low diagnostic performance of CT and MRI may be partly explained by the definition of metastatic lymph nodes according to size criteria, with the largest short axis of 10 mm usually used as the cut-off. Lowering the cut-off leads to increase sensitivity while decreasing specificity, as differentiating nodal metastasis from hyperplastic enlargement is more difficult in small nodes. A few studies have assessed region based or node based analysis separately.23 Diffusion weighted MRI is sensitive to diffusion of water molecules in tissue, and adds functional information that can improve characterization of malignant lymph nodes. Quantitative information may be obtained by using apparent diffusion coefficient values. A meta-analysis by Shen et al showed a pool sensitivity of 0.86 (95% confidence interval (CI) 0.84 to 0.89) and specificity of 0.84 (95% CI 0.83 to 0.86).25 However, the meta-analysis was limited by the heterogeneity between the studies, explained by various protocols for diffusion weighted imaging, and different magnetic field strength and sequences.25 A radiomics model of intratumoral and peritumoral tissues may also improve preoperative identification of lymph node metastasis in locally advanced cervical cancer.26
PET/CT fails to detect small volume disease below 5 mm, and between 10% and 15% of cases of aortic lymph node involvement will remain undertreated.4 27–29 According to these data, in a cohort of 100 patients without para-aortic lymph node PET/CT uptake, 85–90 patients will undergo unnecessary surgical staging. From these 10–15 patients with positive para-aortic nodes, almost half will have small volume nodal disease. The overall false negative rate for PET/CT is relatively low; the increased incidence in high risk populations may be related to the efficiency of surgical staging. Indeed, the prevalence of undetected para-aortic metastasis at preoperative PET/CT can be higher than 50% in patients with pelvic lymph nodes presenting high metabolic activity.29
Pelvic lymph node uptake is the most significant factor associated with para-aortic lymph node extension.4 The risk of para-aortic extension increases with the number of pelvic lymph nodes involved.30 Patients without pelvic lymph node involvement have less than a 5% risk of para-aortic lymph node metastasis.4 27 29 Patients with suspicious pelvic lymph node metastasis and negative uptake in the para-aortic area at preoperative PET/CT have metastases to the para-aortic nodes in 20–25% of cases on pathology.4 27 This false negative rate is probably related to the limited spatial resolution of PET/CT, as patients with negative para-aortic lymph node uptake are more likely to have small volume lymph node metastasis.4 31 Low volume para-aortic lymph node metastasis, measuring less than 5 mm, is found in approximately half of patients with positive nodes on pathology and negative para-aortic lymph nodes on preoperative PET/CT.4 32 Metabolic parameters of the tumor and pelvic lymph nodes may help define the risk of para-aortic lymph node metastasis. The best trade-off between sensitivity and specificity in predicting para-aortic lymph node involvement is the ratio between pelvic lymph node and tumor maximum standardized uptake value (node SUVmax/tumor SUVmax).29
In some institutions, laparoscopic surgical aortic staging is offered to tailor the radiotherapy field and avoid both undertreatment of missed stage IIIC2 and unnecessary extended field radiation of stage IIIC1, the latter resulting in increased morbidity and impaired quality of life.33 34 Para-aortic dissection is the most accurate method of providing information on lymph node extension to the para-aortic area. Para-aortic nodal metastasis can be identified in 5.9–33.3% of patients with negative preoperative imaging, depending on the imaging modalities used (Table 1). The safety and feasibility of para-aortic surgical staging by minimally invasive surgery has been demonstrated in multiple retrospective and prospective studies.4 10 35 36 Surgical assessment may also identify peritoneal spread, which may be found in up to 10% of patients.37 Compared with the open approach, laparoscopic staging retrieves a similar lymph count,24 38 and is associated with less postoperative morbidity and improved recovery. The extraperitoneal approach may further reduce adhesions and the rate of intestinal complications associated with radiotherapy.35 39
Accuracy of positron emission tomography/computed tomography to detect para-aortic lymph node metastases in selected series with locally advanced cervical cancer
However, the benefit of surgical staging remains unclear and depends on three main questions. First, what is the prognostic impact of removal of tumor lymph nodes? Second, does para-aortic lymph node extension modify the treatment strategy with an increase in survival? Third, what is the associated morbidity from surgery and the delay to chemoradiotherapy when surgical staging is performed?
Survival Impact of Para-aortic Lymph Node Staging
Reports addressing the survival benefit of para-aortic lymph node dissection remain controversial (Table 2).4 16 17 30 36 A systematic review including 22 articles assessed pretreatment retroperitoneal para-aortic staging in locally advanced cervical cancer. The authors concluded that surgical staging led to treatment modification in 7–58% of cases (mean 20%), and may improve disease free survival and overall survival.11 40 A Cochrane review did not find evidence that surgical staging was beneficial, and concluded that the decision to offer lymphadenectomy in locally advanced cervical cancer should be individualized.40 Two randomized clinical trials comparing radiological staging with CT imaging and surgical staging have been published. A randomized trial performed by Lai et al was the first to address this question. A total of 61 patients with locally advanced cervical cancer were randomized to surgical (32 patients) versus radiological (29 patients) staging using CT imaging. Survival analysis was based on intention to treat. Patients who underwent surgical staging had significantly worse progression free survival, with a hazard ratio (HR) of relapse or persistent disease of 3.13 (95% CI 1.42 to 6.89, p=0.005), and an HR for mortality of 1.76 (95% CI 0.81 to 3.79, p=0.150). Overall survival difference became significant as data matured. Delay to chemoradiotherapy was significantly longer in the surgical arm, and grade 3 toxicity was not significantly increased in the clinical staging arm. This study was, however, weakened by methodological flaws.14 First, this study only included 62 patients and was closed prematurely. Second, the groups were not well balanced. Patients in the surgical group had more advanced disease (stage III vs II, more >6 cm tumors, and more patients with radiological pelvic nodes involved), had more unfavorable histology, and were less frequently treated with chemoradiation. Two patients with para-aortic lymph node involvement did not receive extended field radiotherapy. Third, two of the eight deaths in the surgical group were not related to disease progression but to treatment related complications.14
Studies comparing survival between surgical and radiological para-aortic staging in patients with locally advanced cervical cancer
Results of the randomized controlled trial, UTERUS 11, presented at the International Gynecologic Cancer Society 2019 meeting, included 240 patients with locally advanced cervical cancer randomized to radiological staging by CT scan or surgical staging.18 This study failed to show a significant difference in overall survival between surgical and radiologic staging. An ad hoc analysis of the data showed that surgical staging led to superior cancer specific survival compared with clinical staging with CT scan. However, it should be noted that cancer specific survival was not the objective of the study. Surgical staging did not result in significant delay of chemoradiation, and perioperative morbidity was low. High risk of distant metastasis in both arms highlighted the need for intensified treatment in para-aortic lymph node positive patients. As patients without pelvic lymph node metastasis represented up to 65–80% of patients with locally advanced cervical cancer,4 29 even if a randomized controlled trial using PET/CT was performed, a low rate of para-aortic lymph node involvement in patients without pelvic lymph node uptake would require a very large population to have enough statistical power. Unfortunately, the randomized controlled trial LiLACs (Lymphadenectomy in Locally Advanced Cervical Cancer, NCT 02848716), designed to determine the survival difference of surgical and radiologic staging in patients with pelvic lymph node uptake on preoperative PET/CT, was closed prematurely due to low accrual.
Gold et al performed a post hoc analysis including 685 patients from three different randomized Gynecologic Oncology Group (GOG) trials, evaluating different chemoradiation combinations, totaling 550 patients that had negative para-aortic lymph nodes determined by surgical staging (mandatory in GOG 85 and GOG 120, and optional in GOG 165). A total of 130 patients had negative para-aortic lymph nodes determined by an imaging technique (GOG 165).16 Even though patients in the radiology group had less advanced disease, smaller tumor size, and better performance status, disease free survival and overall survival were significantly improved in the surgical group. This difference was most evident in patients with more advanced disease (stages III–IV), with an estimated 4 year disease free survival of 36.2% versus 48.9%, and 4 year overall survival of 40% versus 54.3% in the radiologic and surgical groups, respectively. In multivariate analysis, patients staged by imaging had a poorer prognosis than those who underwent para-aortic lymph node surgical staging. Concerning patterns of recurrence, there were significantly more recurrences, including the para-aortic area, in the radiological group, and recurrences outside the pelvis were 64% in the radiological staging group compared with 51% in the surgical group. There was a 17% increase in para-aortic recurrences in the radiologic group that translated to a 111% increase in the relative risk of para-aortic lymph node recurrence.16 This study was, however, limited by possible selection bias due to a combination of randomized arms from three different trials.
Removal of Micrometastatic Disease
Some have suggested that the survival benefit of lymphadenectomy might be associated with removal of small volume disease. Leblanc et al showed that patients with microscopically positive and resected para-aortic lymph nodes who received tailored extended field radiotherapy had the same survival as patients with negative lymph nodes who received pelvic irradiation only.36 Gouy et al also reported similar survival data between patients with negative para-aortic lymph nodes and positive para-aortic lymph nodes less than 5 mm in diameter treated with extended field chemoradiation.4 Three year disease free survival was 74%, 69%, and 17% in patients with no para-aortic lymph node involvement, and with para-aortic lymph node involvement measuring less than and more than 5 mm, respectively. However, we do not know if patients with low volume disease in the para-aortic lymph nodes would have had the same survival if treated only with pelvic radiotherapy and concomitant chemotherapy. Furthermore, radiation has been shown to enhance antitumor immunity through different mechanisms, including better antigen presentation and changes in the cytokine profile toward a proinflammatory profile, allowing for attraction of effector cells, and leading to distant tumor regression in the so-called abscopal effect after radiotherapy.41 This biologic effect after chemoradiation may be sufficient to treat microscopic disease in the para-aortic lymph nodes. Furthermore, the lack of systematic ultrastaging underestimates detection of small volume disease. Micrometastatic disease using the definition of the American Joint Committee on Cancer was identified in 8.3%, and an additional 4.1% submicrometastases were found after serial sections and immunohistochemistry in a series of patients with negative aortic lymph nodes.42
Impact of Debulking Para-aortic Lymph Nodes
Bulky para-aortic lymph nodes constitute a therapeutic challenge when treating with chemoradiation. Patients with para-aortic bulky nodes have decreased overall survival. The dose required to sterilize bulky nodes above 2 cm are limited by toxicity to adjacent tissues, in particular the small bowel. Some studies have shown the feasibility of surgical resection prior to chemoradiation with morbidity rates ranging from 6.9% to 23.4%, including patients who underwent additional surgical procedures.35 39 43 The additional value of surgical removal of enlarged nodes has been found in some studies.39 44 Marnitz et al found increased survival in patients with para-aortic metastasis and more than five para-aortic lymph nodes removed.44 Nevertheless, bulky nodes in the para-aortic area are more likely detected by imaging, and therefore, treated by extended chemoradiation therapy or systemic chemotherapy prior to any surgery.
Surgical Morbidity and Delay to Chemoradiotherapy
Historical series of surgical staging by the open approach have reported perioperative complication rates of 5–24%, and up to 51% of radiation associated toxicities.45–47 Staging by the minimally invasive approach has considerably reduced associated morbidity. Grade III–IV morbidity is found in 4–16% of patients after the trans- or retroperitoneal laparoscopic approach,4 11 35–37 48 with higher rates in series performing both pelvic and para-aortic lymph node staging.36 48 49 The UTERUS 11 study reported intraoperative complications in 1.6%, early postoperative complications in 7.6%, and no perioperative mortality.50 Conversion to laparotomy is reported in a minority of cases.11 36 49 51 The most important complication after lymph node dissection is lymphocysts, which account for more than half of the postoperative complications after surgical staging, and which are treated in a conservative manner in the majority of cases 4 11 35–37 48 Preventive fenestration of the peritoneum (marsupialization) may be used to decrease the incidence of lymphocysts.35 39 A low rate of postoperative complications together with a short hospital stay enable the start of chemoradiation at about 10–21 days after surgical staging.11 The proportion of patients with a delay in chemoradiation of more than 30 days after surgery due to associated morbidity is less than 5%.48 There is no evidence that the delay between surgery and chemoradiation has a prognostic impact. In the UTERUS-11 trial, no significant difference in chemoradiation delay between surgical and radiological staging was found.18 When retroperitoneal aortic lymphadenectomy is performed by expert teams, intraoperative morbidity occurs in only 1% of patients due to vascular injuries, all above the inferior mesenteric artery, and perioperative morbidity is identified in 6.5% of cases.32 The risk of radiation associated morbidity, in particular radiation enteritis, has been improved with the extraperitoneal laparoscopic approach, and accounts for less than 5% when surgical staging is performed by the retroperitoneal approach.35 39 It is important to consider that the quality of para-aortic lymph node staging, number of lymph nodes removed, and morbidity are related to the experience and expertise of the surgical team, and systematic staging performed by non-selected teams may be associated with increased rates of complications and delay in treatment initiation.
As lymph node progression occurs in a stepwise manner, Leblanc et al suggested limiting staging to the inferior mesenteric artery, with less than a 5% risk of misdiagnosing aortic lymphatic involvement.32 Dissection up to the inferior mesenteric artery decreases operative time as well as perioperative complications associated with extensive dissection and possible delay to chemoradiotherapy.
Tailoring Adjuvant Treatment
Extended Field Chemoradiotherapy
Concurrent chemoradiation has been considered the standard treatment for locally advanced cervical cancer for the past 20 years based on the results of five phase III randomized controlled trials,5 6 52 53 with an alert raised by the National Cancer Institute. A combination of concurrent chemoradiation compared with extended field chemoradiation was evaluated in patients with locally advanced cervical cancer and negative radiologic para-aortic lymph nodes in the RTOG92-10 trial. This study only included 74 patients and showed that extended field chemoradiotherapy decreased para-aortic, distant metastasis and improved disease free survival and overall survival in patients with positive pelvic lymph nodes. No difference in pelvic lymph node control was found between groups. There were no significant differences between both groups regarding the risk of acute severe toxicities.54 This and previous studies used conventional two-dimensional radiotherapy. Recent studies using concurrent extended field chemoradiation with intensity modulated radiation therapy have demonstrated the lower morbidity of extended field radiotherapy, with less than 5% grade 3 toxicity.15 55 Another randomized controlled trial evaluated the effect of PET/CT compared with CT staging in patients with locally advanced cervical cancer. The authors reported non-significant more extensive chemoradiotherapy in patients staged with PET/CT and no survival difference between the two groups. This study was closed prematurely, and there was also more extensive chemoradiation in patients without lymph node involvement in the PET/CT group.56
A Cochrane systematic review assessed effectiveness and toxicity of extended field radiotherapy in patients with locally advanced cervical cancer.13 The analysis included five studies, three comparing extended field radiotherapy versus pelvic radiotherapy, one comparing extended field radiotherapy with pelvic chemoradiation, and one comparing extended field chemoradiotherapy versus pelvic chemoradiation. The authors concluded that, compared with pelvic radiotherapy alone, extended field radiotherapy decreased para-aortic recurrence rate and improved overall survival. There was low certainty evidence that extended field chemoradiation improved progression free survival and overall survival compared with pelvic chemoradiation. A systematic review and meta-analysis including 1309 studies and six randomized controlled trials with extended field radiotherapy also showed that it significantly decreased the risk of para-aortic failure and distant metastasis.57
Prophylactic extended field radiotherapy has been associated with decreased distant and para-aortic lymph node failure in retrospective studies. There are a lack of data to affirm the survival benefit of extended field radiation in locally advanced cervical cancer, with most studies including unbalanced baseline characteristics from the control and the extended field groups.58 Other studies support tailoring the radiation field based on the number and location of the metastatic lymph nodes. Patients with multiple pelvic lymph nodes or common iliac lymph node metastasis are at very high risk of subclinical para-aortic spread, and prophylactic extended field radiation may increase cancer specific survival in this population.59 60 Prophylactic extended field radiation may be considered to the level of the presacral nodes up to the common iliac when pelvic lymph node involvement is identified, and extended to the para-aortic nodes up to the renal vessels when common iliac nodes are involved, especially when intensity modulated radiation therapy is available.61
Adjuvant/Consolidation Chemotherapy
In an attempt to reduce systemic failures in para-aortic lymph node positive patients, adjuvant chemotherapy after chemoradiation has emerged as a therapeutic option to improve survival. When para-aortic lymph node involvement is undiagnosed, the potential benefit of adjuvant systemic treatment is missed (Table 3). Four randomized controlled trials have assessed the benefit of adjuvant chemotherapy after chemoradiation compared with chemoradiation alone for locally advanced cervical cancer. The study by Lorvidhaya et al randomized 926 patients in four arms: conventional radiotherapy, conventional radiotherapy and adjuvant chemotherapy, conventional radiotherapy with concurrent chemotherapy, and conventional radiotherapy with concurrent chemotherapy and adjuvant chemotherapy. Chemotherapy regimens consisted of mitomycin and 5-fluorouracil for concurrent chemotherapy and 5-fluorouracil for adjuvant chemotherapy. There was a significant increase in locoregional failures in the non-concurrent chemoradiotherapy arm, without significant differences in distant failures rates. There was no survival difference between chemoradiotherapy alone and chemoradiotherapy followed by adjuvant chemotherapy.62
Studies evaluating adjuvant chemotherapy after chemoradiation
The second randomized controlled trial by Duenas Gonzalez et al showed improved overall survival and time to progressive disease in patients treated with cisplatin–gemcitabine chemoradiotherapy followed by two cycles of cisplatin and gemcitabine compared with chemoradiation using cisplatin alone.63 Distant failures were significantly reduced in the chemoradiation and adjuvant chemotherapy arm (8.1% vs 16.4%). The benefit of the adjuvant chemotherapy regimen was increased in patients with larger tumor size, more advanced disease, extensive lymph node involvement, and age younger than 55 years. Patients in the chemoradiation plus adjuvant chemotherapy arm had significantly increased grade 3–4 toxicities (87% vs 46%), a greater number of hospitalizations, and more blood transfusions. Another randomized controlled trial, aiming to evaluate one cycle of neoadjuvant chemotherapy with paclitaxel and cisplatin followed by chemoradiation and two cycles of adjuvant chemotherapy, found a significantly longer disease free survival and cumulative survival, and lower distant and local failure control in patients receiving adjuvant chemotherapy.64
The third trial including 256 patients with locally advanced cervical cancer and negative para-aortic involvement did not show a significant survival difference between patients treated with chemoradiation compared with patients treated with chemoradiation followed by three cycles of paclitaxel plus carboplatin. Distant failures were significantly reduced in the group treated with additional chemotherapy.65 Another randomized trial including 880 patients with locally advanced cervical adenocarcinoma compared chemoradiation with one cycle of neoadjuvant chemotherapy with paclitaxel and cisplatin followed by chemoradiation and two cycles of adjuvant chemotherapy using the same drugs. Patients treated with adjuvant chemotherapy had significantly longer disease free and cumulative survival, and long term local control, as well as a lower risk of distant and pelvic failure than patients treated with chemoradiation alone.64 The optimal number of adjuvant chemotherapy has been evaluated in one randomized controlled trial after neoadjuvant chemotherapy and radical surgery. A study comparing six versus three cycles of adjuvant platinum based chemotherapy in patients previously treated with neoadjuvant chemotherapy plus radical surgery showed similar results in terms of survival, with a significantly increased toxicity profile in the six cycles arm.66
Two ongoing randomized trials, OUTBACK (NCT 01414608) and INTERLACE (NCT 01566240) are evaluating the benefit of adjuvant and neoadjuvant chemotherapy, respectively, in locally advanced cervical cancer. The French multicenter study, ONCOCOL01 (NCT 03534713), will address the role of neoadjuvant chemotherapy specifically in para-aortic lymph node positive patients.
The study by Lorvidhaya et al did not show increased hematologic toxicity or late side effects in patients treated with adjuvant chemotherapy.62 Duenas-Gonzalez found significantly more grade 3 and 4 toxicities, mainly hematologic toxicity (71.9% vs 23.9% in the chemoradiation arm) and gastrointestinal toxicities (34.6% vs 10.6% in the chemoradiation arm), in the chemoradiation followed by adjuvant chemotherapy arm. There were more treatment discontinuations in the adjuvant chemotherapy arm, most frequently related to toxicity, such as decreased creatinine clearance, neutropenia, and diarrhea.63 The ACTLACC trial showed a low rate of grade III–IV toxicity, with hematologic toxicity being the most frequent, and a grade III neutropenia of 13.1% in the adjuvant chemotherapy arm compared with 6.2% in the chemoradiation arm.65 Tang et al also reported significantly increased hematologic toxicity in the additional chemotherapy arm, and all patients recovered after medical treatment.64
Conclusion
Accurate assessment of para-aortic lymph node status enables treatment planning. Patients with positive para-aortic lymph nodes are offered extended field chemoradiation, and may be considered for subsequent adjuvant chemotherapy. PET/CT is the most accurate imaging tool to assess para-aortic extension in patients with locally advanced cervical cancer. However, PET/CT fails to detect between 10% and 15% of patients with negative PET/CT aortic nodes who have lymph node metastasis on pathologic staging and are eligible for treatment plan modifications. The risk of para-aortic lymph node involvement in patients with negative para-aortic lymph node uptake on PET/CT depends on disease in the pelvic lymph nodes. The potential overall survival benefit of surgical staging is low in patients with a low prevalence of para-aortic disease. Patients with negative pelvic lymph node spread on PET/CT imaging have less than a 5% risk of para-aortic extension, and surgical staging should not be performed. Surgical staging can be considered for patients with pelvic lymph node uptake, as more than 20% have disease in the para-aortic nodes undetected on PET/CT, leading to treatment modification and improved control of para-aortic and distant recurrences. Surgical staging avoids unnecessary toxicity associated with extended field radiation in approximately 75% of patients with pelvic lymph node metastasis. The decision to undergo surgical staging or prophylactic extended field radiation in patients with multiple pelvic lymph nodes should be balanced between the expertise of the surgical team, which is directly correlated with perioperative complications, and access to intensity modulated radiation therapy, which is correlated with decreased radiation toxicity. The field of chemoradiotherapy may be extended to the para-aortic area in patients with lymph node disease up to the common iliac lymph nodes without pretreatment staging.
Acknowledgments
MAA acknowledges grant support from 'La Caixa' Foundation, Barcelona, Spain.
References
Footnotes
Twitter @Alejandra, @AngelesFite
Contributors AM: conceptualization, project administration, methodology, and writing–original draft. MAA, DQ, GF, and CP: conceptualization, data curation, methodology, and writing–review.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.