Scores and Misses With New Technology—Walking the Narrow Path of Evidence

Abstract

Advances in radiation or surgical techniques in oncology are often adopted much faster than newer chemotherapy drugs because these adoptions are made based on safety rather than efficacy. Improved efficacy is usually assumed based on a lower level of evidence, such as retrospective or modeling studies, without any prospective studies. A problem with this approach is that newer technology is integrated into practice without knowledge of its true impact on meaningful cancer outcomes. This Oncology Scan covers recent prospective studies in gynecologic cancer, evaluating advances in local therapy (surgery or radiation) with mixed results and emphasizing the importance of prospective studies before acceptance of newer technologies. For years, minimally invasive radical hysterectomy for early stage cervical cancers was routinely performed and was considered the standard approach in national guidelines,1National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Cervical Cancer Version 1.2018https://www.nccn.org/professionals/physician_gls/PDF/cervical.pdfDate accessed: February 1, 2019Google Scholar based on single-institution studies showing shorter hospital stays, less acute surgical morbidity, and similar cancer outcome compared with open (O) surgery. However, a recent prospective randomized trial by Ramirez et al2Ramirez P.T. Frumovitz M. Pareja R. et al.Minimally invasive versus abdominal radical hysterectomy for cervical cancer.N Engl J Med. 2018; 379: 1895-1904Crossref PubMed Scopus (683) Google Scholar showed increased locoregional recurrences and worse disease-free survival with minimally invasive surgery (MIS) in comparison to O surgery. The reason for this worse outcome is still not clear, but it has led to a change in practice from MIS to O surgery for early stage cervical cancer. Two other studies covered in this issue established the negative and positive predictive value of sentinel lymph node (SLN) biopsy for vulvar3Van der Zee A.G. Oonk M.H. De Hullu J.A. et al.Sentinel node dissection is safe in the treatment of early-stage vulvar cancer.J Clin Oncol. 2008; 26: 884-889Crossref PubMed Scopus (541) Google Scholar, 4Te Grootenhuis N.C. van der Zee A.G. van Doorn H.C. et al.Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I.Gynecol Oncol. 2016; 140: 8-14Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar and endometrial cancer5Rossi E.C. Kowalski L.D. Scalici J. et al.A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): A multicentre, prospective, cohort study.Lancet Oncol. 2017; 18: 384-392Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar in a multi-institutional setting, thereby confirming the data from single-institution studies. These studies will help establish SLN biopsy as the accepted standard of care with less morbidity and similar pathologic yield compared with nodal dissection. However, with this new technique emerges new problems; it is not clear how best to manage low-volume nodal disease such as isolated tumor cells or micrometastases identified on SLN biopsy for endometrial cancer. We need additional studies to determine the impact of any adjuvant treatment for low-volume disease because recently presented prospective randomized studies for stage III disease (Gynecologic Oncology Group 258 and Post-Operative Radiation Therapy in Endometrial Carcinoma 3) were done in the non–sentinel node biopsy era and included patients with predominantly macrometastases. By contrast, initial results for the Groningen International Study on Sentinel Nodes in Vulvar cancer (GROINSS-V) II prospective study for vulvar cancer showed that RT is effective for low-volume SLN disease, but despite strong rationale for radiation, the recurrence rates for macrometastases were surprisingly higher than expected, again showing the value of prospective studies in evaluating efficacy of treatment. Based on this, GROINSS-VIII is attempting to determine whether increasing radiation dose and adding concurrent chemotherapy can improve outcome in patients with macrometastases. The last study6Klopp A.H. Yeung A.R. Deshmukh S. et al.Patient-reported toxicity during pelvic intensity-modulated radiation therapy: NRG Oncology-RTOG 1203.J Clin Oncol. 2018; 36: 2538-2544Crossref PubMed Scopus (102) Google Scholar covered in this Oncology Scan is among few prospective randomized trials comparing 3-dimensional versus intensity modulated RT (IMRT) for any disease site, despite widespread adoption of IMRT in the radiation oncology community.7Shumway D.A. Griffith K.A. Pierce L.J. et al.Wide variation in the diffusion of a new technology: Practice-based trends in intensity-modulated radiation therapy (IMRT) use in the state of Michigan, with implications for IMRT use nationally.J Oncol Pract. 2015; 11: e373-e379Crossref PubMed Scopus (14) Google Scholar This study showed that for postoperative treatment for gynecologic cancers, patient-reported gastrointestinal (GI) and urinary morbidity was significantly better with IMRT than with 3-dimensional conformal RT, thus providing level 1 evidence for use of IMRT. The authors made a commendable effort to run this trial successfully and provide a higher level of evidence to support the use of this more advanced and expensive technology. We need more studies like this, especially when RT research shows that only 5% of publications are devoted to clinical trials despite rapid advances in technology.8Atun R. Jaffray D.A. Barton M.B. et al.Expanding global access to radiotherapy.Lancet Oncol. 2015; 16: 1153-1186Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar Laparoscopic Approach to Cervical Cancer (LACC) Trial2Ramirez P.T. Frumovitz M. Pareja R. et al.Minimally invasive versus abdominal radical hysterectomy for cervical cancer.N Engl J Med. 2018; 379: 1895-1904Crossref PubMed Scopus (683) Google Scholar Summary: This phase 3 randomized multicenter clinical trial compared survival outcomes after laparoscopic or robot-assisted radical hysterectomy (MIS) to outcomes after open abdominal radical hysterectomy (O surgery) among women with early-stage cervical cancer. This study prospectively assigned patients with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer to MIS or O abdominal radical hysterectomy to test the noninferiority of MIS in reference to the disease-free survival rate at 4.5 years. Three hundred nineteen patients were assigned to the MIS arm (84.4% underwent laparoscopy and 15.6% robot-assisted surgery) and 312 to the O arm. Most patients (91.9%) had stage IB1 disease. The 2 groups had similar baseline clinicopathologic characteristics. Because of an imbalance in deaths between the 2 arms favoring the O arm, the study was closed prematurely. MIS was associated with a lower rate of disease-free survival than O surgery (3-year rate, 91.2% vs 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% confidence interval [CI], 1.63-8.58), a difference that remained after adjusting for age, body mass index, stage of disease, lymphovascular invasion, and lymph node involvement. More importantly, in this landmark study MIS was also associated with a lower rate of overall survival for early stage operable cervix cancer (3-year rate, 93.8% vs 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77-20.30). The rate of disease-free survival calculated at 4.5 years was 86.0% with MIS and 96.5% with O surgery, a difference of –10.6 percentage points (95% CI, –16.4 to –4.7), not meeting the noninferiority criteria for MIS compared with O surgery. Commentary: For early stage cervical cancer, apart from O radical hysterectomy, many individualized surgical approaches are available.9Ramirez P.T. Pareja R. Rendon G.J. et al.Management of low-risk early-stage cervical cancer: Should conization, simple trachelectomy, or simple hysterectomy replace radical surgery as the new standard of care?.Gynecol Oncol. 2014; 132: 254-259Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 10Tomao F. Corrado G. Peccatori F.A. et al.Fertility-sparing options in young women with cervical cancer.Curr Treat Options Oncol. 2016; 17: 5Crossref Scopus (18) Google Scholar, 11Shah C.A. Beck T. Liao J.B. et al.Surgical and oncologic outcomes after robotic radical hysterectomy as compared to open radical hysterectomy in the treatment of early cervical cancer.J Gynecol Oncol. 2017; 28: e82Crossref PubMed Scopus (66) Google Scholar The newer MIS (laparoscopic or robotic) approaches have been shown by limited retrospective data to have a clinical benefit, with shorter hospital stays and reduced complications compared with O surgery.12Park D.A. Yun J.E. Kim S.W. et al.Surgical and clinical safety and effectiveness of robot-assisted laparoscopic hysterectomy compared to conventional laparoscopy and laparotomy for cervical cancer: A systematic review and meta-analysis.Eur J Surg Oncol. 2017; 43: 994-1002Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 13Wallin E. Floter Radestad A. Falconer H. Introduction of robot-assisted radical hysterectomy for early stage cervical cancer: Impact on complications, costs and oncologic outcome.Acta Obstet Gynecol Scand. 2017; 96: 536-542Crossref PubMed Scopus (34) Google Scholar In a recent large meta-analysis12Park D.A. Yun J.E. Kim S.W. et al.Surgical and clinical safety and effectiveness of robot-assisted laparoscopic hysterectomy compared to conventional laparoscopy and laparotomy for cervical cancer: A systematic review and meta-analysis.Eur J Surg Oncol. 2017; 43: 994-1002Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar comparing the robotic approach to other methods, only 4 studies reported survival outcomes, and no differences were seen between the groups; however, the follow-up periods for the different surgical approaches varied, and therefore no firm conclusions could be made with regard to survival. By contrast, equivalent outcomes between MIS and O approaches have been demonstrated through phase 3 trials for other gynecologic sites such as uterine cancer14Mourits M.J. Bijen C.B. Arts H.J. et al.Safety of laparoscopy versus laparotomy in early-stage endometrial cancer: a randomised trial.Lancet Oncol. 2010; 11: 763-771Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 15Walker J.L. Piedmonte M.R. Spirtos N.M. et al.Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study.J Clin Oncol. 2012; 30: 695-700Crossref PubMed Scopus (431) Google Scholar and other body sites such as colon cancer.16Buunen M. Veldkamp R. Hop W.C. et al.Survival after laparoscopic surgery versus open surgery for colon cancer: Long-term outcome of a randomised clinical trial.Lancet Oncol. 2009; 10: 44-52Abstract Full Text Full Text PDF PubMed Scopus (976) Google Scholar, 17Deijen C.L. Vasmel J.E. de Lange-de Klerk E.S.M. et al.Ten-year outcomes of a randomised trial of laparoscopic versus open surgery for colon cancer.Surg Endosc. 2017; 31: 2607-2615Crossref PubMed Scopus (57) Google Scholar The LACC study sought to compare these 2 techniques for cervix cancer in a phase 3 randomized clinical trial. This study was initially envisioned with a hypothesis that MIS is equivalent in efficacy to O radical hysterectomy. However, the results are to the contrary. The study was well designed, with participating sites requiring accreditation to ensure proper surgical technique during MIS. All surgeons had to submit their surgical videos to show that they adequately knew how to perform MIS. The rates of parametrial/margin/nodal involvement on surgical pathology were equivalent in the 2 groups. Despite this, the recurrence rate was 27 of 319 (8.5%) in the MIS arm compared with 7 of 312 (3.3%) in the O arm. Simultaneously, in the same issue of the New England Journal of Medicine, a large retrospective study showed similar results.18Melamed A. Margul D.J. Chen L. et al.Survival after minimally invasive radical hysterectomy for early-stage cervical cancer.N Engl J Med. 2018; 379: 1905-1914Crossref PubMed Scopus (307) Google Scholar In this study, the U.S. National Cancer Database was used to compare MIS and O surgery in patients with early stage cervical cancer diagnosed between 2010 and 2013. This study had a larger sample size (2461 patients), and the majority of the MIS cohort (79.8%) had robot-assisted laparoscopy. There was a significant difference in the 4-year mortality for MIS (9.1%) compared with O surgery (5.3%) and a 65% higher risk of death from any cause for MIS compared with O. The results of these 2 studies have been practice-changing, with centers all over the United States now no longer offering MIS, but only O surgery for these patients. The National Comprehensive Cancer Network (NCCN) has changed its recommendation for this group of patients, suggesting that MIS is not preferred and that women should be carefully counseled regarding the long-term outcomes and oncological risks of different surgical approaches.19National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Cervical Cancer (Version 4.2019).https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdfDate accessed: March 30, 2019Google Scholar A different view of these results has been put forward in an editorial from the Journal of Minimally Invasive Gynecology, suggesting that there is a need for a second US randomized trial before these results are accepted.20Naumann R.W. Minimally invasive radical hysterectomy has many benefits compared with open radical hysterectomy: Will the LACC trial cause the premature demise of this procedure?.J Minim Invasive Gynecol. 2019; 26: 379-380Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The editorial also states that the disease-free survival and overall survival in the O arm were abnormally high compared with other series of abdominal radical hysterectomy. Previously, patient preference for MIS precluded adequate accrual, but the LACC data should rekindle an interest and make such a trial feasible. A similarly cautious “wait and analyze” approach is suggested by the Society of Gynecology Oncology of Canada, which recommends awaiting results of the Canadian SHAPE trial,21Canadian Cancer Trials GroupRadical Versus Simple Hysterectomy and Pelvic Node Dissection in Patients With Low-risk Early Stage Cervical Cancer (SHAPE). NCT01658930.ClinicalTrials.govDate: 2019Google Scholar which is comparing radical versus simple hysterectomy for low-risk cervix cancer and allows MIS or O surgery in both arms. Another factor of importance may be tumor size. Subgroup analysis in the retrospective study by Melamed et al showed that decreased survival for MIS compared with O surgery was only seen in tumors ≥2 cm.18Melamed A. Margul D.J. Chen L. et al.Survival after minimally invasive radical hysterectomy for early-stage cervical cancer.N Engl J Med. 2018; 379: 1905-1914Crossref PubMed Scopus (307) Google Scholar Some investigators suggest that the use of uterine manipulators and intracorporeal colpotomy in the MIS group has the potential risk of causing tumor recurrence.22Kanao H. Aoki Y. Takeshima N. Unexpected result of minimally invasive surgery for cervical cancer.J Gynecol Oncol. 2018; 29: e73Crossref Scopus (26) Google Scholar Hence, in planning new trials comparing MIS to O, very careful standardization of procedures, such as surgical techniques for colpotomy and uterine manipulators, must be considered. In addition, it may be necessary to target patients with a tumor size less than 2 cm and no lymph nodes on preoperative evaluation.23Pyeon S.Y. Hur Y.J. Lee J.M. Rethinking the next step after unexpected results associated with minimally invasive radical hysterectomy for early cervical cancer.J Gynecol Oncol. 2019; 30: e43Crossref Scopus (4) Google Scholar Because these patients are unlikely to receive adjuvant RT after surgery, the efficacy and safety of the 2 surgeries should be accurately assessed. GROINSS-V I Trial3Van der Zee A.G. Oonk M.H. De Hullu J.A. et al.Sentinel node dissection is safe in the treatment of early-stage vulvar cancer.J Clin Oncol. 2008; 26: 884-889Crossref PubMed Scopus (541) Google Scholar, 4Te Grootenhuis N.C. van der Zee A.G. van Doorn H.C. et al.Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I.Gynecol Oncol. 2016; 140: 8-14Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Summary: The GROINSS-V I study was a landmark in the treatment of vulvar cancer when it was initially published in 2008.3Van der Zee A.G. Oonk M.H. De Hullu J.A. et al.Sentinel node dissection is safe in the treatment of early-stage vulvar cancer.J Clin Oncol. 2008; 26: 884-889Crossref PubMed Scopus (541) Google Scholar Previously, the standard of care for vulvar cancers with more than 1 mm of invasion was an inguinal lymph node dissection, a highly morbid procedure. Using a sentinel nodal dissection resulted in a reduction of acute infectious complications from 34% to 12% and long-term lymphedema rates from 25% to 2%. Moreover, the risk of groin recurrence in those with negative sentinel nodes and no further treatment was exceedingly low at 2%. The current publication updates this study to a median follow-up of almost 9 years, with essentially no change in the recurrence rates in the sentinel node negative cohort and with an isolated groin recurrence rate of 2.5% at 5 years and a 10-year disease-specific survival of 91%.4Te Grootenhuis N.C. van der Zee A.G. van Doorn H.C. et al.Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I.Gynecol Oncol. 2016; 140: 8-14Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Commentary: These excellent results only apply to those who met the entry criteria of the trial, which was limited to primaries <4 cm in size and was amended early in accrual to exclude those with multifocal disease. Centers also had to have at least 10 prior sentinel node cases performed with confirmatory lymphadenectomies to participate. Nonetheless, the use of sentinel node biopsy in vulvar cancer now is a robust part of the standard of care. This leads us to the next step of determining when a full lymph node dissection is needed, if ever. This is the subject of the GROINS-V II study, which was designed as a single-arm study including those with clinically negative nodes but a positive sentinel node. These women were treated with 50 Gy pelvic/inguinal radiation in an effort to eliminate the need for a full dissection and the attendant high risk of lymphedema. Accrual completed in 2016, and results are eagerly awaited. Unfortunately, this trial was revised during accrual after an unacceptably high recurrence rate at interim analysis was found in a subgroup of women with more than 2 mm of disease in the sentinel node, or extracapsular extension (9 recurrences of 45 women). On revision, women with either of these 2 pathologic characteristics instead undergo a full dissection and postoperative RT. It is quite possible that a higher dose, better targeting using IMRT (not allowed on protocol), and/or the use of concurrent chemotherapy might improve results and forgo the need for completion dissection. This, indeed, is the very subject of the GROINS-V III study. This study will include those with >2 mm of disease in the sentinel node and will treat to 56 Gy with concurrent weekly cisplatin, with the hope of making full inguinal dissections a thing of the past. Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) Trial5Rossi E.C. Kowalski L.D. Scalici J. et al.A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): A multicentre, prospective, cohort study.Lancet Oncol. 2017; 18: 384-392Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar Summary: The FIRES trial was a multicenter, prospective cohort study of 385 patients with clinical stage I endometrial cancer, inclusive of all grades and histologic subtypes, who underwent SLN mapping followed by completion lymphadenectomy. The primary aim of the study was to report the sensitivity and negative predictive value of SLN biopsy for stage I endometrial cancer compared with the gold standard of lymph node dissection. After cervical injection of indocyanine green, fluorescence imaging was used to visualize the tracer in a lymphatic channel leading to at least 1 SLN. Complete pelvic lymphadenectomy was performed per the Gynecologic Oncology Group surgical handbook with removal of nodal tissue from the distal common iliac arteries, proximal half of the external iliac artery and vein, and distal half of the obturator fat. Paraortic dissection was performed at the surgeon's discretion. Pathologic evaluation of the nodes followed a standardized ultrastaging protocol: If no metastatic disease was identified by hematoxylin and eosin staining, a second slide was stained for pancytokeratins. Of the 385 patients enrolled, 340 had pelvic lymphadenectomy and 196 (58%) had paraortic dissection, with successful mapping of at least 1 SLN in 86% (293 of 340). SLNs were identified in the following locations: external iliac (38%), obturator (25%), inframesenteric paraortic (14%), common iliac (8%), internal iliac (10%), presacral (3%), infrarenal paraortic (1%), and other (including parametrium [1%]). The overall rate of nodal positivity was 12%, and nodal metastases were correctly identified by SLN mapping in 35 of 36 patients, resulting in a sensitivity of 97.2% and a negative predictive value of 99.6%. The positive SLNs were most commonly located in the obturator (47%) and external iliac (37%) basins. Of the 35 patients with positive SLNs, 6 (17%) had positive SLNs in regions outside routine lymphadenectomy, such as presacral or internal iliac regions, with negative nonsentinel nodes in conventional spaces. Ultrastaging identified isolated tumor cells or micrometastatic disease by pancytokeratin staining only in 19 patients (54%). The risk of additional positive nonsentinel macrometastatic disease varied by SLN disease volume and was 29% for isolated tumor cells/micrometastatic SLN disease compared with 64% for macrometastatic SLNs. In 20% of patients, there was additional nonsentinel nodal disease distal to the involved SLN. Commentary: The FIRES trial is a landmark publication for the use of SLN mapping in early stage endometrial cancer. Before its publication, the evidence for SLN evaluation was limited to large, single-institutional retrospective reports24Barlin J.N. Khoury-Collado F. Kim C.H. et al.The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: Beyond removal of blue nodes.Gynecol Oncol. 2012; 125: 531-535Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar and smaller prospective trials,25How J. Gotlieb W.H. Press J.Z. et al.Comparing indocyanine green, technetium, and blue dye for sentinel lymph node mapping in endometrial cancer.Gynecol Oncol. 2015; 137: 436-442Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 26Darai E. Dubernard G. Bats A.S. et al.Sentinel node biopsy for the management of early stage endometrial cancer: Long-term results of the SENTI-ENDO study.Gynecol Oncol. 2015; 136: 54-59Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 27Backes F.J. Cohen D. Salani R. et al.Prospective clinical trial of robotic sentinel lymph node assessment with isosulfane blue (ISB) and indocyanine green (ICG) in endometrial cancer and the impact of ultrastaging.Gynecol Oncol. 2019; 153: 496-499Abstract Full Text Full Text PDF Scopus (25) Google Scholar leading to a category 2B recommendation in the NCCN guidelines as an acceptable staging procedure. These studies and others consistently showed the accuracy and feasibility of SLN assessment for endometrial cancer, although the evidence was considered to be of moderate quality. In the single-institutional series, the mapping technique was performed by expert surgeons at highly experienced centers, highlighting the need for a multicenter trial that demonstrated the generalizability of the technique with newly trained surgeons in a variety of practice settings. The Sentinel Node and Endometrial Cancer (SENTI-ENDO) study was a multicenter prospective study of SLN biopsy in 133 patients with stage I or II endometrial cancer that reported a sensitivity of 84% and negative predictive value of 97%.26Darai E. Dubernard G. Bats A.S. et al.Sentinel node biopsy for the management of early stage endometrial cancer: Long-term results of the SENTI-ENDO study.Gynecol Oncol. 2015; 136: 54-59Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar The study was limited by a low frequency of comprehensive pelvic and paraortic lymphadenectomy and overall low nodal counts, leading to concerns about incomplete staging and lack of statistical power. The FIRES trial validates the previously published data with a larger cohort size and a high frequency of complete pelvic and paraortic lymphadenectomy. The FIRES study also affirms the generalizability of this technique, which was rapidly adopted by novice surgeons and successfully implemented in both large academic centers and community practices. The operating characteristics of SLN mapping for endometrial cancer are similar to that of melanoma, breast, and vulvar cancer, disease sites in which nodal assessment is standard of care. Assessment of nodal status in endometrial cancer is important for accurate stage determination, prognostication, and selection of adjuvant therapy modalities. An implication of SLN mapping is the potential for upstaging with detection of isolated tumor cells by ultrastaging, and future study is needed to evaluate the importance of adjuvant therapy in this setting. In patients with node-positive disease for which external beam RT is recommended, there are unanswered questions about the extent of the radiation field and elective nodal volumes. From the FIRES data, 17% of patients with involved SLNs had positive SLNs that were outside the standard lymphadenectomy basin, indicating primary nodal drainage to the low paraortics and presacral region was not uncommon. Furthermore, a substantial proportion of patients (20%) had nodal involvement distal to the involved SLN, such that elective nodal coverage at least 1 nodal echelon above the positive SLN may be appropriate. In the absence of pelvic and/or paraortic nodal dissection, the overall burden of nodal involvement is unknown, and the radiation oncologist is challenged with tailoring the external beam fields with less pathologic information. Nevertheless, SLN mapping represents an advance for our patients, with a greater ability to detect metastatic nodal disease and less associated morbidity. The morbidity of comprehensive lymphadenectomy includes lymphedema, lymphocyst formation, and genitofemoral nerve injury, which are expected to be significantly less with SLN biopsy. The NCCN guidelines now incorporate an SLN algorithm, which requires a side-specific nodal dissection in cases of failed mapping and removal of suspicious or enlarged nodes regardless of mapping.28National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Uterine neoplasms. (Version 3.2019). Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed February 1, 2019.Google Scholar Furthermore, SLN mapping in patients with high-risk histologies has been reported with promising results,29Soliman P.T. Westin S.N. Dioun S. et al.A prospective validation study of sentinel lymph node mapping for high-risk endometrial cancer.Gynecol Oncol. 2017; 146: 234-239Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 30Naoura I. Canlorbe G. Bendifallah S. et al.Relevance of sentinel lymph node procedure for patients with high risk endometrial cancer.Gynecol Oncol. 2015; 136: 60-64Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar and these patients were also relatively well represented in the FIRES trial (29% with grade 3 endometrioid or nonendometrioid histology). NRG Oncology-RTOG 1203 Summary: This trial was designed to compare patient-reported acute toxicity and health-related quality of life during treatment for patients with cervical or endometrial cancer treated with standard postoperative pelvic radiation versus IMRT in a randomized setting. The primary endpoint was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary endpoints included change in patient-reported urinary toxicity and quality of life as measured by the Trial Outcome Index score. From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group (P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group (P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group (P = .06). At the end of RT, more women who received standard RT reported frequent or almost constant diarrhea (51.9% vs 33.7%; P = .01), and more patients who received standard RT were taking antidiarrheal medications 4 or more times daily (20.4% vs 7.8%; P = .04). Overall, this trial showed that compared with standard 3-dimensional pelvic RT, pelvic IMRT was associated with significantly less patient-reported GI and urinary toxicity. Commentary: IMRT has been used for gynecologic cancers for an increasing number of patients over the past decade. The dosimetric benefits of IMRT are well documented, and single-arm and retrospective studies have suggested that IMRT may reduce toxicity. To investigate this directly, NRG 1203 embarked on a randomized trial measuring the clinical impact of IMRT using a patient-reported measure of toxicity. The study enrolled patients with cervical and endometrial cancer with indications for postoperative treatment. Concurrent chemotherapy was delivered at physician discretion according to protocol-defined parameters. Toxicity was assessed with the EPIC instrument, which assessed the symptom burden for common toxicities from pelvic radiation, including diarrhea, dysuria, and abdominal pain, and the degree to which these symptoms bothered patients. These toxicity scores were compiled into a summary score for both GI and genitourinary function. The primary endpoint of the study was the decline in this composite score evaluating GI toxicity from baseline to the last week of radiation. Overall, patients treated with IMRT experienced less decline in bowel function during the 5 weeks of radiation compared with patients treated with standard approaches. This difference was seen despite the more frequent use of antidiarrheal medications for patients in the standard arm. More severe toxicity was also noted in the standard arm; 9% of patients in the standard arm reported fecal incontinence compared with only 1% in the IMRT arm. Urinary toxicity similarly declined more in the standard arm than in the IMRT arm. The differences between the 2 arms narrowed between the end of treatment and 4 to 6 weeks after completing treatment. The impact of IMRT on longer term toxicity remains to be seen, but the study provides support for using IMRT in postoperative treatment for gynecologic cancers to reduce acute toxicity.