www.redjournal.

org

Reports From Four International Clinical Trials

for Cancers of the Cervix, Uterus and Vulva, and
a New Guideline for Cervical Cancer
Shari Damast, MD,* Emma Fields, MD,y Elizabeth Kidd, MD, Matthew Harkenrider, MD,z Supriya Chopra, MD,x and Junzo Chino, MDk
*
Smilow Cancer Hospital at Yale New Haven, New Haven, CT; yVirginia Commonwealth University, Richmond, VA; zStritch School of
Medicine Loyola University, Chicago, IL; xTata Memorial Centre, Mumbai, India; and kDepartment of Radiation Oncology, Duke Cancer
Center, Durham, NC

Received Apr 23, 2021; Accepted for publication May 2, 2021

Treating gynecologic malignancies can be challenging late grade 2 or 3 bowel toxicity with the use of IMRT at
owing to the complex interactions between the 3 primary 4 years, with no evidence of reduced disease free survival,
treatment modalities of surgery, chemotherapy, and radia- cementing the role of IMRT as a standard of care. Of note,
tion therapy. Navigating these modalities is based on risk PARCER primarily used physician reported outcomes
stratification from patient and tumor specific factors, with rather than patient reported outcomes; TIME-C did find
the aim at maximizing treatment benefit while minimizing some discrepancies between these methods.3 Also of import
risk. This article will review reports from 4 recent interna- is the use of routine image guidance in the IMRT arm,
tional clinical trials, 2 for cervical cancer, and 1 each for which helped to ensure appropriate coverage throughout
uterine and vulvar cancers, all of which add to our under- the treatment course.
standing of how to maximize the therapeutic ratio for each The comparison of different subsequent treatments after
patient. It also covers the recently published American radical surgery (STARS) trial from China also attempts to
Society for Radiation Oncology (ASTRO) guidelines in improve the postoperative management of cervical cancer
cervical cancer which advocates for many key new advan- by randomizing women with risk factors after hysterectomy
ces in radiation therapy. between radiation alone, concurrent chemoradiation, and
The phase III randomized trial of postoperative adjuvant sequential chemoradiation.4 They found improved disease-
conventional radiation (3DCRT) versus image guided free survival with sequential chemoradiation (2 cycles cis-
intensity modulated radiotherapy (IGIMRT) in cervical platin/paclitaxel before radiation therapy [RT] and 2 cycles
cancer (PARCER) trial from India follows on the random- after); however, the generalizability is limited by the mixed
ized phase III study of standard vs. IMRT pelvic radiation population of both intermediate (“Sedlis criteria”) and high
for post-operative treatment of endometrial and cervical (“Peters criteria”) factors, and the use of neoadjuvant chemo-
cancer (TIME-C)/radiation therapy oncology group therapy in many cases.5,6 The arms were also imbalanced
(RTOG) 1203 study, both of which compared 3-dimen- with regards to lymph node positivity, one of the strongest
sional (3D) versus intensity modulated radiation therapy pathologic factors associated with outcome. Ultimately, a
(IMRT) treatment in the postoperative management of cer- change in the standard of care may await the results of 2 key
vical cancers.1,2 PARCER was a slightly larger study than ongoing clinical trials discussed in the commentary.
TIME-C and benefitted from being limited only to cervical The ASTRO guideline for cervical cancer aims to aid
cancers (the majority of the TIME-C population was uterine practitioners in defining an optimal treatment algorithm
cancer). PARCER found a persistent reduction in the rate of for the use of radiation therapy for the disease.7 Key

Corresponding author: Junzo Chino, MD; E-mail: junzo.chino@duke. Disclosures: The authors have no conflicts of interest to disclose and
edu have no external funding to declare.

Int J Radiation Oncol Biol Phys, Vol. 111, No. 2, pp. 299−306, 2021
0360-3016/$ - see front matter Ó 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ijrobp.2021.05.002
300 Oncology Scan International Journal of Radiation Oncology  Biology  Physics

recommendations in this guideline include the use of IMRT 50 Gy in 25 fractions for 5 weeks § weekly cisplatin
in both the intact and postoperative settings, as well as the 40 mg/m2 followed by high-dose-rate vaginal brachyther-
use of image guidance in the placement and planning of apy 12 Gy in 2 fractions.
brachytherapy implants. These recommendations are aimed The study reported on 279 randomized patients with a
at outlining the current standard of care for the majority of median follow-up of 49 months. The primary endpoint of
clinical scenarios, as well as encouraging the use of optimal grade ≥2 late GI toxicity-free survival was significantly
techniques (such as IMRT and image-guided brachyther- less with IG-IMRT compared with 3D-CRT (78% vs 57%,
apy) when available. hazard ratio [HR] 0.47; 95% confidence interval [CI],
Turning to uterine cancer, the European based Post- 0.30%-0.74%; P = .009). The symptoms most improved by
Operative Radiation Therapy in Endometrial Cancer Trial 3 IG-IMRT were abdominal bloating, anorexia, and bowel
(PORTEC-3) previously demonstrated a benefit to overall obstruction. Grade ≥3 late GI toxicity-free survival also
and failure-free survival for women with high-risk uterine was improved with IG-IMRT compared with 3DCRT (98%
cancer when treated with chemoradiation therapy compared vs 82%, HR 0.22; 95% CI, 0.08%-0.59%; P = .001). A
with radiation therapy alone.8 They have now reported the majority of patients received chemotherapy on this study
results of a predefined molecular subgroup analysis, looking (77%) and the effect of IG-IMRT was even greater for
at those with Polymerase e (POLE) ultramutated, p53 patients receiving chemotherapy. There was no interaction
abnormal, and MMR-deficient tumors, compared with those between radiation therapy modality and type of surgery
with no specific profiles.9 These molecular factors were performed.
independently associated with clinical outcomes and pro-
Comment: PARCER provides level 1 evidence that IG-
vide a basis for risk-stratification beyond conventional clin-
IMRT improves grade ≥2 and grade ≥3 late GI toxicity for
icopathologic features. Given recent negative clinical trials
patients undergoing postoperative radiation therapy for cer-
in uterine cancer (such as Gynecology Oncology Group
vical cancer, and this effect is even greater for patients
[GOG] 249 and GOG 258), use of these factors may allow
undergoing concurrent adjuvant chemotherapy. With its
more refinement in patient selection for future trials, better
late GI toxicity endpoint, PARCER compliments TIME-C
identifying those who may benefit from treatment intensifi-
(with its acute GI toxicity primary endpoint) to demonstrate
cation (in the case of p53 abnormal), de-escalation (POLE
that IG-IMRT improves clinically meaningful GI toxicity at
ultramutated), or immune modulation (MMR-deficient).
all phases in the treatment and follow-up period. TIME-C
Finally, the Groningen International Study on Sentinel
predominantly accrued patients with endometrial cancer
Nodes in Vulvar Cancer II (GROINSS-V II) trial was a pro-
(84%) and those who did not receive concurrent chemother-
spective single arm study attempting to replace completion
apy (75%). PARCER additionally addresses the cervical
inguinal dissections with radiation therapy for women with
cancer population, predominantly receiving chemotherapy
sentinel node positive vulvar cancer.10 Presented in abstract
(77%), to support improved GI toxicity across these postop-
form at Society of Gynecologic Oncology (SGO) 2020,
erative gynecologic disease sites with or without chemo-
they found excellent local control with radiation for those
therapy. This data further support IG-IMRT as standard of
with <2 mm of disease in the submitted node, provided
care for postoperative cervical cancer.
there was no extracapsular extension. For those with more
advanced disease, as the recurrence rates were unacceptably
The STARS Trial: A Guiding Light or Another Orb in the
high, treatment intensification may be indicated with the
Constellation of Trials for Postoperative Cervical Cancer
use of a higher dose, and concurrent chemotherapy. This
Management?
strategy is being investigated in the ongoing GROINSS-V
III study. Summary: The STARS, Subsequent Treatments After Radi-
cal Surgery, trial is a large, randomized trial conducted in
China and includes 1048 women with International Federa-
The PARCER Trial: IG-IMRT for Postoperative Cervical
tion of Gynaecology and Obstetrics (FIGO) 1994 stage IB1
Cancer
to IIA2 (which is the same as FIGO 2009 for these stages)
Summary: The role of postoperative radiation therapy for after radical hysterectomy with adverse pathologic fea-
women with cervical cancer and intermediate or high-risk tures.4 To be included, women had to have at least one
factors has been well established.5,6 RTOG 1203 (TIME-C) adverse feature including either intermediate or Sedlis crite-
demonstrated improved acute gastrointestinal (GI) toxicity ria of deep stromal invasion or lymphovascular space inva-
as the primary endpoint with postoperative IMRT compared sion or high-risk Peters criteria including positive margins
with 3D conformal radiation therapy (3D-CRT) among or positive lymph nodes.5,6 Women were randomized
postoperative patients with endometrial cancer (84%) and 1:1:1 to either RT alone of 45 to 50 Gy, concurrent
cervical cancer (16%).2 PARCER is a phase 3 randomized chemoradiation (CCRT) with weekly cisplatin 30 to 40
trial of postoperative 3D-CRT compared with image-guided mg/m2, or sequential chemoradiation (SCRT) with 2
IMRT (IG-IMRT) for cervical cancer patients with interme- cycles of cisplatin 60 to 75 mg/m2 and paclitaxel 135 to
diate or high-risk factors with the primary endpoint of 175 mg/m2 before and after pelvic radiation therapy.
late grade ≥2 GI toxicity-free survival.1 Patients received The groups were well balanced with the exception of
Volume 111  Number 2  2021 Oncology Scan 301

lower rates of lymph node positivity in the RT group were no differences in outcomes between CCRT and RT.
(18.3%) compared with approximately 30% in the other This could be due to the imbalance in nodal positivity
2 groups. between the groups seen in this study, as it was not a
In the intention-to-treat population, SCRT showed a stratification factor. Nodal positivity is the strongest
benefit for the primary endpoint of disease-free survival driver of recurrence in cervical cancer and the most sig-
(DFS) at 3 years compared with either CCRT or RT nificant predictor of benefit from the addition of chemo-
(90% vs 82% vs 85%, respectively). There was also a therapy, shown in a large database study of patients who
decreased rate of distant metastatic disease (6.5% vs would have qualified for GOG 109.13
11% vs 10.6%) and improved cancer-specific survival In conclusion, the STARS trial will fit into the constella-
(7.6% vs 11.1% vs 9.9%) in the SCRT group. In a sub- tion of modern data for cervical cancer; however, before we
group analysis of patients with high-risk factors only, group intermediate and high-risk factors and give our patients
SCRT continued to show benefit compared with the adjuvant SCRT we must await the results of 2 ongoing NRG
other 2 groups. There was no difference in DFS or over- trials. The NRG has one trial for intermediate-risk features
all survival (OS) between CCRT or RT groups, even in (GOG 0263) randomizing between CCRT and RT, and one
subgroup analysis by risk groups. for high-risk features (RTOG 0724) with CCRT § adjuvant
chemotherapy after hysterectomy. These may give clarity
Comment: The authors conclude that SCRT may be the and some more granularity to the treatment paradigm after
optimal adjuvant therapy for women with adverse features hysterectomy for early-staged cervical cancer.
after a hysterectomy. However, several components of this
trial are inconsistent with current treatment paradigms in
Radiation Therapy for Cervical Cancer: Executive
the United States and Europe, making the results difficult to
Summary of an ASTRO Clinical Practice Guideline
integrate into practice. These include the routine use of neo-
adjuvant chemotherapy in patients with larger tumors, high Summary: This ASTRO guideline addresses the manage-
rates of toxicity reported in the women treated with chemo- ment of curative cervical cancer, quantifying the strength of
radiation, and the grouping of intermediate and high-risk the recommendation and the corresponding level of evi-
features in determining adjuvant therapy. dence, while focusing on 5 key questions approved by the
In this trial, about 20% of women, well distributed ASTRO board relating to postoperative and definitive exter-
among groups, received neoadjuvant chemotherapy, includ- nal beam radiation (EBRT) with or without systemic ther-
ing 84.4% of women with tumors larger than 4 cm at apy, use of IMRT, and indications and techniques of
the time of diagnosis. In this subgroup of patients, there brachytherapy.7
was no difference in DFS between the treatment groups, Based on the high quality data of the randomized con-
suggesting that in women who receive chemotherapy trolled studies of GOG 92 and GOG 109, the guideline
upfront, there may be no additional benefit to adding che- gives a strong recommendation for adjuvant EBRT for post-
motherapy postoperatively. However, this practice is not operative patients with intermediate-risk cervix cancer and
commonly used elsewhere and leads to dilution of the treat- adjuvant EBRT plus concurrent platinum-based chemother-
ment groups. apy for patients with high-risk cervix cancer.5,6 With multi-
Despite the tremendous amount of information that is ple randomized controlled studies supporting concurrent
provided by the authors in the form of supplemental platinum-based chemotherapy for definitive treatment of
materials, the details of radiation therapy planning are intact cervix cancer for FIGO stages IB3 to IVA EBRT
scarce providing only bony landmarks and dose points with no adjuvant hysterectomy are strongly recommended,
while leaving technique and dose constraints to the while for stages IA1 to IB2, EBRT with or without chemo-
providers’ discretion. It is possible that the increased therapy is conditionally recommended based on expert
rates of grade 3 and 4 gastrointestinal toxicity, seen in opinion.
women treated with CCRT compared with both SCRT The published data of the phase 3 study RTOG 1203
and RT, is related to small bowel dose without the use (TIME-C) evaluating patient reported outcomes of 3D ver-
of intensity modulated radiation therapy and appropriate sus IMRT for postoperative treatment of cervical or endo-
constraints on the bowel bag.3 metrial cancer supports the strong recommendation for
Currently, adjuvant therapy for patients with cervical IMRT to decrease acute and chronic toxicity. The guideline
cancer is determined from trials completed in the 1980s was written before the presentation of the previously men-
and 1990s, which categorize patients into low-, intermedi- tioned PARCER trial; however, these results only add more
ate-, and high-risk of recurrence based on pathologic strength to the recommendation. IMRT for intact cervix
features.5,11,12 Based on these trials, we know that women cancer is conditionally recommended based on a mix of
with intermediate-risk features have a progression-free institutional series and small randomized and nonrandom-
survival benefit with the addition of radiation therapy ized prospective studies.2
and that woman with high-risk features have a progres- Using moderate quality evidence of database and ret-
sion-free and OS benefit with the addition of chemother- rospective studies, the treatment of intact cervix cancer
apy to radiation therapy. However, in this study, there patients with brachytherapy is strongly recommended,
302 Oncology Scan International Journal of Radiation Oncology  Biology  Physics

whereas a brachytherapy boost for a positive margin in opposed to 2D/point based brachytherapy, the specific struc-
postoperative patients with cervix cancer is conditionally ture of the guideline strongly recommends both with the
recommended. For brachytherapy technique, the guide- qualification of using 2D/point based approach if volume-
line endorses a strong recommendation for intraproce- based planning cannot be performed. It begs the question of
dure imaging such as with transrectal or abdominal how to handle inadequate resources for a particular treat-
ultrasound, use of CT or MRI for volume-based plan- ment approach, such as lack or limited availability of during
ning, and 2-dimensional (2D)/point based planning if procedure imaging or MRI with the applicator in place.
volume-based planning is not available. Besides imaging resources, 3D volume-based planning gen-
After the Groupe Europeen de Curietherapie - European erally requires more time, so if both approaches have a sim-
Society for Radiotherapy & Oncology (GEC-ESTRO) ilar level of recommendation, could the motivation of
−based guidelines, as further refined by data from the changing from one to the other be made more explicit?
image guided intensity modulated external beam radioche- The article also discusses how the guideline will be re-
motherapy and MRI based adaptive brachytherapy in evaluated annually starting 2 years after publication to
locally advanced cervical cancer study, there is a strong rec- address new practice changing studies, which is likely bene-
ommendation for volume-based contouring and the total ficial given the quick pace of new and emerging data, per-
equivalent dose at 2 gray per fraction (EQD2) dose of haps even some referenced in this present article.
EBRT and brachytherapy to be greater than 80 Gy. Addi-
tionally, the guideline conditionally recommends greater
PORTEC 3: Molecular Classification of High-risk Uterine
than 85 Gy for poorly responding or tumors over 4 cm and
Cancer
suggests that combination intracavitary and interstitial
approaches may help reach this aim while respecting nor- Summary: PORTEC-3 was designed to test the hypothe-
mal tissue dose limits. sis that combined adjuvant chemotherapy and radiation
therapy improves failure-free survival and overall sur-
Comment: The ASTRO Cervix Cancer Clinical Practice vival compared with radiation therapy alone for high-
Guideline provides a useful reference for the vast majority risk endometrial cancer. The study randomized 660 eli-
of cervix cases and the corresponding references for the gible patients to receive pelvic radiation therapy alone
underlying data but does not provide guidance for the more (48.6 Gy in 28 fractions) or radiation therapy and con-
challenging and rare cases. These situations include if a current and sequential chemotherapy (cisplatin 50 mg/
postoperative cervix patient with a close (1 mm) margin m2 for 2 cycles during radiation therapy followed by
should receive a brachytherapy boost, when to treat carboplatin area under the curve 5 and paclitaxel 175
extended field or add adjuvant chemotherapy, or how to mg/m2 for 4 cycles).8 At a median follow-up of 72
balance the conflicting treatment goals of lymph node boost months, the study reported an absolute 5% improvement
and sparing adjacent normal tissue. The lack of recommen- in overall survival with combination of chemotherapy
dation on particular topics in large part relates to the scope and radiation. On subgroup analyses, overall survival
of the questions approved by the ASTRO board or the lack was significantly improved for stage 3 patients and those
of data to support a particular recommendation. with serous histology, but at the cost of increased
The conflicts between quality of evidence and strength adverse effects and detriment in quality of life.14
of recommendation are particularly highlighted with the The present study reports on the effect of molecular
recommendations for IMRT and brachytherapy technique. subtype on prognosis and reports benefit from adjuvant
Postoperative IMRT is strongly recommended with moder- therapy in patients with high-risk endometrial cancer who
ate evidence for acute toxicity and low evidence for chronic harbor p53 mutation and raises the possibility of deintensifi-
in large part based on TIME-C, which included 45 cervix cation of adjuvant treatment in those with POLE mutation.9
cancer patients and 233 endometrial cancer patients, Of the 660 randomized patients, tissue for molecular
whereas intact cervix IMRT is conditionally recommended subtype analysis was available in 423 consenting patients.
with moderate evidence for decreasing acute and chronic Immunohistochemical staining was performed for p53
toxicity, including 3 randomized studies including up to and mismatch repair proteins and POLE mutation status
122 cervix patients and a meta-analysis of >1000 cervix was assessed by next generation sequencing. Of the 410
patients. With a large phase 3 study comparing IMRT to 3D patients with adequate samples 22.7%, 12.4%, 33.4%, and
for intact cervix cancer unlikely to occur, the conditional 31.5% were reported to have p53 abnormal, POLE muta-
recommendation will stand until all or almost all informed tion, MMR-deficient and nonspecific molecular profile,
people would make the recommended choice (as per the respectively.
definition of strong recommendation). Although the 5-year relapse-free survival was lowest
Similarly, the guideline has challenges of dealing with in patients with p53 mutation (48%), it was relatively
conflicting data or the evolution of intact cervical cancer better in patients with MMR-deficient tumors (71%) and
brachytherapy approach. Although studies have shown the best in those with POLE mutation (98%). On multivari-
improved local control and decreased toxicity benefits ate analysis, p53 mutations were identified to have inde-
of 3D image guided and volumetric-based planning, as pendent negative prognostic effect and were also more
Volume 111  Number 2  2021 Oncology Scan 303

likely to have significant benefit from adjuvant com- study may be needed for this subgroup to provide fur-
bined chemoradiation approach (relapse-free survival ther clarification.
58.6% with CRT vs 36.2% with RT; HR 0.52; 95% CI, The results also clearly demonstrate that despite adding
0.30%-0.91%; P = .02) as well as an overall survival systemic chemotherapy in p53 mutant cancers, the out-
benefit. POLE mutation was identified to be the most comes leave much to be desired. Additional work into
important favorable prognostic factor both for RFS (HR tumor biology will be needed to identify new agents in both
0.08; 95% CI, 0.01%-0.58%; P = .01) and OS (HR the concurrent and adjuvant setting. Examples of such
0.12; 95% CI, 0.02%-0.87%). approach could be addition of anti epidermal growth factor
receptor 2 (HER-2) therapeutics in the adjuvant setting in
Comment: The post hoc analysis of PORTEC-3 trial pro- those with HER-2 positive tumors or poly (ADP-ribose)
vides important information regarding distribution of polymerase inhibitors in those with homologous recombi-
molecular risk groups in patients determined to be at nant deficiency.19 Additionally, although the benefit of
high-risk on standard pathologic risk stratification. This combination approach is not clear for stage I or II tumors
analysis reports that p53 mutation can be expected in with mismatch repair gene deficiencies, prospective inte-
20% to 25% of patients and is associated with poor gration of immunotherapy in adjuvant setting may improve
prognosis. However, outcomes can be improved by outcomes. Integration of new agents in the adjuvant setting,
using a multimodality treatment approach. These results such as anti PDL-1 and anti vascular endothelial growth
may help in individualization of care in women with factor (fibroblast growth factor receptor 2), need additional
stage I or II cancers who harbor p53 mutation. Should investigation.20
chemotherapy be considered in stage I or II high-risk It is also important to determine whether these results are
patients with nonserous histology and p53 mutation to strong enough to allow recommendation for observation or
improve relapse-free survival? Although the recommen- deintensification of treatment in stage I to III POLE mutant
dations are not based on a prospective randomized data, tumors. Although the natural response is to consider dein-
the molecular analysis is performed in a well-balanced tensification of therapeutics in stage III POLE mutant
large patient cohort which identifies the use of chemo- tumors, it is important to note that these excellent results
therapy as an independent predictor of improved out- are derived from a trial which received radiation in both
comes in patients with p53 mutation. In clinical arms. Additional analyses of POLE cohorts is needed to
practice, individualization of care using the molecular understand the feasibility of treatment deintensification,
stratification results will likely be critical to improve especially if omission of radiation is considered.21 The
outcomes. ongoing PORTEC 4a trial will also aid in determining
These observations of post hoc molecular classification whether this feasible as it will omit all treatment for POLE
though applied to use of concurrent chemotherapy in POR- mutated stage I tumors.17
TEC-3 raise very important questions also for other patient Overall, although newer therapeutics are being tested for
subgroups recruited in other completed and ongoing trials. these molecular subtypes, the role of radiation therapy in
For example, could many stage III or IV patients recruited local and distant salvage will be paramount in improving
in GOG-258 have been p53 positive, explaining the benefit overall survival. Therefore, a structured evaluation of pat-
of 6 cycles of systemic chemotherapy.15 Also, it is possible terns of relapse according to molecular pathways will be
that a p53 mutated population in GOG 258 could have important in near future along with registries of patients
experienced excessive local recurrences. Would p53 with limited sites of relapse. Although ESGO-ESTRO-ESP
mutant patients in GOG 258 benefit from addition of radia- guidelines already propose a prognostic risk grouping based
tion therapy? Clearly additional molecular studies are on molecular markers, further work is needed to define the
needed within recently completed trials to understand the best therapeutic approach for the future.22
effect of molecular subtype on overall outcomes. Unlike
molecular classification in high-intermediate risk patients,
GROINSS-V-II: Management of the Groins in Early Stage
the independent role of other markers like L1-CAM is not
Vulvar Cancer With Positive Sentinel Lymph Nodes:
reported for PORTEC-3 high-risk population.16 In future
Distinction Between Micro- and Macrometastases
analysis, it will be worthwhile to see if L1-CAM expression
provides additional prognostic information in this cohort of Summary: The GROINSS-V-II study was a large, prospec-
patients. This could help to better define outcomes espe- tive, observational study of patients with early stage vulvar
cially in patients with nonspecific molecular profile. squamous cell carcinoma (primary tumor diameter <4 cm,
The adverse results of the p53 mutated subgroup also clinically negative lymph nodes) who had undergone senti-
raise important questions for the ongoing PORTEC 4a nel lymph node (SLN) staging. At the SGO 2020 meeting,
trial,6,7 where patients with high-intermediate risk endo- the results of this study were presented in 2 parts. In part 1,
metrial cancer and p53 mutation (unfavorable subtype) the results of the SLN-negative cohort were presented,
receive external radiation therapy alone.17,18 Is this which represented 1222 of the full cohort of 1552
unfavorable group treated better with combined chemo- (~79%).23 After SLN biopsies, no additional therapy was
therapy and radiation therapy? A future registration recommended in this group. Reassuringly, the groin
304 Oncology Scan International Journal of Radiation Oncology  Biology  Physics

recurrence rate was low at 3.1%, confirming the initial find- depth 3 cm below anterior skin surface with 50% of the pre-
ings of the GROINSS-V-I study, and the safety of omitting scribed dose delivered with electrons to spare the femoral
inguinofemoral lymphadenectomies (IFL) in early stage neck regions.26 This strategy similarly proved inferior to
patients who have SLN-negative disease.24 In part 2, the groin dissection due to excess recurrences in the groin in
results of the SLN-positive cohort were presented.10 One of the RT arm. Despite numerous criticisms of this trial, espe-
the study’s aims was to investigate whether RT to 50 Gy cially related to the RT technique, IFL has remained the
would be a safe alternative to IFL in this SLN-positive standard of care, with RT used postoperatively.27 After
group. The SLN-positive cohort was composed of 322 IFL, RT to both the groins and pelvis is a critical aspect
patients, or 21% of the overall cohort. in the care of node-positive vulvar cancer and improves
This cohort was further subdivided into patients with survival, but again morbidity rates with the combined thera-
micro- (≤2 mm) versus macro- (>2 mm) metastases in the pies are high.28,29
SLNs. After 54 months, an interim analysis revealed that The advent of SLN mapping was a game-changer. This
without IFL, there was an increased risk for groin recur- technology has been a major advance in the management of
rence among those with macrometastatic SLN (>2 mm) or small early stage operable vulvar cancer with negative clin-
with extracapsular extension (ECE) (n = 162). Specifically, ical node status. GOG 273 demonstrated the high sensitivity
in this group, the rate of groin recurrence with RT-only at and specificity of SLN mapping, especially for women with
2 years was 25% versus 8.2% with IFL § RT. In contrast, vulvar tumors <4 cm.30 This was a proof-of-concept study
in patients whose SLN was ≤2 mm (n = 160), RT-alone to as all patients received a completion lymphadenectomy.
the groin was an effective treatment, with an isolated groin This trial closely resembled the GROINSS-V-I study,
recurrence rate at 2 years of only 1.8%. Morbidity in terms which had shown isolated groin recurrence rate of 2.5% at
of infections and lymphedema was significantly reduced in 5 years among patients with a negative SLN and primary
patients who received RT as opposed to IFL. In summary, tumor size 4 cm or less who were observed.24 The SLN
safety of omission of additional therapy (IFL or RT) for negative arm of the GROINSS-V or II trial confirms the
patients with SLN-negative groins was confirmed, and RT safety of omitting IFL in SLN negative early stage vulvar
to 50 Gy was found to be a safe alternative to IFL for cancer, similar to these earlier studies. SLN mapping
patients with micrometastatic SLN-positive groins. How- can be considered an acceptable standard of care for man-
ever, for patients with macrometastatic SLN-positive agement of the clinically negative groin. When implement-
groins, RT-alone to 50 Gy was not a safe alternative to IFL ing SLN staging, it is important to consider the surgeon’s
and optimal therapy for this group remains unknown. technique, which improves with skill and experience;
also, pathologic ultrastaging is needed to confirm the pres-
Comment: Evaluation of the lymph nodes is critical for ence of disease. Furthermore, preoperative imaging should
both the staging and management of vulvar cancer. In one be used to identify clinically enlarged (but not palpable)
of the earliest clinicopathologic studies, Homesley et al groin disease, and thereby exclude patients who would not
investigated prognostic factors associated with vulvar can- be appropriate for SLN staging. With these concepts and
cer spread to the groins which included age, clinical node criteria for SLN mapping, the GOG and international com-
status, degree of tumor differentiation, LVSI, tumor size, munities have successfully found a safe pathway to avoid
and depth of invasion.25 For patients with these risk factors, IFL in the 80% of early stage vulvar cancer with clinically
IFL has been standard of care for decades. Beyond its prog- negative groins that do not need it.
nostic implications, IFL has therapeutic benefit in women Although SLN can replace IFL as a diagnostic procedure
with node-positive disease, as groin nodal recurrences are in early stage patients with clinically negative groins, is IFL
commonly lethal. still indicated as a therapeutic procedure for those with
Despite the prognostic and therapeutic benefits of pathologically positive SLNs? From the earlier GROINSS-
IFL, multiple attempts have been made over the years to V-I study, we learned that the size of the metastasis in the
eliminate or lessen the extent of the IFL procedure for SLN is prognostic, and that the prognosis of patients with
women with early stage vulvar cancer with clinically SLN met >2 mm is poor. There is also no size cutoff for
negative groins. A majority of these patients (~80%) which the chances of nonsentinel additional LNs approach
will have pathologically negative groins and coupled zero, therefore it is clear that additional therapy after a posi-
with the high morbidity associated with IFL (including tive SLN biopsy is needed.31 What is the appropriate addi-
lymphedema, lymphocysts, skin infections, and wound tional therapy? The GROINSS-V-II study put RT head to
complications), the search for a diagnostically sensitive head with IFL. RT to a dose of 50 Gy may be an appropriate
and but less morbid procedure is justified. adjuvant therapy for patients with positive SLN with size
Unfortunately, the early trials investigating alternative ≤2 mm, but not for those with SLN met >2 mm (macrome-
strategies to IFL were not successful. The GOG tested the tastasis) or with ECE due to the high rate of groin recur-
utility of a superficial-only inguinal lymphadenectomy rences, which are oftentimes fatal.
rather than a deeper IFL; however, this approach was aban- How can we understand the high failure rate in the
doned due to unexpectedly high groin relapse rates.25 GOG groins containing SLN-positive disease >2 mm? Can the
88 sought to replace IFL with 50 Gy RT prescribed to poor results be related to an insufficient dose or radiation
Volume 111  Number 2  2021 Oncology Scan 305

technique? The importance of technique in vulvar cancer treatment after hysterectomy for cervical cancer: The stars phase 3
contouring cannot be underestimated, and atlases are now randomized clinical trial. JAMA Oncol 2021;7:361–369.
5. Peters 3rd WA, Liu PY, Barrett 2nd RJ, et al. Concurrent chemother-
available for proper contouring of the groins.32 Perhaps a apy and pelvic radiation therapy compared with pelvic radiation ther-
higher dose than 50 Gy is necessary due to the likelihood of apy alone as adjuvant therapy after radical surgery in high-risk early-
there being unidentified gross residual disease, which may stage cancer of the cervix. J Clin Oncol 2000;18:1606–1613.
not be well-visualized on standard CT or PET imaging after 6. Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic
a SLN procedure. A recent retrospective Chinese study radiation therapy versus no further therapy in selected patients with
stage Ib carcinoma of the cervix after radical hysterectomy and pelvic
found relatively high rates of control with doses of 60 to 70 lymphadenectomy: A gynecologic oncology group study. Gynecol
Gy after positive SLN identification.33 Chemotherapy as a Oncol 1999;73:177–183.
radiosensitizer is a proven strategy in the neoadjuvant treat- 7. Chino J, Annunziata CM, Beriwal S, et al. The ASTRO clinical prac-
ment of locally advanced vulvar cancer, and although pro- tice guidelines in cervical cancer: Optimizing radiation therapy for
improved outcomes. Gynecol Oncol 2020;159:607–610.
spective data in the postoperative setting is lacking, this
8. de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemora-
may be another strategy by which to improve locoregional diotherapy versus radiotherapy alone in women with high-risk
control.34 Lastly, how the biology may effect radiosensitiv- endometrial cancer (PORTEC-3): Patterns of recurrence and
ity and outcomes is an exciting area of research that we are post-hoc survival analysis of a randomised phase 3 trial. Lancet
only beginning to understand. Preliminary data suggest that Oncol 2019;20:1273–1285.
expression of p53 or human papilloma virus positivity may 9. Leon-Castillo A, de Boer SM, Powell ME, et al. Molecular classifica-
tion of the PORTEC-3 trial for high-risk endometrial cancer: Impact
drive behavior and ultimately help guide management deci- on prognosis and benefit from adjuvant therapy. J Clin Oncol
sions, whether surgery, RT or both.35 2020;38:3388–3397.
We are left asking, what is the appropriate contemporary 10. van Der Zee AG, Slomovitz B, Covens AL, et al. Radiotherapy as an
management of SLN-positive macrometastasis? Off alternative treatment for inguinofemoral lymphadenectomy in vulvar
cancer patients with a metastatic sentinel node: Results of GROINSS-
trial, The NCCN guidelines suggest IFL as the preferred
V II. Gynecol Oncol 2020;159:3.
regimen. Otherwise, we have little data to guide practice 11. Rotman M, Sedlis A, Piedmonte MR, et al. A phase III random-
at the present time.36 Acknowledging the morbidity of ized trial of postoperative pelvic irradiation in stage Ib cervical
IFL, alternative strategies such as chemoradiation or carcinoma with poor prognostic features: Follow-up of a gyneco-
radiation dose escalation beyond 50 Gy may be reason- logic oncology group study. Int J Radiat Oncol Biol Phys
able, with suggested dose ranges up to 54 to 64 Gy 2006;65:169–176.
12. Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic
depending on risk factors. The proposed GROINSS-V- radiation therapy versus no further therapy in selected patients with
III/NRG-GY024 trial is a prospective phase 2 trial stage Ib carcinoma of the cervix after radical hysterectomy and pelvic
examining optimal treatment of SLN-positive vulvar lymphadenectomy: A gynecologic oncology group study. Gynecol
cancer. For micrometastasis, patients will have RT Oncol 1999;73:177–183.
alone. Patients with macrometastasis will have groin 13. Trifiletti DM, Swisher-McClure S, Showalter TN, et al. Postoperative
chemoradiation therapy in high-risk cervical cancer: Re-evaluating
boosts up to 56 Gy with concurrent weekly cisplatin. the findings of gynecologic oncology group study 109 in a large, popu-
The GROINSS-V-II trial has demonstrated the impor- lation-based cohort. Int J Radiat Oncol Biol Phys 2015;93:1032–1044.
tant role of SLN staging in early stage vulvar cancer 14. Post CCB, de Boer SM, Powell ME, et al. Long-term toxicity
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apy or radiation therapy alone for high-risk endometrial cancer in
regarding management of those with SLN-positive mac-
the randomized PORTEC-3 trial. Int J Radiat Oncol Biol Phys
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