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Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North CarolinaDuke Cancer Institute–Biostatistics Shared Resource, Durham, North Carolina
In this prospective trial, we aim to determine whether fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT)–based adaptive radiation therapy (ART) improves dosimetry outcomes for patients treated with definitive radiation for locally advanced vulvar cancer.
Methods and Materials
Patients were enrolled in 2 sequential institutional review board–approved prospective protocols for PET/CT ART from 2012 to 2020. Patients were planned with pretreatment PET/CT to 45 to 56 Gy in 1.8 Gy/fraction, followed by a boost to gross disease (nodal and/or primary) to a total of 64 to 66 Gy. Intratreatment PET/CT was obtained at 30 to 36 Gy, and all patients were replanned to the same dose goals with revised organ at risk (OAR), gross tumor volume, and planned target volume contours. Radiation therapy consisted of either intensity modulated radiation therapy or volumetric modulated arc therapy. Toxicity was graded by Common Terminology Criteria for Adverse Events, version 5.0. Local control, disease-free survival, overall survival, and time to toxicity were estimated using the Kaplan-Meier method. Dosimetry metrics for OARs were compared using the Wilcoxon signed rank test.
Results
Twenty patients were eligible for analysis. Median follow-up among surviving patients was 5.5 years. Local control, disease-free survival, and overall survival at 2 years were 63%, 43%, and 68%, respectively. ART significantly reduced the following OAR doses: bladder, maximum dose (Dmax; median reduction [MR], 1.1 Gy; interquartile range [IQR], 0.48-2.3 Gy; P < .001) and D2cc (MR, 1.5 Gy; IQR, 0.51-2.1 Gy; P < .001); bowel, Dmax (MR, 1.0 Gy; IQR, 0.11-2.9 Gy; P < .001), D2cc (MR, 0.39 Gy; IQR, 0.023-1.7 Gy; P < .001), and D15cc (MR, 0.19 Gy; IQR, 0.026-0.47 Gy; P = .002); and rectal, mean dose (MR, 0.66 Gy; IQR, 0.17-1.7 Gy; P = .006) and D2cc (MR, 0.46 Gy; IQR, 0.17-0.80 Gy; P = .006). No patients experienced any grade ≥3 acute toxicities. There were no reported late grade ≥2 vaginal toxicities. Lymphedema at 2 years was 17% (95% confidence interval, 0%-34%).
Conclusions
Doses to bladder, bowel, and rectum were significantly improved with ART, though the median magnitudes were modest. Which patients benefit most from adaptive treatment is a matter for future investigation.
Introduction
Vulvar carcinoma accounts for 6% of all cancers of the female reproductive organs, with 6330 new cases and 1560 deaths projected in 2022.
For patients with locally advanced vulvar cancer (LAVC), the mainstay of treatment includes a combination of chemotherapy and radiation therapy (RT), and surgery is reserved for salvage treatment.
Although radiation techniques have improved over the past few decades, patients often experience toxicities from treatment, including damage to the gastrointestinal (GI) and genitourinary (GU) system, sexual dysfunction, and lymphedema.
Fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) is an important tool for staging, treatment planning, and assessing treatment response after definitive chemoradiotherapy or RT.
In head and neck, thoracic, GI, and other gynecologic cancers, intratreatment FDG-PET/CT has been investigated as a method for adaptive radiation planning to mitigate toxicities and personalize treatment plans.
Effect of midtreatment PET/CT-adapted radiation therapy with concurrent chemotherapy in patients with locally advanced non-small-cell lung cancer: A phase 2 clinical trial.
To date, there are no known studies investigating the use of FDG-PET/CT adaptive radiation planning (ART) for patients with LAVC. In this prospective trial, we aim to determine whether FDG-PET/CT adaptive RT improves dosimetric outcomes and treatment toxicity for patients treated with chemoradiotherapy or RT alone in LAVC.
Methods and Materials
Patient selection, follow-up, and planning
Patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVB vulvar cancer who were scheduled for definitive chemoradiation (CRT) or RT were enrolled in 2 sequential institutional review board–approved prospective protocols (NCT01908504 and NCT03403465) for PET/CT ART from April 2012 through July 2020. Both studies included the same methodology for midtreatment evaluation and treatment planning. The only difference between the 2 approved studies was eligibility for enrollment by treatment site (ie, the first protocol included a head and neck cohort [not analyzed in this work] and the second did not). Exclusion criteria included patients who were younger than 18 years old, inability to provide informed consent, uncontrolled diabetes mellitus, pregnancy, those who were breastfeeding, or synchronous primary malignancy.
All enrolled patients were planned to receive standard institutional regimen or CRT or RT by the recommendations of a multidisciplinary tumor board consisting of radiation oncologists and gynecologic oncologists. RT consisted of either intensity modulated RT (IMRT) or volumetric modulated arc therapy with 1.8 Gy once daily to a total of 45 to 50.4 Gy and simultaneous integrated boosts to involved pelvic or para-aortic (PA) lymph nodes. The primary tumor was treated to 64.4 to 66.4 Gy with sequential boosts. Simultaneous integrated boost doses ranged from a total of 64.4 Gy to 66.4 Gy in 25 fractions determined by the treating physician and organ-at-risk (OAR) tolerance. OARs of interest included the bladder, bowel, and rectum. Imaging was obtained per protocol, which included FDG-PET/CT scans before treatment, an intratreatment scan at 30 to 36 Gy for ART, and a posttreatment scan 3 months after completing CRT or RT. The decision for intratreatment PET at 30 to 36 Gy was adapted from previously reported data for cervical cancer.
Metabolic response of pelvic and para-aortic lymph nodes during radiotherapy for carcinoma of the uterine cervix: Using positron emission tomography/computed tomography.
Prognostic significance of tumor response as assessed by sequential 18F-fluorodeoxyglucose-positron emission tomography/computed tomography during concurrent chemoradiation therapy for cervical cancer.
All patients were then replanned at 30 to 36 Gy to the same dose goals with revised OAR, gross tumor volume, and planning target volume (PTV) contours. The gross tumor volume primary was defined as gross disease within the vulva. Clinical target volume primary included a 10- to 15-mm expansion and areas of high-risk disease within the primary site. A 5- to 7-mm expansion was added for a final PTV. A dose of 45 to 50.4 Gy was prescribed to a PTV_low with a boost to 64 to 66 Gy to the involved lymph nodes and gross disease.
High-dose PTVs were only altered in the case when large nodes or gross tumor had significantly reduced in size. The elective volume included the inferior aspect of the vagina, the inguinal lymph node basins, internal and external iliac nodes, and presacral lymph nodes to the level of the bifurcation of the common iliac vessels. PA nodes were included if there was suspicion for involvement based on imaging. The total dose to positive nodes or to elective volume was unchanged in all cases. Planning turn around was 3 to 5 business days without any treatment pauses with intent to change to a new plan for the last 5 to 10 fractions of external beam RT in the initial plan and the subsequent sequential boost plan.
For those patients who received CRT, chemotherapy consisted of 5 weekly cycles of cisplatin during RT at a dose of 40 mg/m2. Chemotherapy was prescribed and given at the discretion of the managing gynecologic oncologist. Patients were seen on a weekly basis in on-treatment visits to discuss management of toxicities and side effects.
After the completion of treatment, patients were seen in follow-up by either the radiation oncologist or gynecologic oncologist every 3 months for 2 years, then every 6 months up to 5 years. Patients were evaluated as needed if there was a new concern. No routine imaging or laboratory tests were performed after the 3 months posttreatment PET/CT unless clinically indicated at the discretion of the evaluating physician.
Imaging details
FDG-PET/CT scans were performed on a Biograph mCT PET/CT System with 128-detector CT (Siemens Medical Solutions, Erlangen, Germany) with a set scanning protocol. Patients were instructed to fast for 4 hours before intravenous administration of FDG. The scanning protocol continued if fasting glucose was measured to be less than 200 mg/dL. Exceptions to this were handled at the discretion of the treating radiation oncologist and principal investigator of the study. The FDG was obtained by PETNET Solutions Inc, and the amount administered was 8 to 15 mCi, depending on patient weight (0.14-0.21 mCi/kg). There was then a 1 hour wait before image acquisition after injection. Images were obtained in 16-slice helical scanning mode, 16- × 1.2-mm collimation, 0.75 pitch, and 3-mm slice thickness. The PET reconstruction algorithm was ordered subset expectation maximization incorporating time of flight, with a CT matrix size of 512 × 512 and PET matrix size of 200 × 200. CT and PET images were fused directly from the Biograph console.
Statistical analysis
Patient demographics, FIGO stage at diagnosis, lymph node status and location (pelvis vs PA), tumor histology and grade, radiation prescribed dose, and toxicity during and after treatment as defined by Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, were recorded. Staging was determined by clinical examination and per PET/CT imaging. Local control (LC), disease free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method. LC was defined as freedom from recurrence within the treatment field. Further workup and biopsy confirmation was only performed if there was clinical suspicion for recurrence. DFS was defined as freedom from recurrence at any site or death from any cause. OS was defined as death from any cause. All time-to-event endpoints were measured from the end of RT; censoring was at time of last follow-up. Late toxicity was calculated as a cumulative incidence at time points after completion of RT.
Dosimetry metrics of OARs of interest including bladder, bowel, and rectum were collected for pre- and intratreatment plans. Dosimetry metrics for OARs in the unadapted versus the adapted intratreatment plan were compared using the Wilcoxon signed rank test. It was determined that, assuming that a clinically relevant dosimetric benefit would be achieved when >66% of the adaptive plans were superior to the initial plans, a sample size of 40 would be sufficient to achieve a significance test of <.05 (specifically, if 26 of 40 plans are dosimetrically superior, an exact 2-tailed test would result in a P value of .038). The study was closed before 40 patients because of slow accrual. All statistics were performed using SPSS, version 27, and R, version 3.6.0. Definition of significance was defined as P < .05. Adjustments for multiple comparisons were not applied because of the rarity of the malignancy.
Results
Patient and treatment characteristics
Twenty-two patients were enrolled, and 20 were eligible for analysis. Median follow-up among surviving patients was 5.5 years. Table 1 summarizes patient demographics and disease characteristics. The majority had FIGO stage II vulvar cancer (8 of 20 patients, 40%). Ninety-five percent of patients received concurrent chemotherapy with weekly cisplatin (19 of 20 patients). The median dose to the tumor volume was 65.5 Gy. All patients completed pre- and intratreatment FDG-PET/CT scans. The median time between pre- and intratreatment PET was 38 days. Cumulative incidence of LC, DFS, and OS (Fig. 1) at 2 years was 63% (95% confidence interval [CI], 41%-85%), 43% (95% CI, 21%-66%), and 68% (95% CI, 47%-89%), respectively. Mean reduction of volume of high dose PTV from pre- to midtreatment planning was 65.9 cc (median, 53.24; interquartile range [IQR], 19.09-84.78 cc). Mean reduction of volume of low-dose PTV from pre- to midtreatment planning was 129.5 cc (median, 48.74; IQR, 26.41-136.45 cc). Individual reduction of PTV by patient is summarized in Table E1.
Table 1Baseline patient demographics (n = 20)
No.
%
FIGO stage*
IA
0
0
IB
2
10
II
7
35
IIIA
3
15
IIIB
2
10
IIIC
2
10
IVA
4
20
IVB
0
0
LN status
LN–
6
30
Pelvic LN+
13
65
PA LN+
0
0
Unknown
1
5
Histology
SSC
19
95
Adenocarcinoma
1
5
Grade
1
1
5
2
2
10
3
3
15
N/A
14
70
Chemotherapy
Yes
19
95
No
1
5
Median
Range
Age at diagnosis
64
48-77
Dose to primary, Gy
50.4
45-56
Boost dose, Gy
16
10-20
Abbreviations: FIGO = International Federation of Gynecology and Obstetrics; LN = lymph nodes; N/A = not applicable; PA = para-aortic; SSC = squamous cell carcinoma.
Forty-five percent of patients experienced at least grade 2 (G2) acute GI toxicity. Twenty percent of patients experienced at least grade 2 (G2) acute GU toxicity. No patients experienced acute vaginal toxicity. No patients experienced any grade 3 or higher acute toxicity. G2 or more late GI toxicity at 2 years was 5% (95% CI, 0%-15%). G2 or more late GU toxicity at 2 years was 11% (95% CI, 0%-26%). There were no reported late ≥G2 vaginal toxicities. Lymphedema at 2 years was 17% (95% CI, 0%-34%). Cumulative incidence of late GI toxicity, GU toxicity, and lymphedema is displayed in Fig. 2. All patients (100%) experienced G2 skin toxicity around the tumor site (moist desquamation) within the acute setting, as expected in this treatment. No patients experienced a treatment break, and toxicity was conservatively managed as needed.
ART significantly reduced all dosimetric constraints for the bladder, including maximum dose (Dmax) (median reduction, 1.1 Gy; IQR, 0.48-2.3 Gy; P < .001), mean dose (Dmean) (median reduction, 0.91 Gy; IQR, 0.09-1.1 Gy; P = .001), and D2cc (median reduction, 1.5 Gy; IQR, 0.51-2.1 Gy; P < .001). For bowel, all dosimetric constraints were significantly reduced by ART. Dmax (median reduction, 1.0 Gy; IQR, 0.11-2.9 Gy; P < .001), D2cc (median reduction, 0.39 Gy; IQR, 0.023-1.7 Gy; P < .001), and D15cc (median reduction, 0.19 Gy; IQR, 0.026-0.47 Gy; P = .002) were the most reduced in order of magnitude. For rectum, the Dmean (median reduction, 0.66 Gy; IQR, 0.17-1.7 Gy; P = .006), Dmedian (median reduction, 0.43 Gy; IQR, –0.052-1.61 Gy; P = .007), and D2cc (median reduction, 0.46 Gy; IQR, 0.17-0.80 Gy; P = .006) were significantly reduced with ART. Rectal Dmax, V45, and V50 were not significantly changed with ART. A summary of dosimetric outcomes is reported in Table 2. The absolute magnitude of dose by each constraint was recorded and reported in Table E2. Because of the small numbers within this study, further analysis associating dose and patient toxicity was not possible. An example of before and after PTVs based on ART is illustrated in Fig. 3.
Table 2Dosimetric constraints and reductions
OAR
Dosimetric constraint
P value
Median reduction (Gy)
IQR (Gy)
Bladder
Dmax
<.001
1.1
0.48-2.3
Dmean
.001
0.91
0.09-1.1
Dmedian
.007
0.64
0.08-1.1
D2cc
<.001
1.5
0.51-2.1
V56
.010
0.01
0.003-0.04
Bowel
Dmax
.001
1.0
0.11-2.9
Dmean
.011
0.06
–0.005 to 0.49
Dmedian
.039
0.03
–0.007 to 0.46
D2cc
.001
0.39
0.023-1.7
D15cc
.002
0.19
0.026-0.47
V15
.012
0.002
–0.0002 to 0.032
V45
.015
0.013
–0.001 to 0.12
Rectum
Dmax
.083
0.49
0.045-1.13
Dmean
.006
0.66
0.17-1.7
Dmedian
.007
0.43
–0.052 to 1.61
D2cc
.006
0.46
0.17-0.80
V45
.074
0.092
–0.0018 to 0.02
V50
.053
0.012
–0.0023 to 0.03
Abbreviations: IQR = interquartile range; OAR = organ at risk.
In this prospective study involving patients with LAVC treated with chemoradiotherapy or RT alone, dose to normal organs is significantly improved with an acceptable level of toxicity using ART. Survival outcomes, including LC, is similar or improved compared with historical experiences in vulvar cancer.
A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: A gynecologic oncology group study.
Although surgery has been a mainstay of treatment for vulvar cancer, results of effective CRT and radiation treatments are promising. In a National Cancer Database analysis of 2046 women, the authors find that outcomes among patients who receive doses more than 55 Gy with chemotherapy were not significantly different from those who receive preoperative radiation or CRT (hazard ratio, 1.139; 95% CI, 0.969-1.338; P = .116).
However, toxicities from treatment may be debilitating to patients, and the present study aims to provide effective doses of radiation treatment while minimizing dose to normal organs.
As technology improves with treatment planning, including the use of IMRT, doses needed for effective disease control are able to be administered more safely. IMRT is an advanced method of administering RT that modulates the intensity of radiation from the beam during the path of radiation. In the setting of gynecologic malignancies, the emerging use of IMRT has provided excellent tumor control with sparing of the normal pelvic organs.
IMRT was superior to 3-dimensional conformal treatment in reducing dose to OARs and toxicity for patients with vulvar cancer. Both Gynecologic Oncology Group (GOG) 101 and 205 sought out to treat locally advanced disease with neoadjuvant CRT, with the aim of converting to resectable disease.
A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: A gynecologic oncology group study.
Although GOG 205 was able to achieve dose escalation to 57.6 Gy in 1.8 Gy/fraction and improved outcomes in pathologic complete response in patients who were initially unresectable, IMRT was not allowed in the study. In our present study, radiation techniques included both IMRT and ART, as well as dose escalation higher than GOG 205. Although it is possible that the use of IMRT rather than 3-dimensional RT planning may be a reason for ongoing improvement in toxicity, the use of ART may be important when dose escalating. In a retrospective study by Rao et al,
39 patients with vulvar cancer were treated with IMRT, either postoperatively, preoperatively, or definitively, and patients had limited grade 3 to 4 toxicity. It is of note, however, that the LC and OS for the patients who were treated with definitive treatment at 3 years was 42% and 49%, which is notably lower than historical controls and our study.
In the present study, only 1 patient experienced a late grade 3 GI toxicity and 1 patient experienced grade 3 GU toxicity. By nature of this study as a single arm, feasibility study, without a direct comparison as a randomized trial, we are unable to draw firm conclusions that ART has improved toxicity. However, the current study has achieved a relatively higher LC while also administering high doses of definitive CRT with acceptable toxicities.
In the present study, we find that multiple dosimetric parameters improved and were statistically significant after ART. In a phase 2 trial that evaluated cisplatin and gemcitabine concurrent with IMRT for LAVC (GOG 0279), which has recently closed to accrual, constraints for bowel, rectum, and bladder were specified as follows: <30% of the bowel to receive ≥40% of the dose, Dmax ≤ 51 Gy; <80% of rectum to receive ≥40 Gy, Dmax < 65 Gy; and <50% of bladder to receive ≥45 Gy, Dmax ≤ 65 Gy.
ClinicalTrials.gov. Radiation therapy, gemcitabine hydrochloride, and cisplatin in treating patients with locally advanced squamous cell cancer of the vulva. Available at: https://clinicaltrials.gov/ct2/results?term=gog-0279&Search=Search. Accessed January 13, 2023.
In our study, we aimed to achieve similar goals while balancing the need to adequately cover gross disease. With many of our patients enrolled in this study, we were able to achieve reduction of dose to surrounding structures using adaptive planning safely, without apparent compromise of LC.
ART is a method that is commonly used in RT when treating a volume disease that may change in size as a result of treatment response.
Per the most recent consensus guidelines for contouring gynecologic malignancies, there is explicit recommendation that adaptive planning should be considered when there are significant clinical changes during the treatment.
Because of the rarity of vulvar cancer treated with definitive CRT or radiation, there is limited knowledge on the use of ART in this setting. One retrospective study by Abuhijla et al
showed that out of 22 patients with nonoperable vulvar cancer at their hospital, 13 plans required ART, with the change of tumor volume ranging from 3 to 41 cc. This study differs from the present study as this group did not routinely use PET/CT for staging or planning and did not report dose changes to OARs. To date, our study is the first to prospectively assess the dosimetric constraints to OARs and toxicity using PET/CT ART. Although the changes are modest in the current study, the dose reduction of normal organs may be clinically effective in long-term follow-up.
This study has several limitations. Given the rarity of this disease, the smaller sample size and limited follow-up result in low statistical power to explore associations between baseline characteristics and toxicity and time-to-event endpoints. Future studies should include analysis of predictors of response during intratreatment PET on clinical outcomes, such as LC and survival. In addition, future studies would need larger sample sizes to further correlate toxicity to dosimetric constraints.
Conclusion
In this prospective study, doses to bladder, bowel, and rectum were significantly reduced, though the median magnitudes were modest. Which patients benefit most from adaptive treatment is a matter for future investigation. Treatment overall was well tolerated. LC is similar to historical experiences, and efforts are indicated to improve on these results. PET/CT ART may be considered a reasonable option for the treatment of LAVC in future studies and may allow for dose escalation or the inclusion of novel radiation sensitizers while limiting potential toxicities.
Effect of midtreatment PET/CT-adapted radiation therapy with concurrent chemotherapy in patients with locally advanced non-small-cell lung cancer: A phase 2 clinical trial.
Metabolic response of pelvic and para-aortic lymph nodes during radiotherapy for carcinoma of the uterine cervix: Using positron emission tomography/computed tomography.
Prognostic significance of tumor response as assessed by sequential 18F-fluorodeoxyglucose-positron emission tomography/computed tomography during concurrent chemoradiation therapy for cervical cancer.
A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: A gynecologic oncology group study.
ClinicalTrials.gov. Radiation therapy, gemcitabine hydrochloride, and cisplatin in treating patients with locally advanced squamous cell cancer of the vulva. Available at: https://clinicaltrials.gov/ct2/results?term=gog-0279&Search=Search. Accessed January 13, 2023.
Presented in abstract form at the American Society for Radiation Oncology Annual Meeting in 2022.
Sources of support: This work had no specific funding.
Disclosures: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
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