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Imaging to optimize gynecological radiation oncology
  1. Elizabeth A Kidd
  1. Stanford University School of Medicine, Stanford, California, USA
  1. Correspondence to Dr Elizabeth A Kidd, Stanford University School of Medicine, Stanford, CA 94305, USA; ekidd{at}stanford.edu

Abstract

Gynecological cancers have particularly benefited from the increasing use of imaging to guide radiation treatment planning for both external beam radiation and brachytherapy. While the different gynecological cancers have varying use of imaging, certain trends predominate. CT represents an economical choice for evaluating initial disease extent or potential metastasis at follow-up, particularly for endometrial and ovarian cancers. F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is particularly useful for assessing the initial disease extent and longer term treatment response of squamous predominant cancers, including cervical, vaginal, and vulvar cancers. With its excellent pelvic soft tissue discrimination, MRI provides the greatest assistance in evaluating the local extent of gynecological tumors, including initial evaluation for non-operative endometrial and vulvar cancer, and assessment before, after and during brachytherapy for cervix, locally recurrent endometrial, and primary vaginal cancers. With more limited availability of MRI, ultrasound can also help guide brachytherapy, particularly during procedures. The benefits of using imaging to better spare bone marrow or earlier assessment of treatment response are topics still being explored, in particular for cervical cancer. As imaging along with radiation oncology technologies continue to evolve and develop, such as with MRI-linacs and ultra high dose rate (FLASH) radiation, we may continue to see increasing use of imaging for advancing gynecological radiation oncology.

  • vulvar and vaginal cancer
  • cervical cancer
  • uterine cancer
  • radiotherapy
  • image-guided

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Cervix Cancer

Cervical cancer is the fourth most common cause of cancer and cancer death in women worldwide, with an estimated 604 000 new cases and 342 000 deaths in 2020.1 Despite being more prominent in the developing world, imaging with F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT and MRI plays an important role for work-up and staging, prognosis, radiation treatment planning, and follow-up.

Work-up and Staging

Cervical cancers are generally FDG avid, making FDG-PET/CT particularly useful for evaluating the primary tumor, lymph node, and distant metastases for cervical cancer. Two meta-analyses have shown FDG-PET/CT to be more effective at detecting involved lymph nodes for cervical cancer compared with CT or MRI.2 3 Cervical cancer spreads in an orderly fashion from the primary tumor to the pelvic lymph nodes, then to the para-aortic lymph nodes, followed by the supraclavicular region and distantly. From the prospective ACRIN6671/GOG0233 trial that included 153 patients with 43 having involved lymph nodes, PET/CT had a sensitivity of 0.83 and 0.50, and specificity of 0.63 and 0.85 for pelvic and abdominal metastases, respectively.4

Lymph node involvement represents one of the main determinants of treatment approach, extent of radiation field, and overall prognosis. Figure 1A,B shows example FDG-PET/CT images for a patient with cervical cancer and bilateral pelvic lymph node metastases (use of patient radiology images was approved by Stanford Institutional Review Board 38480). It is recommended that patients fast for 5–6 hours prior to FDG injection and ideally urinate immediately before the scan to help decrease the FDG signal from the bladder. The National Comprehensive Cancer Network (NCCN) recommends PET/CT for cervical cancers stage IB1 and above.5 FIGO 2018 cervical cancer staging was updated to incorporate lymph node involvement on imaging (r) or pathology (p).3 6

Figure 1

Example FDG-PET/CT and MRI images for cervical cancer. (A) Maximum intensity projection showing FDG-avid primary cervix and bilateral pelvic lymph nodes. (B) Corresponding axial PET/CT images just above femoral head showing FDG-avid primary cervix and bilateral pelvic lymph nodes. (C) Axial T2 pelvic MRI image showing bladder invasion on the right. (D) Axial T2 pelvic MRI image showing rectal invasion.

MRI (1.5 Tesla or higher) provides excellent soft tissue contrast, allowing highly accurate delineation of the extent of the primary cervical tumor. Performing the MRI scan with intravaginal gel helps define the vaginal portion of the cervical tumor on T2-weighted sequences. Gadolinium-enhanced T1-weighted and diffusion-weighted images can be useful for detecting smaller cervical tumors.7 Cervical tumors frequently spread locally into the parametrium and the accuracy of MRI for assessing parametrial extension ranges from 88% to 97%, significantly exceeding clinical assessment.8 MRI is generally superior to PET/CT for determining bladder and rectal invasion (see Figure 1C,D for example MRI images). Determination of lymph node metastases using MRI is primarily based on a size criterion of 1 cm or greater in short-axis diameter. Additionally, round shape, heterogeneous enhancement, and central necrosis are also suggestive of nodal metastases.9

The combination of information from FDG-PET/CT and MRI can define the need for radiation, such as with the presence of lymph node metastases, large tumor size, parametrial or vaginal involvement. Additionally, information from both the PET and MRI can help with delineating the radiation volume and extent for both the primary cervix tumor and lymph node regions.

FDG-PET/CT, MRI and Prognosis

Several FDG-PET features, as assessed from the pretreatment FDG-PET/CT, have been shown to be associated with cervical cancer prognosis, including primary tumor maximum standardized uptake value,10 metabolic tumor volume,11 tumor heterogeneity,12 extent of lymph node involvement,13 and pelvic lymph node maximum standardized uptake volume.

Additionally, changes in PET/CT images during the course of chemoradiation have been associated with cervical cancer treatment response and prognosis. Several groups have found that changes in maximum standardized uptake volume and/or metabolic tumor volume on a PET/CT performed at approximately 4 weeks into chemoradiation predicts post-treatment response at 1 or 3 months after chemoradiation PET/CT and longer-term survival outcomes.14–17 Additionally, Yoon and colleagues found that complete metabolic response of nodal disease on inter-RT PET/CT had excellent overall survival, disease-free survival, and distant metastasis-free survival rates.18

Changes in MRI parameters during chemoradiation have also been associated with prognosis, with improved perfusion as measured on dynamic contrast-enhanced MRI being associated with more favorable outcomes.19 A pilot study evaluating perfusion CT for cervical cancer also found that increasing mean tumor blood volume during treatment was significantly correlated with complete metabolic response on 3‐month post-treatment PET/CT.20

External Beam Radiation Treatment Planning

Early stage cervical cancer (FIGO IB1 or smaller) will often be treated with surgery. NCCN recommends PET/CT for cervical cancers that are found incidentally during a hysterectomy.5 FDG-PET/CT should also be considered for patients with cervical cancer treated with surgery who are found to have involved lymph nodes to ensure no residual nodal disease that requires boosting with radiation.

As discussed above, both PET/CT and MRI are important for planning external beam radiation and in particular intensity modulated radiation therapy for patients with intact cervical cancer undergoing definitive chemoradiation treatment. MRI and FDG-PET/CT are both useful for delineating the primary cervical tumor and if obtained at separate times can also be helpful for demonstrating tumor movement and aid in creating an internal target volume encompassing that variability of positioning. Grigsby and colleagues have studied FDG-PET-guided intensity modulated radiation therapy as an alternative to needing an internal target volume by giving a relatively low cervix or central pelvis radiation dose with intensity modulated radiation therapy along with an interdigitated higher brachytherapy dose to achieve a dose of 85 Gy to point A. They found favorable disease and toxicity outcomes.21 22 With this or other approaches, FDG-PET/CT in treatment position or fused accordingly can also be helpful for identifying involved lymph nodes and boosting treatment with radiation.

Additionally, data from the INTERTECC study suggest the possibility of using lumbar spine and pelvic bone FDG uptake to identify the most active bone marrow to spare with intensity modulated radiation therapy planning. In a select group of patients, treatment with this bone marrow sparing intensity modulated radiation therapy approach showed significantly lower grade 3 neutropenia without any significant increase in gastrointestinal or other toxicity.23 This finding is being further evaluated in NRG-GYN006.

MRI and Brachytherapy Planning

Image-guided adaptive brachytherapy is based on the recommendations of the Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology, and findings from EMBRACE and retro-EMBRACE.24 25 This approach relies on patients having a pre-radiation MRI and an MRI before or during brachytherapy for defining the initial extent of disease based on clinical exam and T2 MRI, treatment response to external beam radiation, volume of residual cervical disease, and also the adjacent organs at risk if MRI is performed with the applicator in place. See Figure 2 for example images of cervical cancer before radiation, before brachytherapy, and with the applicator in place. The recently reported longer term outcomes for EMBRACE with a median follow-up of 51 months found a 5-year local control rate of 92% and grade 3–5 morbidity of 6.8% for genitourinary, 8.5% for gastrointestinal, and 5.7% for vaginal disease, and 3.2% for fistulae.26 Trans-abdominal, trans-rectal or trans-vaginal ultrasound can also help provide imaging guidance during brachytherapy procedures.27

Figure 2

T2 MRI images from the same patient pre-radiation in sagittal (A) and axial (B) view with parametrial invasion and left ureter encasement (arrow), then pre-brachytherapy in sagittal (C) and axial (D) view showing interval decrease in cervical tumor size, parametrial invasion no longer evident and resolution of left-sided hydroureter. (E) and (F) show the sagittal and axial T2 images with the brachytherapy applicators, balloon, and packing in place.

FDG-PET/MRI

The combination of diagnostic MRI and FDG-PET is a somewhat new imaging approach that combines the high soft tissue contrast of MRI and benefits of PET for nodal and distant metastasis. While some studies show the superiority of FDG-PET/MRI over each imaging modality individually,28 this combined imaging is not yet standard of care and can frequently present challenges for obtaining insurance approval.

Follow-up/Recurrence Work-up

PET/CT has been shown to be useful for assessing response after radiation and chemoradiation, with the response at 3 months after treatment predicting longer term outcome.29 NCCN recommends PET/CT 3–6 months after treatment for patients with FIGO stage IB3-IV or earlier stage cervical cancer that requires postoperative radiation or chemoradiation.5 PET/CT and/or MRI should also be performed for suspected local tumor recurrence.

Uterine Cancer

Uterine cancer is the sixth most common cancer in women worldwide, with 417 000 new cases and 97 000 deaths in 2020 and significantly higher incidence in developed countries.1 With surgery being the standard upfront approach for treatment and staging, imaging has a slightly smaller role than with cervical cancer, but is important for planning definitive radiation and for treatment planning for more advanced stage endometrial cancer.

Work-up and Staging

Surgical staging with total abdominal hysterectomy and salpingo-oopherectomy with or without lymph node assessment represents standard management for uterine cancer. NCCN recommends pelvic MRI when considering fertility sparing surgery, and to consider pelvic MRI for assessing local extent and for evaluation of endocervical versus endometrial primary.30 For high-grade histology or incompletely surgically staged disease, NCCN recommends CT chest/abdomen/pelvis for further evaluation. PET/CT is recommended if metastatic disease is suspected. A meta-analysis of 16 studies evaluating PET/CT for staging endometrial cancer reported the sensitivity and specificity for primary lesions (82%, 90%), lymph nodes (72%, 93%), and distant disease (96%, 95%).31 Similarly, the American College of Radiology appropriateness criteria recommend MRI when pretreatment assessment of local tumor extent is indicated and PET/CT if distant metastatic disease is suspected.32

For patients with uterine cancer who cannot undergo upfront surgery due to the local extent of the tumor (See Figure 3A–D for representative images) or any surgical staging due to medical comorbidities or other factors, pelvic MRI can be helpful for assessing the local extent of disease and for guiding treatment planning.33

Figure 3

T2 MRI images of locally advanced, initially unresectable uterine cancer in sagittal (A) and axial (B) views and then following external radiation with shrinkage of uterine tumor in sagittal (C) and axial (D) views. PET/CT images from a separate patient with stage III uterine cancer who underwent surgical resection followed by six cycles of chemotherapy with repeat imaging prior to radiation showing residual/recurrent lymph nodes in the maximum intensity projection (E) and a representative axial image (F) from the pelvis.

Radiation Treatment Planning

Adjuvant radiation in the form of brachytherapy is generally recommended for early stage endometrial cancer with high intermediate risk features, while pelvic radiation can be considered for early stage endometrial cancer with more unfavorable features, including multifocal lymphovascular space invasion, abnormal P53 expression, or stage III disease.34

If a patient is to undergo brachytherapy and has had surgical staging, additional diagnostic imaging is generally not needed but three-dimensional imaging such as with CT can be helpful for planning brachytherapy treatment to ensure the applicator is at the vaginal apex and there are no air gaps; this approach is recommended by the American Brachytherapy Society.

For patients with uterine cancer receiving pelvic radiation, especially if there is a high risk of disease or a long interval between surgery and radiation, it can be beneficial to have the patient undergo repeat diagnostic imaging with CT chest/abdomen/pelvis or PET/CT to ensure no disease has developed in the interim. Simcock and colleagues found that PET/CT prior to radiation found additional disease in 35% of postoperative patients, changing planned treatment in 31%.35 These changes could include not pursuing radiation, modifying extent of radiation treatment field, and/or boosting involved lymph nodes. Figure 3E,F shows FDG-PET/CT images from a patient with endometrial cancer with residual/recurrent lymph nodes shortly after chemotherapy.

Follow-up/Recurrence Work-up

In regards to imaging for endometrial cancer follow-up, the Society for Gynecologic Oncology points out that the combination of physical exam and review of systems has a recurrence detection rate that exceeds 80%.36 NCCN and the American College of Radiology similarly recommend imaging based on symptoms or clinical concern.30 32

For uterine cancers with a vaginal recurrence, NCCN recommends CT chest/abdomen/pelvis to evaluate extent of disease.30 Simcock and colleagues found particular benefit of adding PET/CT for recurrent endometrial cancer because additional disease was found in 72% of patients and changed management in 36%.35 If no metastatic disease is found on three-dimensional imaging, and therefore when planning for a definitive treatment approach, pelvic MRI with vaginal gel should be performed to better define the local extent of the vaginal disease and to guide radiation treatment planning. NCCN allows PET/CT and abdominal/pelvic MRI in the recurrent setting as clinically indicated.30

MRI should be repeated at the end of external beam radiation to plan for brachytherapy to assess response and to determine the optimal brachytherapy approach. See Figure 4A–D for an example of pretreatment and post-treatment external beam radiation images. The degree of shrinkage has not been shown to correlate with overall recurrence-free survival, but pretreatment rim enhancement was associated with longer recurrence-free survival.37 Similar to cervical cancer, my group and others have also found it useful to perform a MRI with the interstitial needles in place to help guide brachytherapy target delineation. (Figure 4E–G)

Figure 4

T2 MRI images from a patient with early stage, low-grade endometrial cancer that recurred at the vaginal apex as shown in the sagittal (A) and axial (B) images before external beam radiation and then after external beam radiation with significant decrease in size in sagittal (C) and axial (D) images. For a separate patient with recurrent endometrial cancer with an interstitial implant, (E) shows CT images with the needles in axial view and corresponding T2 axial (F) and coronal (G) MRI images along with the clinical target volume in pink.

Vulvar Cancer

Vulvar cancer is relatively rare, with 45 240 new cases and 17 427 deaths in 2020.1 The vast majority or around 90% are squamous histology with a mix of human papilloma virus (HPV)-related and non-HPV-associated disease tending to be related to lichen sclerosis or vulvar inflammation. In general, HPV-related disease has a more favorable prognosis.38

Work-up and Staging

NCCN recommends considering pelvic MRI to guide surgery and/or radiation treatment planning, and PET/CT or CT chest/abdomen/pelvis for T2 or larger tumors or if metastasis is suspected.39 For 54 patients with vulvar cancer included in the National Oncologic PET Registry, PET changed the diagnostic impression 54% of the time compared with CT and MRI alone, with a higher detection of lymph node and distant metastases.40 Ultrasound, with or without cytology, has been shown to have high accuracy for preoperative assessment of inguinal lymph node status in patients with vulvar cancer using a combination of short-axis length and cortical-to-medulla thickness ratio.41

Radiation Treatment Planning

Most early stage vulvar cancers are treated with surgery and then adjuvant radiation may be added for close or positive margins or lymph node metastases. If imaging is not performed before surgery or there is a long interval between surgery and radiation, consider PET/CT to evaluate for residual/recurrent disease. Of note, lymphatic drainage from the vulva is primarily through the superficial inguinal lymph nodes.42 The superficial inguinal lymph nodes can be subdivided into three groups: a medial group, medial to the femoral vein and greater saphenous vein; an intermediate group near the femoral and saphenous vein; and a lateral group in the lateral third of the groin. The deep inguinal or femoral lymph nodes are located medial to the femoral vein and drain to the external iliac lymph nodes.

Preoperative or definitive chemoradiation is generally recommended for unresectable nodal disease or primary disease that would require an exenteration due to size or close proximity to critical normal structures. The consensus recommendations for vulvar radiation therapy contouring for postoperative and preoperative treatment are based on the volumes created by experts in radiation oncology who received the diagnostic PET/CT and CT simulation to formulate the volumes.43 The postoperative and preoperative radiation volumes are similar in regards to regions included, but have variability related to dose because gross disease will require a higher radiation dose. Figure 5 shows example pre-radiation FDG-PET/CT images for a patient with vulvar cancer and inguinal and pelvic lymph node metastases.

Figure 5

FDG-PET/CT images for a patient with stage IVb locally advanced vulvar cancer with the FDG-PET/CT maximum intensity projection and corresponding axial images showing involvement of right labia majora greater than left labia majora, bilateral inguinal lymph nodes, and right external iliac lymph node.

Follow-Up

NCCN recommends PET/CT to assess response for patients treated definitively with radiation and for patients with suspected recurrence or metastasis.39

Vaginal Cancer

Vaginal cancer is an even more rare gynecological malignancy, with 17 908 new cases and 7995 deaths in 2020.1 Squamous cell carcinoma is the most common histology, accounting for 85%–90% of cases and tends to have a better prognosis than vaginal adenocarcinomas.

Work-up and Staging

The work-up or staging of primary vaginal cancer mirrors that of a vaginal recurrence from endometrial cancer, but the benefit of PET/CT may be even more useful because vaginal cancers tend to be squamous cell carcinomas which are highly FDG avid. For 29 patients with vaginal cancer included in the National Oncologic PET Registry, PET changed the diagnostic impression 45% of the time compared with CT and MRI alone.40 MRI is the preferred imaging modality for evaluating the soft tissue and local extent of the vaginal primary.44

Treatment Planning

Vaginal cancers are most commonly treated with definitive radiation or chemoradiation, paralleling the management of cervical cancer. The extent of lymph node and/or distant disease can be evaluated with PET/CT, while MRI with vaginal gel is most useful for assessing the primary vaginal tumor. The lymph node drainage pattern for the vaginal primary depends on the location within the vaginal cancer, with the upper third draining to the obturator, internal iliac, and external iliac lymph nodes. The lower one third of the vagina drains to the inguinal and femoral lymph nodes, while the middle third can drain to either or both routes.42

Similar to cervical or recurrent endometrial cancer, repeating the pelvic MRI after external beam radiation to assess response and potentially with interstitial needles in place can aid brachytherapy treatment planning. A study using data from the National Cancer Database showed improved survival with the inclusion of brachytherapy for treatment of vaginal cancer.45 A few small, single institution studies have shown encouraging results for treating primary vaginal cancer with image-guided adaptive brachytherapy by applying cervix-based Groupe Européen de Curiethérapie and European Society for Radiotherapy & Oncology recommendations.46–49 Figure 6 shows example pre-external beam radiation, pre-brachytherapy, and 3 month post-treatment PET and MRI images for a patient with vaginal cancer.

Figure 6

Primary vaginal cancer T2 sagittal MRI and FDG-PET/CT maximum intensity projection (MIP) images obtained before radiation, with (A, B) showing a large posterior vaginal wall tumor distinct from the cervix and multiple inguinal, pelvic, and para-aortic lymph nodes. Repeat T2 sagittal MRI (C) and FDG-PET/CT MIP images (D) obtained after chemoradiation and before brachytherapy show significant decrease in lymph nodes and primary vaginal tumor but still with some residual disease. T2 sagittal MRI (E) and FDG-PET/CT MIP images (F) obtained 3 months after radiation show complete resolution of primary vaginal tumor and previous lymph nodes, but now with isolated high para-aortic lymph node metastases (red arrow).

Follow-up

Given the parallels with cervical cancer, repeating a PET/CT 3 months after therapy may be useful to assess response in patients with vaginal cancer (see Figure 6E).

Ovarian Cancer

Ovarian cancer is the eighth most common cancer diagnosis and the fifth most common cause of cancer death in women.1 Surgery is the main method for staging, but preoperative imaging, commonly with CT, can help determine if maximal surgical resection can be achieved upfront or if the patient would require neoadjuvant chemotherapy.

In current practice, radiation has a very limited role in the upfront management of ovarian cancer, with most patients being treated with surgery and chemotherapy. Historically, whole abdominal pelvic radiation therapy was used after surgery or recurrence, but this approach has mostly been discontinued due to the high gastrointestinal toxicity. Some data from British Columbia by Hoskins and colleagues suggest that patients with early stage clear cell ovarian cancer may have a more favorable outcome with whole abdominal pelvic radiation therapy and chemotherapy compared with chemotherapy alone.50

Additionally, some limited institutional studies suggest localized radiation can be beneficial in select clinical situations. Data from MD Anderson Cancer center for 102 patients with ovarian cancer treated with localized radiation showed field control of over 70% at 5 years and that the use of radiation can help increase the time to subsequent chemotherapy.51 Similarly, data from Washington University for 33 patients with ovarian cancer with chemorefractory recurrences showed high rates of local control with FDG-PET-guided intensity modulated radiation therapy.52 Recent data also suggest the potential benefit of stereotactic radiation for select patients with oligometastatic ovarian cancer, with high rates of local control and relatively low toxicity.53 54 With emerging preclinical data of ultra high dose rate radiation for ovarian cancer mice models showing significantly decreased gastrointestinal toxicity but similar disease control benefits,55 perhaps this opens the door for more use of radiation for ovarian cancer in the near future.

Conclusion

Treatment approaches for gynecological cancers vary, and different imaging modalities are most useful depending on the clinical situation. Given the importance of imaging to guide radiation treatment planning, gynecological cancers that have a larger role for radiation, such as definitive management of cervical cancer, locally recurrent endometrial cancer, advanced endometrial cancer, and vaginal cancer, rely more heavily on imaging, particularly MRI and FDG-PET/CT. Choosing the most appropriate diagnostic imaging modality can significantly facilitate gynecological radiation oncology treatment planning.

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References

Footnotes

  • Contributors EAK is the sole author of the Contribution.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.