Abstract
Background/Aim: Bulky gynecological tumors are a rare entity of large primary tumors, for which only a limited range of therapeutic options is available. Among these, when surgical approach is deemed unsuitable based on comorbidities and/or technical feasibility, radiotherapy is administered at low doses with palliative intent only. Aggressive treatment of such large primary tumors might significantly prolong patient survival and improve their quality of life by effectively delaying tumor progression to extra-pelvic sites. Lattice radiotherapy is a type of Spatially Fractionated Radiation Therapy, specifically devoted to treat and debulk large tumor masses, which are not candidates for normofractionated homogeneous high-dose radiotherapy schedules due to potential harmful dose-volume effects. The aim of this case study was to report on the feasibility of a Magnetic Resonance Imaging-based Lattice approach. Case Report: Herein we report a case of a patient with a locally advanced uterine serous papillary carcinoma submitted to radical surgery and rapidly experiencing a painful large pelvic recurrence eroding the sacrum. The patient was submitted to Magnetic Resonance Imaging-based Lattice radiotherapy consisting of an Apparent Diffusion Coefficient Map-Based boost followed by a normofractionated radiotherapy course. The patient impressively developed an almost complete clinical response with a long-lasting symptom relief. Subsequently, the disease course was burdened by limited extra- and in-field recurrences amenable of re-irradiation as long as the cumulative radiation dose did not seriously threaten the tolerance of neighboring organs at risk (especially the bowel). The patient is still alive 20 months after Lattice radiotherapy delivery with no radiation-related toxicities. Conclusion: Magnetic resonance imaging (MRI)-based Lattice radiotherapy might be safe and effective for the treatment of inoperable bulky gynecological tumors.
- Magnetic resonance imaging
- Lattice radiotherapy
- spatially fractionated radiation therapy
- gynecological cancer
- inoperable bulky tumors
- palliative care
- palliative radiotherapy
Uterine neoplasms are the fourth most common gynecological cancers worldwide. Serous papillary carcinoma (SPC) is a rare high-grade histology cancer that heralds a worse prognosis than the endometrioid type even in node-negative disease (1). Surgery, chemotherapy, and radiotherapy (both vaginal brachytherapy and pelvic external beam radiotherapy) are often combined to counteract its natural tendency toward metastatic progression. Moreover, such tumors may also have locally aggressive behaviors due to direct extension into nearby structures (cervix, bladder, rectum, pelvic bones). When this happens, disabling symptoms appear and radical therapy including surgery is not an option (2). Indeed, in this clinical setting the only viable options are chemotherapy and radiotherapy (RT), the latter being mainly employed for a merely palliative purpose. Actually, curative radiation doses could be not used in case of a bulky infiltrative mass due to a potentially harmful dose-volume effect: the greater the peripheral target dose, the greater the amount of nearby healthy tissues unavoidably exposed to deleterious radiation. Thus, in very large tumors low palliative doses are effectively used solely to control pain or bleeding (3). Such a dose range, however, could be unable to achieve a satisfying local control, as predicted by mathematical radiobiological models (4), paving the way for possibly symptomatic progression. Conversely, some preliminary clinical reports with locally advanced tumors reported that a radiation boost allows to significantly improve local control (5, 6). In addition, the clinical benefit of radiation boost has also been proven in critical palliation-needing conditions (7). In bulky lesions the uncomplicated achievement of the same results is challenging due to the aforementioned reasons. A novel approach for debulking large tumors is the Spatially Fractionated Radiation Therapy (SFRT) that adopts a particular radiation dose delivery, characterized by spatially alternating high (peaks) and low (valleys) doses in a Grid or Lattice pattern (8). Such a technique permits to escalate radiation dose inhomogeneously within the tumor mass by keeping a low tolerable dose in the peripheral area at the boundary with organs at risk (OARs). Since our previous clinical experience in pelvic area proved that a radically curative approach is suitable also for frail patients (9), we were motivated to pursue a successful result in a case of locally advanced SPC, by employing an anticipated Lattice boost followed by conventionally fractionated radiotherapy. We herein, in detail present the results, both in terms of disease control and toxicity of this approach.
Case Report
In March 2020, a 61-year-old female with a history of lap-band surgery due to severe obesity as the only clinically relevant event underwent total hysterectomy and bilateral salpingo-oophorectomy and surgical staging for treating a biopsy-proven SPC. Since pathological findings were consistent with a FIGO stage IIIC1 (pT2 pN1a cM0) with negative surgical margins, the patient was candidate for adjuvant chemotherapy with carboplatin and paclitaxel. Unfortunately, a life-threatening allergic reaction happened at the first administration. Even the following chemotherapy regimen, with only paclitaxel once a week combined with high-dose corticosteroids, was not tolerated. Because of these episodes, any attempt of systemic therapy was abandoned. In September 2020, after severe painful symptoms have occurred in the lumbosacral area, a restaging computed tomography (CT) scan reported the appearance of a large tumor mass in the presacral space, measuring 84×62 mm and eroding the sacrum until invading the cauda equina through the sacral foramina. The patient required for palliative radiotherapy. To obtain a cytoreductive effect and improve local control, we planned an anticipated radiation boost to be delivered by the Lattice technique to certain crucial tumor subvolumes (vertices). To determine the latter, we used an apparent diffusion coefficient (ADC) map from a magnetic resonance imaging (MRI) performed in the same set-up as the simulation CT (Figure 1). After merging MRI and CT scans, we located three high-dose 1 cm-diameter vertices at the level of tumor areas with the highest ADC signal intensity. We prescribed 9 Gy × 3 daily fractions to the sphere-shaped vertices followed by 1.8 Gy × 25 daily fractions to the entire clinical target volume (CTV). The latter included the Gross Tumor Volume (GTV) that was the macroscopic disease. The CTV was contoured on the basis of clinical suspicion about spreading of subclinical microscopic disease, including a large portion of the sacrum and soft tissues immediately around the GTV (Figure 2). As the aim of radiotherapy was mainly palliative, the undissected locoregional lymph nodes were not routinely irradiated. No additional margin from CTV to Planning Target Volume (PTV) was deemed necessary since everyday fraction delivery was image-guided using ConeBeam CT (CBCT). Each vertex measured 0.5 cm3, GTV 542.8 cm3 and CTV 1,180.6 cm3. The most difficult challenge for radiation treatment planning was keeping a tolerable peripheral target dose by combination of the two courses (27 Gy + 45 Gy), especially for the bowel. The cumulative dosemax for such an OAR was 52 Gy. The Lattice course was delivered with a Volumetric Modulated Arc Therapy (VMAT) technique (RapidArc) and a stereotactic equipment by a Novalis TrueBeam STx (Varian Medical Systems, Palo Alto, CA, USA) linear accelerator. For the sequential conventionally fractionated course the Varian Trilogy™ linear accelerator was used because of the large size of the radiotherapy target. In total, 28 fractions were administered in 44 days (14 October – 26 November 2020). The time elapsed between the Lattice hypofractionated doses (9 Gy × 3 daily fractions) and the normofractionated ones (1.8 Gy × 25 daily fractions) was six days. This time interval was chosen to duly prime the radiosensitive circulating lymphocytes recruited in the tumor mass without eliminating them by a too early RT prosecution. During the last three weeks of treatment the patient had a significant pain relief. This further improved at the first follow-up two months later, from the initial score of 10 according to the Visual Analogue Scale (VAS) to the final 3. Three months after completion of radiotherapy, a 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) documented an essentially complete regression of the bulky tumor and only a small metabolically active out-of-field recurrence at the level of vaginal cuff (SUVmax 20.3) (Figure 3). This was targeted with an ablative dose of 21 Gy in 3 consecutive fractions by means of stereotactic body radiotherapy in a brachytherapy-like manner. In June 2021, a new 18F-FDG-PET documented a complete response at the level of vaginal cuff and a limited local relapse (SUV max 9.66) on the anterior aspect of the body of the fifth lumbar vertebra at the field edge of the first radiotherapy treatment. Due to the unavoidable field overlap, we treated this disease site by including the entire fifth lumbar and first sacral vertebra in a low dose volume (4 Gy × 5 fractions) and simultaneously boosting only the metabolic tumor volume (MTV) to a dose of 30 Gy in 5 fractions so as not to exceed the radiation tolerance of the cauda equina. In September 2021, a new 18F-FDG-PET did not detect any residual tumor. On 21 January 2022, a further PET re-evaluation evidenced a lumbo-aortic lymphadenopathy located cranially to the previous irradiation fields and, therefore, judged as amenable of a stereotactic boost irradiation within a lumbo-aortic radiotherapy in an attempt to stop the regional progression. The dose prescribed was: 18 Gy in 3 daily fractions to the 18F-FDG avid lymph node followed by 45.1 Gy in 22 daily fractions to the para-aortic nodes. Unfortunately, the treatment was interrupted after only two fractions (2 and 3 February 2022, 6 Gy each day) of the stereotactic RT course due to occurrence of COVID-19 infection needing hospitalization for respiratory symptoms. The clinical situation was further worsened by an impending severe anemia (7 g/dl) requiring several blood transfusions. As the clinical improvement occurred more than one month later, we felt the need to re-assess the tumor burden before resuming treatment. On 30 March 2022, a 18F-FDG-PET exam documented the volumetric and metabolic progression of the already known lymphadenopathy and an incipient tumor recurrence at the previously irradiated sacral area. In view of the latter finding that prevented any re-irradiation, we definitively gave up on the ambition of submitting the patient to further radiotherapy and we referred her to the medical oncologist for assessment of feasibility of a systemic therapy. Due to the history of severe allergies to the previously administered chemotherapeutic drugs (carboplatin and paclitaxel) and, above all, of a persistent moderate anemia (constantly <9 g/dl), the patient was deemed ineligible for any myelotoxic chemotherapy and, ultimately, referred to palliative treatment with medroxyprogesterone. The lumbo-sacral skeletal pain slightly worsened as a consequence of disease relapse and progression, but it was kept under control with opioid drugs.
View of the apparent diffusion coefficient (ADC) map-guided positioning of vertices on axial (a), coronal (b) and sagittal magnetic resonance imaging (MRI) slices.
The red contour encloses the gross tumor volume and the suspected subclinical extension (clinical target volume, CTV). (a, b and c) show the CTV on the three different planes, (d) offers a 3D-rendering of the treated volume and of its relationship with the three vertices (red spheres) inside.
Coronal positron emission tomography (PET)/computed tomography (CT) slices showing tumor regression. (a) A coronal pre-treatment CT slice shows a large tumor mass eroding the sacrum. (b) The corresponding post-treatment CT slice documented almost complete clinical response, as also confirmed by the PET exam (c).
The patient never complained of any radiotherapy-related toxicity and reported a significant and lasting improvement of quality of life, obtained by slowing disease progression. The time frame from the patient treatment start to the last follow-up (16 June 2022) was 20 months.
The patient gave her informed consent for this case report to be published. This study was conducted in accordance with the Declaration of Helsinki. Study registration and ethics committee approval were unnecessary due to the nature of the study.
Discussion
This case study proves that Lattice radiotherapy is safe and feasible for the treatment of bulky gynecological malignancies. The stereotactic Lattice approach combined with the accurate detection of highly suspicious areas within the tumor targeted by means of MRI offers encouraging results even for other small pelvic cancers, such as the localized prostate (10), wherein the risk for serious adverse events is of particular concern (11).
In order to elaborate on the reported clinical response, we can assume an active interaction between RT and the host immune system. Indeed, RT under special conditions seems able to elicit an immune response against the tumor and upregulate systemic proinflammatory cytokines, locally and in distant sites. Such RT-induced responses are the basis of abscopal and bystander effects, and radiation recall phenomena (8, 12). In silico models that investigate the survival kinetics of irradiated cancer cells exclusively through linear-quadratic radiobiology fail to explain results like the one presented here, again suggesting a possible immune intervention (13). After all, an immunostimulant action of LRT was confirmed in preclinical murine tumor models (14). The Lattice approach was developed in the recent era of cutting-edge technological advances aiming at improving the dose conformity to the RT target and reducing the radiation exposure of OARs (15-18) and can be considered a technology-supported innovative refinement of the old Grid technique. Lattice radiotherapy differs from the Grid approach on the spatial arrangement of high doses: geometrically rigid and bi-dimensional through physical blocks in the Grid technique, flexible and three-dimensional by the multileaf collimator (MLC) versatility in the Lattice radiotherapy. Current technologies allow to direct the positioning of vertices at will, also according to the tumor oxygen landscape. We assume that such an oxygen-guided approach may be preferable to the one of Amendola et al. (2), for at least two reasons: 1) a selective radiation boost could overcome the radioresistance of hypoxic clones within an inhomogeneous bulky lesion, and 2) evoke a more effective immune response by triggering hypoxia-specific signals. PET imaging is the one most commonly used for assessing tumor oxygenation, but also MRI in radiotherapy practice is evolving from a mere role of morphologic tumor detection, to also accomplishing functional tasks (19, 20). In particular, preclinical imaging, such as blood oxygenation level-dependent (BOLD) and tissue oxygenation level dependent (TOLD), is specifically dedicated to study oxygen partial pressure of the tumor tissue. In addition, widely available clinical MRI techniques, such as ADC and diffusion-weighted imaging (DWI), have proven their ability to distinguish between cancer and normal tissues, as well as monitoring tumor response during or early after chemo-radiotherapy (19). Within a bulky tumor, it is likely that the well-oxygenated cells are more densely packed than hypoxic ones. Such a condition could result in a non-homogeneous ADC (or DWI) map, as this reflects the cellular composition of the tumor: the lower the ADC values, the greater the cell density, as also shown in uterine cervical cancer (21). Indeed, ADC parameters quantitatively correlate with histopathologic tumor cellularity and stroma content in some other abdominopelvic cancers (22-24). If we consider that oxygen supply is fundamental for the proliferative capacity of cancer cells, we can assume that the highest ADC values within an inhomogeneous bulky tumor could be a sensitive marker for hypoxic and slow-growing subvolumes, which is where the movement of water molecules is not impeded by cell membranes. As a matter of fact, the ADC values correlate positively with the microvascular density in some uterine neoplasms (25). For these reasons, we chose to place the high dose vertices into the tumor regions with the highest ADC signal intensity, making sure to spare those areas at the boundary with OARs. Towards achieving the latter goal, our case is similar to those presented by Amendola et al. (2) but differs due to a non-random layout of vertices, which was guided by MRI. Our aim was not only to ensure a peripheral target dose not exceeding the normal tissue tolerance, but also deliver the Lattice radiation boost in a hypothetical oxygen-guided manner based on the ADC map. Experience on both sectors is too meager to determine which approach, random vs. ADC map-based, is better. However, our case suggests that our approach is effective and safe at least as much as that adopted by Amendola et al. Unlike all ten patients reported by these authors, of particular note is that our patient was clinically disease-free surviving one year after Lattice radiotherapy treatment without the use of any chemotherapy. These results warrant further investigation in specific and large clinical trials.
Conclusion
MRI-based Lattice radiotherapy might be safe and effective for the treatment of inoperable bulky gynecological tumors. The promising results deriving from the use of spatially fractionated radiation therapy techniques could make a shift in the RT intent from a merely palliative role towards a more curative-oriented one in these challenging clinical scenarios. The MRI-based approach described herein is truly innovative and, in view of the reported outstanding outcome, deserves further investigation.
Footnotes
Authors’ Contributions
Gianluca Ferini: Conceptualization, methodology, data analysis, writing – original draft preparation; Vito Valenti: Resources, writing – reviewing and editing; Anna Viola: Resources, writing – reviewing and editing; Giuseppe Emmanuele Umana: Resources, writing – reviewing and editing; Salvatore Ivan Illari: Resources, writing – reviewing and editing; Silvana Parisi: Resources, writing – reviewing and editing; Antonio Pontoriero: Resources, writing – reviewing and editing; Stefano Pergolizzi: Methodology, resources, writing – reviewing and editing, supervision.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received July 8, 2022.
- Revision received July 23, 2022.
- Accepted July 28, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
