Spot scanning proton therapy for unresectable bulky retroperitoneal dedifferentiated liposarcoma: a case report

Abstract

The development of effective treatment strategies for unresectable retroperitoneal sarcoma is desirable. Herein, we suggest that definitive proton therapy (PT) could be a promising treatment option, regardless of the large size of the tumor. A 52-year-old man presented with a discomfort of the lower abdomen. Computed tomography revealed a retroperitoneal tumor, measuring over 20 cm in the largest dimensions, which was surrounded by the gastrointestinal (GI) tract. Biopsy revealed dedifferentiated liposarcoma. Neoadjuvant chemotherapy was ineffective, and the tumor was ultimately deemed unresectable. The patient opted to receive PT instead of continuation of chemotherapy. Spot scanning PT (SSPT) at a total dose of 60.8 Gy (relative biological effectiveness) in 16 fractions was employed. SSPT administered a dose to the tumor while successfully sparing the surrounding GI tract. He did not receive any maintenance systemic therapy after PT. The tumor gradually shrunk over more than 7 years, with no evidence of recurrence outside the irradiation field. The initial measurable tumor volume of 2925 cc decreased to 214 cc at the final follow-up, seven and a half years after PT. The patient is alive without any severe complications.

Background

Retroperitoneal sarcoma (RPS) is a rare malignancy. RPS accounts for ∼15% of soft-tissue sarcomas (STS) in adults [1]. Complete surgical resection is the standard treatment for RPS; however, it is often unresectable because of its large size and proximity to vital structures. For unresectable RPS, systemic therapy is selected as the first-line therapy, and it also plays a role as neoadjuvant therapy. Radiation therapy (RT) is also applied in the neoadjuvant setting for RPS [2, 3], but it is not typically used with curative intent. Furthermore, most subtypes of STS are known to be radioresistant. RT for the treatment of RPS is challenging because of the proximity to radiosensitive organs such as the gastrointestinal (GI) tract. Charged particle therapy, especially carbon-ion radiation therapy (CIRT), has been used for unresectable RPS with curative intent [4, 5].

Proton therapy (PT) is a main form of charged particle therapy along with CIRT. The primary physical advantage of charged particle therapy is its Bragg peak profile, offering superior dose distribution compared to conventional photon (X ray or gamma ray) therapy and allowing dose escalation to the target while sparing critical surrounding organs. These two therapies are primarily distinguished by differences in radiobiological effects. CIRT has been used for treating radioresistant sarcomas due to its unique radiobiological capabilities. However, recent studies have reported that PT also provided favorable local control (LC) of radioresistant tumors [6, 7]. However, little evidence is available regarding definitive PT for RPS.

Retroperitoneal liposarcoma (RPLS) is the most common subtype of RPS, accounting for approximately 30% [8]. In this report, we report a case of bulky unresectable dedifferentiated RPLS. The patient received PT and achieved long-term local control and tumor-free survival.

Case presentation

A 52-year-old man without any significant past medical history presented with a discomfort of the lower abdomen. Computed tomography (CT) revealed an irregular mass in the retroperitoneal space, measuring 206 mm × 117 mm × 144 mm in the largest dimensions (Fig. 1a, b). A biopsy was performed for the histologic diagnosis (Fig. 2). Hematoxylin and eosin staining of the biopsy specimens revealed atypical spindle cells. Immunohistochemistry revealed positive staining for MDM2, CDK4, p16 and CD34, and negative staining for S-100 and α-SMA. Ki-67 index was approximately 10%. The tumor was diagnosed as dedifferentiated RPLS. He was referred to a general surgeon. CT and magnetic resonance imaging (MRI) 1 month after biopsy revealed further growth of the tumor (Fig. 1c–e). At the time, the surgeon judged it unresectable and administered neoadjuvant chemotherapy with doxorubicin and ifosfamide. The patient developed grade 2 nausea and anorexia, and grade 4 neutropenia and febrile neutropenia. However, after two courses of neoadjuvant chemotherapy with doxorubicin and ifosfamide, the tumor enlarged further. The patient opted to receive PT instead of continuation of chemotherapy.

Fig. 1.

CT scans (13 days before PT) reveals an abdominal lesion measuring 24 × 15 × 19 cm. This lesion exhibits heterogeneous contrast enhancement with regions of poor contrast. MRI (11 days before PT) shows the lesion with septations. It displayed predominantly low T1 and heterogeneous high T2 signals, indicating a soft-tissue component. The lesion had multiple areas of heterogeneous enhancement in contrast-enhanced T1 images, suggesting possible dedifferentiation. A fatty component, exhibiting mildly high T1 and low fat-suppressed T2 signals, is identified in a part of the lesion. On the left side of the lesion, an area showed poor enhancement, indicative of potential hemorrhage or necrosis. The diffusion-weighted images showed a general lack of diffusion restriction. PET scan (12 days before PT) indicated mild uptake with a maximum standardized uptake value of 2.6. a Coronal contrast-enhanced CT. b Axial contrast-enhanced CT. c T2-weighted fat-suppressed MRI. d Gadolinium-enhanced T1-weighted MRI. e Diffusion-weighted MRI. f F-18 deoxyglucose positron emission tomography CT. PT, proton therapy; CT, computed tomography; MRI, magnetic resonance imaging

Fig. 2.

Microscopic images of hematoxylin and eosin-stained biopsy specimen and immunohistochemistry

Three months after the initial diagnosis, he visited our hospital to receive PT. Administering an adequate high-dose deposition to the whole target volume was difficult due to the proximity to the GI tract; therefore, we attained consent from the patient to administer PT. Positron emission tomography was performed once before PT, 38 days after the initial administration of chemotherapy. It showed heterogeneous F-18 fluorodeoxyglucose uptake in the retroperitoneal mass, with a maximum standard uptake value (SUVmax) of 2.6 (Fig. 1f). Simulation CT revealed that the tumor was 243 mm × 143 mm × 195 mm in size. We employed the spot-scanning PT (SSPT) method to attain more precise dose distribution. The gross tumor volume (GTV) was defined as the visible lesion on CT or MRI. In the present case, the clinical target volume (CTV) was equal to GTV (volume was 2925 cc). We prescribed a dose of 3.8 Gy (relative biological effectiveness [RBE]) per fraction, five times per week, for a total dose of 60.8 Gy (RBE). The PT method used was previously described in detail [9, 10]. Dose distribution and dose–volume histogram (DVH) are shown in Fig. 3. The DVH revealed that the dose to the GI tracts was low, and the doses covering 90% of the volume (D90%) and D95% for estimating CTV were 41 Gy (RBE) and 31 Gy (RBE), respectively. Verification CT was carried out 9 days after the beginning of PT (at eight fractions) and it found tumor shrinkage; therefore, we performed adaptive replanning to reduce the dose to the GI tract. PT was completed without interruption. The only acute adverse event observed was mild erythema in the irradiated skin.

Fig. 3.

Dose distribution of proton therapy; isodose curves on axial (a), coronal (b), and sagittal (c) images, and dose–volume histogram (d) for the CTV, PTV, colon, small intestine, and spinal cord. CTV, clinical target volume; PTV, planning target volume

After PT, the patient did not receive any maintenance chemotherapy. Serial CT images and the tumor volume regression curve after PT are shown in Fig. 4. The tumor shrank over time, and at seven and half years after PT (the last follow-up), it was 69 mm × 27 mm × 60 mm in size (214 cc). We performed follow-up and, to date, no metastases or grade two or higher PT-related late adverse events have been observed.

Fig. 4.

Serial CT images (a). The tumor volume regression curve after proton therapy (b) shows continuous shrinkage of the tumor over a period of seven and a half years. CT, computed tomography

Discussion

Although treatment strategy for unresectable RPS is still controversial, this case indicated that definitive PT could be a promising treatment option. Moreover, long-term tumor LC was achieved despite the peripheral portion of the tumor receiving a low dose of radiation.

Proton therapy, particularly SSPT, shows promise for the treatment of complex tumors such as the present case [10, 11]. In a retrospective study of photon RT for unresected STS, Kepka et al. [12] demonstrated that LC rate decreased as tumor size increased. Furthermore, they showed that higher radiation doses gained superior tumor control and survival, but increased complications. The 5-year LC rate for tumors of < 5 cm after RT using higher than 63 Gy was 72%. They suggested that photon RT achieves long-term favorable LC for smaller tumors; however, high-dose administration to larger tumors should be avoided. Thus, PT may be an effective treatment option, because it can safely administer high doses even to large and challenging tumors.

Most subtypes of STS exhibit radioresistance [13]. Compared to low linear energy transfer (LET) beams, such as photon or proton beams, high LET beams, such as carbon-ion beams, have a higher biological effect [14]. Table 1 summarizes the results of RT for sarcomas from other institutions [4, 5, 12, 15]. In a retrospective study of 24 unresectable RPS cases, CIRT of 52.8 − 73.6 Gy (RBE) in 16 fractions showed 5-year LC and OS rates of 69% and 50%, respectively [4]. More recently, Imai et al. reported data on 128 patients with axial STS after CIRT with mainly 70.4 Gy (RBE) in 16 fractions showing 5-year LC and OS rates of 65% and 46%, respectively; furthermore, tumor size did not influence LC rates [5]. These findings suggest that CIRT would be an effective RT modality against radioresistant STS.

Table 1.

Representative reported results of radiation therapy for sarcomas

Author, Year	N	Anatomical site	Histology	Modality	Total dose	5-yr LC	5-yr OS	Toxicity
Kepka et al. 2005 [12]	112	Whole body	Various (S)	Photon	25–87.5 Gy	45%	35%	14%*
Serizawa et al. 2009 [4]	24	Retroperitoneum	Various (S)	Carbon ion	52.8–73.6 Gy (RBE)	69%	50%	≥ G3: 0%
Imai et al. 2018 [5]	128	Axis	Various (S)	Carbon ion	64–73.6 Gy (RBE)	65%	46%	≥ G3: 3%
Cuccia et al. 2020 [15]	54	Axis	Various (B,S)	Carbon ion	70.4–76.8 Gy (RBE)	67% (3 yr)	64% (3 yr)	≥ G3: 4%

S, soft-tissue sarcoma; B, bone sarcoma; RBE, relative biological effectiveness

^* Original definition as major treatment complication

The definitive PT for STS remains to be elucidated. Previous studies reported preoperative PT for RPS [16]; however, data concerning short-term oncocytotoxic effects may not predict the long-term impact of definitive PT, as there are occasionally cases whose tumor gradually shrinks over a long period as in this case or cases whose tumor temporarily shrinks and then rapidly grows larger. To further investigate the clinical value of PT for RPS with curative intent, long-term follow-up of a greater number of cases is crucial.

We achieved tumor control for over 7 years, even though a peripheral portion of the tumor (at least 10% of the total volume) received a low dose of radiation (less than 40 Gy). Such a relatively low dose might have some anti-tumor effects, as indicated by a study showing that adjuvant postoperative RT exceeding 35 Gy delayed local recurrence in RPS [17]. However, this dosage appears to be inadequate for controlling typical malignant tumors, although there is a lack of literature on using doses lower than 50 Gy for RPLS treatments with curative intent. The reasons for the result in this case were not clear, but several explanations are possible. First, radiation may have caused stenosis in the core feeding vessels, limiting blood supply and thereby achieving slow tumor reduction. Second, radiation-induced immunogenic cell death may have enhanced anti-tumor immune responses, resulting in increased anti-tumor efficacy against adjacent cells. Third, low-dose regions may have primarily contained low-grade tumors, because large RPLS often contains high- and low-grade tumor components within the same mass. Alternatively, the entire tumor could be of low-grade dedifferentiated RPLS, as suggested by the low SUVmax of 2.6. SUVmax has been reported as a predictor of histologic malignancy [18]. However, caution is required, because the PET scan was conducted after chemotherapy. These hypotheses could advocate for the extensive utilization of PT for RPLS, even for the treatment of tumors deemed to be challenging. However, it is critically important to devise ways to improve dose coverage in PT. For example, the use of intensity-modulated PT [19] and surgical spacer placement [20, 21] is considered highly beneficial.

In conclusion, PT achieved long-term LC for unresectable bulky dedifferentiated RPLS without serious complications. The potential clinical value of PT remains underexplored. We recognize that the favorable outcome in this case might be solely due to the low-grade malignancy of the tumor and that PT does not necessarily yield similar results for all RPLS. Nevertheless, given the advent of new technologies, PT could be an effective treatment modality for RPLS and any other subtypes of RPS. Further case accumulation is crucial.

Funding

The authors received no specific funding for this work.

Data availability

The data are not available for public access because of the patient privacy concerns but are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Our institution does not require reviews for case report.

Informed consent

Informed consent was obtained from the participant included in this study.