Radiotherapy in the management of Kaposi´s sarcoma: a cross-sectional study in a single institution, literature review, and analysis of different techniques

¹Radiotherapist, Department of Radiation Oncology, Mohammed VI University Hospital, Marrakech, Morocco

^&Corresponding author
Tariq Igarramen, Department of Radiation Oncology, Mohammed VI University Hospital, Marrakech, Morocco

Introduction    

Kaposi sarcoma (KS), originating in 1872, is an angioproliferative neoplasm primarily linked to Kaposi sarcoma-related herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8) [1]. Kaposi sarcoma (KS) presents four epidemiologic subtypes, each with distinct characteristics and risk factors. Classic KS affects older individuals of specific descent, African endemic KS is aggressive in sub-Saharan Africa, immunosuppression-related KS arises post-transplantation, and AIDS-related KS is prevalent in HIV-infected men [2]. Kaposi sarcoma (KS) patients face an increased risk of secondary cancers, highlighting the need for early diagnosis and treatment. Pathogenesis involves KSHV, hypoxia, oxidative stress, viral coinfection, and immune suppression. Clinically, KS presents with varied cutaneous lesions, and extracutaneous involvement may occur. Microscopic characteristics include disorganized endothelial cell proliferation, blood-filled vascular clefts, and an inflammatory infiltrate [3].

The KS is highly sensitive to radiation therapy and chemotherapy but with no standard guidelines due to its high heterogeneity. The treatment options include localized therapies such as radiotherapy (RT), cryotherapy, surgery, cream application (imiquimod, alitretinoin), and intralesional injection of Vinblastine, which are suitable for limited cases, while systemic treatments come into play for more extensive or symptomatic disease. In immunosuppression, modifying or discontinuing immunosuppressive medications can lead to regression. For AIDS-related KS, combination antiretroviral therapy remains a cornerstone, but additional chemotherapeutic agents may be necessary, especially in cases of immune reconstitution syndrome [4]. Intriguingly, new therapies, including immune checkpoint inhibitors, are under investigation, providing hope for better management and outcomes for patients with KS [5].

This study aims to elucidate and assess the treatment outcomes observed in patients with Kaposi sarcoma undergoing radiotherapy (RT). The primary endpoints of this study were to assess whether patients had an adequate response after radiotherapy (complete, partial, or no response) and to evaluate the evolution of this response (stabilisation or relapse/progression).

Methods     

Study design: this retrospective cross-sectional study analyzed data from Mohammed VI University Hospital over ten years. It aimed to elucidate and assess the treatment outcomes observed in patients with Kaposi sarcoma undergoing radiotherapy (RT).

Setting: the study was conducted at Mohammed VI University Hospital in Marrakech, Morocco. Recruitment and data collection occurred between January 1, 2013, and December 31, 2022.

Study population and variables: all patients with a histopathological diagnosis of Kaposi Sarcoma were included in the study. We used medical records archived within the Oncology-Radiotherapy Department, the Mohammed VI University Hospital information system (Hosix), the computerized radiotherapy record and verify system (Mosaiq), and the radiotherapy treatment planning system Xio to collect epidemiological, clinical, anatomopathological and therapeutic data, including patient follow-up and treatment results. Descriptive statistics are provided for all variables. Results for continuous variables are expressed as means and standard deviation. Categorical variables are expressed as numbers and percentages. Statistical analysis to investigate differences in responses to radiotherapy (complete or partial response) and patient evolution (stabilization or relapse/progression), evaluated by the treating radiotherapists, was performed using Fisher's exact test for categorical variables and Mann-Whitney U tests for numeric variables. A p-value < 0.05 was considered statistically significant. Data were single-entered into Excel Microsoft Office Professional 2016, and analysis was done using the International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) software, specifically version 25.

Ethical approval: the study's realization agreement was taken from the responsible authorities, and the confidentiality of the patients was respected.

Results     

Between January 1, 2013, and December 31, 2022, 18 KS patients were treated in the Department of Radiation-Oncology of Mohammed VI University Hospital-Marrakech. The study revealed a mean age of 59.44 years, ranging from 36 to 80 years, predominantly male (n=14, sex ratio = 3.5). The mean age was 61 years in Classical KS and 40.5 years in VIH KS. Of the participants, 66.67% were of urban origin, and all had medical insurance. Only four individuals exhibited no comorbidities, while two patients were diagnosed with HIV, 8 cases of diabetes (44.44%), and 6 cases of hypertension were observed (33.33%). The majority had an ocular motor score (OMS) score of 0 or 1 (27.78% and 61.11% respectively). The average consultation delay was 15.27 months (Table 1). Erythematous macules and plaques (Figure 1) were observed in most of our patients (66%), followed by papulonodular lesions in 61% of cases. Ulcerative lesions were present in 3 patients (16.67%). These lesions were disseminated in 11 patients (61.11%), 55.55% had a Kriegel stage III, 2.22% a Stage II, and 1 patient had a stage IV with pulmonary involvement.

The most affected site was the lower limbs, followed by the upper limbs, the trunk, and then the face (77.78%, 61.11%, and 22.22%, respectively). Two patients had mucous involvement: plate and tongue (Figure 2), and the presence of adenopathies was observed in two patients. Sixteen patients had classic forms of KS and 2 AIDS-related KS. (Table 2). In all patients, radiotherapy was indicated after the failure of initial treatment: one patient underwent surgery leading to the amputation because of severe lower limb cellulitis, two patients had intralesional chemotherapy, and 14 patients had systemic chemotherapy for disseminated disease, one of which had it after failing of intralesional chemotherapy. Eight patients received treatment with Cobalt 60, 6 with electrons, and 4 using X-ray with Volumetric Modulated Arc Therapy (VMAT) and Intensity-Modulated Radiation Therapy (IMRT) techniques (Figure 3).

The clinical target volume (CTV) was obtained by adding 1 cm to the gross tumor volume (GTV) and then from 0.5 to 1 cm to obtain the provisional target volume (PTV). The water bolus was used in some patients to even out the surface irregularities of the extremities and remove the skin-sparing effect (Figure 4). In our investigation, patients received different radiotherapy doses, with the following distribution: the most frequently administered doses were 20 Gy per 10 fractions for eight patients (36.36%), followed by 20 Gy per 5 fractions for five patients (22.73%), 8 Gy per 1 fraction for three patients (13.64%), and 30 Gy per 15 fractions for two patients (9.09%). Regarding the results, all patients responded to radiation; 78% exhibited a complete response to radiotherapy, while 22% showed a partial response (Figure 5). After a median follow-up of 36 months, only three patients experienced recurrence after achieving a complete response: two patients of them were lost to follow-up, and one patient received re-irradiation with electrons, resulting in a complete response. The response to the initial radiotherapy was sustained in all other patients (Figure 5, Table 3).

The analytic study shows that the age difference was statistically significant in the evolution groups; the mean age was 56 years in patients with stable disease and 76 years for patients who progressed or relapsed (p=0.02). Also, 100% of patients with mucosal involvement relapsed, which was statistically significant (p=0.015). All patients with Kreigel Stade I and II showed stable disease, as well as 80% of Kreigel Stade III, and the only patient that had a Kreigel Stade VI relapsed; the difference was close to significance (p=0.057). Concerning the RT energy used, 75% of patients treated with conformal radiotherapy using high-energy photons from a linear accelerator relapsed in the treatment field margins, and all patients treated with electrons or gamma therapy stayed with stable disease, and this difference was statistically significant (p=0.005). The complete response after radiotherapy was higher in patients treated with 20 Gy per 10 fx (100 %), with a statistically significant difference (p=0.016). This difference was also observed in patients who received previous systemic chemotherapy (p=0.019).

Discussion     

Kaposi sarcoma is a multicentric neoplasm of lymphatic endothelium-derived cells infected with Kaposi's sarcoma associated herpesvirus (KSHV), otherwise called human herpesvirus-8 (HHV-8), KS is more frequently observed in men [3]. In our study, the sex ratio was 3.5. Incidence of the Classical form increase with age, and it varies between 50-70 years in multiple studies, including ours [6,7], and it generally occurs in young to middle-aged adults aged 20-54 years for the AIDS related KS [8,9]. Macules and nodules are the most frequent lesions in the KS [2]. The literature generally agrees that radiotherapy can control local disease, especially maculonodaluar lesions, and since 1900, KS's high radiosensitivity has been known [10] and has thus become a primary treatment for localized forms and a palliative approach for disseminated forms, effectively reducing local symptoms such as bleeding or pain. It is one of the most efficient treatments for all forms of localized KS. Overall response rates range from 47% to 99% [11,12]. In our study, all patients have responded to radiotherapy (78% showed a complete response and 22% a partial response). The factors influencing the response to radiotherapy remain understudied in the literature. Limited data are available on the gender treatment response. In our study, no statistically significant difference in terms of response to radiotherapy was observed. In contrast, in a Turkish study conducted by Gonca Altinisik Inan et al. the response rate was significantly higher in men [13], and the same results were seen in Phipps et al. study conducted on 197 epidemic KS, which demonstrated a significant lower CD4 T cell count in women and a less favorable response in the latter [14].

In our study, the mean age of patients who relapsed or had a disease progression was 76 years versus 56 years in those who stayed with stable disease, and this difference was statistically significant; the difference was not significant in terms of response to radiotherapy. In Gonca Altinisik Inan et al. study, the relationship between age and radiotherapy reported outcome was not statistically significant, and there was no data concerning the long-term response [13]. Mucosal involvement is present in 5% of KS, especially in VIH KS [15]. Our study's two patients with mucosal lesions relapsed after a complete response to radiotherapy. In a multicenter clinical trial on mucosal KS, complete control rates ranged from 60 to 93% with minimal toxicity, median survival of 66.9 months, and 5-year disease-free survival rates of 81.6 with radiotherapy [16]. Bolus materials were used in some of our patients when lesions were located on irregular surfaces, as it was known long ago that it ensures homogeneous dose distribution.

Different irradiation techniques are possible: contact radiotherapy using low-energy X-ray photons, electron beam, Cobalt-60 teletherapy beam conformal radiotherapy/IMRT using high-energy photons from a linear accelerator. In our study, all patients treated with Cobal60 radiotherapy and electron therapy stayed with stable disease, and 75% of patients treated with X-ray using a linear accelerator relapsed. This difference was statistically significant (p=0.01). In Gonca Altinisik Inan et al. study that compared X-ray versus Electron beam therapy in KS, the visual response was higher in electron treatments [13]. European consensus-based interdisciplinary guidelines recommend prescribing radiotherapy doses between 30 to 36 Gy in 2 to 3 Gy daily fractions using low-energy photons and/or electrons. Higher dose per fraction (>3 Gy per fraction) and concomitant administration of systemic therapies should be avoided to reduce the risk of long-term sequelae. In our study, the best response rate after radiotherapy was observed with 20 Gy per 10 fractions (100% of complete response), followed by 20 Gy per 5 fractions (80% of complete response), then 8 Gy per 1 fraction (66.7% of complete response), and lastly, 30 Gy per 10 fractions (All patients showed only partial response) and these differences were statistically significant (p=0.016). Concerning the long-term evolution, there was only a numerical difference in favor of the classical fractions of 20 Gy and 30 Gy, where all patients stayed stable.

In various studies, different dosages were explored. The overall response rates were consistently high across different arms in these studies. Harrison et al. [17] compared doses of 16 Gy per 4 fractions with 8 Gy per 1 fraction and found no significant difference in response. Stelzer et al. [18] observed a significantly higher complete response (CR) in fractionated treatments when comparing 8 Gy per 1 fraction, 20 Gy per 10 fractions, and 40 Gy per 20 fractions. Sing et al. [11] conducted a prospective randomized study comparing 24 Gy per 12 fractions with 20 Gy per 5 fractions, revealing no significant differences in treatment response or side effects. Oysul et al. [19] reported higher CR at doses of 20 Gy and above in their study of 18 KS patients. Kandaz et al. [20] found a CR of 91.6% in treatments over 20 Gy, slightly higher than the 89.6% reported for the 8 Gy per 1 fraction arm.

Limitations: this study on Kaposi's sarcoma radiotherapy is limited by the small sample size, which may affect the generalizability and statistical power of the findings.

Conclusion     

This study affirms the efficacy of radiotherapy as a successful treatment for Kaposi's sarcoma, demonstrating high response rates and a low incidence of relapses. Factors such as age, clinical presentation, and radiotherapy modalities may impact the response to radiotherapy and long-term outcomes. Further prospective studies with larger sample sizes are warranted to elucidate these factors and enhance our understanding of their implications.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Igarramen Tariq was responsible for designing the study, supervising data collection, analyzing the data, and writing the manuscript. All the other authors contributed at each stage of the development, and reviewed and approved the current version of this manuscript. All the authors have read and agreed to the final manuscript.

Tables and figures     

Table 1: patients demographics

Table 2: clinical presentations

Table 3: treatments

Figure 1: purple-red macules and plaques on the lower limbs in a patient

Figure 2: mucosal Kaposi's Sarcoma (KS) with lingual involvement

Figure 3: (A,B,C) Kaposi's Sarcoma (KS) of the lower limb treated with the Volumetric Modulated Arc Therapy (VMAT) technique

Figure 4: the water bolus used for radiotherapy in Kaposi's Sarcoma (KS) of lower limbs

Figure 5: (A,B,C,D,E),responses to radiotherapy in patients with Kaposi's Sarcoma (KS) (images show evolution before, during, and after radiotherapy)

References