Metronomic Chemotherapy After Palliative Radiotherapy in Rare Soft Tissue Sarcomas: An Insight into Radiation Therapy and the Immune Response

Abstract

Soft tissue sarcomas (STSs) account for less than 1% of the overall human burden of malignant tumors. The intent of treatment in metastatic STSs is palliative and prognosis is dismal. This study aims to evaluate the role of low-dose radiotherapy and low-dose oral metronomic therapy in heavily pretreated metastatic infrequent STSs. This study was conducted in a prospective observational manner in a tertiary care center. A total of 16 cases met the inclusion criteria for enrollment in the study group. The diagnosis of all subtypes of STS was confirmed by histopathology and immunohistochemistry or cytogenetic studies. All the enrolled patients with metastatic STSs who were treated with surgery and two lines of chemotherapy were initially treated with low-dose radiotherapy of 20 Gy in 5 fractions or 30 Gy in 10 fractions according to the ECOG performance status of the patient. Out of 16 patients, seven patients (43.75%) were treated with 20 Gy, 5#, and 9 patients (56.25%) were treated with 30 Gy, 10# radiotherapy (RT). Out of 16 patients, four were of malignant fibrohistiocytic sarcoma, three were angiosarcoma, three were malignant phylloides tumor of the breast, two were fibrosarcoma, and one patient from each of the following subtypes inflammatory myofiroblastic tumor, leiomyosarcoma, synovial sarcoma, and dermato fibrosarcoma protuberance. Out of 16 patients, seven (43.75%) had a partial response (PR), nine (56.25%) had stable disease (SD) at 3 months, and all the patients had SD at 6 months of evaluation. All the patients had enjoyed a better quality of life as compared to their life during injectable chemotherapy. Targeted low-dose radiation and metronomic chemotherapy leads to quantifiable antiangiogeneic effects and immune effects in the local tumor microenvironment, and influences circulating immune mediators and anti-angiogenesis that could potentially help eradicate disease both within and outside the radiation treatment field.

Introduction

Soft tissue sarcomas (STSs) account for less than 1% of the overall human burden of malignant tumors [1]. Nevertheless, it remains life-threatening, and approximately 40% of the newly diagnosed STS patients die of the disease. When diagnosed at an early stage, it is eminently curable, and when it is diagnosed at the time of extensive local or metastatic disease, it is infrequently curable. Multimodality treatment approaches including surgery, radiotherapy, and chemotherapy are an integral part of the management of early-stage or metastatic STSs. Median survival from the time of metastases is approximately 12 months, and 22–25% of patients are alive at 2 years. The typical backbone of the combination regimen in metastatic settings is doxorubicin with or without another regimen, which gives a response rate of 10–30%, median survival of 7–11 months [2].

The role of low-dose radiotherapy (RT) in metastatic STSs is mainly for palliation. The role of metronomic chemotherapy has already established in solid malignancies like metastatic breast cancer. Management options for heavily pretreated metastatic atypical soft tissue sarcomas (STSs) are scarce. It includes palliative chemotherapy and often radiotherapy (RT) to local and/or metastatic sites. There are often chemotherapy-related inevitable toxicities that poorly affect the quality of life of patients without any significant survival gain. Therefore, this tricky situation can be managed by either clinical trial or best supportive care. We hypothesized that low-dose radiotherapy and oral metronomic chemotherapy (MCT) synergize at the tumor microenvironment level, thereby acting at multiple levels of tumor progression and the development of further metastasis.

Patients and Methods

This study was conducted in a prospective observational manner in a tertiary care center at the Department of Medical and Pediatric Oncology over a period of 3 years. The study was approved by the Ethics Committee of our institute. Written informed consent was obtained from the patients or the parent/ guardian for publication of the clinical details in this report. We enrolled the patients who are diagnosed to have atypical sarcomas soft tissue sarcoma (STS) treated with a minimum of two lines of chemotherapy. A total of 16 cases met the inclusion criteria for the enrollment in the study group. Diagnosis of all subtypes of STS was confirmed by histopathology and immunohistochemistry (IHC) or cytogenetic studies.

Inclusion Criteria

The inclusion criteria are as follows: All the patients of atypical STSs who received at least two lines of chemotherapy and or not willing for further injectable chemotherapy.

Exclusion Criteria

1. Patients who are not willing to give consent for enrollment in the study.

2. Patients with altered RFT and/or LFT.

3. ECOG performance status (PS) 4.

4. Newly diagnosed atypical STS patients or those who have not received at least two lines of chemotherapy.

All the enrolled patients were initially treated with low-dose radiotherapy of 20 Gy in 5 fractions or 30 Gy in 10 fractions according to the ECOG PS of the patient. After the completion of radiotherapy, all the patients were advised 2 weeks of rest to heal normal tissues. Subsequently, all the patients were put on oral low-dose metronomic chemotherapy consisting of cyclophosphamide, methotrexate, and celecoxib, after discussing with the patients and their family members regarding the benefits and pitfalls of the therapy.

The dosing schedule of the metronomic chemotherapy is oral cyclophosphamide 50 mg once a day on days 1 to15; oral methotrexate 5 mg once a day on Monday, Wednesday, and Friday; and oral celecoxib 200 mg once a day on Tuesday, Thursday, and Saturday at the interval of 21 days. All the patients were monitored with history and physical examination, complete blood counts, renal function tests, and liver function tests on the first day of every cycle. All the patients were monitored for their disease status with specific imaging studies for the concerned diseases at an interval of every 3 months according to RECIST 1.1 criteria.

Results and Statistical Analysis

This prospective observational study was conducted in a tertiary care center, situated in the southern part of India. From January 2016 to March 2019, 16 patients were diagnosed with different types of atypical STSs by clinical signs, symptoms, imaging, histopathological, and immunohistochemistry studies. These 16 patients constituted the study cohort. All 16 patients were treated initially by surgery, followed by first-line chemotherapy at a recurrence of the disease. All the patients initially have some response followed by progression. At progression on first-line chemotherapy, those with good performance status were given second-line chemotherapy. Those who progressed on second-line chemotherapy were counseled thoroughly regarding disease status, prognosis, treatment options available, the option of best supportive care, and clinical trial enrollment. Those who are not willing for best supportive care or further injectable chemotherapy were given the option of low-dose radiotherapy to local site recurrence followed by oral low-dose metronomic chemotherapy, as per our study protocol.

After explaining the side effects, benefits, and cost of low-dose radiotherapy and metronomic chemotherapy along with supportive management, high-risk consent was taken for the study enrollment from the patient and their relatives. Baseline investigations like complete blood counts, renal function tests, electrolytes, and liver function tests were within the normal range for their respective age and sex.

Disease Evaluation

Disease evaluation was done with computed tomography [CT], magnetic resonance imaging [MRI], and ultrasonography depending on the initial investigations that were done at the time of metastatic workup. According to the imaging reports, patients were stratified as partial responders [PR], complete response [CR], stable disease [SD], or progressive disease [PD] as per the RECIST 1.1 criteria.

The details of the various types of diagnosis of STSs, age, sex, treatment given, and other details were given concisely in Table 1. All the 16 patients with their demographic profile, diagnosis, treatment given, and their disease status were explained in detail in the following paragraphs.

1. Malignant fibrohistiocytic sarcoma (MFH): A total of four patients were of MFH type of STS, three patients had SD (one = breast, 1 = lung, 1 = maxillary sinus), and one had PR (kidney MFH) at 3 months of evaluation with our study drugs. All four patients had SD at 6 months of evaluation.

2. Angiosarcoma: A total of three patients were of angiosarcoma type of STS, two were primary breast, and one was primary lung angiosarcoma. All three patients who progressed on the second-line CT were given our study protocol treatment. Two patients had partial response [PR] (one = breast, 1 = lung) and one had a stable disease [SD] at 3 months of evaluation. All three patients had SD at 6 months of evaluation.

3. Malignant phylloides tumor of the breast (MPT): A total of three patients were of MPT type of STS, two patients had SD, and one had PR at 3 months of evaluation. All three patients had SD at 6 months of evaluation.

4. Fibro sarcoma: A total of two patients were of fibro sarcoma type of STS, had SD at 3 and at 6 months of evaluation following catering of our study drugs.

5. Inflammatory myofiroblastic tumor (IMT): One patient was found to be of IMT of retro peritoneum, had PR and SD at 3 and at 6 months of evaluation, respectively.

6. Leiomyosarcoma (LMS): One patient was found to be of LMS of uterus, had PR and SD at 3 and at 6 months of evaluation, respectively.

7. Synovial sarcoma: One patient was found to be of synovial sarcoma of the right kidney, had SD at 3 and at 6 months of evaluation.

8. Dermatofibrosarcoma protuberans (DFSP): One patient was found to be of DFSP of anterior abdominal wall, had PR and SD at 3 and at 6 months of evaluation, respectively.

Table 1.

Details of the study patients

Sr. no	Age/sex	Primary diagnosis	Site	Initial treatment	Metastatic sites	First-line CT (no. of cycles)	Second-line CT (no. of cycles)	Palliative RT (local site)	Disease status at 3 mo of metronomic CT	Disease status at 6 mo of metronomic CT
1)	35/ F	Angiosarcoma	Right breast	Surgery	Bone marrow	I + A (6)	T (5)	20 Gy, 5#	PR	SD
2)	47/ M	Angiosarcoma	Left lung	Surgery	Liver	I + A (6)	G (6)	30 Gy, 10#	PR	SD
3)	42/ F	Angiosarcoma	Left breast	Surgery	Lung	I + A (6)	G (6)	30 Gy, 10#	SD	SD
4)	32/ F	IMT	Retro peritoneum	Surgery	Liver	P + A (6)	I (5)	30 Gy, 10#	PR	SD
5)	55/ M	Fibro sarcoma	Right lung	Surgery	Bone	MAID (6)	V (6)	30 Gy, 10#	SD	SD
6)	51/ M	Fibro sarcoma	Left lung	Surgery	Brain	WBRT, I + A (6)	G (6)	30 Gy, 10#	SD	SD
7)	38/ F	MFH	Right breast	Surgery	Brain	WBRT, I + A (6)	G (5)	20 Gy, 5#	SD	SD
8)	31/ M	MFH	Left kidney	Surgery	Liver	I + A (6)	T (6)	20 Gy, 5#	PR	SD
9)	15/ M	MFH	Right maxillary sinus	Surgery	Brain	WBRT, D (6)	Pazopanib (6 mo)	20 Gy, 5#	SD	SD
10)	47/ M	MFH	Right lung	Surgery	Lung	I + A (6)	T (6)	20 Gy, 5#	SD	SD
11)	28/ F	MPT	Right breast	Surgery	Liver	I (6)	D (6)	30 Gy, 10#	SD	SD
12)	38/ F	MPT	Right breast	Surgery	Liver	I + A (6)	G (5)	30 Gy, 10#	SD	SD
13)	42/ F	MPT	Left breast	Surgery	Lung	I(6)	D (6)	30 Gy, 10#	PR	SD
14)	61/ F	LMS	Uterus	Surgery	Liver	D + G (6)	I (6)	30 Gy, 10#	PR	SD
15)	42/ M	DFSP	Anterior abdominal wall	Surgery	Lung, liver	Imatinib (8 mo)	Sorafenib (5 mo)	20 Gy, 5#	PR	SD
16)	45/ M	Synovial	Right	Surgery	Liver, brain	WBRT, D	I (6)	20 Gy, 5#	SD	SD

MFH, malignant fibrohistiocytic sarcoma; DFSP, dermatofibrosarcoma protuberance; CT, chemotherapy; RT, radiotherapy; M, male; F, female; DFS, disease-free survival; MAID, mesna, doxorubicin, ifosfamide, dacarbazine; WBRT, whole brain radiotherapy; SA, single agent; IMT, inflammatory myofiroblastic tumor; + A, adriamycin + ifosfamide; P + A, cisplatin + adriamycin; G, gemcitabine; D, doxorubicin; I, ifosfamide; D + G, docetaxel + gemcitabine; G, gemcitabine; T, paclitaxel; V, vinorelbine; mo, months; SD, stable disease; PR, partial response; PD, progressive disease; LMS, leiomyosarcoma; MPT, malignant phylloides tumor

Quality of Life

All the patients were evaluated for the quality of life using EORTC QLQ-C30, the 3-item Cancer-Related Symptoms Questionnaire. All the patients had enjoyed a better quality of life as compared to their life during injectable chemotherapy as evidenced in the subjective improvement in their symptoms in the form of an increase in the appetite, sleeping time, weight gain, decrease in the pain, and maintaining their day-to-day activities.

Toxicity Profile of Patients

All the 16 patients are under regular follow-up at our center without any toxicity and tolerance issues of the study drugs.

Discussion

The intent of treatment in metastatic STSs is palliative and prognosis is dismal. Ionizing radiation is a non-specific but highly effective way to kill malignant cells, but tumor recurrence upheld by a minor fraction of surviving tumor cells is a commonplace phenomenon owing to activation of both cancer cell intrinsic resistance mechanisms, and also extrinsic intermediaries of therapy resistance, represented by non-malignant cells and structural components of the tumor stroma. Radiation causes severe vascular damages leading to strong alterations of the tumor microenvironment and indirect death of tumor cells, exposure of tumor fibroblasts induces permanent DNA-damage responses and irreversible cellular senescence, which in turn might influence therapeutic upshots by the altered release of cytokines, chemokines, and growth factors.

The important effects of radiation include the following: the response of un-irradiated cells to signals from irradiated cells called “bystander effects”; consequences of dose exposure to the rest of the body, after localized radiotherapy; radiation effects on the tumor microenvironment (TME) that result in systemic effects; and abscopal effects [3]. Low-dose radiotherapy on sarcoma cells sporadically induces the regression of metastatic cancer at distant sites, which have not been irradiated actually through stimulation of endogenous anti-tumor innate adaptive immune responses, a phenomenon, called as “abscopal effect.”

Radiotherapy causes activation of systemic anti-tumor immune response, cytotoxic T lymphocytes, regulatory T cells, dendritic cells, MHC class I and II, release of immune modulators like high nuclear mobility group protein-1 (HMGB-1) and toll-like receptors (TLRs), and upregulation of adhesion molecules such as ICAM-1 and E-selectin on tumor cells as well as chemokines in tumor microenvironment, helping immune cells trafficking. The penultimate of radiation therapy effects involves multiple pathways leading to increased antigen availability, antigen presentation, tumor sensitization, and immune cell trafficking. Radiation-induced acute tissue damage causes the release of several chemokines and cytokines like, proinflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor-α, and pro-fibrotic factors such as TGF-Beta produced mainly by tissue-resident macrophages. IFN-β also plays an important role in the anti-tumor response. Tumor cells killed by RT may be a good source of antigens for dendritic cell (DC) uptake and presentation to T cells [4–7].

The tumor microenvironment of solid tumors includes neoplastic cells and atypical vascular network that results from angiogenesis and vasculogenesis, fibroblasts, and a variety of inflammatory cells like dendritic cells, regulatory T cells, and tumor-associated macrophages. This promotes tumor progression by secreting a variety of factors, including matrix metalloproteinase’s and immunosuppressive cytokines like vascular endothelial growth factor (VEGF), interleukin (IL)-10, and TGF-β, and inhibits their maturation into effective antigen-presenting cells [3].

The mechanisms of radiation effect on TME which leads to an increase in the apoptotic fraction of ECs includes damage to endothelial cells (earliest change), apoptosis of endothelial cells, activation of endothelial-independent G1 damage, and increase in the local ceramide levels [8]. The other mechanisms of anti-tumor response by radiotherapy are stronger immune response, increased accumulation of effector CD8 + T cells, and their activation: a marked increase in cell-surface MHC class-I expression, danger signals released by dying cells, intratumoral production of IFN-β, tumor-specific immunity by activation of tumor-associated DCs and CD8 + T cells, and the response of the normal immune cells to the radiation injury. Lymphocytic infiltration at the original tumor site and metastatic site results in the acquisition of a tumor-specific immunity able to attack both the original tumor site as well as the metastatic sites, influencing the patient’s survival. Rarely de novo generation of T cells to cancer-associated antigens, a phenomenon described as “antigen cascade,” can be seen.

Radiotherapy causes a direct effect on the primary tumor site, thereby potentially reverting some of the established immunosuppressive barriers present within the tumor microenvironment, and converts the primary tumor as an effective immunogenic hub. A complex relationship between dying cells, their microenvironment, and the host immunological habitus is emerging as an important active role of the patient’s immune system in anti-tumor response [9]. Dying tumor cells cause priming DCs after external-beam radiation therapy has been shown in the preclinical trials.

Even though radiation to larger areas as in total body irradiation for conditioning in hematopoietic stem cell transplantation (HSCT) patients harms the immune system by acting on the rapidly dividing immune cells, locally targeted radiation therapy has a more complex relationship with the immune system particularly anti-tumor immunity.

The rest periods between the chemotherapeutic drugs with maximum tolerated dose (MTD) are usually practiced in day to day practice of oncology. This not only allows the re-growth of tumor cells, but also the growth of selected clones resistant to the therapy. Perhaps this is because of the proportion of dividing endothelial cells in tumor-associated blood vessels is simply too low for chemotherapy to have a significant therapeutic impact and because the damage to the vasculature of the tumor was largely repaired during the long (2–3 weeks) rest/recovery periods between successive cycles of MTD-based therapy. That is why, the beneficial effects obtained during the first cycles of chemotherapy reverts in the course of growth of additional malignant metastatic tumors with no salutary response. Fidler and Ellis in the year 2000 described, “Cancer as a never ending, non-communicable, chronic disease and should be treated like other non-communicable diseases (NCDs) like diabetes, hypertension and chronic heart failure with continuous low-dose therapy without affecting the quality of life” [10].

Metronomic chemotherapy [MCT] also known as “multi-targeted therapy” involves repeated administration of conventional anti-neoplastic agents at very low doses (1/10th–1/3rd of the maximum tolerated dose [MTD]) without long drug-free period with minimal or no adverse effects and a rare chance of developing acquired drug resistance. The scientific basis for MCT is that in conventional chemotherapy, the vascular endothelial cell death effect cannot be sustained because endothelial cells get a chance to recover during treatment breaks and this may be overcome by frequent administration of chemotherapy drugs at doses below the MTD and with no prolonged drug-free break, thus achieving a sustained low blood level of the drug without significant toxic side effects [11].

Angiogenesis plays a crucial role in the metastatic progression of soft tissue sarcomas (STS). Activated endothelial cells of the tumor microenvironment are the primary target of metronomic chemotherapy [12]. The most extensively practiced MCT drugs administered constantly in small doses act as anti-vasculogenic agents, as a result implying a dissimilar cell target control (aiming at the tumor endothelial cells), in concert with an alteration in the schedule and dosage of drug administration. There is significantly less opportunity for the repair of the damaged endothelium and the anti-angiogenic effects of the chemotherapy would irreversibly accumulate.

The endothelial cells of newly forming capillaries in the tumor microenvironment are highly susceptible to very small doses of a variety of chemotherapeutic agents like endoxan, methotrexate, and celecoxib [13]. Small-dose endoxan inhibits cancer growth by inducing fastidious apoptosis of endothelial cells contained by the tumor vascular bed by enhancing the endogenous angiogenesis inhibitor TSP-1 which has a pessimistic effect on endothelial cell endurance. Other mechanisms are inhibition of tumor growth, stimulation of discriminatory apoptosis of endothelial cells contained by the tumor vascular couch by upregulating the endogenous angiogenesis inhibitor TSP-1, inhibition of circulating endothelial progenitor cells (CEPs), stimulation of the immune response, reversal of the state of acquired drug resistance, and last but not the least, direct effect on tumor cells.

The most common tumor types treated with low-dose metronomic chemotherapy (MCT) were breast cancer, adeno-squamous lung cancer, lymphoma, pediatric solid tumors, melanoma, and prostate carcinoma. Administration of endoxan at low doses on a 3-times weekly duration eradicated established rat lymphomas and sarcomas, without any metastatic growth or recurrence at primary sites occurred for 100% of the lymphomas and 83% of the sarcomas. And this treatment schedule was devoid of weight loss, hematologic, cardio toxicity, hepato toxicity, and nephro toxicity. The dosing schedule and treatment strategies have not been clearly defined in the literature. We used in this study a schedule of three weekly cycle comprising oral cyclophosphamide (50 mg once a day on days 1–15), oral methotrexate (5 mg once a day on Mondays, Wednesdays, and Fridays), and oral celecoxib (200 mg once a day on Tuesdays, Thursdays, and Saturdays) [14, 15].

MCT reduces the level of toxicity and lessens or even removes the need for growth-factor support to accelerate recovery from myelosuppression. The most important drawback of MCT is that the most efficient dose and schedule have yet to be defined. Biomarkers for monitoring anti-angiogenic drug activity, which in turn predicts disease-free and overall survival, are VEGF, circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and TSP-1 [16].

The use of low-dose radiotherapy and MCT in different types of atypical soft tissue sarcoma has not yet been documented in the literature. So, combining low-dose targeted radiotherapy with low-dose oral metronomic chemotherapy, in heavily pretreated atypical soft tissue sarcomas, may have multiple effects to synergize at the tumor microenvironment level leading to activation of anti-tumor effects through different pathways.

Conclusion

In conclusion, the application of targeted clinical radiotherapy as a partner to metronomic chemotherapy is opening a new field of investigations. Targeted low-dose radiation and metronomic chemotherapy leads to quantifiable anti-angiogenic effects and immune effects in the local tumor microenvironment, and influences circulating immune mediators and anti-angiogenesis that could potentially help eradicate disease both within and outside the radiation treatment field. Low-dose ionizing radiation, along with low-dose oral metronomic chemotherapy, offers a localized synergistic anti-tumor effect through selective induction of a proinflammatory milieu because of the release of tumor antigens from necrotic tumor cells with improved T cell infiltration and depletion of regulatory T cells leading to potential enhancement in the immunity. Further prospective interventional studies are obligatory to identify those patients who are more likely to benefit from this type of treatment interventions in the management of heavily pretreated metastatic infrequent soft tissue sarcomas.

High Yielding Facts

• Cancer is a chronic non-communicable disease and should be treated like other NCDs like diabetes, hypertension, and chronic heart failure with continuous low-dose therapy without affecting the quality of life.

• Low-dose radiotherapy on sarcoma cells sporadically induces the regression of metastatic cancer at distant sites, which have not been irradiated actually through stimulation of endogenous anti-tumor innate adaptive immune responses, a phenomenon, called as “abscopal effect.”

• The endothelial cells of newly forming capillaries in the tumor microenvironment are highly susceptible to very small doses of various chemotherapeutic drugs like cyclophosphamide, methotrexate, and celecoxib.

• Combining low-dose targeted radiotherapy with low-dose oral metronomic chemotherapy, in extensively pretreated atypical soft tissue sarcomas, may have multiple effects to synergize at the tumor microenvironment level leading to activation of anti-tumor effects through different pathways.