Integrative Oncology Approach in Advanced Myxofibrosarcoma: A Case Report of Prolonged Survival with High-Dose Vitamin C and Viscum album

Abstract

Introduction

Myxofibrosarcoma (MFS) is a rare and aggressive soft tissue sarcoma with high recurrence and metastasis rates. The prognosis in advanced metastatic disease is poor, with median survival time ranging from 12 to 24 months despite multimodal therapy. Integrative oncology approaches, such as high-dose vitamin C and Viscum album, are increasingly explored as adjuncts in both curative and palliative cancer care.

Case Presentation

We present the case of a 59-year-old male with high-grade unresectable MFS of the right buttock and spinal metastases. Standard palliative treatments (systemic chemo- and radiotherapy, followed by targeted and immunotherapy) were combined with high-dose intravenous vitamin C and V. album extracts given intravenously, subcutaneously, and intratumorally. Despite the progression of the disease and COVID-19 comorbidity, the patient survived for 48 months, exceeding conventional survival estimates.

Conclusion

This case suggests that integrative oncology combining systemic anticancer therapy with high-dose vitamin C and V. album extracts may enhance tolerance and extend survival in advanced MFS. Further prospective studies are warranted to corroborate the value of complementary therapy in sarcoma management.

Introduction

Myxofibrosarcoma (MFS) is a highly aggressive soft tissue tumor. Despite that it constitutes approximately 5% of all soft tissue sarcomas, this type is very commonly observed among elderly patients and predominantly affects the lower extremities. Clinically, it manifests as a slow-growing nodule, either solitary (deep-seated) or multiple (superficial), usually painless, presenting as a bulging lump as the first sign [1, 2]. While high-grade MFS has a significant potential for metastatic dissemination, low-grade MFS frequently recurs locally [1, 2]. Cytomorphological observations are a primary diagnostic tool, with no specific molecular pathology indicators for differential diagnosis [3]. The prognosis is affected by various factors, including the age at diagnosis (≥65 years), the tumor’s size (<5 cm or >5 cm), the degree of infiltration, the location (proximal vs. distal), and histological features of the tumor [4]. Extensive surgical resection (R0) is the gold standard of treatment, although adjuvant radiation or chemotherapy can be considered to prevent local recurrence in high-risk patients. Surgical intervention for all types of soft tissue sarcoma remains impractical when the disease is advanced; consequently, the prognosis is bad. Anthracycline chemotherapy (e.g., doxorubicin) as a first-line treatment is suggested for advanced soft tissue sarcoma [5]. After six cycles of doxorubicin-based chemotherapy (alone or in combination with ifosfamide), median progression-free survival for diverse histology soft tissue sarcoma patients, who did not progress before completing chemotherapy, was 4.2 months, while median overall survival was 15.7 months, and only 13.9% of patients underwent complete surgery before chemotherapy [6]. Other studies show that median overall survival for patients with advanced (unresectable or metastatic) soft tissue sarcomas has improved over the past decades varying between 12.6 months and 24 months [7–11]. Immunotherapy and targeted therapy have been recently introduced into the treatment arsenal, and in some cases, they have achieved modest improvements in survival. Nevertheless, effective management of advanced high-grade sarcomas remains a challenge for modern medicine.

The semiparasitic plant known as Viscum (European mistletoe, Viscum album) grows on trees like apple, pine, oak, elm, and ash. Under the concepts of anthroposophical medicine, water-based V. album extracts (VAE) are used as a complementary cancer therapy for improving quality of life and are commercially available as injectables, especially in German-speaking countries [12, 13]. VAE have been shown in vitro to induce apoptosis, to inhibit angiogenesis and proliferation. They also have immunomodulatory effects on various types of cancer, including Ewing’s sarcoma [14–16]. The active ingredients of VAE are flavonoids, oligo- and polysaccharides, lectins, and viscotoxins. In practice, VAE are applied both in adjuvant and in palliative treatment situations, mainly complementing conventional tumor therapy. The main anticancer compounds isolated from Viscum species are lectins and viscotoxins. For aggressive tumors, lectin-rich extracts (Helixor P, Iscucin Tiliae, V. album Fraxini) are advised, as lectin concentration varies by a host tree. Despite the existing of numerous successful case reports and small observational studies and systematic reviews with meta‐analyses, there is a longstanding debate about the efficacy of mistletoe treatment in cancer patients.

Since the 1970s, vitamin C (ascorbic acid) has drawn interest due to its anticancer properties, which include immunomodulation, collagen synthesis promotion, HIF-1 deactivation, DNA demethylation, and pro-oxidant activity [17–19]. Low plasma vitamin C is common in cancer patients, particularly when they are undergoing active treatment [20]. Due to the pharmacokinetics of vitamin C, only high-dose intravenous administration provides such high plasma concentrations of vitamin C (20–30 mmol/L) that contribute to clinically significant cytotoxic effects on cancer cells. The recommended therapeutic dose is no less than 1 g/kg; however, in clinical practice, the dose ranges from 20 to 100 g/day [21, 22]. High-dose intravenous vitamin C (IVC) could enhance quality of life and lessen the side effects of radiation and chemotherapy [23, 24].

While the use of VAE has been studied in other types of sarcomas [25–28], to the best of our knowledge, this is the first reported case of MFS treated with VAE in combination with IVC. The case report follows the CARE Guidelines [29].

Case Presentation

A 59-year-old Caucasian male (BMI 18; 51 kg) presented with a hard bulge in the lateral middle third of his right buttock, a history of lumbago-like back pain extending to his right leg, and unexplained weight loss. He had no family history of cancer, radiation exposure, or unhealthy practices. MRI revealed a soft tissue tumor of 6.4 × 12 cm with malignant involvement of the pubic and ischial bones (Fig. 1). A low T1 lesion in the T7 vertebra was detected using spinal MRI and chest CT with no clear interpretation. A high-grade MFS was diagnosed through biopsy and pathologic studies. Subsequent 3-Tesla STIR MRI scans showed hyperintense lesions in Th7, Th12, L2 vertebral bodies. The tumor finally was classified as T3N0M1G3 (stage IV; FNCLCC grade 2).

Fig. 1.

Coronal T1-weighed contrast enhanced MRI scan of tumor main lesion in right buttock with invasion to seat bones.

The patient got high-dose IVC infusions, starting at 10 g each session and gradually increasing to 20 g in lactated Ringer’s solution provided twice weekly. The therapy was well tolerated with no reported side effects. This medication was started alongside a planned chemotherapy course of gemcitabine and docetaxel (675 mg/85 mg). After 6 cycles, due to a slow progression of the disease (7.2 × 13.5 cm), systemic therapy was switched to anthracycline-based therapy (2 cycles of AIM with subsequent 4 cycles of monotherapy with doxorubicin 75 mg/m²). The patient asked for additional treatment in the frame of integrative medicine and received VAE as subcutaneous (Helixor P 1–10 mg three time per week with slow induction) and intravenous (Helixor P 80 mg once weekly) injections in addition to the chemotherapy (Table 1). Side effects, which included fever-associated symptoms such as body aches, shivering, rising body temperature up to 37.3°C and skin reactions at the injection sites, were self-limiting within 1–5 days. This treatment was chosen to increase the quality of life and to contribute to tumor control. Disease stabilization was achieved during the last three cycles of doxorubicin. Anthracycline-induced side effects included nausea, fatigue, mucositis, diarrhea, and neutropenia (grade 2 after the second cycle and grade 3 febrile after six cycles without the need for hospitalization). After 1 year of an initial diagnosis, the treatment with pazopanib 800 mg/day was started. However, clinical progression became obvious (local mass enlargement, local pain, and antalgic gait), confirming with the MRI study (10.8 × 15.5 cm). Integrative therapy management was taken over by a recognized expert (M.O.). After 12 months of treatment, intratumoral injections of mistletoe started (5 injections of Iscucin Tiliae H 15–180 mg and 5 injections of Abnoba Viscum Fraxini 20–60 mg interrupted with local radiotherapy of main lesion for pain control (50 Gy over 20 sessions) in combination with im and sc administration. Further intratumoral injections were stopped due to intolerance to pain. A fever inducing intravenous infusion of VAE was performed within a period of 5 months (12–17 months postdiagnosis). IV dose of VAE was increased (different combination of Helixor P up to 400 mg, Abnoba Viscum Fraxini up to 100 mg, and Iscucin Tiliae H up to 100 mg). During the next 12 cycles of pegylated liposomal doxorubicin (45–50 mg/m²), a short period of stabilization (for 5 months) was observed at 21 months. Multiple small lung metastases were observed for the first time at 26 months postdiagnosis. Due to the disease progression, systemic chemotherapy was discontinued and a multitargeted tyrosine kinase inhibitor (TKI) regorafenib was started later (tapered from 160 to 80 mg daily). Intravenous VAE regiment was changed to Helixor P 300–400 mg weekly. To improve respiratory function, short stereotactic body radiation therapy (4 Gy per fraction over 12 sessions at 31 months) was successfully performed on the lesion overlying the upper lobe and superior segment (LB6) of the lower lobe of the left lung, which rapidly grew invading the upper lobe bronchus airway and causing cough, dyspnea, wheezing and hemoptysis (Fig. 2). At 39 months after diagnosis, a subcutaneous lesion developed on the posterior upper third of the affected thigh (infiltrative growth of the main lesion on MRI), prompting administration of nivolumab at 3 mg/kg in conjunction with targeted and palliative radiation therapy (6 Gy per fraction over 5 sessions). VAE (iv and sc) and vitamin C therapy were prolonged.

Table 1.

Timeline

​	​	​	​	​	Chemo-/targeted/immuno	Radio	​	​
​	​	​	IVC	10.2018	​	​	MRI, CT	6.4 × 12 cm initial diagnosis
​	​	​	10–20 g	​	Gem+Docetaxel	​	​	​
​	​	​	​	​	​	​	​	​
​	​	​	​	1.2019	​	​	MRI	Metastases Th7, Th12, L2
​	​	​	​	​	​	​	​	T3N0M1
​	​	​	6–12 g	​	​	​	​	​
​	​	VAE sc	20–35 g	4.2019	​	​	MRI	7.2 × 13.5 cm
​	VAE iv	Hel P	​	​	AIM	​	Minor prog	​
​	Hel P 80 mg	1–10 mg	​	​	​	​	​	​
​	Isc T H	Isc T H	​	7.2019	Doxorubicin	​	MRI	8.8 × 14.5 cm
​	35–150 mg	1–5 mg	​	​	​	​	Minor prog	​
​	​	​	​	​	​	​	​	​
​	​	12–20 mg	​	10.2019	​	​	MRI	​
VAE it	Hel M	​	​	​	Pazopanib	​	Stable	​
Isc TH	200–400 mg	​	​	​	​	​	MRI	10.8 × 16.5 cm
15–180 mg (5 times)	Isc+Hel M/P	25 mg	​	1.2020	​	R buttock	Progression	​
AVF	​	​	​	​	​	50 Gy/20 fr	​	​
20–60 mg (5 times)	AVF+Isc T+Hel P	​	​	​	LipoDoxorubicin	​	MRI	11.2 × 16.5 cm + Th5
​	40–100 mg+	​	​	4.2020	​	Th5,12, L2	Progression	​
​	50–100 mg+	​	​	​	​	30 Gy/10 fr	​	​
​	100–400 mg	​	​	​	​	​	​	​
​	​	​	​	7.2020	​	​	​	​
​	​	​	​	​	​	​	MRI	11.5 × 15.8 cm
​	​	​	​	​	​	​	Stable	​
​	​	​	​	10.2020	​	​	​	​
​	​	​	​	​	​	​	​	​
​	​	​	​	​	​	​	CT Lung	Multiple metastases
​	​	​	​	1.2021	​	​	Progression	​
​	Hel P	AVF 10–15 mg	​	​	Regorafenib	​	​	​
​	300–400 mg	Isc T or AVF	​	​	​	​	CT	​
​	or	(25–50 mg or	​	4.2021	​	​	Stable	​
​	AVF	10 mg)	​	​	​	L lung	​	CT lung
​	60–80 mg	​	​	​	​	48 Gy/12 fr	​	Progression
​	​	​	​	7.2021	​	​	CT lung	​
​	​	​	​	​	​	​	Stable	​
​	​	AVF 20 mg	​	​	​	​	​	CT Lung
​	​	or	​	10.2021	​	​	​	Progression
​	​	Isc T 50 mg	​	​	Regorafenib	​	​	​
​	​	​	​	​	​	R thigh	MRI	2.5 × 3.5 cm thigh+L3
​	​	​	​	1.2022	+Nivolumab x2	30 Gy/5 fr	Progression	​
​	​	​	​	​	​	​	​	​
​	​	​	​	​	+Nivolumab x2	​	COVID-19	Hospital
​	​	​	​	4.2022	​	​	MRI	Necrosis
​	​	​	​	​	​	​	Progression	​
​	​	​	​	​	​	​	​	​
​	​	​	​	7.2022	+Nivolumab x2	​	​	​
​	​	​	​	​		​	Radip Prog	R leg lymphedema
​	​	​	​	9.2022	​	​	O2	​

Overview clinical course, integrative treatment, imaging (MRI, CT scan), lesions size. VAE, V. album extracts; IVC, intravenous vitamin C; Isc H, Iscucin Tiliae H; AVF, Abnoba Viscum Fraxini; Hel, Helixor; O2, supplemental oxygen therapy; +, combined therapy; x2, twice-monthly infusions.

Fig. 2.

Lung CT scan: large metastatic parenchymal foci in left lung with invasion to bronchial lumen.

During the anticancer therapy, the patient encountered the following multiple complications: palmar-plantar erythrodysesthesia, oral mucositis, dyspnea, hoarseness, cough, meteorism, diarrhea, radiation recall dermatitis, pain in the affected area, lymphostasis and lymphorrhea, nocturia, infection, and a COVID-19 episode (at 42 months). After a rapid progression of the disease and deterioration of overall health, the patient died. Notwithstanding the severity of these adverse events, the widespread metastatic disease, and multiple features of a very poor prognosis, the patient demonstrated overall survival of 48 months after the initial diagnosis and Eastern Cooperative Oncology Group performance status 1–2 except for the last 3 months. This highlights the capability of a carefully coordinated multimodal integrative oncology strategy to prolong survival and preserve functional and symptomatic well-being in advanced MFS cases.

Discussion

Although the median survival for advanced metastatic soft tissue sarcoma is 1.5 years, studies have shown that a small cohort of such patients (8–24%) is alive after 5 years [10, 11]. Negative prognostic factors include the following: gender (male), high tumor grade, liver metastases, tumor size (>5 cm), and low physical activity at diagnosis. Palliative treatment for such patients generally consists of radiotherapy for locally advanced “inoperable” recurrence and systemic chemotherapy for widespread metastatic disease. Anthracycline class doxorubicin is the standard systemic therapy. However, the clinical response is limited and varied, which might be ascribed to the nature of high heterogeneity. A variety of other regimens (gemcitabine plus docetaxel, trabectedin) including anthracycline combinations have been used, but none of them have increased overall survival when compared with doxorubicin alone [30]. In order to avoid cardiomyopathy, the maximum lifetime cumulative dose of doxorubicin is restricted to 550 mg/m². A good therapeutic response to doxorubicin is considered a positive predictor of survival [7, 10]. In our case, the best therapeutic effect was short-term stabilization observed precisely both with doxorubicin and later with pegylated liposomal doxorubicin systemic treatment. However, in relation to our patient, the prognostically negative factors were high malignancy, gender, and large tumor size. Metastases that have developed in the spine since the disease onset should also be considered among negative prognostic factors. When chemotherapy is no more effective, other therapy modalities may be considered. Recent advances in cancer treatment have shown possible benefits from immunotherapy and targeted therapy. Immune checkpoint inhibition (ICI) pembrolizumab was the first drug to have shown a certain meaningful response in advanced sarcoma patients with dedifferentiated/pleomorphic liposarcoma and undifferentiated pleomorphic sarcoma (UPS) histologic subtypes [31]. Among other immunotherapy drugs, nivolumab was studied in advanced sarcoma; however, only combination therapy with ipilimumab demonstrated a clinical response in several subtypes of sarcoma and MFS among them [32]. Although MFS has been separated from UPS due to its fibroblastic differentiation with myxoid stroma, UPS and MFS have been still identified as a sarcoma group in terms of molecular landscapes [33, 34]. A recent gene sequencing study suggested that common adult soft tissue sarcomas, MFS, and UPS exhibited a lower tumor mutation burden and significant overlap in their genomic and transcriptomic characteristics [34]. Given their similarity, common treatment approaches for both subtypes may be appropriate. The study comparing response rate on immunotherapy among UPS and MFS patients has shown that immune checkpoint blockade may be considering as a treatment option for unresectable or metastatic MFS refractory to standard chemotherapy [35]. The most recent trials have yielded less promising results, prompting a shift toward the combination of ICI with another immunotherapy, chemotherapy, small molecular inhibitor, and/or radiation therapy [36]. Although the combination of ICI and TKI has demonstrated activity in certain sarcoma subtypes, it has shown varying efficacy in UPS and MFS [37].

At the end of 2020, when the disease progression was obvious, the patient was switched to targeted therapy, which has not shown the expected efficacy, except in combination with stereotaxic radiotherapy of a larger lung metastasis. Combination therapy with ICI was discussed. Pembrolizumab probably would be the first choice; however, due to lower drug accessibility, we started off with nivolumab as soon as it became available on our market. Unfortunately, the disease progressed more rapidly after the COVID-19 infection, which is increasingly associated with the dysregulation of crucial oncogenic pathways, highlighting its potential role in cancer development and progression [38, 39]. The combination of ICI and TKI did not show any meaningful clinical response in our case.

Publications describing the use of VAE in patients with soft tissue sarcomas are very scarce – available patient case reports described successful therapy of recurrences (or metastases) after a complete resection [25, 26], or arrest of growth of a large recurrent sarcoma mass (left inguinal) after several resections and tumor shrinkage with subcutaneous, intravenous, and intratumoral administration of Helixor P [27]. Although there is a partial overlap of the latter publication and our case – large size of the tumor (13 cm), its aggressiveness and location in the periphery, the difference is noticeable – our patient had distant metastases and the therapeutic regimen of VAE in our case was more conservative (during the first phase of treatment). Integrative oncology has adopted two different approaches to the initiation (induction) of VAE therapy: the first approach involves a gradual increase of the dose by subcutaneous or subcutaneous and intravenous administration of the drug, while the second approach involves a rapid increase of the dose using all the three routes of VAE administration [40, 41]. Since this has been one of the first cases of multimodal administration of high-dose Viscum at a national level, we started off with the first approach, by doubling and tripling the dose over a period of 2 months (both subcutaneously and intravenously) and intratumoral administration was carried out 6 months after the application of VAE. We can assume that in going through rapid induction treatment plan, we might have obtained a different (better) clinical effect, namely due to the use of Abnoba Viscum Fraxini at the very beginning, but we cannot confirm this assumption. While undergoing integrative oncology management, the patient used an opioid drug very rarely to relieve pain syndrome (up to 30 mg/day of morphine in pills), and its regular use became only during the last 5 weeks. Until the terminal stage, pain control was better achieved with dexamethasone and nonsteroidal analgesics. Despite the prolonged mono or combination oncotherapy, the liver and cardiac function were within normal limits, and only two neutropenic events were observed. However, other side effects that were noted included the following: agitation, hand-foot syndrome (grade 2 with two short episodes up to grade 3), mucositis, weakness, polyuria, hoarseness, high blood pressure, weight loss (sarcopenia), etc. It is known that VAE have the properties to reduce the side effects of oncological treatment and improve the quality of life [12, 41]. This also applies to targeted and immunotherapy [42, 43]. However, the reported side effects in our case, while numerous and irritable, were the adverse effects common for systemic anticancer therapy [44, 45]. Supportive therapy (VAE and high-dose IVC) did not seem to significantly reduce anticancer drug adverse reactions; however, overall daily activities were maintained at a good level and no severe fatigue or other symptoms were reported throughout the entire treatment duration to cause the discontinuation of anticancer treatment. The effect of VAE as a concomitant therapy on targeted and immunotherapy should not have led to an increase in side effects and to a decrease in the effectiveness of antitumor effect, since the dosage of VAE (Helixor P iv) in combination with systemic therapy did not exceed 400 mg per infusion, which is not the maximum tolerated dose of VAE [46].

There is only one anecdotal report of IVC efficacy as monotherapy in a reticulum cell sarcoma patient [47]. However, no relevant data can be found in modern literature on the efficacy of IVC as a single agent against sarcoma. On the contrary, Adibi and colleagues [48] reported a significant response to IVC in combination with PARP inhibitors in 2 patients with advanced Ewing’s sarcoma. The dose of IVC in the above study was set at 1.5 g/kg (2–4 times a week). Another report [49] described three cases of metastatic leiomyosarcoma with a prolonged (no less than 12 months) partial response after starting ICI pembrolizumab in combination with ascorbate, but the latter in a lower dose of 25 g weekly. Even less data exist on the combination use of intravenous ascorbate and VA in cancer patients. One report describes long progression-free survival on IVC and VA combination in a patient with advanced adenocarcinoma of the lung after failure of conventional chemotherapy [50]. Again, high-dose IVC (75 g per infusion twice per week) was utilized. While the data about the synergy between V. album and IVC in cancer treatment are limited, nonetheless combination is still used in complementary medicine. Due to the limited availability, suboptimal therapeutic dose of vitamin C (0.5–0.7 g/kg) was used per infusion in our case. According to some clinical studies, a dose between 0.4 and 1 g/kg, while did not show any clear anticancer effect, may increase the quality of life in cancer patients [24, 51, 52].

Since IVC administration does not appear to adversely interfere with chemotherapy and radiotherapy [18, 23, 49], we hypothesized that a modest intravenous dose (20–35 g per infusion) would potent VAE antitumor effect and decrease the toxic effects of the conventional cancer therapies. In such combination, we believe that VAE are the key factor in combined complementary cancer therapy due to its multiple routes of administration and high therapeutic dose applied.

Our case represents a long-term 48-month survival of the patient, despite many prognostically negative clinical factors. It can be assumed that naturopathic therapy enhanced an antitumor cytotoxic effect of a conventional anticancer treatment (no lung metastasis during the period of 25 months) and also contributed to enhancing immune processes [53]. It improved the patient’s quality of life and eventually prolonged his survival. We believe that the above case is a unique example to demonstrate that integrative oncology care may have a modest, but significant effect on survival of a patient with surgically unresectable, metastatic soft tissue sarcoma. The primary challenge in managing the advanced MFS is the absence of effective systemic treatments. MFS frequently exhibits partial drug resistance or variable efficacy in response to standardized anticancer therapy. Therefore, complementary therapy may be considered as an option to improve therapeutic efficacy of standardized therapy. Further studies on the safety and effectiveness of high-dose subcutaneous, intravenous, and intralesional VAE, particularly in MFS, may be warranted.

Acknowledgments

We would like firstly to acknowledge the support and help of the late Dr. Maurice Orange (coauthor). His contribution as an expert in creating and implementing complementary cancer therapy is invaluable. We express our thanks to Dr. Tatiana Mermanishvili from the Aladashvili Clinic, Tbilisi, who provided the confirmation of the histologic diagnosis of the patient, and to Dr. Micheil Jangavadze from the Institute of Morphology, Tbilisi, for immunohistochemistry testing. Further, we are grateful to the members of the Department of Radiology (MRI section), Todua Clinic, Tbilisi (Drs. Sophio Kakhadze, Micheil Okujava, and Merab Beraia) for their professional support and radiological reassessment.

Statement of Ethics

The present study protocol was reviewed, and the need for its approval was waived by the Institutional Review Board of the Medicine Faculty of Tbilisi State University. Written informed consent for the publication of the report and the accompanying images was provided by the patient’s next of kin (D.G.). The CARE Checklist for this case report is available as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550177)

Conflict of Interest Statement

The authors declare that they have no conflicts of interest.

Funding Sources

No funding was received for this work.

Author Contributions

Conceptualization: D.G. Methodology: D.G., T.R., and M.O. Investigation: D.G. and T.R. Resources: D.G. and M.O. Writing – original draft, revising, and visualization: D.G. Writing – review and editing: D.G. and R.T.

Funding Statement

No funding was received for this work.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed at the corresponding author.