|Ahead of print publication
Complementary and alternative medicine in sarcoma patients treated in an Italian sarcoma center
Alessandra Longhi1, Elisabetta Setola1, Cristina Ferrari1, Elisa Carretta2
1 Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy
2 Statistical Service, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy
|Date of Submission||19-Mar-2020|
|Date of Decision||16-Jul-2020|
|Date of Acceptance||04-Sep-2020|
|Date of Web Publication||09-Mar-2021|
Istituto Ortopedico Rizzoli, IRCCS, Via Pupilli 1, 40136 Bologna
Source of Support: None, Conflict of Interest: None
Background: Bone and soft-tissue sarcoma are rare tumors. Complementary and alternative medicine (CAM) is often used in cancer patients however limited data are available in sarcoma patients. The aim of the present study is to explore the use of CAM in patients with bone and soft-tissue sarcoma.
Methods: Patients in follow-up visit for high grade bone or soft-tissue sarcoma at the Rizzoli outpatient clinic from September 1, 2014, to December 31, 2015, were asked, after written consent, to fill out a questionnaire with items pertaining to sociodemographic factors and their use of CAM before, during, or after chemotherapy.
Results: Four hundred and sixty-nine participated to the survey: 409 were adults and 60 were <18 years old. The percentage of use of CAM in adults was 44.7% and in minors 38.3%. The most common type of CAM was vitamins and minerals, followed by phytotherapy and homeopathy. The majority of patients used CAM after the sarcoma diagnosis. None used CAM alone instead of conventional chemotherapy. Benefits from use of CAM were reported by 75% of patients (some benefit in 53% plus high benefit in others 22%) and side effects in 6.7%. A significant correlation was found with CAM use and female gender, young age (18–44) and higher education. Disclosure to the oncologist was 56% and 69% to their family doctors.
Conclusions: This study shows that CAM use is frequent among adults and pediatric patients with bone and soft tissue sarcoma as in other cancer patients. Moreover, the profile of these Italian CAM consumers in sarcoma patients is similar to other studies. Patients disclosure to their oncologist or physician about the use of CAM was similar to other Italian studies, but higher compared to other international studies.
Keywords: Complementary and alternative medicine, sarcoma, complementary medicine, integrative oncology
| > Introduction|| |
High-grade sarcoma is a group of rare and heterogeneous tumors. Osteosarcoma and Ewing's sarcoma are the most frequent bone tumors in adolescents with a second spike of incidence in adulthood at about the age of 50 years, while chondrosarcoma and other histology are more frequent in adults. High grade soft-tissue sarcomas are more frequent than bone sarcoma but are still rare diseases that occur mainly in adult patients. Localized and advanced bone sarcomas are treated with neoadjuvant chemotherapy and chemotherapy regimens used today do not differ significantly from the 1980s. This is especially true for osteogenic sarcoma where cisplatin, high-dose methotrexate, doxorubicin, and ifosfamide were first used. In localized osteosarcoma, the 5-year overall survival (OS) has reached a plateau of 60%–70%, more or less the same is true for localized Ewing's sarcoma.
In high grade soft-tissue sarcoma, neoadjuvant or adjuvant chemotherapy is suggested for deep tumors larger than 5 cm, but it is not the standard everywhere else, while radiotherapy is commonly accepted as standard treatment.
The term “complementary and alternative medicine” (CAM) refers to alternative medical therapies outside the orthodox western medical system. The term alternative medicine is used when a different nonwestern medicine is employed in place of conventional medicine while complementary medicine is used together with conventional medicine. There are five domains of CAM: (1) manipulative and body based methods (i.e., massage); (2) body energy systems (acupuncture); (3) alternative medical system (i.e., traditional Chinese medicine, ayurvedic, homeopathy, etc.); (4) mind body medicine (i.e., meditation); and (5) biologically based therapy (including herbs, diet, and supplements). More recently, a new term “Integrative Oncology” has been used. The term CAM is still more popular and it was chosen in this paper.
In Italy, it has been estimated that cancer patients recur to CAM in a percentage between 35% and 48.9%,,,, similar to the incidence reported in Europe (20%–50%), and in the USA in a large adult population survey from the National Health Interview Survey where CAM use has been described in 32%–35% of cancer patients.
The utilization of CAM is frequent also in pediatric cancer patients: In a systematic-review that evaluated 28 studies between 1975 and 2005 in pediatric cancer patients the CAM use was between 6% and 91%. Another, nonsystematic review in 20 European countries found a prevalence of 52% of CAM use in pediatric cancer patients (range 5%–90%).
Diets and dietary supplements (27.5%), herbs (10.8%), homeopathy (6.4%), and mind-body therapies (5.5%) are the most commonly used CAM in Italy, as shown in Italian study on 803 cancer patients in six oncologic centers. A high percentage of patients informed their physicians about CAM use (66.3%) and 89.6% experienced benefits, two-thirds of the patients of this study had used CAM in the past before their cancer diagnosis, 66% disclosed to their physician their use of CAM. A more recent survey in five Italian cancer hospitals reported a 48.9% use of CAM on 468 patients with different cancer diagnosis (47% had lung cancer) in different stages of disease (42% were metastatic). More than 90% used CAM together with conventional chemotherapy and were satisfied with it. A higher percentage of users of CAM was found in high specialized cancer centers compared to peripheral centers.
The reasons for using CAM in cancer patients include the aim to boost conventional treatment, to decrease chemotherapy side effects and to boost the immune system, and most cancer patients use conventional treatment together with CAM and are satisfied with conventional treatment.
Few data are available so far about the use of CAM in sarcoma patient's adults and children while more studies were done in other cancers and CAM employ about costs, effectiveness, and side effects.
The aim of this study was to explore the use of different CAM therapy among adult and pediatric patients treated for bone and soft-tissue sarcoma at Istituto Ortopedico Rizzoli (IOR), an Italian Public Orthopedic Hospital.
| > Methods|| |
Italy has a National Healthcare Service (NHS) that is funded by the central government and administered on a regional basis. It provides all citizens and residents universal coverage. IOR is a hospital located in the Emilia-Romagna region, in Northern Italy. It is a national reference center for orthopedics, and ~50% of its admissions come from outside the Emilia-Romagna region. Moreover, IOR is the regional reference center for the treatment of primary oncological pathology of the skeletal muscle system. CAM is not reimbursed by the Italian Health System. Incidentally, in a recent period, some CAM practices such as acupuncture were offered in few public hospitals
The patients involved in this study are those evaluated in the outpatient clinic for their usual follow-up visit after the end of chemotherapy.
Routine follow-up for patients treated for high-grade sarcoma was as follows: Physical examination, orthopedic and oncology clinic evaluation with radiologic examination every 3–4 months for the 1st 3 years, every 6 months visit for years 4 and 5, then yearly until 10 years from completion of chemotherapy. After 10 years patients could be followed at the Rizzoli clinic or by their local physician, with physical examination and laboratory work. After the 10th year, further radiologic examinations were carried out at the discretion of the treating oncologist.
Inclusion criteria were: High-grade bone or soft-tissue sarcoma, localized or metastatic at diagnosis and chemotherapy treatment performed at Rizzoli or at least in part. There were no restrictions on patient's age.
It was an observational prospective study. A questionnaire based on Molassiotis questionnaire and adapted to Italian population was prepared and underwent ethical committee approval.
Ethics committees approval (protocol No. 59/14 of Rizzoli Ethical Comm) was obtained in July 2014.
The questionnaire included the following questions: General info (name, sex, and birthdate), education level (graduation/high school/other), civil status (married/single/cohabitant/widowed), town of residence, type of sarcoma, date of start of chemotherapy, and date of questionnaire administration. Questions specific about CAM were: “Have you ever used Complementary or Alternative medicine? Y/N, if Yes when (before, during after chemotherapy), which type and for each type of CAM used write the name of products, period of use; in case of vitamins or minerals also specify if it was a combination or single vitamin product; a question about motivation for CAM use had 6 items (1) fighting cancer, (2) to boost immune system, (3) just for general well-being, (4) for psychical health, (5) to fight chemotherapy side effects, (6) just to do something for themselves); did you had benefit from CAM (in a scale from 1 to 4, from none to very high); did you experienced any side effects from CAM (self-reported description); CAM was prescribed by a doctor or self-prescribed?; how did you get information on CAM before using them? and from what source?; did you inform your physician and your oncologist about your use of CAM?”
Data collection procedure
Patients who came to the outpatient clinic from September 1, 2014, to December 31, 2015, were asked to participate in this study with a questionnaire regarding use of CAM in patients treated with chemotherapy for bone or soft-tissue sarcoma after informed written consent was obtained; in cases of minors, consent was obtained from parents and instructions for the completion of the questionnaire by parents was carried out by the oncologist during the visit.
Data from paper questionnaires were copied in an electronic file for analysis.
CAM use was defined as a utilization of one or more type of complementary medicine according to NCCAM-NIHCC five domains at any time before or after their oncologic diagnosis of sarcoma, whatever the prescription (self-prescribed, prescribed by CAM provider o by other doctors) alone or together with other therapies (chemo or radiotherapy).
Continuous variables were summarized as mean or median and range; discrete and categorical variables were summarized as frequencies and percentage. Socio-demographic characteristics and type of diagnoses were compared between CAM user and nonuser using Chi-square test or Fisher's exact test, as appropriate. A multivariate logistic regression model was used to assess potential predictors of CAM use. Data were analyzed using SAS software 9.4 (SAS Institute Inc., Cary, NC, USA) and a P = 0.05 was considered statistically significant.
| > Results|| |
A total of 1367 patients were identified from our electronic database to be treated for a bone or soft tissue sarcoma between January 1, 1996, and December 2014. Among those, 691 who came to the oncology clinic in the 16 months of study period (September 1, 2014, to December 31, 2015) one or more time, 469 (67.8%) participated to the study. All patients who gave informed consent returned the questionnaire once and were included in the analysis [Figure 1]. Demographic characteristics of patients included in the study were comparable to the ones of the patients treated in the same period of time, but not included in the study because they did not come for a visit in the study period or were not interested in participating in the study (gender P = 0.8; age P = 0.27, and residence P = 0.4).
Of the 469 patients, 196 were female and 273 males. Of these, 409 were adults (age ≥18 years) and 60 were minors (age <18 years). Osteosarcoma was diagnosed in 249 (53.2%) patients, Ewing's sarcoma in 111 patients (23.7%), soft-tissue sarcoma in 93 (19.9%), other diagnosis in 15 (3.2%) patients. Mean age at diagnoses was 29.5 years (3.1–77), mean age at time of interview was 35.6 years (7.7–80.7). Median time lapse from diagnoses to interview was 59 months (3–236). Education level was university degree in 19%, high school diploma in 46.5%. The mean age of minors was 14 years,,,,,,,,,,,, [Table 1].
The users of CAM overall were 206/469 (43.9%). The percentage of use of CAM in adults was 44.7% (183/409) while the percentage of use of CAM in minors was 38.3% (23/60).
None of the interviewed patients used one of the CAM as an “alternative” to conventional chemotherapy treatment. The majority of patients, both adults and minors, used vitamins and minerals in 51%, followed by phytotherapy (43.2%) and homeopathy (34.5%). Phytotherapy use was higher in adults (45.9%) compared to minors (21.7%) while homeopathy registered a slightly higher percentage in minors compared to adults (47.8% vs. 32.8%). Diet intervention was frequently used only in adults (26.2%). Other types of CAM including naturopathy, mind-body therapy, manual therapy (chiropractic), energetic therapy, acupuncture, ayurvedic medicine, and traditional Chinese medicine showed a frequency of <10% [Table 2].
|Table 2: Type of complementary and alternative medicine by adult and minor patients|
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Overall, the highest use of CAM in our sample was after chemotherapy. Phytotherapy was used mostly during treatment while naturopathy and homeopathy were used with a large percentage both before and during treatment [Table 3]. The most common vitamins and minerals used by these patients were multivitamins, vitamin D, potassium and magnesium as single agents. While Aloe was the most commonly used herbal medicine, few patients used Viscum (herbal medicine more popular in Northern Europe Countries).
|Table 3: Complementary and alternative medicine used before, during, and after treatment|
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In adult patients, factors statistically associated with the use of CAM were female gender, young age and a higher educational level [Table 4]. A multivariate model of these factors showed that the stronger predictor of CAM use was female gender (P = 0.0484). The main purpose of CAM use was to improve general well-being (66.9%), to improve the immune system (56.8%), and to improve tolerance to chemotherapy side effects (33.3%). Only 17.8% of patients used CAM with the aim to fight cancer; 22.1% of patients said they received high benefit from CAM employ, 53.0% reported few benefits, 16.8% reported they did not know if they received benefits from CAM and 8.1% declared no benefits. Side effects were mild and reported by just a few patients (6.7%). They included fever, diarrhea, constipation, nausea, and skin reaction.
|Table 4: Factors associated with the use of complementary and alternative medicine in adult patients|
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Self-prescription of CAM was done without consulting a doctor in 44.5% of patients and 76.1% sought information autonomously. The most frequent sources of information about CAM were the internet (63.2%) and friends (50.4%). Disclosure to their family doctor was done in 69% and disclosure to oncology team in 56.2%.
Over time, the use of CAM had a slight decline in our sample from 48.3% in the 1st 5 years to 43.6% in the last period [Figure 2].
| > Discussion|| |
This study is the larger of few studies on the use of CAM in sarcoma patients and it reports CAM use in both adult and pediatric sarcoma patients. Being based on a questionnaire, memory recall could be a bias.
The use of CAM in our study was 43.9% in line with few other studies done on sarcoma. The use of CAM in patients was more frequent in female, young and highly educated patients. In our study, income was not collected, but high levels of education associated with the use of CAM, could suggest as a proxy, a similar trend between economic level and education level in CAM user as previously reported in Italian statistic and with the previous Italian multicenter studies, and similar to western countries.
No one in this group of survivors decided to decline chemotherapy treatment at diagnosis and none opted for alternative therapy different from chemotherapy for their sarcoma.
CAM satisfaction among users was reported by about 75% (some benefit 53%+, high benefit 22%) in accordance with another Italian study.
Among different types of CAM, vitamins and minerals, followed by phytotherapy and homeopathy were more often used in this current sample. Homeopathy was the most common type of CAM in pediatric patients while diet and lifestyle change were used by a quarter of subjects in our study exclusively by adults. Vitamins were used more as multivitamins instead of a specific one but Vitamin D as single drug was the most used, as in other studies.
Due to the rarity of sarcoma, only a few studies are available about the use of CAM in sarcoma patients. In 2018, a survey was carried out on 325 outpatients at a sarcoma clinic from the University Hospital in Mannheim, Germany; 51% of patients interviewed had used CAM, 35% employed CAM for a long time before cancer diagnosis, 44% utilized CAM since their tumor diagnosis and 15% of them only used CAM during sarcoma treatment, 24% were currently using some form of CAM. Less than 30% of patients reported using vitamin and mineral supplement, especially Vitamin D. Herbal medicine and homeopathic approaches were reported in another third each.
Another study was presented in 2018 from a French specialized cancer center on the use of CAM in sarcoma patients and its potential drug-drug interaction. In this study, the authors reported that in 202 sarcoma patients 18% patients experienced drug-drug interactions and one-third of these interactions (29%) were associated with CAM use.
Even fewer trials exist on the results usage of some specific CAM in sarcoma while more studies were carried out in other more common cancers such as breast, lung, or colorectal cancer. The results of a small randomized study on the use of Viscum Album Fermentatum Pini were reported in 2014. Viscum Album Fermentatum P is a phytotherapy drug used in anthroposophic medicine. In that study, the drug was used for 1 year versus oral etoposide for 6 months as maintenance therapy in osteosarcoma patients in complete remission after a second relapse. Long-term follow-up (10 years) results were reported.
In the last decade, many studies have shown the safety of some CAM and few complementary therapies have been integrated in medical treatment. For instance, the ESMO 2018 Guideline for Advanced Breast cancer has recognized the benefits of mindfulness-based stress reduction program (MBSR), yoga, acupuncture in integrated therapy while the use of antioxidants supplements, high-dose vitamins, herbs, minerals, and ozone therapy were not recommended. The use of CAM together with cancer treatment is quite popular in Italy as in other European Countries and this was confirmed by the current study. However, a trend of reduced CAM use from 2000 to 2014 was reported, as in other studies, most likely due to economic factors.
It is important to note that some vitamins or herbal products can produce antioxidant activity and therefore could interfere with the reactive oxygen species generated by radiation and certain chemotherapeutic agents, such as alkylating agents, platinum and antitumor antibiotics, which exert cytotoxicity by generating free radicals to kill cancer cells. Therefore, supplements with antioxidant activity can contrast the effects of conventional treatment, as observed in one randomized study in patients with head and neck cancer treated with radiotherapy with and without vitamin C and E; in this specific study, the arm of those patients who received Vitamin C and E injections had a worst outcome.
Moreover, the value of vitamin supplements in prevention of cancer is not clear and a meta-analysis did not conclude for certainty of detrimental or positive effect of antioxidant during chemo or radiotherapy.
Thus, in patients undergoing chemotherapy treatment, vitamin supplements should be reserved for those with overt deficit of specific vitamins.
Among phytocompounds the most utilized herbal product in our sample was aloe. Furthermore, in another Italian study, 75% of the CAM user among cancer patients used aloe.
The popularity of aloe in Italy is probably due to Father Zago's (a Brazilian friar) recipe. The compound is a mixture of aloe arborescens, honey and alcohol, which is very popular among Brazilians and it was promoted in one of Zago's book in Italy. An Italian randomized study was conducted by Lissoni on 240 patients with metastatic solid tumors (lung and GI cancers). In that study, the aloe arborescence mixture (the same Zago recipe) was administrated three times daily combined with conventional chemotherapy in a randomized trial. The author reported an objective response (CR + PR) of 34% versus 19% in favor of aloe. These results, however, were never confirmed by other studies.
Moreover, diet changes were implemented by about a quarter of adult patients in this sample, the same percentage as in another Italian study. Diet changes and weight control showed some relevance in pediatric cancer: For example, in osteosarcoma patients, a negative association between high body mass index (BMI) at diagnosis and OS was reported by the Children's Oncology Group. Obesity is increased in many survivors of bone cancer and may be due in part to limitations in mobility and second to amputation or limb salvage surgery. In children with pediatric cancer, an increase of body weight is common at the end of treatment and it is a risk factor for later chronic illness. Overweight and obesity can in part be prevented by lifestyle and diet modifications for instance, a study showed that in children who were long-term cancer survivors, specifically of childhood leukemia, the adoption of the healthy diet intervention (such as Mediterranean diet) resulted to be useful and reduced the risk of developing a metabolic syndrome by 31%.
In our current study, we show that most than half of our patients disclosed their use of CAM to their oncologist or Family doctor. This rate of disclosure is similar to other Italian studies (Bonacchi, e.g., reported a rate of 66%) but it is higher compared to other international studies. A systematic review reported a rate of 33% (95% CI 24%–43%) of disclosure of CAM use (biological therapy) in different populations (USA and different European countries but not Italy). It is probable that Italian patients have a good level of trust and a long-established relationship with their referent health-care provider that allows them to feel comfortable in disclosing such information.
This communication is crucial for both the patient and physician to be aware of possible interaction and collateral effects. It is imperative that the oncologist is well informed on potentially positive or negative effects of complementary medical therapies and discuss these with the patient. For example, acupuncture for nausea and vomiting associated with chemotherapy and Mindfulness Based Programs for Stress Reduction are useful tools with some clinical evidence, while turmeric can interfere negatively with some antineoplastic drugs (cisplatin) through cytochrome inhibition. In the Patient-Centered Medicine, it is important that health professionals keep an open-minded attitude toward their patients' desire to integrate CAM in their plan of treatment to build a safe alliance for cure.
For pediatric cancer patients, the International Society of Pediatric Oncology developed guidelines to guide the use of integrative oncology into cancer care pediatric patients and suggestions for an open nonjudgmental discussions with their families.
Further prospective studies should be encouraged to evaluate outcomes of CAM users during chemotherapy and during follow-up periods as “healthcare maintenance” compared to non-CAM users.
Thanks to Dr Cindy Steele for her revision.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]