Abstract
Despite effective chemotherapy and other available oncology treatments, recurrence rates for non-muscle invasive bladder cancer (NMIBC) remain high, with as many as 60% of patients requiring repeat intravesical treatments with BCG or other agents within a 24-month period. The botanical formula LCS103 has displayed anti-cancer activity on bladder cancer cells, though its clinical efficacy remains to be proven. A consecutive series of 30 patients with bladder cancer was examined retrospectively, of which a cohort of 20 patients (18 with NMIBC, 2 with metastatic disease) was treated with LCS103 for between 14 months and 16 years, in addition to their conventional oncology care. Only 3 patients (15%) had a single tumor recurrence after initiation of the botanical treatment, as opposed to pre-treatment recurrence reported among 11 patients (55%; range, 1-5). The majority of LCS103-treated patients reported reduced severity for urological symptoms (pain, frequency, and urgency on urination; and nocturia), as well as for weakness and fatigue, and for general wellbeing. No adverse events were associated with use of the botanical formula. Further prospective randomized trials are needed to confirm and better understand these initial findings.
Introduction
Each year, approximately 80 000 patients in the U.S. are diagnosed and treated for cancer of the urinary bladder, of which 90% present with urothelial carcinoma. Most tumors are of the non-muscle invasive bladder cancer (NMIBC) type, with nearly 1 in 4 progressing to muscle invasive disease, with increased risk for developing metastatic disease. 1 Current conventional treatments for bladder cancer include surgical resection and adjuvant intravesical instillation with Bacillus Calmette–Guérin (BCG) or mitomycin C (MMC), as well as other regimens. 2 Despite an initially high rate of response to treatment, recurrence rates for bladder cancer remain high: 65%, 81%, and 88% at 5-, 10-, and 15 years following transurethral resection, respectively. 3 These high rates of tumor recurrence and risk of progression may explain why mortality rates for bladder cancer have decreased far less than for those observed among patients with other solid tumors, such as prostate, breast, lung, and colon cancer. 4
Recurrence of bladder cancer is associated with a significant impairment in quality of life (QoL)-related outcomes. In addition to the need for patients to undergo repeat cystoscopies and imaging, repeat intravesical BCG treatments can be accompanied by a wide range of adverse effects, either related to the bladder and urination (burning pain, increased frequency and urgency, hematuria), or to more general symptoms such as flu-like symptoms with fever, chills and fatigue, which can last for up to 3 days after treatment. 5 It is therefore of utmost importance that therapeutic options reducing recurrence rates of bladder cancer be explored and tested.
The use of complementary and integrative medicine is widespread among patients with cancer, with as many as half of patients in the U.S. reporting the use of at least one such treatment during the previous year, 91% of them during active chemotherapy and radiation treatments. 6 Herbal medicine is especially popular, though despite the fact that a number of botanical-based drugs are being used as chemotherapy agents, such as paclitaxel (derived from the Pacific yew tree), etoposide/VP-16 (derived from the wild mandrake or mayapple plant), and others, 7 the efficacy and safety of non-prescription products remain unclear. In Traditional Chinese medicine (TCM), the role of herbal medicine differs from that of conventional oncology, which targets specific receptor molecules and other components of carcinogenesis. TCM takes a more holistic and multidimensional approach to the treatment of cancer, addressing primarily QoL-related concerns. Cancer is perceived as a multifactorial condition, requiring a combined regimen of modalities such as acupuncture and other manual therapies, along with dietary changes and the use of herbal medicinal products. TCM uses multicomponent herbal formulas, with each component addressing a different aspect of the disease, symptom, or “imbalance” in the body’s “energy force.” 8
The present study examined a series of patients with bladder cancer who were treated with the TCM botanical formula LCS103, in addition to their conventional oncology regimen. The rates for tumor recurrence in the cohort were examined, both before and during LCS103 treatments, as was the impact of the formula on symptom severity and QoL-related concerns. The safety of the botanical formula was addressed as well.
Materials and Methods
Characteristics of Patient Cohort
A consecutive series of 30 patients with bladder cancer was examined retrospectively, of which a cohort of 20 patients (18 with NMIBC, 2 with metastatic disease) was treated with LCS103 for between 14 months and 16 years, in addition to their conventional oncology care. Treatment with LCS103 was initiated within 1 to 18 months from either the initial diagnosis, or else from the last recurrence. Of the 20 patients whose data were analyzed, 6 had a diagnosis of low and 14 high-grade NMIBC, and 2 with metastatic disease (Table 1). All patients underwent an integrative medicine consultation and follow-up at the Marpe Integrative Medical Center in Tel Aviv, Israel, from 2006 to 2023. Data were derived retrospectively from the patient files, and verbal informed consent was obtained from the patients for their anonymized information to be published in this article, and entered into their chart. Our institution does not require ethical approval of reporting individual cases or case series.
Characteristics of the Study Cohort.
Current smokers.
Study Outcomes
Demographic and cancer-related data, including tumor recurrence, were recorded in patient files throughout the treatment period. Patient symptoms, both bladder-related (pain on urination; frequency of urination; and nocturia), and general (weakness/fatigue; general well-being) were recorded as well. Patient-reported adverse events attributed to the botanical treatment were entered into the patient file if and when they were reported.
LCS103 Treatment Regimen
The LCS103 botanical formula was given as an add-on to the patient’s conventional oncology treatment regimen, with the knowledge and consent of their urology oncologist. Each patient was instructed to prepare and ingest 3 g of dried herbal extract powder of the LCS103 formula, which was then mixed with warm water and taken twice daily. The formula was compiled from a number of herbal components, in accordance with the principles of TCM knowledge, data mining, and clinical experience: Astragalus membranaceus, Scutellaria barbata, Oldenlandia diffusa, Ligustrum lucidum, Poria cocos, Prunella vulgaris, Ophiopogon japonicus, Paeonia lactiflora, Taraxaci mongolici cum radice herba, Panax notoginseng, Polyporus umbellatus, Ganoderma lucidum, Vaccaria hispanica. All of the herbal compounds in the formula are imported by Bara Inc (Yokneam, Israel), manufactured under Good Medical Practice (GMP) conditions, and imported under license in accordance with the regulations of the Israel Ministry of Health. The botanical formula has been tested for batch-to-batch consistency, with a certificate of analysis containing chemical and physical identification, as well as undergoing high-performance liquid chromatography (HPLC) and inductively coupled plasma (ICP) spectrometry. All batches were analyzed and certified to be free of heavy metals, microbial contamination, pesticide residues, or mycotoxins. Pre-clinical research found a dose-dependent cytotoxic effect of LCS103 on T24 and HTB-9 bladder transitional cell carcinoma human cancer cell lines (Figure 1; unpublished).
T-24 and HTB-9 bladder cancer cell lines (3000/w) were examined in 96w plates, with overnight incubation and treatment with incremental concentrations of LCS103 for 72 h, performed for each cell line in triplicate. Viability was analyzed by SRB staining (unpublished data).
Results
Demographic and Cancer-Related Characteristics
Demographic and cancer-related characteristics of the study cohort are presented in Table 2. All patients had a diagnosis of Transitional Cell bladder Cancer (TCC), with 13 receiving intravesical BCG instillations, Mitomycin C or undergoing TURBT; 3 received systemic chemotherapy (combinations of any of the following: cisplatin, gemcitabine, mitomycin and paclitaxel); and 4 had only routine follow-up cystoscopies. All 20 patients in the cohort began treatment with LCS103 from 1 to 18 months after their initial diagnosis of bladder cancer or last recurrence (median: 6 months); and for a period ranging from 14 months to 16 years (median: 6 years). None of the patients were using other complementary and integrative medicine modalities in addition to the botanical formula.
Patient-Reported Symptom Severity Before and After LCS103 Treatment.
Recurrence of Bladder Cancer
Of the 20 patients undergoing continuous treatment with LCS103, only 3 (15%) were found to have a single tumor recurrence (#4, #13, and #14), as opposed to 11 patients (55%) with tumor recurrence (range, 1-5) before initiation of the botanical treatment. Of the 11 patients with pre-LCS103 recurrences, only 1 patient (#13) had one recurrence after LCS103 treatment was initiated. Neither of the 2 patients in the cohort who continued to smoke during the study period had tumor recurrence, either before or during LCS103 treatment.
Quality of Life-Related Concerns
Following initiation of treatment with LCS103, the majority of patients reported reduced severity of urologic symptoms, which had been reported before treatment with the botanical formula (pain, frequency and urgency on urination; and nocturia); as well as less severe weakness and fatigue, with an improvement in general wellbeing (Table 2).
Safety-Related Concerns
The botanical formula was well-tolerated by patients, though some patients reported difficulty in adhering to the twice-daily dose regimen. No adverse effects attributed to the use of the botanical formula were reported by any of the patients throughout the treatment period.
Discussion
The present study retrospectively examined a cohort of 20 patients, 18 with NMIBC and 2 with metastatic disease, who were treated with the botanical formula LCS103, in addition to their conventional oncology treatment. Before treatment with the formula, more than half of the cohort had experienced a recurrence of their tumor (range, 1-5), which is similar to rates of recurrence reported in the literature. 3 However, among patients who were taking the botanical treatment for a period ranging from 14 months to 16 years (median, 6 years), only 3 had a single recurrence. At the same time, during the pre-LCS103 period, the majority of patients reported significant urological symptoms (pain, frequency, and urgency on urination; and nocturia), as well as weakness and fatigue. Most of the LCS103-treated patients reported a reduction in the severity of their symptoms, as well as an improvement in their feeling of general well-being.
The prevalence of QoL-related symptoms reported by the study cohort during the pre-LCS103 period, both urological and general, is similar to that reported among patients treated with intravesical BCG and systemic chemotherapy, as reported in the literature. 5 This reduction in symptom severity, as well as improvement in general well-being with the botanical treatment may, at least in part, reflect the possible reduction in rates of tumor recurrence and thus the need for repeat chemotherapy. A similar effect on symptom severity was reported with a related TCM-based botanical formula, administered to a cohort of female patients with breast cancer. 9 Safety-related issues have also been addressed for these related formulas, with the herbal components found to be without direct toxic effects or potentially negative interactions with conventional oncology drugs. 8
There are several methodological limitations in the present study which need to be addressed in future research. The small sample size of 20 patients precludes reaching any conclusions regarding the ability of the botanical formula to prevent the recurrence of bladder cancer, and may not be representative of the entire bladder cancer patient population, as additional confounders could not be addressed in our cohort. The absence of a control group, such as the 10 patients who did not continue treatment with the LCS103 formula and were thus lost to follow-up, needs to be addressed within a randomized and controlled clinical trial. Additionally, since we observed significant improvement in bladder-related symptoms and QOL in patients started on this treatment compared to self-reported pre-treatment symptoms, without the use of validated patient-reported outcome measures, additional clinical research incorporating randomization in a prospective, randomized controlled trial is warranted to support these findings. Finally, the impact of LCS103 on patient symptoms was self-reported and thus subjective, as opposed to being assessed using objective measures or validated questionnaires. Nevertheless, the possibility for lower rates of bladder cancer recurrence observed during the period of LCS103 treatment, as well as the reduction in the severity of patient-reported symptoms and improved QoL, are encouraging and need to be explored.
In conclusion, the present retrospective case series examined the impact of the botanical formula LCS103 on the recurrence of bladder cancer and QoL-related concerns. Pre-treatment recurrence rates were found to be similar to those reported in the literature, though much lower during treatment with the botanical formula. Reported symptom severity was also found to improve with LCS103 treatment, for both urological symptoms as well as for general symptoms and wellbeing, with no adverse events attributed to the botanical treatment. These findings need to be confirmed in larger prospective randomized clinical trials.
Footnotes
Acknowledgements
None.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Yair Maimon is a founder of LifeBiotics Ltd.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
