To our knowledge, this is the first study that analyzed the response of tumors after NCRT, comparing MG and NMG of patients with locally advanced rectal cancer. The current study represents that additional administration of mistletoe extract combined with NCRT shows promising results for tumor responses, including T-stage, lymphovascular invasion, TNM stage, TRG, and pCR. These results proposed that mistletoe extract may lead to more improved oncologic outcomes.
Rectal cancer, which is approximately one-third out of colorectal cancer, has relatively higher locoregional recurrence rates than colon cancer because mid-to-lower rectum has no serosa to protect tumor invasion through the muscle layer, and it is technically more demanding to obtain enough safety margin [19]. In addition, it is technically challenging to achieve sufficient resection margin to prevent locoregional recurrence due to the close proximity to pelvic structures and organs.
Chemoradiotherapy for rectal cancer usually is needed locoregional therapy due to the relatively high risk of locoregional recurrence compared to colon cancer. Preoperative irradiation is more effective because tumor oxygenation is better with preoperative therapy than postoperative therapy [20]. NCRT improved locoregional control and associated with reduced toxicity compared to postoperative chemoradiotherapy [2, 21]. NCRT using 5-FU or capecitabine is usually used as standard therapy for locally advanced rectal cancer before radical surgery [22, 23]. NCRT of stage II or III of rectal cancer before surgery improves locoregional control and reduces the toxicity of chemoradiation [2, 24]. Despite these treatment efforts, the 5-year incidence of locoregional recurrence rates of rectal cancer is reported to range from 6 to 10.7% [2, 8, 25, 26]. Tumor downstaging and pCR after NCRT facilitate increased overall survival and disease-free survival, including locoregional therapy [4–8]. Therefore, it is crucial to get more tumor downstaging and pCR to achieve good oncological results in patients with rectal cancer treated with NCRT.
In terms of the period from the completion of NCRT to surgery, curative surgery is recommended within 5 ~ 12 weeks. Longer intervals (more than the classical 6 ~ 8 weeks) from completion of NCRT increase the rate of pCR by 6% in rectal cancer [27]. The interval over 8 weeks is associated with increased odds of pCR compared with an interval of 6 to 8weeks [28]. The median interval to surgery in current study was 8.6 weeks in MG and 8.7 weeks in NMG.
Mistletoe is a parasitic plant that parasite on trees. It was first introduced as a cancer treatment by Rudolf Steiner [29]. Cancerostatic protein components from Viscum album were identified later as the cytotoxic viscotoxins and mistletoe lectins [30]. The mistletoe extract induces apoptosis and cytotoxicity to cancer [31]. It also stimulates immunocompetent cells to promote immunomodulation by mistletoe lectin as beta-galactoside-specific lectin [32]. The most important pharmacological components of mistletoe extract are lectins and viscotoxins, which exhibited antitumoral and immunomodulating effects. Mistletoe extract had been considered as a proven old medicine for various cancer patients. However, so far mistletoe therapy to patients with cancer has been controversial in terms of quality of life and oncologic outcomes in the literature [33–36].
Abnoba Viscum Q® showed the radioprotective effect, and it was similar to the effect of amifostine that was approved as a clinical radioprotectant [37]. Viscotoxin in mistletoe extract had potential antioxidant activity [38]. Mistletoe extract combined with chemotherapy and/or radiotherapy was used for the stage I-III colorectal cancer, showing reduced adverse reaction after adjuvant therapy and better oncologic outcomes in terms of disease-free survival [39]. We adopted Abnoba Viscum Q®, which was expected as the dual effects, radioprotectivity and tumor regression, in the patients with locally advanced rectal cancer.
Tumor regression after conventional NCRT appears in the majority of patients, and approximately 12–38% of patients can achieve pathologic complete response (pCR) [40]. To enhance pathologic tumor response and improve locoregional control, more toxic chemoagents and biologics, including oxaliplatin or target agents, have been tried to add to conventional NCRT to increase pCR and improve oncologic outcomes including reduced recurrence in patients with rectal cancer. However, oxaliplatin as a radiation sensitizer did not improve clinical outcomes, including pathologic complete response, and patients’ survival, while it increased chemotoxicity [9, 10, 41–43]. Clinical studies including target agents such as cetuximab, panitumumab, and bevacizumab in NCRT for advanced rectal cancer did not increase pCR, but instead increased significant toxicities [11, 12, 44, 45]. It is needed a new agent to enhance tumor regression for the patient with rectal cancer with less toxicity. Recently, metformin was applied to NCRT together in rectal cancer, and a good tumor response rate and cancer-specific survival as well as lower risk of cancer recurrence were reported [46]. We applied mistletoe extract approved by the Korean Food and Drug Administration (KFDA) as an anti-malignant drug to NCRT for advanced rectal cancer to enhance tumor response. The pCR rates in the mistletoe and NMG were 53.3% and 21.6%, respectively, showing almost twice the effect, and statistically significant. T downstaging and overall downstaging in MG and NMG show 86.7% vs 43.2% and 86.7% vs 56.8%, respectively with significant differences. Lymphovascular invasion was less frequently detected in MG than NMG (13.3% vs 32.4% vs p = 0.04). Although this study is retrospective and not randomized, the results are very encouraging compared to previous studies [9, 10, 27, 40–42]. We expect good oncological results in the future by using additional mistletoe extract for NCRT in rectal cancer with these pathological results.
Patients receiving NCRT with more toxic chemoagent, including oxaliplatin or bevacizumab, experienced increased rates of grade 3 or 4 toxicity [9–11, 43, 45]. On the other hand, mistletoe extract with chemotherapeutical regimes for solid tumors can improve in health related quality of life [15, 47]. Mistletoe extract reduced the rate of gastrointestinal adverse effects such as diarrhea in gastric cancer during adjuvant chemotherapy [15]. In the present study, all adverse events, including gastrointestinal symptoms, oral mucositis, and peripheral neuropathy, were grade I. Only NMG had grade II neutropenia, and grade III anemia; on the other hand, pruritus was observed in MG. There were no statistical differences between MG and NMG. It shows that mistletoe extract is safe and less toxic agents for the treatment of rectal cancer patients at NCRT. Mistletoe extracts help reduce chemotherapy-induced toxicity and enhance treatment tolerability.
Our study had some limitations. First, the number of patients who received NCRT may not be enough to analyze the effect of mistletoe extract for locally advanced rectal cancer. We had practical constraints of patients’ financial strain because the mistletoe extract does not be reimbursed under the national insurance system. Second, this is a retrospective nonrandomized study. Third, downstaging assessment of rectal tumor after NCRT has unavoidable limitations in its accuracy because the evaluation of preoperative tumor staging was based on image studies. Fourth, it is not fully known how mistletoe extract works to tumor regression. Nevertheless, the strength of this study is significant in that it is the first study to achieve good results using mistletoe extract together during NCRT for locally advanced rectal cancer.