A novel approach to translymphatic chemotherapy targeting sentinel lymph nodes of patients with oral cancer using intra-arterial chemotherapy - preliminary study
© Yokoyama et al; licensee BioMed Central Ltd. 2011
Received: 2 August 2011
Accepted: 19 September 2011
Published: 19 September 2011
Recent progress in ICG (indocyanine green) fluorescence imaging has provided a means by which we can detect sentinel lymph nodes (SLNs) without the risk of exposing patients to radiation. Neck metastasis is the most significant prognostic factor. It is imperative that early metastasis can be controlled. Intra-arterial chemotherapy is performed in order to preserve organs and to improve prognosis when treating oral cancer.
Evaluate translymphatic chemotherapy targeting SLNs in patients with oral cancer using intra-arterial chemotherapy. Evaluation will be carried out through the measurement of CDDP concentrations in SLNs.
Five patients with tongue cancer (T3N0M0) were treated by intra-arterial chemotherapy as neoadjuvant chemotherapy from November 2010 to June 2011. After a week of chemotherapy, patients underwent surgical treatment including the partial resection of the tongue and neck dissection. Intra-arterial chemotherapy was administered at 50 mg/m2 of CDDP either one or two times weekly. 5 mg of ICG was administered to the lingual artery at the beginning of surgery. SLNs were detected using ICG fluorescence imaging. 0.1 g of SLNs and non-SLNs were resected in order to measure CDDP concentrations. The rests of each of the SLNs were examined intraoperatively by routine frozen pathological examination. SLNs were also identified using radioactive injection the day prior to surgery.
The mean CDDP concentrations in the SLNs and non-SLNs were 1.2 μg/g and 0.35 μg/g, respectively. Our intra- arterial infusion revealed that all metastatic lymph nodes, including SLNs, were without false negative SLNs. However, of 7 metastatic lymph nodes, one was not identified by means of conventional method.
Our findings verified the possibility that intra-arterial chemotherapy may be effective not only for organ preservation therapy, but also efficient in translymphatic chemotherapy targeting SLNs in patients with oral cancer through the use of ICG fluorescence imaging.
The sentinel lymph node (SLN) is defined as the lymph node that firstly receives lymphatic drainage from the primary cancer . The SLN is thought to be the first possible micrometastatic site via lymphatic drainage from the primary cancer. Thus, the pathological status of the SLN can predict the status of all regional lymph nodes. If the SLN is recognized as being negative for cancer metastasis, unnecessary dissection may be avoided and a positive prognosis achieved. This SLN concept is well established in the treatment of patients with several types of solid carcinomas, such as melanoma and breast cancer [2–4]. The SLN concept has revolutionized the approach to surgical staging of both the melanoma and breast cancer, and these techniques can benefit patients by preventing various complications due to unnecessary prophylactic dissection when the SLN is negative for cancer metastasis. Recently, the SLN concept has been extended to many other solid tumors, including head and neck cancers [5, 6]. In this study, we consider a newly developed translymphatic chemotherapy procedure targeting the SLN using intra-arterial chemotherapy for oral cancer to improve prognosis and to preserve significant organs [7–9].
Evaluate CDDP concentrations in SLNs and non-SLNs. Determine the usefulness of translymphatic chemotherapy targeting SLNs in patients with oral cancer using intra-arterial chemotherapy.
Method and Patients
No of SLNs by radiocolloid
No of SLNs by ICG
No of non-SLNs
Patients' informed consent was obtained prior to treatment, and this study was approved by the Human Ethics Review Committee of Juntendo University.
The difference between the two groups CDDP concentrations were tested by Student's t- test and Wilcoxon test.; p values < 0.05 were considered to indicate significance.
Histopathological examination was performed for 29 SLNs and 90 non-SLNs (Table 1). All 5 patients with histopathologically verified metastasis in their SLNs demonstrated positive results in ICG fluorescence imaging. No false negative cases were identified within each SLN basin. However, of the 7 metastatic lymph nodes, one was not identified by means of conventional methods.
The mean CDDP concentrations of SLNs and non-SNLs were 1.2 μg/g and 0.35 μg/g respectively. The CDDP concentration of SLNs was significantly higher than non-SLNs. The mean CDDP concentration of tongue cancer was 2.3 μg/g.
No hematological complications were caused by intra-arterial chemotherapy. All patients are alive with no evidence of disease and are able to consume food as they were able to before surgery.
Chemoradiation therapy has significantly enhanced the preservation of important organs in the treatment of head and neck cancer. However, because of severe mucositis and low sensitivity to chemotherapy, tongue cancer has not been treated by chemoradiation as often as other sites of head and neck cancer . CDDP is a most promising drug for the treatment of head and neck cancers. To increase the CDDP concentration in tongue cancer resistant to chemotherapy we have adopted intra-arterial chemotherapy for the treatment of advanced tongue cancer. This procedure has resulted in a positive prognosis and good organ preservation [7, 9]. We found that the administration of CDDP to the primary tongue cancer has a powerful effect on the primary cancer as well as occult neck metastasis.
An additional reason for difficulties in detecting SLNs was the close proximity of the primary tumor to the lymph node basin. This caused difficulties for both preoperative lymphoscintigraphy and intraoperative radiolocalization, because of the well described phenomena of "shine-through'' radioactivity and scatter from the primary site . Specifically, it was particularly difficult to detect SLNs on the floor of the mouth in any other sites of head and neck cancers [12, 13]. In order to avoid the influence of 'shine-through' we firstly resected the close primary tumor before sentinel mapping. However, it was difficult to completely avoid the influence of 'shine-through' after resection of the primary tumor. As for ICG fluorescence imaging, SLNs were clearly detected even in close proximity to the primary tumor and 'shine-through' could be avoided. The ICG fluorescence imaging procedure demonstrated better success rates of detecting SLNs for patients with tumors in the floor of the mouth than the radioactivity method.
Further studies will be required to verify the effectiveness and safety of intra-arterial chemotherapy as a method of lymphatic chemotherapy for the treatment of occult lymph node metastatsis. Our results suggest that a drug delivery system based on the SLN concept should be developed for local chemotherapy targeting SLNs in patients with cN0 oral cancer, for whom there is potential for metastasis in SLNs.
Further investigations may lead to the development of a new minimally invasive multimodal therapy targeting both the primary tumor and SLNs in the near future.
Our study verified the possibility that intra-arterial chemotherapy may be effective not only for organ preservation therapy, but also serve as an efficient procedure for translymphatic chemotherapy targeting SLNs in patients with oral cancer through the use of ICG fluorescence imaging. The CDDP concentrations recorded in SLNs were significantly higher than in non-SNLs.
This novel drug delivery system is feasible for translymphatic chemotherapy targeting SLNs in patients with cT3N0 oral cancer with the possibility of occult metastasis in SLNs.
This research was funded in part by a Grant for Clinical Cancer Research from the Ministry of Health, Labor, and Welfare of Japan.
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