Intensity-modulated radiation therapy for lymph node oligo-recurrence

概要

1. Introduction
Radical local therapy is generally not considered for patients with cancer metastasis or recurrence because the cancer has already spread throughout the body at the time of diagnosis and is thus difficult to cure. However, an increasing number of reports have suggested that the prognosis of these patients can be improved by local therapies such as surgery or radiotherapy if the number of affected regions is limited. This pathological condition was first defined as oligometastases by Hellman and Weichselbaum in 1995. They suggested that for many cancer types, a few metastases initially exist during the oligometastatic phase, after which the malignant cells acquire widespread metastatic potential. Theoretically, delivery of radical local therapy during the oligometastatic phase might improve the prognosis of patients who would otherwise be offered exclusively systemic therapy or palliative care. Oligo-recurrence, as a specific oligometastatic situation, was a concept proposed by Niibe in 2006. In oligorecurrence, the primary site should be controlled and all gross metastatic lesions can be treated by local therapy with radical intent (Niibe et al, 2010). In contrast, oligometastases is defined as a few metastases regardless of the status of the primary lesion. Patients with oligo- recurrence are more likely to be cured compared with those with oligometastases.
　High-precision radiation therapies, such as stereotactic radiotherapy (SRT) and intensity- modulated radiation therapy (IMRT), have undergone rapid developments in recent years. SRT has demonstrated good local control for oligometastatic lesions of around 80% (Tree et al, 2013). However, it is limited to small lesions (diameter <3 cm), considering the balance between the antitumor effects and adverse effects on the surrounding normal tissues. IMRT can provide an adequate dose to the target whilst sparing the normal organs at risk (OARs), even if the target is large or has a complex shape, such as the lymph node (LN) area. IMRT may thus be more widely applicable than SRT. However, reports on the use of IMRT for oligorecurrence are still lacking.
　In this study, we retrospectively evaluated the treatment outcomes and prognostic factors in patients with LN oligorecurrence treated with IMRT.

2. Materials and Methods
We retrospectively reviewed the medical records of 21 patients diagnosed with LN oligo-recurrence who received IMRT between October 2010 and August 2017 in Shonan Kamakura General Hospital. The inclusion criteria were as follows: 1) oligo-recurrence occurred exclusively in LNs, 2) all detectable involved LNs were treated with curative intent, and 3) primary lesion was controlled. Treatment plans were generated using Hi-Art system TomoTherapy (Accuray Inc., Sunnyvale, CA, USA) inverse planning software based on superposition dose calculation. The planning goals were as follows: 1) the prescribed dose was defined for the 50% isodoses of the PTV; 2) 95% of the PTV should receive ≥95% of the prescribed dose; and 3) 80%--90% of the GTV should receive at ≥100% of the prescribed dose. The dose to the OAR around the PTV was gradually restricted to the lowest possible dose. For image-guided radiation therapy (IGRT), a megavolt CT scan was performed daily immediately before irradiation. The overall survival (OS), in-field PFS, and out-of-field PFS rates were estimated by the Kaplan--Meier method. The Cox hazard regression model was used for univariate and multivariate analyses. Differences between subgroups were analyzed by log-rank tests. For all analyses, P<0.05 was considered statistically significant.

3. Results
The median age at the start of IMRT was 67 years (range: 39-81 years). The site of the primary lesion was the lung in five patients, breast in four, uterus in four, esophagus in two, and other in six. The primary histopathology was adenocarcinoma in eight patients, squamous cell carcinoma in five, and other in eight. The median gross tumor volume (GTV) was 9.6 cm3 (range: 1.4-80.0 cm3). Seventeen patients (81.0%) received IMRT including the regional LN area. The median IMRT dose to the GTV was 60 Gy (range: 50-70 Gy). The median follow-up period after IMRT was 33.7 months (range: 6.2- 71.3 months). The 3-year overall survival (OS), in-field progression-free survival (PFS), and out-of- field PFS rates were 75%, 52%, and 44%, respectively. Statistical analysis showed that lower dose to GTV and larger GTV were significantly associated with poorer OS, adenocarcinoma and lower dose to GTV were significantly associated with poorer in-field PFS, and older age and squamous cell carcinoma were associated with better out-of-field PFS. No patients experienced acute or late adverse events ≥grade 3, except for one case of acute grade 3 leukopenia.

4. Conclusion
The best of our knowledge, this study provides the first report of the clinical outcomes and prognostic factors in patients treated with IMRT for LN oligo-recurrence from various primary tumor types. The 3-year OS, in-field PFS, and out-of-field PFS rates were 75%, 52%, and 44%, respectively. Lower dose to GTV and larger GTV were significantly associated with poorer OS, adenocarcinoma and lower dose to GTV were significantly associated with poorer in-field PFS, and older age and squamous cell carcinoma were associated with better out-of-field PFS. Based on these findings, we concluded that IMRT may be a safe and effective strategy in patients with LN oligo-recurrence and curative in selected cases.

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