Appropriate delineation of the PA region is crucial in radiotherapy for cervical cancer patients, especially in a 3D or IMRT setting, in which a precise target delineation is highly necessary. However, to the best of our knowledge, only a limited number of studies are available about the delineation of the PA region of cervical cancer since the era of conformal radiotherapy (14, 15, 17–19), and no study to date has reported patterns of PA recurrence after curative-intent treatment for cervical cancer. The current study, which presents recurrence patterns of PALNs and validation of PA CTVs proposed in previous studies, could provide further information for appropriate radiotherapy of the PA region in cervical cancer patients.
PALN distribution in relation to major vessels might be the key in appropriate PA CTV delineation. In the horizontal direction, Takiar et al. (18) reported a mean distance from the center of the PALNs to major vessels of 8.3 mm to the aorta and 5.6 mm to the IVC. Keenan et al. (14) reported mean distances from PALNs to the aorta of 8 mm for lymph nodes located at LPA and AC. And mean distances were 6 mm from the IVC to lymph nodes located at AC and 5 mm to lymph nodes located at RPC. In the current study, mean distances from PALNs to the aorta were 8.2 mm for LPA lymph nodes and 7.1 mm for AC lymph nodes, and mean distances from PALNs to the IVC were 5.8 mm for AC lymph nodes and 3.9 mm for RPC lymph nodes. Our results are in agreement with those of Takiar et al. and Keenan et al. (14, 18), showing that mean distances from PALNs to major vessels are different based on the locations of lymph nodes. Therefore, a uniform margin around major vessels, such as the CTVM of our study, seems not suitable for cervical cancer.
Validation results of PA CTVs showed that for horizontal direction, CTVRTOG was the most appropriate CTV for management of PA recurrences in our study. CTV suggested by Keenan et al. (CTVK) required an additional margin around the IVC but little benefit compared to CTVRTOG (PALN coverage of 87.0% versus 88.0%). PALN coverage of CTV suggested by Milby et al. (CTVM) was unacceptably poor compared to CTVRTOG (PALN coverage of 87.0% versus 62.0%).
The recent update of RTOG guidelines recommended a minimal margin on the right, within 3 to 5 mm around IVC (15). The reason for recommending a small margin was because there was minimal evidence of nodal involvement to the right of the IVC. However, in the current study, 14 PALNs were located in the RPC region (15.2%). If a 3 mm margin was given around the IVC, only 3 nodes out of 14 (21.4 %) were covered by the CTV. Our data suggest at least a 5 mm margin around the IVC is needed to encompass PALNs located on the right of IVC, covering 10 nodes out of 14 (71.4 %).
While CTVRTOG generally showed good coverage of recurred lymph nodes, there was a group of patients with recurred lymph nodes above the left renal vein. By extending the upper margin of CTVRTOG from the left renal vein to SMA (CTVnew), all missed nodes above the left renal vein could be covered. However, routine extension of PA CTV up to SMA could result in excessive toxicity and finding a group of patients who could benefit from extending the upper margin might be required. In the current study, PALN involvement at diagnosis was significantly associated with PALN recurrence above the left renal vein (p = 0.043). In general, PALN involvement above the left renal vein at initial diagnosis seems to be rare. Keenan et al. (14) reported that all PALNs were inferior to the left renal vein. Takiar et al. (18) reported that only 4 % of PALNs were in the upper third, with 2 lymph nodes located on the T12 level. Kabolizadeh et al. (17) reported that all PALNs were located inferior to or at the level of renal vessels. But the recurrence patterns of the current study show that there are recurred PALNs above the left renal vein, and there may be a group of patients who could benefit from extending the upper border of PA CTV. For patients at high risk of PALN recurrence above the left renal vein, such as patients with PALN involvement at the time of diagnosis, we could carefully consider extending the upper margin of PA CTV up to SMA, instead of the left renal vein.
In the vertical direction, Keenan et al. (14) reported that 2 PALNs (3 %) were located on the upper third, 46 (68 %) were on the middle third, and 20 (29 %) were on the lower third. And the most superiorly located PALN was on the L1 level. Takiar et al. (18) reported that 3 PALNs (4 %) were located on the upper third, 26 (36 %) were on the middle third, and 43 (60 %) were on the lower third. Compared to the vertical location of PALNs in other studies, our data showed a tendency of PALNs to distribute upward (Table 2 and Fig. 2). The difference seems to be related to the patient cohort; while other studies were about cervical cancer patients with PA metastasis at initial diagnosis, our study is about cervical cancer patients with PA recurrence after curative-intent therapy. Curative therapy of cervical cancer includes management of the pelvis, which could lead to irradiating the lower PA region, resulting in a lower incidence of PALN recurrence in the lower third of the PA region in the current study.
There are few potential limitations of the current study. First, due to a small number of patients included, PA CTV validation results could have been biased. Second, other potential risk factors related to PALN recurrence above the left renal vein could have been overestimated or underestimated. And due to the retrospective nature of this study with heterogeneous radiotherapy delivery techniques applied, the results could have been confounded. However, as the current study is about patients with PALN recurrence after definitive treatment for cervical cancer with available PET/CT, we believe 35 patients with 92 PALNs are an acceptable number considering the rigid inclusion criteria. Lastly, recurrences were defined based on FDG-avidity on PET/CT, and there could be a potential issue in defining PALN recurrence, about whether an imaging result of PET CT can represent PALN recurrences without pathological confirmation. It is clear that the most exact method to define PALN recurrence is pathologic confirmation by surgical approach. However, a surgical approach provides broad topographic information, and we cannot acquire the information needed for PA CTV contouring such as exact distance from major vessels (20). That critical information can only be acquired through imaging studies. A meta-analysis by Choi et al. (21) reported that the diagnostic performance of PET/CT was acceptable, with 82% sensitivity and 95% specificity. CT and magnetic resonance imaging showed worse results compared to PET/CT, with 50% sensitivity and 92% specificity, and 56% sensitivity and 91% specificity, respectively. Considering those factors, using PET/CT for detection of PALN recurrence and mapping seems to be a reasonable approach.
In our study, PA CTV based on RTOG guidelines successfully encompassed PALN recurrences in most cases. As distances from major vessels to PALNs were different between locations, a uniform margin around vessels seems not to be appropriate. For high-risk patients, such as having PALN involvement at diagnosis, extending the superior border of the CTV up to the SMA could be considered.