The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy

We enrolled patients diagnosed with cervical cancer, classified as stages IB to IVA according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, between April 2009 and December 2017. None of the enrolled patients had distant metastases at treatment onset, and all patients received radical CCRT. The exclusion criteria for this study included any history of prior malignancy before treatment, any history of prior radiotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status > 2.

All patients underwent pretreatment workup and cancer staging using modern approaches, including a physical examination by a gynecologic oncologist, a tumor biopsy, a history review, chest X-ray, abdominal and pelvic computed tomography (CT,) or pelvic magnetic resonance imaging (MRI). Cystoscopy or sigmoidoscopy was performed by a specialist to exclude adjacent organ invasion for patients with locally advanced disease. In addition, routine laboratory biomarker studies, including squamous cell carcinoma antigen (SCC Ag), carcinoembryonic antigen (CEA), and cancer antigen 125 (CA125), were measured among the cohort. The median follow-up was 52 months (range 6–137 months). The cancer stage was classified according to the seventh edition of the American Joint Committee on Cancer (AJCC) TNM classification and the 2008 International FIGO staging system for cervical cancer. The retrospective study (KMUHIRB-E(I)-20190054) was approved by the Institutional Review Board (IRB) of Kaohsiung Medical University Hospital, and the need for informed consent was waived by the IRB due to the nature of this study as a chart review.

All patients received a consultation with a radiation oncologist and underwent an evaluation of clinical status to ensure the necessity and safety of radiotherapy. Following bladder preparation, patients were placed in a supine position with cast or cushion immobilization and underwent CT simulation, using a 3–5 mm slice thickness, from the upper edge of the lumbar spine to 5 cm below the lower border of the obturator foramen. For 3DCRT, a four-field box technique was planned using corner shielding in anteroposterior/posteroanterior (AP/PA) portals. The radiation portal fields were designed as follows: (1) superior border: L4–5 interspace, which covers the common iliac lymph nodes; (2) inferior border: 3 cm below the most inferior vaginal involvement, which is often below the inferior obturator foramen and can be as low as the introitus in cases of vaginal tumor extension; and (3) lateral border: 1.5–2 cm outside of the pelvic rim. For the lateral fields, the superior and inferior borders were consistent with the design of the AP/PA portals. The anterior border covered the front of the pubic symphysis, and the posterior edge included the entire sacrum. Pelvic radiotherapy was delivered at 1.8–2.0 Gy per fraction, 1–5 days each week, for a total of 25 fractions comprising 45–50 Gy, followed by the delivery of 5.4–9 Gy in 3–5 fractions delivered by AP/PA portals using a midline block. The superior border of the midline block was the midsacroiliac joint, and the width was 4 cm. If a parametrial tumor persists after 50–54 Gy, the side wall or parametrium may receive up to 60 Gy. For VMAT or tomotherapy, the clinical target volume (CTV) was defined as the gross tumor plus microscopic disease, including the cervix, uterus, upper third of the vagina (or upper half of the vagina, if a gross tumor is involved), the parametrium, and the pelvic nodal drainage. The patients were treated with simultaneous integrated boost doses of 48.6–50.4 Gy, delivered in 1.8 to 2-Gy fractions, to the primary tumor, 54–60 Gy delivered to the pelvic nodal drainage, including parametrial, obturator, internal iliac, external iliac, common iliac and gross lymph nodes, and 45–48 Gy, delivered in 1.6 to 1.8-Gy fractions, to elective nodal regions, such as presacral and paraaortic area. The planning target volume (PTV) was defined as the 8–10 mm margin around the CTV and could be modified according to the clinical condition. Target planning constraints were standardized as follows: (1) the PTV in all directions to receive > 95% of the prescribed dose; (2) volumes receiving more than 110% of the dose prescribed to the PTV were minimized. The typical organs at risk (OARs) included the rectum, bladder, intestine, large bowel, peritoneum, bilateral femoral heads, and the pelvic bone marrow [7]. The external contours of all bones within the pelvis were delineated on the planning CT images, as surrogates for the bone marrow, to enhance the reproducibility and consistency of the contours. The intestine and large bowel contours consisted of the bowel loops from 3 cm superior to the upper border of the PTV to its lowest extent in the pelvis. The dosimetric parameters for OARs were recorded as Vx, which represented the percentage of the organ volume that received X Gy or higher. For the individual patients, the selection of respective EBRT technique was decided by radiation oncologist on the basis of clinical scenario.

After EBRT, all patients underwent afterloading brachytherapy, which consisted of high-dose-rate ¹⁹²Ir intracavitary brachytherapy intended to deliver a dose of 4–5 Gy/time to Point A twice per week, with 5 to 6 total treatments. During RT, chemotherapy was concurrently prescribed, consisting of weekly cisplatin for 6 weeks. The regimen was shifted to carboplatin for those patients with impaired renal function and paclitaxel-based treatment for prescribed for patients with locally advanced disease.

In general, the patients returned for a first follow-up visit one month after the completion of treatment, followed by every 2–3 months during the first year and every 3–6 months thereafter. Physical examination including pelvic examination was performed at every follow-up visit. Patients should have follow-up imaging, either abdominal and pelvic CT or pelvic MRI, at least every 3–6 months after the completion of treatment. Chest X-ray is acquired annually at least after treatment. A serum test for tumor markers was performed every 3–6 months after the completion of CCRT. The gynecologic oncologists and radiation oncologists recorded treatment-related toxicity events according to the Common Terminology Criteria of Adverse Events (CTCAE), VERSION 4.03 [28]. Using these criteria, acute complications were defined as those with onset during RT and were assessed once per week during EBRT. Chronic complications were scored retrospectively based on chart records. The overall treatment time (OTT) of RT was defined as the time interval between the first and last date of RT. The primary endpoints were locoregional recurrence–free survival (LRRFS), progression-free survival (PFS), distant metastasis–free survival (DMFS), and overall survival (OS). The length of follow-up was defined as the time from CCRT to the date of death or the last follow-up. Locoregional failure was defined as any recurrent or persistent disease involving the pelvis. Any disease failure outside of the pelvis was defined as a distant failure. Pathological reports, including those associated with surgical intervention, biopsy, and cytology, in addition to radiology reports from radiology examinations, including chest radiography, CT, MRI, technetium-99 bone scintigraphy, or positron emission tomography (PET), were reviewed to determine disease status.

A total of 93 patients diagnosed with stage IB-IVA cervical cancer were enrolled in this retrospective study. The median age of the retrospective cohort was 61 years (range 34–93 years). Table 1 summarizes the patients’ clinical baseline characteristics, grouped according to the three radiotherapy techniques. Nine patients (9.7%) received 3DCRT, 43 patients (46.2%) underwent VMAT, and 41 patients (44.1%) received tomotherapy. The median EBRT dose was 54 Gy (range 45–64 Gy), and the median equivalent dose in 2-Gy fractions (EQD2) of Point A was 79.8 Gy (range 49.1–93.1 Gy). No significant differences were observed for OTT of RT, clinical T classification, histological type, mean EBRT dose, EQD2 of Point A, pre- and post-treatment SCC Ag, or follow-up duration between the three techniques. One patient in the 3DCRT group and one patient in the VMAT group were lost to follow-up.

We further investigated clinical outcomes based on different patient and tumor characteristics, including age (≥ 60 vs. < 60 years), OTT of RT (> 61 days vs. ≤ 61 days), T classification (T1/T2 vs. T3/T4), N classification (nodal negative vs. nodal positive), pretreatment SCC Ag (≤ 10 vs. > 10 ng/mL), post-treatment SCC Ag (≤ 1.5 vs. > 1.5 ng/mL), the EQD2 of Point A (≥ 81 vs. < 81 Gy), and the RT technique (3DCRT vs. VMAT vs. Tomotherapy). In the OS analysis, using the Kaplan–Meier method (Fig. 1), the OTT of RT, T classification, N classification, pretreatment SCC Ag, and post-treatment SCC Ag were significant factors (P = 0.01, 0.001, 0.006, 0.034, and 0.018, respectively). Table 2 presents a multivariate analysis of these characteristics. Only an OTT of RT > 61 days and T3/T4 disease were significant factors associated with OS in the Cox proportional hazards regression analysis (hazard ratio [HR] 2.99, 95% confidence interval [CI] 1.03–8.70, P = 0.045; and HR 2.97, 95% CI 1.24–7.11, P = 0.015, respectively). A post-treatment SCC Ag > 1.5 ng/mL was associated with a lower OS, but did not achieve significance (P = 0.069).

In the PFS analysis using the Kaplan–Meier method (Fig. 2), T classification, N classification, and pretreatment SCC Ag were significant factors (P ≤ 0.001, 0.004, and 0.005, respectively). The OTT of RT showed an effect on PFS by the log-rank test, but did not achieve significance (P = 0.071). Table 3 presents the multivariate analysis of these characteristics. T3/T4 disease, nodal positive, and pretreatment SCC Ag > 10 ng/mL remained significant factors affecting PFS in the Cox proportional hazards regression analysis (HR 2.72, 95% CI 1.30–5.71, P = 0.008; HR 2.55, 95% CI 1.15–5.63, P = 0.021; and HR 2.20, 95% CI 1.03–4.71, P = 0.041, respectively).

In the LRRFS analysis using the Kaplan–Meier method (Fig. 3), only T classification and pretreatment SCC Ag were significant factors (P = 0.032 and 0.038, respectively). Table 4 presents the multivariate analysis of these characteristics. Only pretreatment SCC Ag > 10 ng/mL remained significant in the Cox proportional hazards regression analysis (HR 3.48, 95% CI 1.07–11.26, P = 0.038). The T3/T4 classification showed an effect on LRRFS but failed to reach significance (P = 0.082).

In the DMFS analysis using the Kaplan–Meier method (Fig. 4), T classification, N classification, and pretreatment SCC Ag were significant factors (P = 0.001, < 0.001, and 0.001, respectively). The OTT of RT showed an effect on DMFS by the log-rank test but failed to reach significance (P = 0.071). Table 5 presents the multivariate analysis of these characteristics. All three factors remained significant in the Cox proportional hazards regression analysis (HR 2.88, 95% CI 1.01–8.22, P = 0.048; HR 6.17, 95% CI 2.01–18.89, P = 0.001; and HR 2.80, 95% CI 1.02–7.67, P = 0.045, respectively). OTT of RT > 61 days failed to demonstrate significance following after covariate adjustment (P = 0.161).

In the T1/T2N0 subgroup analysis using the Kaplan–Meier method (Fig. 5), pretreatment SCC Ag > 10 ng/mL trended toward worse DMFS but not OS, PFS, or LRRFS. The 5-year DMFS was 93.8% for the group with pretreatment SCC Ag ≤ 10 ng/mL, compared with 79.4% for the group with pretreatment SCC Ag > 10 ng/mL (P = 0.057). Furthermore, in the Cox proportional hazards regression analysis (Table 6), pretreatment SCC Ag > 10 ng/mL suggested an increased risk of distant metastasis and nearly reached a significant effect on DMFS (HR 12.4, 95% CI 0.85–181.4, P = 0.066). However, all other factors, such as age, OTT of RT, post-treatment SCC Ag, EQD2 of Point A, and RT technique, failed to show significant effects after covariate adjustment (P = 0.161, 0.767, 0.863, 0.921, and 0.991, respectively).

The dosimetric parameters and RT-related toxicity are summarized in Table 7. The relationships between toxicity and OAR doses were analyzed by logistic regression. Due to clinical limitations, only the last 30 patients were able to be analyzed.

The dose delivered to the colon did not affect the likelihood of experience Grade 2 or worse acute diarrhea. The colon V₃₅, V₂₅, and V₁₅ values were analyzed, and no correlation was observed between these dosimetric parameters and the occurrence of Grade 2 or worse acute diarrhea. We also analyzed the dosimetric parameters for the peritoneum and noted a trend toward the increased occurrence of Grade 2 or worse acute diarrhea with an increasing peritoneum V₄₀ value (odds ratio [OR] 1.62, 95% CI 0.97–2.71, P = 0.068) but not for the peritoneum V_50.4, V₃₀, or V₂₅ values. The dosimetric parameters for the rectum showed a significant increase in the occurrence of Grade 2 or worse acute diarrhea with an increasing rectum V₃₀ value (OR 1.15, 95% CI 1.10–1.30, P = 0.030) but not for the rectum V_50.4 and V₄₀ values.

The doses delivered to the colon and peritoneum did not affect the likelihood of Grade 2 or worse colitis. The colon V₃₅, V₂₅, and V₁₅ and the peritoneum V_50.4, V₄₀, V₃₀, and V₂₅ values were analyzed, and no correlations were observed between these dosimetric parameters and the occurrence of Grade 2 or worse colitis. However, we found a trend toward the increased likelihood of Grade 2 or worse colitis correlated with an increasing rectum V₃₀ value (OR 1.14, 95% CI 0.99–1.33, P = 0.073), although this did not achieve significance. Except for the rectum V₃₀ value, the occurrence of Grade 2 or worse colitis was not correlated with any other dosimetric parameters for the rectum.

To compare differences in the radiation exposure for OARs between the 3 treatment plans, the last 30 patients were analyzed, including 9 patients (30%) in the 3DCRT group, 11 patients (36.7%) in the VMAT group, and 10 patients (33.3%) in the tomotherapy group. Since we were also interested in OARs and toxicity difference between the 3 treatment plans, our group initiated the comparison of dosimetric outcomes and clinical toxicities in the mid-term of study and led to only the last 30 patients were included. Furthermore, the improved conformality achievable with IMRT can potentially mitigate adverse effects and contribute to the low utilization of 3DCRT. Table 8 presents the dosimetric comparisons for OARs across the 3 treatment plans. Three dosimetric parameters were analyzed for the colon, including the V₃₅, V₂₅, and V₁₅ values. 3DCRT was associated with higher colon V₃₅ and V₂₅ values than VMAT and tomotherapy (P = 0.002 and 0.020, respectively). However, the colon V₁₅ values were similar across the three groups. In addition, no dosimetric differences for the colon were found between VMAT and tomotherapy groups. Four dosimetric parameters were analyzed for the peritoneum, including the V_50.4, V₄₀, V_30, and V₂₅ values. We also found that the 3DCRT group had higher peritoneum V_50.4, V₄₀, and V₃₀ values than the VMAT and tomotherapy groups (P = 0.001, 0.002, and 0.013, respectively). In the analysis of peritoneum V₂₅ values, the 3DCRT values were higher than those for the other two techniques, but this difference did not achieve significance (P = 0. 147). No significant differences in the dosimetric parameters for the peritoneum were observed between the VMAT and tomotherapy groups. Three dosimetric parameters were analyzed for the rectum, including the V_50.4, V₄₀, and V₃₀ values. All three of these parameters were much higher for the 3DCRT group than for the VMAT and tomotherapy groups (P = 0. 003, < 0.001, and < 0.001, respectively). More importantly, the median rectum V₃₀ values were 56.4% and 86.5% in the tomotherapy and VMAT groups, respectively. Tomotherapy further reduced the V₃₀ value for the rectum compared with VMAT (P < 0.005). Figure 6 presents the isodose distributions in a representative T2N0 patient treated with VMAT and a T3N0 patient treated with tomotherapy, showing that the spiral delivery pattern associated with tomotherapy reduced the unnecessary dosing of the rectum. Three dosimetric parameters were analyzed for the bladder, including the V_50.4, V₄₀, and V₃₀ values. The median V_50.4, V₄₀, and V₃₀ values for the bladder in the 3DCRT group were 40.7%, 100%, and 100%, respectively. By contrast, the VMAT values were 2.0%, 28.0%, and 59.5%, respectively, and the tomotherapy values were 5.7%, 28.6%, and 50.5%. For all three parameters, the values for the 3DCRT group were much higher than for the VMAT and tomotherapy groups (P = 0. 001, < 0.001, and < 0.001, respectively). Similar to the finding for the colon and peritoneum, no significant differences were observed among the dosimetric parameters of the bladder between the VMAT and tomotherapy groups. Finally, five dosimetric parameters were analyzed for the bone marrow, including the V₅₀, V₄₀, V₃₀, V₂₀, and V₁₀ values. Compared with VMAT and tomotherapy, we found that 3DCRT results in higher marrow V₅₀, V₄₀, V₃₀, and V₂₀ values (P < 0.001, < 0.001, < 0.001, and = 0.002, respectively) but not marrow V₁₀ values. Similarly, no significant differences in dosimetric parameters for the bone marrow were observed between VMAT and tomotherapy.

Table 9 presents the percentages of gastrointestinal (GI) and genitourinary complications associated with 3DCRT, VMAT, and tomotherapy. Acute Grade 2 or worse diarrhea for 3DCRT, VMAT, and tomotherapy occurred in 66.7% (6/9), 54.5% (6/11), and 10.0% (1/10) of patients, respectively. Tomotherapy substantially and significantly reduced the severity of acute diarrhea (P = 0.029). None of the patients suffered from Grade 4 diarrhea. Grade 2 or worse chronic colitis occurred in 22.2% (2/9) of the 3DCRT group, 18.2% (2/11) of the VMAT group, and 20.0% (2/10) of the tomotherapy group, with no significant differences noted between the three groups. For Grade 2 or worse acute cystitis, the incidences for the 3DCRT, VMAT, and tomotherapy groups were 33.3% (3/9), 63.6% (7/11), and 30.0% (3/10), with no significant difference noted between groups.