As far as we know, the current study represents the first publication investigating the efficacy and safety of incorporating IMRT and adjuvant TP regimen into the treatment of high risk LACC patients. We found that such a paradigm was associated with a markedly improved survival with well-tolerated side effects, as estimated 5-year OS, DFS, LRRFS, and DMFS was 92.1%, 80.5%, 90.3%, and 88.0%, respectively, which compared favorably with most previous reports composed of similar study population.
In the early years, a median of summed EQD2 dose of 77.1 Gy had been used, which was soon proved to be insufficient for bulky tumors . In a recent study, Meng et al. revealed that higher EQD2 dosage to Point A (≥ 98Gy) was associated a significant LRRFS advantage . In our series, a median EQD2 of 93.8Gy for stage ⅡB-ⅢA patients and 99.6Gy for stage ⅢB-ⅣA yielded a complete response of 96.2%, reiterating that higher radiation dosage prescribed to point A still constitutes the cornerstone for the definitive treatment of LACC even in the era of modulated radiotherapy.
It has been reported that approximately 40% patients with adenopathy were not able to obtain a complete nodal response if treated with conventional radiotherapy, and 46.2% of them would recur at 2 years . By contrast, nearly 90%-100% involved nodes resolved completely when IMRT boost was used, and only 0%-8% of them relapsed [23, 26–29]. Consistently promising results were reported in the current study when a median IMRT boost of 60Gy was prescribed. All the involved nodes remised completely, and only one in-field regional relapse occurred synchronously with pelvic and distant recurrence. These findings suggested that IMRT boost was highly effective in nodal sterilization; it should be considered as an indispensable component of treatment for LACC, especially when positive nodes were present.
Except for escalated radiation dosage, SIB technique might be another underlying reason for improved loco-regional control, as it allowed for a maximum of 65Gy EBRT to be delivered at 2.6Gy per fraction within a median OTT of 46.5 days . In Guckenberger’ study, increased dose per fraction and reduced OTT through SIB allowed for an iso-toxic dose escalation of 8.0 Gy on average, which consequently yielded an improved tumor control probability from 15–28% . It had been recommended that radiotherapy should be completed within 56 days so that potential accelerated cancer cell repopulation could be avoided [32–34]. In an undergoing multicenter study aiming to benchmark a high level of disease control, SIB was regarded as an evolution over the past decades and required in all the participants with pathologic nodes . Its beneficial effect is expected to be further verified.
Occult paraaortic metastases might occur in approximately10 ~ 20% patients with apparently negative PALNs [36–37]. Yet, Lee et al. revealed that it was in patients with common iliac or > 3 pelvic LNs involvements that EF-IMRT was associated with a superior PALNs recurrence free survival over standard pelvic radiation (100% vs. 56.8%). By contrast, no significant survival difference was observed (100% vs. 93.8%) in patients without these features . Based on these findings, the authors postulated that a risk-guided EF-IMRT seem to be more reasonable. In the present study, EF-IMRT was reserved for patients with involved common iliac nodes or bulky PLNs. Our reported 5-year PALNs recurrence free survival of 97.9% further validated the highly effectiveness of such a risk-guided policy in the management of paraaortic lymph-node metastasis.
The value of adjuvant chemotherapy might had been underestimated in previous literatures when stage I-Ⅱ patients were enrolled[15, 16]. It was in a study made up of 48.7% stage Ⅲ-Ⅳ patients and 70% patients with LNM that a discernable DMFS advantage (20.5% vs. 30.8%) in favor of consolidating cisplatin plus 5-fluorouracil regimen was observed. Further improved outcomes were reported when more potent cytotoxic combinations were used. In Zhang’s paper, adjuvant paclitaxel plus nedaplatin (TN) regimen was associated with a 3% occurrence of DM in a cohort containing 70% stage Ⅲ patients . In our current series composed entirely of high-risk patients, adjuvant TP regimen led to a 5-year DMFS of 88.0%, which compared favorably with previously reported data achieved in similar population. These observations indicated that in high-risk LACC patients, adjuvant paclitaxel-platinum combination chemotherapy might play an important role for reduced distant metastasis.
Several other first-line regimens for recurrent of metastatic cervical cancer had also been evaluated in the adjuvant setting with encouraging oncologic outcomes, including gemcitabine plus cisplatin (GP) or paclitaxel plus carboplatin (TC) regimen, etc. [18, 19]. However, nearly 90% of the participants prescribed with GP regimen experienced grade 3–4 complications including 2 possibly toxicity-related deaths, whereas TC -based CCRT followed by adjuvant chemotherapy was associated with a 60.0% occurrence of grade 3–4 acute hematological toxicity or even higher [18, 20]. In comparison, TP or TN regimen seem to be more tolerable, as severe hematological toxicities were reported to be 36% and 21.8% in the present study and in Zhang’s study, respectively . In this regard, TP or TN regimens seemed to be preferred adjuvant options following CCRT.
Yet, Choi et al. revealed that although hematological relapse was statistically reduced by adjuvant PF regimen, the occurrence of non-regional lymphogenous relapse remained unaffected . In a series consisted entirely of patients with lymphadenopathy, Abe et al. even failed to disclose an improved DFS when adjuvant TC regimen was administered. . A similar trend was observed in the current study, as hematological spread was diminished to the low of 3.8%, while out-field lymphogenous metastasis occurred in 9.6% of the patients. Therefore, further investigations should be focused on exploring novel agents more effective in sterilizing tumor cells harbored in lymph nodes.
Due to the relatively small study population and lack of valid control group, a selection bias could not be avoided in the current study. Besides, although designed to identify an optimal treatment regimen for advanced LACC, several emerging radiation techniques which might further improve therapeutic-ratio, such as pet-CT based planning and image-guided adaptive brachytherapy, were not included in the current study. Nevertheless, the strength of this study lies in that it represents the largest study composed homogeneously of high-risk patients treated with a well-established highly effective cytotoxic regimen, so that confounding effects of the enrollment of low-risk patients or less potent regimens were minimized.