In this study, we established and evaluated prognostic factors for locally advanced cervical cancer patients in southern China and their impact on both PFS and OS. In univariate analysis, 10 predictive factors showed statistical significance (bulky tumors; chemotherapy; chemotherapeutic agents; different cumulative cisplatin dose; ICBT; HLB in early stages of the treatment; PLT pre-treatment and in early stages of the treatment; NEU pre-treatment and in early stages of the treatment). Within the complete multivariable Cox regression, three predictors were confirmed significant for PFS (bulky tumors, ICBT, different cumulative cisplatin dose, thrombopenia pre-treatment,), and four significant predictors for OS (bulky tumors, different cumulative cisplatin dose, ICBT, high NEU level in early stages of the treatment). As a consequence, the nomograms for 3-year and 5-year survival were constructed with all the significant factors.
Moreover, we further took the nomogram score into the evaluation to perform different risk stratification. The subsequent Kaplan–Meier analysis showed a significant difference in survival time between three groups of stratification, suggesting that the nomogram can distinguish between patients at different risks. The 5-year PFS in the low-risk, intermediate-risk, and high-risk group were 80.0%, 60.1%, and 31.8%, and the 5-year OS were 83.1%, 51.8%, and 38.5%, respectively. Considering the obviously lower survival rate in the high-risk group, more individualized and intense treatment may be required for this group of patients.
As is reported, age is closely related to the prognosis of patients with LACC, especially patients younger than 35 years old, which were considered to be more susceptible to local recurrence or distant metastasis9. Nevertheless, our study didn’t reveal that age has a statistically significant effect on OS or PFS, probably due to the lack of detailed stratification and fewer patients in the younger age group. As for pathological type, with an increasing incidence in recent years, adenocarcinoma is considered a poor prognostic factor in patients with LACC10. Compared with SCC, adenocarcinoma is more likely to make larger primary lesions and lead to distant metastasis. However, Galic Vijaya et al. reported that despite the lower complete remission rate of 86.5%, patients with adenocarcinoma receiving CCRT had no apparent difference in long-term survival11. Likewise, our study found that patients who received CCRT have no statistical difference in OS and PFS between adenocarcinoma and SCC.
As is known, pelvic and para-aortic LNM plays a key role in the poor prognosis of cervical cancer. Liu et al. indicated that the overall survival was 91% for pelvic LNM negative cohort and 67% for that positive cohort12, Most nomograms estimating PFS or OS for LACC include pelvic lymph node status as a significant risk factor, regardless of diagnostic methods: lymphadenectomy, PET/CT, or multiple imaging8,13. In 2018, FIGO revised the 2014 system into the 2018 staging system of cervical cancer14. One crucial difference from the previous staging system is that the latest 2018 system designates patients with regional lymph node metastasis into new stage Ⅲ category, in which patients with pelvic lymph node metastasis only are allocated to stage ⅢC1, and with positive para-aortic lymph node (PALN) allocated to stage ⅢC2. Our study comprehensively evaluated patients diagnosed with the previous staging system before 2018 and restaged those who met the ⅢC category in 2018 FIGO. A total of 38 were diagnosed as ⅢC. However, we failed to analyze that the FIGO stage, the ⅢC category in a particular, is a significant and independent factor, and there is no significant difference in 5-year overall survival between ⅢC and ⅢB (59.9% vs. 54.8%, p>0.05). What calls for attention is that stage ⅢC of the new system doesn’t take primary tumor size and extent as well as the characteristics of LNM into consideration. Liu et al.15 reported that tumor size and number of PLNM are significant prognostic factors for DFS in patients with stage ⅢC1r while confirming the heterogeneity among this group of patients. Therefore, regarding patients with combined and complicated status of large tumor size, lymph node metastasis, or other potential risk factors, the reasonability of new FIGO staging system to evaluate prognosis is limited.
On the other hand, the comparability of clinical stages in different regions and countries in the world has decreased, because the clinical stage in some countries, developed countries especially, is affected by imaging like MRI or PET/CT. In a meta-analysis, PET/CT and DWI-MRI have a high accuracy in detecting LNM. Among several modalities, PET/CT has the highest specificity, and DWI-MRI has the highest sensitivity16,17. What's more, compared to MRI on regional hypogastrium or pelvic, PET/CT has its advantages on detecting long-distant LNMs. Henrik Hansen et al. 16reported that the inclusion of PET/CT in the pre-radiotherapy diagnostic protocol correlated with survival benefits after CCRT in node-negative cervical cancer patients of 23 %, 19 % for OS, and disease-free survival (DFS). Due to the imbalance of regional development, the diagnoses of LACC patients in less developed areas were relatively limited. In our study, only 18 patients were diagnosed as stage ⅢC through PET/CT. A majority of patients refused to perform PET/CT or regional DWI-MRI because of high cost and personal reasons, which possibly lead to underestimates of clinical stage in patients with potential pelvic and para-aortic lymph node metastasis or worse distant organ metastasis. With developments in techniques, the failure pattern of LACC has changed. Lymph node failure has become a sort of main failure site remaining unsolved. It would be necessary to use high-precision imaging equipment like PET/CT or DWI-MRI to define the clinical metastases exactly in future practice.
Large tumor size was strongly suggested as a prognostic factor for LACC18. Similarly, our study demonstrated that patients with bulky tumors had an adverse effect on PFS as well as OS. It is acknowledged that tumor volume is the most direct indicator of tumor burden, representing the number of clones needed to be killed among the tumor19. In addition, large tumor size tends to give rise to a lack of oxygen, radiation resistance, and worse local control. In the relatively less-developed region of southern China, plenty of patients were diagnosed as advanced stages with the large primary site before treatment, leading to poor prognosis.
With advances in Image-guided radiation therapy (IGRT) and techniques, IMRT has gradually taken the place of traditional two-dimensional (2D) and three-dimensional (3D) techniques in EBRT procedure for better radiation protection to surrounding organs, bone marrow sparing as well as lower toxicity20,21. As shown in our study, patients with IMRT had a lower incidence of toxicity compared to those with four-box field, especially severe and unacceptable rectum and sigmoid toxicity. Nevertheless, we failed to observe that IMRT improved overall survival significantly, which may be attributable to the slightly short time follow-up (median of 47 months), representing the low number of patients followed beyond 5 years.
For decades, it is universally acknowledged that the combination of radiotherapy with chemotherapy prolongs disease-free survival while reducing mortality. In our study, chemotherapy was performed using cisplatin alone or with several combinations, and most patients received standard chemotherapy performed at weekly or tri-weekly intervals with the cumulative cisplatin dose of 180 to 200 mg/m2. Interestingly, we observed that not chemotherapy regimens but different cumulative cisplatin doses had an impact on PFS (p<0.05). Except for those who didn’t complete chemotherapy as planned, patients who received higher doses of cisplatin had a better 5-year PFS (74.4% vs 67.0%). Due to the higher incidence of bulky tumor (50.8%) and parametrial involvement (75.2%) among the enrolled cohort, it seemed that dose-intensive or additional adjuvant cisplatin-based chemotherapy not only inhibits accelerated tumor cell repopulation in a period but also further reduces potential systemic micro-metastases, thereby probably increasing the actual local control rate. Likewise, Landoni et al. 22suggested that additional chemotherapy could benefit those patients with intra-cervical residual and suboptimal responses. However, our study did not demonstrate that chemotherapy with higher doses of cisplatin benefited the overall survival of LACC patients, which probably was associated with the higher incidence of hematological toxicity in additional chemotherapy. Therefore, among LACC patients at different risks, it is necessary initially to re-evaluated the best-fit administration and delivery of chemotherapy.
Recently, indicators of blood cell counts have attracted attention as potential prognostic factors in cancer patients. In contrast to the nomograms performed by Rose et al8, we obtained three main complete indicators of blood cell counts at different periods during the treatment, aiming to investigate their dynamic variations and analyzed their prognostic predictive value, in consequence finding that thrombopenia before the treatment had adverse effects on both PFS (p=0.032) and OS (p=0.010), and high NEU level in early stages of the treatment was associated to poor OS (p=0.011). As is identified as a marker of poor prognosis in several forms of cancer, thrombocytopenia represents coagulation disorders and a higher incidence of bleeding risk, potentially leading to less tolerance of CCRT23. The tumor microenvironment plays a key role in growth and metastasis in present studies, which can be visualized by varieties of inflammation-related cells, such as neutrophils, platelets, and lymphocytes, especially neutrophils24. Continuous high level of NEU is one of the paracancerous syndromes of many malignant tumors, representing chronic inflammation in patients. Inflammation could change the systemic microenvironment for inducing the angiogenesis of tumors. What’s more, Inflammation level positively correlated with granulocyte colony-stimulating factor (G-CSF) expression in tumor tissues, which stimulates the production of myeloid-derived suppressor cell (MDSC), thus leading to the rapid development of the tumor and radiation resistance24. Yet there is little high-quality evidence on how to eliminate such chronic inflammatory responses in oncology patients.
In the current study, multivariate analyses were performed based on the elastic net regression model as the best-fit model to select potential risk factors. Moreover, nomograms and risk stratification were established to verify our predictive model accuracy further. As a result, the calibration plots showed an acceptable consistency between the predictive and actual probability of the survivals (cross-validated concordance probability c=0.684 for PFS, and 0.654 for OS), which could be the study's strengths. However, as this is a retrospective observational study, some limitations need to be addressed. First, the follow-up time was slightly short (median of 47 months). Second, not all patients benefited from a uniform and standard therapeutic scheme. Third, all patients were enrolled from a single institution. The factors mentioned above represent the fact that several biases would be inevitable to occur. Therefore, these factors can only be eliminated in prospective randomized studies with a more stratified and larger population.