Advanced Cervical Squamous Carcinoma Research Articles

Locally advanced squamous cervical carcinoma (M0): management and emerging therapeutic options in the precision radiotherapy era.

Squamous cervical carcinoma (SCC) requires particular attention in diagnostic and clinical management. New diagnostic tools, such as (positron emission tomography-magnetic resonance imaging) PET-MRI, consent to ameliorate clinical staging accuracy. The availability of new technologies in radiation therapy permits to deliver higher dose lowering toxicities. In this clinical scenario, new surgical concepts could aid in general management. Lastly, new targeted therapies and immunotherapy will have more room in this setting. The aim of this narrative review is to focus both on clinical management and new therapies in the precision radiotherapy era.

Analysis Of Clinical Outcome, Toxicity And Prognosis On Locally Advanced Cervical Squamous Cell Carcinoma With Normal SCCAg Levels Receiving Intensity-Modulated Radiotherapy, Brachytherapy Combined With Concurrent Chemotherapy

Though SCCAg could be a useful marker in squamous cell carcinoma, rising of SCCAg is not demonstrated in some patients with squamous cell cancer. This study aimed to assess the clinical outcome, toxicity and prognosis on locally advanced cervical squamous carcinoma with normal SCCAg levels receiving concurrent chemoradiotherapy. A total of 294 patients of locally advanced cervical squamous cell carcinoma with normal SCCAg levels before treatment, FIGO 2018 staging from IB to IIIC2 with a median age of 54 years old, who received concurrent chemoradiotherapy from 2007 to 2016 were evaluated in this study. All patients received intensity-modulated external radiotherapy, high-dose-rate brachytherapy and cisplatin-based concurrent chemotherapy. 57 patients (19.39%) were diagnosed with pelvic lymph node metastasis before treatment, 32 (10.88%) of which were unilateral pelvic lymph node metastasis, and 25 (8.5%) were bilateral pelvic lymph node metastasis. The median survival time was 69.1 months, with 5-year OS, DFS, LCR and DMFS 83.6%, 80.6%, 90.3% and 88.1% respectively. 28 patients (9.52%) had local recurrence and 35 (11.9%) had distant metastasis. 11.56% and 1.02% patients had Grade III acute and late adverse effects in urinary system with 8.16% and 1.02% in gastrointestinal tract. The occurrence of the above for Grade IV were only 0%, 0%, 0% and 0.34%. Grade III acute hematological adverse events in leukocytes and neutrophils, lymphocytes, hemoglobin and platelets were 46.26%, 54.42%, 26.87%, 4.76% and 4.08%. Those of grade IV were 3.06%, 30.95%, 3.40%, 0.68% and 0.00%. Grade III late hematological toxicity, leukocytes, neutrophils, hemoglobin and platelets were 2.72%, 0.68%, 3.06% and 0.34%. Those of grade IV all show as 0.34%. As for prognostic factors, EQD2≥8500cGy (P = 0.001 and 0.008) and the courses of concurrent chemotherapy ≥4 cycles (P = 0.024 and 0.018) substantially improve OS and DFS. The performance of brachytherapy (P = 0.000) effectively improved LCR. While the courses of concurrent chemotherapy ≥ 4 cycles (P = 0.024) acted as an independent prognostic factor for DMFS, pelvic lymph node metastasis was an independent prognostic factor for OS, DFS, LC and DMFS, with metastasis of bilateral pelvic lymph nodes leading to worse prognosis than that of unilateral one. Intensity-modulated radiation therapy combined with brachytherapy and at least 4 courses of concurrent chemotherapy could significantly improve the prognosis including local recurrence and distant metastasis of locally advanced cervical squamous cell carcinoma with normal SCCAg level, and substantially reduce incidence of acute and late adverse effects above grade III. Most importantly, metastasis of pelvic lymph nodes acted as a significant prognosis factor. Among metastases of pelvic lymph nodes, bilateral metastases had a worse prognosis than unilateral ones.

A Preoperative Nomogram for Predicting Chemoresistance to Neoadjuvant Chemotherapy in Patients with Locally Advanced Cervical Squamous Carcinoma Treated with Radical Hysterectomy.

PurposeThis study aimed to investigate the factors associated with chemoresistance to neoadjuvant chemotherapy (NACT) followed by radical hysterectomy (RH) and construct a nomogram to predict the chemoresistance in patients with locally advanced cervical squamous carcinoma (LACSC).Materials and MethodsThis retrospective study included 516 patients with International Federation of Gynecology and Obstetrics (2003) stage IB2 and IIA2 cervical cancer treated with NACT and RH between 2007 and 2017. Clinicopathologic data were collected, and patients were assigned to training (n=381) and validation (n=135) sets. Univariate and multivariate analyses were performed to analyze factors associated with chemoresistance to NACT. A nomogram was built using the multivariate logistic regression analysis results. We evaluated the discriminative ability and accuracy of the model using a concordance index and a calibration curve. The predictive probability of chemoresistance to NACT was defined as > 34%.ResultsMultivariate analysis confirmed menopausal status, clinical tumor diameter, serum squamous cell carcinoma antigen level, and parametrial invasion on magnetic resonance imaging before treatment as independent prognostic factors associated with chemoresistance to NACT. The concordance indices of the nomogram for training and validation sets were 0.861 (95% confidence interval [CI], 0.822 to 0.900) and 0.807 (95% CI, 0.807 to 0.888), respectively. Calibration plots revealed a good fit between the model-predicted probabilities and actual probabilities (Hosmer-Lemeshow test, p=0.597). Furthermore, grouping based on the nomogram was associated with progression-free survival.ConclusionWe developed a nomogram for predicting chemoresistance in LACSC patients treated with RH. This nomogram can help physicians make clinical decisions regarding primary management and postoperative follow-up of the patients.

Whole-lesion ADC histogram and texture analysis in predicting recurrence of cervical cancer treated with CCRT.

PurposeTo explore the value of whole-lesion apparent diffusion coefficient (ADC) histogram and texture analysis in predicting tumor recurrence of advanced cervical cancer treated with concurrent chemo-radiotherapy (CCRT).Methods36 women with pathologically confirmed advanced cervical squamous carcinomas were enrolled in this prospective study. 3.0 T pelvic MR examinations including diffusion weighted imaging (b = 0, 800 s/mm2) were performed before CCRT (pre-CCRT) and at the end of 2nd week of CCRT (mid-CCRT). ADC histogram and texture features were derived from the whole volume of cervical cancers.ResultsWith a mean follow-up of 25 months (range, 11 ∼ 43), 10/36 (27.8%) patients ended with recurrence. Pre-CCRT 75th, 90th, correlation, autocorrelation and mid-CCRT ADCmean, 10th, 25th, 50th, 75th, 90th, autocorrelation can effectively differentiate the recurrence from nonrecurrence group with area under the curve ranging from 0.742 to 0.850 (P values range, 0.001 ∼ 0.038).ConclusionsPre- and mid-treatment whole-lesion ADC histogram and texture analysis hold great potential in predicting tumor recurrence of advanced cervical cancer treated with CCRT.

Value of R2* obtained from T2*-weighted imaging in predicting the prognosis of advanced cervical squamous carcinoma treated with concurrent chemoradiotherapy.

To prospectively investigate the value of R2* in predicting the prognosis of advanced cervical squamous carcinoma treated with concurrent chemoradiotherapy. Sixty-five patients with biopsy-proven cervical squamous carcinoma were enrolled in our study. All these subjects underwent multi-echo T2*-weighted MR imaging on a 3.0 Tesla MR scanner, and tumor R2* was calculated. The patients were divided into the responders and the nonresponders according to treatment effect. Tumor R2* values of these two groups were compared. The relationship between tumor R2* and prognosis after therapy was analyzed. The responder group had lower R2* value than the nonresponder group (P = 0.02). The area under the receiver operating characteristics curve for tumor R2* in discriminating responders from nonresponders was 0.769. A cutoff value of 23.87 Hz for tumor R2* resulted in a sensitivity of 78.3% and a specificity of 67.6%. The low R2* group (≤28.37 Hz) had longer median progression-free survival period and overall survival period (P = 0.01, 0.03). Multivariate analysis showed that tumor R2* was a significant prognostic factor for progression-free survival and overall survival (adjusted hazards ratio = 5.34, 4.78; P = 0.02, 0.01). R2* value obtained from T2*-weighted imaging, as an imaging biomarker, may be an important predictor for the prognosis of advanced cervical squamous carcinoma treated with concurrent chemoradiotherapy.

Pretreatment serum hemoglobin level as a predictive factor of response to neoadjuvant chemotherapy in patients with locally advanced squamous cervical carcinoma: A preliminary report

Objective. The aim of this study was to evaluate the predictive value of pretreatment serum hemoglobin level (Hb) together with a series of clinical and pathological variables available before neoadjuvant chemotherapy in locally advanced squamous cervical cancer. Methods. The influence on response to neoadjuvant chemotherapy of a series of pretreatment clinico-pathological features: hemoglobin level at diagnosis, age, parity, menopausal status, body mass index, clinical stage, tumor diameter, and nuclear grading were analyzed on 73 patients with locally advanced cervical cancer treated with platinum-based neoadjuvant chemotherapy followed by radical surgery. The relationships between pretreatment variables and response to chemotherapy were assessed in univariate and multivariate settings. A univariate and multivariate logistic regression model was adapted to predict an “optimal” response (pathological complete response or more than 50% reduction in tumoral diameter) or “sub-optimal” response (<50% reduction in tumoral diameter). Results. Seventy-three patients—clinical stage: Ib2: 29 (39.7%) IIa: 22 (30.1%) IIb: 22 (30.1%)—received 3 cycles of platinum-based neoadjuvant chemotherapy followed by type III radical hysterectomy. A complete response to neoadjuvant chemotherapy was significantly associated with higher level of pretreatment hemoglobin (mean 14.0 mg/dl) compared to patients with ≥50% response (12.7 mg/dl) or <50% (11.9 mg/dl) ( P = 0.002). At multivariate analysis, Hb level was found to be the most powerful and significantly related factor to response to neoadjuvant chemotherapy. A hemoglobin threshold of 12 mg/dl was able to distinguish between patients—with ≥12 mg/dl—at higher probability to respond to neoadjuvant chemotherapy from the ones at lower probability (hemoglobin level under 12 mg/dl). Patients with a complete response to chemotherapy had a 100% survival compared to 93.1% and 53.8% for patients with responses ≥50% and <50% respectively ( P = 0.0001). Patients with a pretreatment hemoglobin level of ≥12 mg/dl showed a survival of 87% compared to 63% for patients with a lower hemoglobin level ( P = 0.008). Conclusions. Pretreatment Hb level showed a prognostic and independent predictive value for response to neoadjuvant chemotherapy in locally advanced cervical cancer. In our preliminary report, performed on a limited sample, a threshold of 12 mg/dl seems to be helpful to distinguish between “optimal” and “non-optimal” response.

Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy

We investigated the possible use of clinical signs of chemotherapy-induced peripheral neurotoxicity (CIPN) or of nerve growth factor (NGF) circulating levels to predict the final outcome of CIPN. Sixty-two women affected by locally advanced squamous cervical carcinoma treated with TP (paclitaxel 175 mg/m2 over a 3 h infusion plus cisplatin 75 mg/m2) or TIP (TP plus ifosphamide 5 mg/m2) were examined and scored according to the Total Neuropathy Score (TNS), before and during chemotherapy. A correlation with the final severity of CIPN was observed with vibration perception and deep tendon reflex evaluation, while pin sensibility, strength, and autonomic symptoms and signs were not informative. A highly significant correlation existed between the decrease in circulating levels of NGF and the severity of CIPN (r = -0.579; P < 0.001; 95% confidence limits -0.702 to -0.423). However, circulating levels of NGF were not effective as predictors of the final neurological outcome of each patient. Our study indicates that a precise clinical evaluation of the peripheral nervous system of patients treated with platinum and taxane combination polychemotherapy not only gives reliable information regarding the course of CIPN, but also can be used to predict the final neurological outcome of the treatment.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 24

The present study was performed with the aim to compare different clinically‐based neurotoxicity scales with a more extended composite scale (Total Neuropathy Scale) already validated in diabetic patients, in order to improve the grading of chemotherapy‐induced peripheral neuropathy (CIPN) severity. The features of CIPN were evaluated in a series of women affected by locally advanced squamous cervical carcinoma treated with cisplatin and paclitaxel– based chemotherapy by clinical examination, neurophysiology and quantitative sensory testing of vibration threshold (VDT); the ECOG, Ajani and NCIC‐CTC grades were assessed by a neurologist after clinical examination and the TNS was calculated after additional instrumental examination. At the same time, the treating oncologist, who was blinded as regards the results of the neurological examination, assessed the NCIC‐CTC sensory neurotoxicity grade. The correlation existing between the different evaluations was evaluated with the Spearman test on a total of 97 visits. Our results indicate for all the neurotoxicity scales commonly used by oncologists and evaluated in this study a significant correlation with TNS; the interexaminer agreement comparison evaluation evidenced that in several cases the neurologist attributed a higher grade in the NCIC‐CTC scale than the oncologist, and this discrepancy was mainly due to a different evaluation of the sensory impairment. In conclusion, the TNS can be used to assess effectively the severity of CIPN and the results of this evaluation can be reliably correlated with the oncological grading of sensory peripheral neurotoxicity; the wider range of TNS values, however, can allow a more accurate grading of the sensory impairment, a feature which can improve the estimate of CIPN changes, particularly in clinical trials; finally, the use of standardized methods of examination of the sensory function (e.g. the semiquantitative measure of vibration sensibility using the 128 Hz tuning fork) may reduce the interexaminer disagreement.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 25

Several effective antineoplastic drugs are severely neurotoxic and induce the onset of disabling peripheral neuropathies. The clinical presentation of this side effect depends on the type of antineoplastic agent administered. The signs and symptoms shown are predominantly motor (e.g. in the case of vinca alkaloids), sensorimotor (e.g. with the taxanes) or sensory (e.g. using platinum‐derived drugs). The pathogenesis of these antineoplastic drug‐induced peripheral neuropathies is still poorly understood, although a relationship has been suggested between some neuronal growth factors (neurotrophins) and the toxic action of cisplatin (CDDP) and paclitaxel. In this study we correlated the changes in the circulating levels of Nerve Growth factor (NGF) in a series of 24 women affected by locally advanced squamous cervical carcinoma treated with cisplatin and paclitaxel‐based chemotherapy with the severity of chemotherapy‐induced peripheral neuropathy (CIPN) as assessed by the Total Neuropathy Score (TNS). After informed consent, blood samples were drawn before chemotherapy and after treatment and NGF circulating levels were determined by ELISA (EmaxTM ImmunoAssay System, Promega, USA; plasma working dilutions NGF 1:80) following the manufacturer protocols. The results obtained in this series of patients evidenced a significant correlation between the severity of CIPN and the reduction in the circulating levels of NGF (r = − 0.480, p = 0.017 by two‐tailed Spearman correlation test, 95% CL −0.745 to −0.082), thus confirming similar results previously obtained in a rat model of CDDP peripheral neurotoxicity. In conclusion, our data suggest that a relationship exists between CIPN and NGF circulating levels in patients treated with cisplatin and paclitaxel. Therefore, this preliminary observation support the need for further studies in order to explore the possibility of reducing the severity of platinum‐drug sensory neurotoxicity with treatments aimed at increasing the circulating levels of NGF.

Role of zinc and alpha2 macroglobulin on thymic endocrine activity and on peripheral immune efficiency (natural killer activity and interleukin 2) in cervical carcinoma.

Decreased natural killer (NK) activity as well as interleukin 2 (IL-2) are risk factors for the progression of cervical carcinoma. NK activity and IL-2 may be thymus controlled. Plasma levels of active thymulin, a zinc-dependent thymic hormone (ZnFTS), are reduced in cancer because of the low peripheral zinc bioavailability. Zinc and thymulin are relevant for normal immune functions. α2-Macroglobulin is an inhibitor of matrix metalloproteases (MMPs) against invasive tumour proliferation. Because α2-macroglobulin has a binding affinity (Kd) for zinc that is higher than does thymulin, it may play a key role in immune efficiency in cancer. Plasma samples of 22 patients (age range 35–60 years) with locally advanced squamous cervical carcinoma and with FIGO stage Ib2–IIb were examined. They showed reduced active thymulin, decreased NK activity and IL-2 production, increased soluble IL-2 receptor (sIL-2R) and augmented α2-macroglobulin in the circulation, whereas plasma zinc levels were within the normal range for age. Significant positive correlations were found between zinc or active thymulin and α2-macroglobulin (r = 0.75, P< 0.01, r = 0.78, P< 0.01, respectively) in cancer patients. In vitro zinc increases IL-2 production from peripheral blood mononuclear cells (PBMCs) of cancer patients. These data suggest that an increase in α2-macroglobulin, which competes with thymulin for zinc binding, may be involved in causing a thymulin deficit with a consequent decrease of IL-2 and NK cytotoxicity. Thus, physiological zinc treatment in cervical carcinoma maybe restores impaired central and peripheral immune efficiency. © 1999 Cancer Research Campaign

Modulation of expression of p53 and cell proliferation in locally advanced cervical carcinoma after neoadjuvant combination chemotherapy

Objective: In the present study, we investigated changes of p53 expression and the cell proliferation index detected with MIB 1 in tumors before and after neoadjuvant combination chemotherapy with respect to the outcome of the disease. Our aim was to define more appropriately the significance of chemotherapy in locally advanced cervical carcinoma. Materials and methods: Our study included 17 women with locally advanced squamous cervical carcinoma who had been admitted to the Institute of Gynecology and Obstetrics Ancona University, between January 1990 and December 1994. The patients received neoadjuvant combination chemotherapy consisting of three cycles of cisplatin (80 mg/m 2) and bleomycin (30 mg/m 2). After chemotherapy, radical surgery was performed. Bioptic specimens were obtained from cervical tumors before and after chemotherapy and processed for immunohistochemical staining with a monoclonal antibody against p53 and with the monoclonal antibody MIB 1. Results: Thirteen patients (76.5%) showed a clinical response (4 complete and 9 partial), while of the remaining 4 cases (23.5%) 3 had no change and 1 showed progression after neoadjuvant combination chemotherapy. A significant relationship was observed between the overexpression of p53 and the sensitivity to chemotherapy; responder patients showed a higher frequency of p53 positive cells than non-responders ( P = 0.03). No significant relationship with MIB 1 index was observed. Both expression of p53 protein ( P < 0.001) and reaction with MIB 1 ( P = 0.003) significantly decreased after chemotherapy. The decrease in expression of p53 protein and staining with antibody MIB 1 was particularly evident in patients who responded to chemotherapy. Discussion: In tumors, p53 protein and index of proliferating cells as determined with MIB 1 showed a significant modulation after treatment, suggesting an association with sensitivity to chemotherapy. However, the limited number of our series of patients does not permit a statement on the clinical implication of expression of p53 and cell proliferation in patients undergoing neoadjuvant combination chemotherapy for locally advanced cervical carcinoma.

Influence of Neoadjuvant Polychemotherapy on Natural Killer Cell Activity in Patients with Locally Advanced Cervical Squamous Carcinoma

Peripheral blood natural killer (NK) cell activity against K562 tumor line was monitored in 16 patients with locally advanced squamous cervical carcinoma (II and III FIGO stages) during neoadjuvant polychemotherapy (cisplatin at 80 mg/m 2 and blemycin at 30 mg/m 2). There was a significant progressive decrease in NK activity during the three cycles of antiblastic treatment ( P = 0.008) without significant depletion of NK cell (CD56 and CD16 monoclonal antibody positive cell percentage and absolute number). A significant relationship was shown between basal NK activity levels and response to polychemotherapy; in fact, nonresponder patients had a significantly lower mean value of NK activity before polychemotherapy than responders ( P = 0.044). In conclusion, NK activity declines as a result of antiblastic therapy; although polychemotherapy reduces tumor spread, its antineoplastic action may be affected by this decreased immune reactivity.

The influence of hematogenous and serosal metastases on advanced (FIGO IIA-IVB) squamous cell carcinoma of the cervix.

Of 120 patients with FIGO stage IIA-IVB squamous cell carcinoma of the cervix treated with standard radiotherapeutic techniques, 41 (34.2%) relapsed with hematogenous or serosal metastases. Development of such metastases was individually associated with patient age less than or equal to 55, bilateral bulky parametrial extension, and histologically positive paraaortic nodes. Poor histologic differentiation exerted significant negative influence only in patients age less than or equal to 55. Neither surgical staging nor vascular injury predisposed to hematogenous dissemination. Radiotherapy techniques differed only in increased time to completion, from 84 to 100 days in clinical IIB and IIIB patients developing metastases. Local or regional pelvic recurrences, although associated with an increase in hematogenous or serosal metastases, were not accompanied by concomitant relapse in extrapelvic nodes. Twenty-six of 41 metastases were limited to single organ systems, with pulmonary sites most common (43.9%). A direct (non-nodal) route of hematogenous dissemination of 31% was documented within clinical stages IIA and IIB. One hundred percent concordance between bilateral bulky parametrial involvement and positive pretreatment paraaortic nodes occurred in clinical stage IIIB and IVA patients with metastatic relapse. Our data from the period 1976-1985 do not substantially differ from earlier reports on the incidence or distribution of hematogenous or serosal metastases, despite our implementation of contemporary local/regional radiotherapy prescriptions. The potential for hematogenous and serosal metastases in high-risk patients with advanced squamous cervical carcinoma merits consideration of alternative treatment protocols and precise definition of the role of pretreatment surgical staging procedures.