Posttreatment Squamous Cell Carcinoma Antigen Research Articles

Role of squamous cell carcinoma antigen (SCC-Ag) in the management of carcinoma cervix in an Indian population: A pilot study

BackgroundEarly detection of recurrence in carcinoma cervix can be challenging but has the potential to improve survival in a subset of patients. Squamous cell carcinoma antigen (SCC-Ag) has been tested in multiple roles in the management of cervical cancer but the evidence from India is limited. MethodsThis was a prospective, cohort pilot study conducted in a tertiary care hospital in central India. Study subjects were patients with locally advanced carcinoma cervix treated with concurrent chemoradiotherapy between June 2017 and May 2018. All patients underwent pre and post-treatment SCC-Ag testing which was continued serially every 3 months for a total follow-up of 24 months. A cut-off value of 1.5 ng/ml or more was used to define a positive test. Chi–Square tests, Pearson's correlation testing and Kaplan Meier plots were used to study the association of different patient and tumour variables with the SCC-Ag levels. Test validity of serial measurements of SCC-Ag was also measured for detection of recurrence. ResultsA total of 45 patients were included. SCC-Ag levels were strongly correlated with tumour stage and presence of lymph nodal metastases. Post-treatment abnormal SCC-Ag levels were significantly associated with a poorer recurrence-free survival (RFS). Serial measurement of SCC-Ag levels proved to be a good screening tool for early detection of recurrences even before clinical symptoms or signs developed with a sensitivity of 90% and specificity of 91.8%. ConclusionOur study has highlighted the benefits of the use of this tumour marker in the management of cervical cancer and has generated useful evidence supporting its use in prognosticating patients, guiding investigations, determining risk for recurrence, assessing tumour response and for early detection of recurrences.

Establishment of a risk stratification model based on the combination of post-treatment serum squamous cell carcinoma antigen levels and FIGO stage of cervical cancer for treatment and surveillance decision-making

ObjectiveTo develop a risk stratification model based on the International Federation of Gynecology and Obstetrics (FIGO) staging combined with squamous cell carcinoma antigen (SCC-Ag) for the classification of patients with cervical squamous cell carcinoma (CSCC) into different risk groups.MethodsWe retrospectively reviewed the data of 664 women with stage IIA–IVB CSCC according to the 2018 FIGO staging system who received definitive radiotherapy from March 2013 to December 2017 at the department of radiation oncology of Sun Yat-sen University Cancer Center. Cutoff values for continuous variables were estimated using receiver operating characteristic curve analysis. Using recursive partitioning analysis (RPA) modeling, overall survival was predicted based on the prognostic factors determined via Cox regression analysis. The predictive performance of the RPA model was assessed using the consistency index (C-index). Intergroup survival differences were determined and compared using Kaplan–Meier analysis and the log-rank test.ResultsMultivariate Cox regression analysis identified post-treatment SCC-Ag (< 1.35 ng/mL and > 1.35 ng/mL; hazard ratio (HR), 4.000; 95% confidence interval (CI), 2.911–5.496; P < 0.0001) and FIGO stage (II, III, and IV; HR, 2.582, 95% CI, 1.947–3.426; P < 0.0001) as the independent outcome predictors for overall survival. The RPA model based on the above prognostic factors divided the patients into high-, intermediate-, and low-risk groups. Significant differences in overall survival were observed among the three groups (5-year overall survival: low vs. intermediate vs. high, 91.3% vs. 76.7% vs. 29.5%, P < 0.0001). The predictive performance of the RPA model (C-index, 0.732; 95% CI, 0.701–0.763) was prominently superior to that of post-treatment SCC-Ag (C-index, 0.668; 95% CI, 0.635–0.702; P < 0.0001) and FIGO stage (C-index, 0.663; 95% CI, 0.631–0.695; P < 0.0001).ConclusionsThe RPA model based on FIGO staging and post-treatment SCC-Ag can predict the overall survival of patients with CSCC, thereby providing a guide for the formulation of risk-adaptive treatment and individualized follow-up strategies.

Clinical value of serum biomarkers, squamous cell carcinoma antigen and apolipoprotein C-II in follow-up of patients with locally advanced cervical squamous cell carcinoma treated with radiation: A multicenter prospective cohort study.

There are currently no reliable, established serum biomarkers to predict the prognosis of radiotherapy for advanced cervical cancer. We aimed to identify serum biomarkers for survival after radiotherapy for cervical cancer. In this multicenter prospective cohort study, the usefulness of pre- and posttreatment serum protein levels of potential biomarkers, including squamous cell carcinoma antigen (SCC-Ag), apolipoprotein C-II (ApoC-II), matrix metalloproteinase (MMP)1, and MMP2, were evaluated together with clinical factors in 145 cervical cancer patients in order to determine their suitability to predict survival. Progression-free survival (PFS) was the primary endpoint, and overall survival (OS), pelvic PFS (PPFS), and distant metastasis-free survival (DMFS) were the secondary endpoints. Blood samples were collected before and 1 month after radiotherapy to measure serum biomarker levels. ApoC-II was measured using a monoclonal antibody-based enzyme-linked immunosorbent assay, which was developed for this purpose. Kaplan-Meier method, log-rank test, and univariate and multivariate Cox proportional hazards models were used for statistical analyses. In multivariate analysis, larger tumor size was independently associated with shorter PFS, OS, PPFS, and DMFS, while longer overall treatment time was independently associated with shorter PPFS. Higher pretreatment SCC-Ag (P < 0.001) was associated with shorter DMFS. Higher posttreatment SCC-Ag (P = 0.017) was also associated with shorter DMFS. Pretreatment ApoC-II was associated with PPFS in univariate analysis (P = 0.048), but not in multivariate analysis. Patients with pretreatment ApoC-II levels ≤ 25.8 μg/ml had shorter PPFS than those with pretreatment ApoC-II levels > 25.8 μg/ml (P = 0.023, log-rank test). Pre- and posttreatment serum SCC-Ag and pretreatment serum ApoC-II levels may be important biomarkers to predict survival outcomes of patients with cervical cancer after radiotherapy. Pre- and posttreatment SCC-Ag and pretreatment ApoC-II might be useful in clinical settings for screening patients to improve treatment strategies in cervical cancer.

Rs2686344 and serum squamous cell carcinoma antigen could predict clinical efficacy of neoadjuvant chemotherapy for cervical cancer

ObjectiveTo evaluate the predictive value of a single nucleotide polymorphism (SNP) rs2686344 and squamous cell carcinoma antigen (SCCAg) levels in the clinical efficacy of neoadjuvant chemotherapy (NACT) for cervical cancer. MethodsA total of 92 patients with stage IB2-IIIB carcinoma of the uterine cervix who received NACT treatment were enrolled. The relationship between the genotypes of SNP rs2686344 which is located on CAMKK2 on chromosome 12, SCCAg levels and the response to NACT was analyzed. The relationship between the SNP rs2686344 genotypes, SCCAg levels, the response to NACT and the five-year survival rate was evaluated. ResultsThe effective group accounted for 84.85% in patients with low level (≤3.5 ng/mL) of post-treatment SCCAg (post-SCCAg), while the ineffective group accounted for 15.15%. The post-SCCAg levels and the genotypes of rs2686344 were significantly correlated with NACT response (P = 0.003, and P = 0.006). In patients with CC or CT genotype of SNP rs2686344, effective group accounted for 81.18%, while ineffective group accounted for 18.82%; For patients with TT genotype, effective response group accounted for 28.57%, ineffective group accounted for 71.43%. Post-SCCAg level >3.5 ng/mL and TT genotype of SNP rs2686344 showed as independent risk factors for NACT response in the multivariate analysis (P = 0.002, and P = 0.048). There was no significant difference in 5-year overall survival and 5-year disease-free survival between patients with different levels of post-SCCAg, or among different rs2686344 genotypes. ConclusionThe high level of post-SCCAg (>3.5 ng/mL) and TT genotype of rs2686344 may suggest a higher risk of poor response to NACT.

Posttreatment squamous cell carcinoma antigen predicts treatment failure in patients with cervical squamous cell carcinoma treated with concurrent chemoradiotherapy

ObjectiveTo analyze the association between posttreatment squamous cell carcinoma antigen (SCC Ag) and treatment failure in patients with cervical SCC treated with concurrent chemoradiotherapy (CCRT). MethodsWe reviewed patients with cervical SCC who were treated with definitive radiotherapy or CCRT between June 2012 and May 2015 at our institute. A receiver operating characteristic (ROC) curve was used to analyze the cutoff value of posttreatment SCC Ag in predicting treatment failure. Log-rank tests and Cox proportional hazards models were used to identify whether posttreatment SCC Ag was significant in predicting disease-free survival (DFS). ResultsA total of 559 patients were included in this study. With the ROC curve, the optimal cutoff posttreatment SCC Ag level was 1.8 ng/mL (sensitivity 27.1%, specificity 96.6%). A posttreatment SCC Ag level ≥ 1.8 ng/mL was observed in 47 patients. The multivariate analysis showed that posttreatment SCC Ag (hazard ratio 5.10; 95% confidence interval, 3.31–7.88; p < 0.001) was an independent prognostic factor of DFS. The 3-year overall survival (OS), DFS, local control, and distant control rates of patients with posttreatment SCC Ag < 1.8 ng/mL and ≥1.8 ng/mL were 90.7% and 46.4% (p < 0.001), 84.8% and 31.9% (p < 0.001), 81.4% and 69.5% (p < 0.001), and 90.4% and 54.1% (p < 0.001), respectively. ConclusionPatients with posttreatment SCC Ag ≥ 1.8 ng/mL suffer due to a high rate of treatment failure and poor survival.

Posttreatment Squamous Cell Carcinoma Antigen in Predicting Treatment Failure for Patients with Cervical Squamous Cell Carcinoma Treated with Concurrent Chemoradiotherapy

To analyze the association between posttreatment squamous cell carcinoma (SCC) antigen and treatment failure for patients with cervical SCC and treated with concurrent chemoradiotherapy (CCRT). We reviewed patients with cervical SCC and treated with definitive CCRT between June 2012 and May 2015 in our institute. A dose of 50.4Gy in 28 fractions was delivered to the pelvic with intensity modulated radiation therapy. With high-dose-rate brachytherapy, 30-36Gy in 5-7 fractions was prescribed to point A. The first line regimen of concurrent chemotherapy was cisplatin weekly. Posttreatment SCC antigen level was checked at 20 to 60 days after the completion of CCRT. A receiver operating characteristic (ROC) curve was performed to analyze the cutoff point of pretreatment and posttreatment SCC Ag in predicting treatment failure. Log-rank test and Cox’s proportional hazard model were used to identify whether pretreatment and posttreatment SCC Ag was significant in predicting disease-free survival (DFS). A total of 559 patients were included in this study. With ROC curve, the optimal cut-off points of pretreatment and posttreatment SCC antigen level were 8.6ng/ml (sensitivity 54.2%, specificity 65.8%) and 1.8 ng/ml (sensitivity 27.1%, specificity 96.6%). Posttreatment SCC antigen level ≥ 1.8ng/ml was observed in 47 patients. Multivariate analysis showed that posttreatment SCC Ag (hazard ratio 5.10, 95% confidence interval 3.31-7.88, p<0.001) was an independent prognostic factor of DFS. However, pretreatment SCC Ag was not significant in predicting DFS. The 3-year overall survival, DFS, local control and distant control rates of patients with posttreatment SCC antigen <1.8 ng/ml and ≥ 1.8 ng/ml were 90.7% and 46.4% (p<0.001), 84.8% and 31.9% (p<0.001), 81.4% and 69.5% (p<0.001), 90.4% and 54.1% (p<0.001), respectively. Cervical SCC patients with posttreatment SCC antigen ≥ 1.8ng/ml experienced high risk of treatment failure and poor survival. Consolidation therapy or extensive follow-up should be considered for these patients.

The predictive value of serum squamous cell carcinoma antigen in patients with cervical cancer who receive neoadjuvant chemotherapy followed by radical surgery: a single-institute study.

ObjectiveNeoadjuvant chemotherapy (NACT) could affect the levels of squamous cell carcinoma antigen (SCC-Ag). This study evaluates the predictive value of pre- and posttreatment SCC-Ag levels in patients with cervical cancer who were treated with NACT followed by radical surgery.MethodsA total of 286 patients with Stage IB1-IIIB squamous cell carcinoma of the uterine cervix who were treated with NACT followed by radical hysterectomy were analyzed retrospectively. The relationship between SCC-Ag levels, the clinicopathologic parameters, the response to NACT and the three-year survival rate was investigated.ResultsThe levels of SCC-Ag were elevated (>3.5 ng/mL) in 43.8% of patients before NACT, and 13.0% of patients after NACT. Pre- and posttreatment levels of SCC-Ag correlated with the response to NACT (P = 0.010, and P<0.001), deep stromal infiltration (P = 0.041, and P = 0.006), and lymph node status (P<0.001, and P<0.001). In the multivariate analysis, the elevated pretreatment level of SCC-Ag was demonstrated to be an independent risk factor for Lymph node metastases (P<0.001). Patients with both pre- and posttreatment SCC-Ag levels ≤3.5 ng/mL showed the best 3-year disease-free survival (DFS) and 3-year overall survival (OS) compared with patients with either pre- or posttreatment levels >3.5 ng/mL (P<0.001, and P<0.001, respectively). A multivariate analysis showed that posttreatment SCC-Ag levels were a strong independent predictor of OS (P = 0.001) and DFS (P = 0.012).ConclusionElevated pretreatment levels of SCC-Ag (>3.5 ng/mL) indicated a poor response to NACT and a higher risk of lymph node metastases. Elevated posttreatment levels of SCC-Ag were correlated with poor DFS and OS.

The prognostic value of squamous cell carcinoma antigen for predicting tumor recurrence in cervical squamous cell carcinoma patients.

ObjectiveThe aim of this study was to evaluate the prognostic value of squamous cell carcinoma antigen (SCC-Ag) and the optimal cut-off value for predicting recurrence in cervical squamous cell carcinoma patients with complete remission after primary treatment.MethodsWe reviewed the records of 783 cervical squamous cell cancer patients who underwent primary therapy and showed complete remission at our institution between January 2000 and April 2014. A receiver operating characteristic curve was used to determine the optimal SCC-Ag threshold to predict recurrence. Cox regression model for disease free survival was used to assess differences in outcome.ResultsThe median follow-up period was 41.2 months, and 154 patients (19.7%) had recurrent disease. The median pretreatment and posttreatment SCC-Ag level was 2.6 ng/mL (range, 0.1 to 532.0 ng/mL) and 0.7 ng/mL (range, 0.0 to 46.8 ng/mL), respectively. Both pretreatment and posttreatment SCC-Ag levels were higher in the recurrence group (P=0.017 and P=0.039). Optimal cut-off value of pretreatment and posttreatment SCC-Ag for predicting recurrence was 1.86 ng/mL (area under the curve, 0.663; P=0.000), and 0.9 ng/mL (area under the curve, 0.581; P=0.002), respectively. In the multivariate Cox regression model, pretreatment SCC-Ag >1.86 ng/mL (odds ratio, 2.11; 95% confidence interval, 1.38 to 3.22; P=0.001) and posttreatment SCC-Ag >0.9 ng/mL (odds ratio, 1.64; 95% confidence interval, 1.18 to 2.28; P=0.003) were significantly associated with poor disease free survival.ConclusionPatients with pretreatment SCC-Ag >1.86 ng/mL or posttreatment SCC-Ag >0.9 ng/mL should be considered at high risk for cancer recurrence after complete remission, and therefore, closer surveillance is needed.

Posttreatment cut-off levels of squamous cell carcinoma antigen as a prognostic factor in patients with locally advanced cervical cancer treated with radiotherapy

ObjectiveThe aim of the present study was to assess prognostic factors for patients with locally advanced cervical cancer treated with radiotherapy as the primary treatment and to assess the posttreatment cut-off levels of squamous cell carcinoma antigen (SCC-Ag) to predict three-year overall survival (OS) rates.MethodsOne hundred and twenty-eight patients with cervical squamous cell carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage IIB-IVA) treated using radiotherapy or concurrent chemoradiotherapy were identified. Of these patients, 116 who had SCC-Ag levels >1.5 ng/mL prior to treatment were analyzed retrospectively.ResultsMedian age was 68 years (range, 27 to 79 years). The complete response rate was 70.7% and the three-year OS rate was 61.1%. The median levels of pretreatment and posttreatment SCC-Ag were 11.5 ng/mL (range, 1.6 to 310.0 ng/mL) and 0.9 ng/mL (range, 0.4 to 41.0 ng/mL), respectively. Multivariate analysis showed that pretreatment anemia (p=0.041), pelvic lymph node metastasis (p=0.016) and posttreatment SCC-Ag levels (p=0.001) were independent prognostic factors for three-year OS. The SCC-Ag level cut-off point for three-year OS rates, calculated using a receiver operating characteristic curve, was 1.15 ng/mL (sensitivity, 80.0%; specificity, 74.0%).ConclusionPretreatment anemia and pelvic lymph node metastasis are poor prognostic factors in locally advanced cervical cancer. Furthermore, posttreatment SCC-Ag levels <1.15 ng/mL predicted better three-year OS rates.

Correlation between the levets of serum squamous carcinoma antigen and the prognosis of cervical squamous carcinoma

Objective To analyze the correlation between the levels of squamous cell carcinoma antigen (SCCAg)and the clinicopathological characteristics of patients with cervical squamous carcinoma.To study the relationship of serum SCCAg levels of patients with recurrent cervical squamous carcinoma and disease prognosis and to investigate the survival rate of patients with recurrent cervical squamous carcinoma.Method ELISA method was used to determine the serum SCCAg levels for the patients,which included 300 cases before treatment and 500 cases after treatment.Results(1)Single factor analysis indicated that,before the treatment,the serum SCCAg levels were closely related to clinical stages,lymphatic metastasis,and deep myometrial invasion (t =3.01,P ＜ O.05 ; t =6.81,P ＜ 0.001 ; t =3.01,P ＜ 0.05 ; respectively).However,they were not related to patient's age,vascular embolization and tumor growth type(t =0.77,t =1.12,t =1.06 ; respectively,all P ＞ 0.05).Multifactor logistic regression analysis showed that the pretreatment SCCAg levels of patients were related to clinical stages,cavum pelvis lymphatic metastasis and myometrial invasion(x2 =2.88,P =0.0084; x2 =2.612,P =0.0156; x2 =2.570,P =0.0171 ; respectively).(2)Overall,recurrent disease developed in 180 of the 500 patients with cervical squamous carcinoma.One hundred and sixty-one recurrent patients showed elevated SCCAg levels(161/180,89.4％).For the 60 patients who showed elevated.SCCAg levels without any clinical symptoms as well as no sign of tumors by iconography,the median time for signs of elevating levels of serum SCCAg was 2.3 months.The longest time range was 150d between the increasing levels of the tumor markers and the appearance of the imaging features of pachygyria while the patients condition was going on.The 160 patients out of the 180 cases with recurrent cervical squamous carci noma who were followed up had a median survival time of 9 months,with an average of 20 months.The total 3 year survival rate and 5 year survival rate was respectively 23.4％ and 17.8％.(3)Single factor analysis indicated that recurrent patients’clinical stages,recurrent region and recurrent post treatment SCCAg levels were closely related with patients' survival time(x2 =10.26,P＜0.005; x2 =14.65,P ＜0.005; x2 =8.97,P＜0.01; respectively).There was no statistical difference between the survival rate of recurrent patients with increased SCCAg level and patients without increased SCCAg levels(x2 =0.89,P ＞ 0.05).Multiple factor analysis indicated that the clinical stages,recurrent post treatment SCCAg levels of patients with recurrence were independent prognostic factors(x2 =10.3372,P =0.0013 ; x2 =4.3889,P =0.0362; respectively).Conclusion The pretreatment SCCAg levels are closely related to patients'clinical stages,cavum pelvis lymphatic metastasis and deep myometrial invasion.Serum SCCAg levels are important for the advanced detection of cervical squamous carcinoma recurrence and prognosis prediction. Key words: Uterine cervical neoplasms; Neoplasms,squamous cell; Prognosis; Squamous cell carcinoma antigen

The clinical values of squamous cell carcinoma antigen and carcinoembryonic antigen in patients with cervical cancer treated with concurrent chemoradiotherapy

The objective of this study was to determine the prognostic significance of the pre- and posttreatment serum levels of the squamous cell carcinoma antigen (SCC-Ag) and carcinoembryonic antigen (CEA). From 2001 to 2005, 211 patients were treated with concurrent chemoradiotherapy (CCRT). The SCC-Ag and CEA levels were measured before treatment, 1 month after treatment, and during the follow-up. The association between the pretreatment tumor marker levels and the clinical prognostic factors was evaluated. The frequency of complete remission (CR) and the normalization of the posttreatment tumor marker were also analyzed. The pretreatment serum levels of CEA and SCC-Ag were elevated in 68 (32.2%) and 148 (70.1%) patients, respectively. The number of patients with an elevated pretreatment SCC-Ag level was associated with the FIGO stage, tumor volume, and pelvic lymph node status. The pretreatment CEA was only significantly related to the tumor volume and pelvic lymph node involvement. One month after completing CCRT, the CEA and SCC-Ag levels were normalized in almost all patients with an incidence of 88.2% (60/68) and 93.2% (138/148), respectively. Among the patients who gained CR with a previously elevated pretreatment CEA and SCC-Ag, the values were normalized in 92.1% (58/63) and 96.4% (134/139) at 1 month, respectively. Combination assays of the pre- and posttreatment serum CEA and SCC-Ag levels appear to be useful for both predicting the prognosis and estimating the clinical response in cervical cancer. However, the routine combined measurement with SCC-Ag of CEA in all patients had limited additional effect in predicting the prognostic significance.

595. Combination Tissue Specific SCC Antigen Promoter with CD/5-FC Gene Therapy Enhances Killing of Human Uterine Cervical Cancer Cells by Radiation

Background: Cervical caner is the leading cause of female cancer death worldwide. The squamous cell carcinoma (SCC) antigen was isolated first from uterine cervical SCC tissue in 1977. SCC antigen is a serologic tumor marker for patients with squamous cell carcinoma of the cervix. Serum concentrations of this marker correlate well with stage of disease, the presence or absence of risk factors, the effect of treatment, and the course of the disease. Moreover, the measurement of posttreatment SCC antigen levels is useful for monitoring the response to therapy and for predicting tumor recurrence and metastasis. In advance or recurrence cervical cancer, radiation with chemotherapy including 5-FU is used clinically. However, the morbidity is relative high. Gene therapy combined with radiation represents a new approach to cervical cancer treatment. In the present study, we investigated whether adenovirally directed, SCC antigen promoter with cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy could induce cell toxicity and radiosensitization through the intracellular production of 5-fluorouracil (5-FU) in uterine cervical cancer.

The role of squamous cell carcinoma antigen in the management of laryngeal and hypopharyngeal cancer

The efficacy of squamous cell carcinoma antigen (SCC-Ag) in laryngeal cancer to predict those patients who will relapse after primary treatment (surgery or radiotherapy) and its utility to detect relapses early and thereby increase salvage rates and cure were assessed. Sixty healthy donors and 168 patients with laryngeal cancer were included in this prospective trial. Squamous cell carcinoma antigen was measured at diagnosis in all patients, 24 hours and 1 week after surgery in 113 patients and every 10 Gy of administered dose and 2 weeks after treatment in 49 patients primarily referred to radiotherapy. The marker was determined every 3-6 months during follow-up. All patients who relapsed had SCC-Ag studies before and after salvage treatment. The selected cut-off value was 1.5 ngr/ml (mean value in control group, 0.65 + 2 standard deviation [0.38]). Seventy-eight percent of patients with cancer had elevated SCC-Ag values at diagnosis. Squamous cell carcinoma antigen was statistically related to TNM categories (T, P < 0.04; N, P < 0.05; Stage, P < 0.01). Seventy-five percent of those patients with previously elevated pretreatment values normalized after treatment. Incomplete surgical resection (P < 0.0001) or persistence of the disease after radiotherapy (P < 0.01) were related to high posttreatment values. Squamous cell carcinoma antigen was elevated in 88% of the patients who relapsed. In 55% of the recurrences, SCC-Ag was elevated 3 months before pathologic confirmation of relapse. Salvage by surgery or radiotherapy was effective in 70% of the patients. Squamous cell carcinoma antigen posttreatment values were the most important factor in predicting disease free survival (DFS) (P < 0.0001) and overall survival (P < 0.03). Squamous cell carcinoma antigen is an excellent marker of residual disease after primary treatment that can lead to the addition of other therapeutic procedures (surgery and postoperative radiotherapy). The absence of posttreatment SCC-Ag is the best predictor of DFS, its presence detects recurrence in early stages, permitting salvage of an increased proportion of patients primarily referred for palliative treatment.