CA-125 can be part of the tumour evaluation criteria in ovarian cancer trials: experience of the GCIG CALYPSO trial

Background:

CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression.

Methods:

In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin–paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression.

Results:

In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66–1.10) and 0.84 (95% CI: 0.72–0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment.

Conclusion:

CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.     

The role of CA 125 in the early diagnosis of progressive disease in ovarian cancer

The role of CA 125 determination in diagnosing progression of ovarian cancer was evaluated in 98 patients of whom forty-nine had progressive disease. An elevated CA 125 level at the time of progression was found in 36 (73%) patients. In 31 (63%) patients CA 125 increase preceded clinical progression for a median time lag of 4.5 months (range 0.5-29.5 months). The combination of serum CA 125, gynecological and general physical examination detected progression in 45 (92%) patients. The additional contribution of second-look surgery, CTscan, chest X-ray and routine laboratory tests was minimal.     

Dedifferentiation in the metastatic progression of prostate carcinoma.

BACKGROUND: Dedifferentiation is a distinctive feature of cancer progression. Detailed histologic analysis of primary prostate carcinoma and synchronous lymph node metastases may improve our understanding of the complex process of cancer progression and metastasis. METHODS: The authors studied 242 regional lymph node positive prostate carcinoma patients who underwent radical prostatectomy and bilateral lymphadenectomy between 1987 and 1992 at the Mayo Clinic. Patients ranged in age from 47-79 years (median, 66 years). The median follow-up was 6.1 years. Gleason scores of lymph node metastases and primary tumors were compared and correlated with systemic disease progression. Histologic dedifferentiation was defined as a higher Gleason grade in the lymph node metastases than in the primary tumor. Systemic disease progression was defined as the presence of distant metastases documented by biopsies, abdominal computed tomography, plain radiograph, or bone scan. RESULTS: The 5-year systemic progression free survival (PFS) rate was 90%. The Gleason score in the lymph node metastases was higher than in the primary tumor in 45% of patients, lower in 12% of patients, and matched exactly in 43% of patients. The 5-year PFS was significantly different between patients with histologic dedifferentiation (88% +/- 3) and those without dedifferentiation (94% +/- 2) (P = 0.04). Adjusting for the Gleason grade of the primary tumor and total lymph node tumor volume, the relative risk for disease progression associated with dedifferentiation was 1.8 (95% confidence interval, 0.7-4.7; P = 0.25). CONCLUSIONS: The findings of the current study demonstrate the morphologic heterogeneity of metastases from prostate carcinoma. There is a trend toward histologic dedifferentiation when prostate carcinoma metastasizes to regional lymph nodes. This dedifferentiation, although univariately significant, was not associated with disease progression when adjusted for lymph node tumor volume.     

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder

Background:

The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients.

Methods:

We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models.

Results:

With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients.

Conclusion:

The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.     

Disruptive events in the life of prostate cancer

Two recent reports in Nature provide evidence for increasingly complex "disruptive" molecular alterations that occur during prostate cancer progression. They shed light on the intricacy of genetic changes that modulate PTEN's control over the phosphoinositide 3-kinase pathway and prostate cancer progression, and identify new potential biomarkers and therapeutic targets.     

Recommendations for the assessment of progression in randomised cancer treatment trials

Progression-free survival (PFS) is an increasingly important end-point in cancer drug development. However, several concerns exist regarding the use of PFS as a basis to compare treatments. Unlike survival, the exact time of progression is unknown, so progression times might be over-estimated (or under-estimated) and, consequently, bias may be introduced when comparing treatments. In addition, the assessment of progression is subject to measurement variability which may introduce error or bias. Ideally trials with PFS as the primary end-point should be randomised and, when feasible, double-blinded. All patients eligible for study should be evaluable for the primary end-point and thus, in general, have measurable disease at baseline. Appropriate definitions should be provided in the protocol and data collected on the case-report forms, if patients with only non-measurable disease are eligible and/or clinical, or symptomatic progression are to be considered progression events for analysis. Protocol defined assessments of disease burden should be obtained at intervals that are symmetrical between arms. Independent review of imaging may be of value in randomised phase II trials and phase III trials as an auditing tool to detect possible bias.     

Karyometry in the early detection and chemoprevention of intraepithelial lesions

The ideal chemopreventive agent targets pre-neoplastic changes and intraepithelial neoplasia, preventing progression over time without notable side effects. Assessment of success of chemopreventive intervention in the short and medium term remains a challenge, and in this review the suggestion is investigated that karyometric measurements constitute suitable markers of chemopreventive efficacy. Karyometry provides the sensitivity required to detect small differences amidst relatively high biological variability. It can help establish progression curves of intraepithelial neoplasia (IEN) to invasive cancer, and thus detect chemopreventive effects. Such effects can be observed in two ways, at the group level (intervention vs. placebo), and at the case (or patient) level. The latter is more difficult to establish, necessitating the development of specialised statistical methods. Analysis of between-case and within-case heterogeneity can reveal useful information about cancer progression and prevention. We suggest that karyometry can objectively quantify IEN progression, providing a framework for statistically securing chemopreventive effects. It can act as an integrating biomarker by detecting chemopreventive activity even when the mechanism for a given progression pathway is unknown, or when multiple pathways exist. The sensitivity of karyometric detection can help optimise the design of clinical trials of novel chemopreventive agents by decreasing trial duration and/or sample size.     

Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases

BackgroundThe GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13.MethodsWe conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain.ResultsWith a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy.ConclusionsBrain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2–3 months of chemotherapy.     

Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression

Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin (IL)-1beta promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity. If inflammation-induced MDSC promote tumor progression by blocking antitumor immunity, then a reduction in inflammation should reduce MDSC levels and delay tumor progression, whereas an increase in inflammation should increase MDSC levels and hasten tumor progression. We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced potential for inflammation, and IL-1R antagonist-deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R-deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC. In contrast, excessive inflammation in IL-1R antagonist-deficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity. These results show that immune suppression by MDSC and tumor growth are regulated by the inflammatory milieu and support the hypothesis that the induction of suppressor cells which down-regulate tumor immunity is one of the mechanisms linking inflammation and cancer.     

Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors

Leukocytes, and macrophages in particular, are an important component of the stroma of neoplastic tissues. Tumor-associated macrophages (TAM) have the properties of a polarized M2 population and are a key component of inflammatory circuits which promote tumor growth and progression. Chemokines play a key role in the recruitment and positioning of TAM and dendritic cells in tumors and contribute to shaping their functional properties. Chemokine-recruited and positioned tumor infiltrating leukocytes are a key component of inflammatory circuits which promote tumor progression.     

血浆EBV DNA监测鼻咽癌治疗疗效意义

目的 探讨血浆EBV DNA监测鼻咽癌治疗疗效的临床意义。方法 回顾分析2016-2017年间本院初诊的799例鼻咽癌根治性调强放疗患者的临床资料。分析疗前血浆EBV DNA与临床分期、肿瘤进展的相关性,比较放疗结束及随访中EBV DNA与肿瘤进展的关系。结果 疗前DNA表达水平与临床分期、肿瘤进展呈正相关(P<0.001)。放疗结束后6~8周,19例(2.3%)血浆EBV DNA持续阳性者预后最差,14例发生了肿瘤进展。9例放疗结束后6~8周转为EBV DNA阴性,3例肿瘤进展。而放疗结束EBV DNA阴性患者肿瘤进展率仅8.3%(64/772),3个组无肿瘤进展生存率不同(P<0.05)。随访中持续性血浆EBV DNA阳性,诊断肿瘤进展的敏感性、特异性、准确性分别为77.6%、100%、98.1%。结论 鼻咽癌患者疗前EBV DNA表达水平与肿瘤负荷和肿瘤进展相关,放疗结束6~8周EBV DNA持续阳性者预后极差,应给予合适的辅助治疗。随访中持续性血浆EBV DNA阳性诊断肿瘤进展的正确性高,是鼻咽癌根治性治疗后可靠的疗效监测指标。     

血浆EBV DNA监测鼻咽癌治疗疗效意义

目的 探讨血浆EBV DNA监测鼻咽癌治疗疗效的临床意义。方法 回顾分析2016-2017年间本院初诊的799例鼻咽癌根治性调强放疗患者的临床资料。分析疗前血浆EBV DNA与临床分期、肿瘤进展的相关性,比较放疗结束及随访中EBV DNA与肿瘤进展的关系。结果 疗前DNA表达水平与临床分期、肿瘤进展呈正相关(P<0.001)。放疗结束后6~8周,19例(2.3%)血浆EBV DNA持续阳性者预后最差,14例发生了肿瘤进展。9例放疗结束后6~8周转为EBV DNA阴性,3例肿瘤进展。而放疗结束EBV DNA阴性患者肿瘤进展率仅8.3%(64/772),3个组无肿瘤进展生存率不同(P<0.05)。随访中持续性血浆EBV DNA阳性,诊断肿瘤进展的敏感性、特异性、准确性分别为77.6%、100%、98.1%。结论 鼻咽癌患者疗前EBV DNA表达水平与肿瘤负荷和肿瘤进展相关,放疗结束6~8周EBV DNA持续阳性者预后极差,应给予合适的辅助治疗。随访中持续性血浆EBV DNA阳性诊断肿瘤进展的正确性高,是鼻咽癌根治性治疗后可靠的疗效监测指标。     

Individual variation and dose dependency in the progression rate of skin telangiectasia

The progression rate of late skin telangiectasia after radiotherapy has been studied prospectively in patients for various fractionation schedules and dose levels. The degree of telangiectasia was scored on an arbitrary scale ranging from no detectable to totally confluent telangiectasia. Skin telangiectasia showed a progressive development at least up to 10 years. The rate of progression was strongly dose dependent. This finding has two important implications: the dose-latency relationship is steep, and the steepness of the dose-response relationship increases with the follow-up time. The most striking finding in this study was that the individual variation in progression rate was very large for the same treatment with a documented small variation in dose. For example, the latency for telangiectasia score 2 ranged between 17 and 90 months after 35 fractions of 1.8 Gy. The reasons for the large individual variation in progression rate are unclear and will be investigated further.     

EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung

Introduction

Recent data show that EGFR pathway and its inhibition maintain their role after progression of disease during EGFR TKI therapy in NSCLCs. We conducted a retrospective study with the aim of evaluating efficacy and feasibility of prosecution of EGFR TKI therapy beyond focal progression associated to locoregional radiotherapy.

Methods

We retrospectively analyzed the data of all NSCLC patients treated with EGFR TKIs in our institution from 2004 to 2012. We included in the analysis patients that after a focal disease progression, meant as a single lesion RECIST progression, have been treated with definitive locoregional radiotherapy, associated to continuation of EGFR TKI therapy until further progression.

Results

15 out of 147 patients (10%) satisfied inclusion criteria. The median progression free survival, measured from the date of focal progression until further progression of disease or death by any cause, was 10,9 months (range 3–32 months). The corresponding 6 and 12 months PFS rates were 73% and 33%, respectively.

Conclusion

The longer disease control observed in our patients suggests that continuation of EGFR TKI beyond focal progression associated to a locoregional treatment is an efficacious therapeutic strategy.     

Burden of pancreatic cancer and disease progression: economic analysis in the US

OBJECTIVES: The few studies that have estimated the costs of pancreatic cancer were limited by small sample sizes, geography or patient age range. Using a large nationwide claims database, this study examines the cost of pancreatic cancer beginning with initial diagnosis and the additional costs when disease progresses. METHODS: A retrospective cohort study was conducted using a claims database of 3 million individuals covered by large US employers. The study population consisted of patients newly diagnosed with pancreatic cancer in 1999-2000 and a demographically matched control group. Utilization and costs were summarized as monthly means. Changes in cancer severity and treatment over time were used to approximate disease progression and its associated costs. RESULTS: The study included 412 pancreatic cancer patients and 1,236 controls. The mean follow-up time was 7.5 months. Regression-adjusted monthly costs attributable to pancreatic cancer were USD 7,279; over 60% resulted from hospitalizations. Patients with disease progression (over 50%) incurred an additional USD 15,143 per month compared to patients without disease progression. CONCLUSION: Compared to patients without cancer, the costs of pancreatic cancer patients were substantial, especially when patients experienced disease progression. New therapies that prevent or delay disease progression could potentially offset the costs to patients, providers and society.     

Use of Different Outcome Measures in Randomised Studies of Malignant Glioma can Significantly Alter the Interpretation of Time to Progression: Reanalysis of the MRC BR2 Study

The Medical Research Council (MRC) BR2 study [1] is a randomised trial of two doses of cranial radiation for patients with malignant glioma. We reanalysed data to examine the effect of using change in ranked scales of neurological status (MRC Neurological Status Scale) and performance (World Health Organisation Scale: WHO) to determine progression rather than clinician's impression.Four hundred and seventy four patients were studied. Where clinicians recorded no progression, ranked scales frequently documented progression (MRC 13%; WHO 13%). Where clinicians recorded progression, ranked scales frequently did not alter (MRC 33%; WHO 30%) or occasionally improved (MRC 5%; WHO 3%). When analysing time to progression based on a variety of measures, the estimated difference between treatments was most extreme (hazard ratio 0.81, logrank p=0.04) when change in WHO status was used, and least extreme when change in MRC neurological status was used (hazard ratio 0.99, p=0.94).This study highlights how different outcome measures can significantly alter the interpretation of randomised studies.     

The role of the androgen receptor in the development and progression of bladder cancer

Men are at a higher risk of developing bladder cancer than women. Since bladder cancer cell lines and tissues were found to express the androgen receptor, efforts have been made to inspect whether androgen-mediated androgen receptor signals are implicated in bladder carcinogenesis as well as cancer progression. Mounting evidence supports the view that bladder cancer is a member of the endocrine-related tumors and may clearly explain the gender-specific difference in the incidence. However, the underlying mechanisms of how androgen receptor signals regulate bladder cancer growth are still far from fully characterized. Moreover, it remains controversial whether the androgen receptor pathway always plays a dominant role in bladder cancer progression. In this review, we summarize the available data on the involvement of androgen receptor signaling in bladder cancer. In particular, current evidence demonstrating the stimulatory effects of androgens on tumor progression or, more convincingly, tumorigenesis via the androgen receptor pathway may offer great potential for androgen deprivation as a therapeutic or chemopreventive option in patients with bladder cancer.     

晚期肺癌奥西替尼获得性耐药进展模式及挽救治疗效果分析

目的探讨伴有表皮生长因子受体(EGFR)敏感突变或经酪氨酸激酶抑制剂(TKI)治疗后T790M突变的肺癌晚期患者接受奥西替尼治疗后的耐药进展模式以及挽救治疗方法和效果。方法收集2017年4月(奥西替尼在中国获批时)至2019年5月在江苏省肿瘤医院采用奥西替尼治疗的145例晚期肺癌患者资料。截至2019年12月最后一次随访,共87例(60.0%)患者发生奥西替尼获得性耐药,其中61例(70.1%)接受挽救治疗,对于耐药后爆发性进展者挽救治疗以化疗为主,对于耐药后缓慢进展或局部进展者,继续靶向药物治疗,并予局部治疗。采用影像学评价及Kaplan-Meier法分析奥西替尼获得性耐药的进展模式及生存情况,比较不同挽救治疗的效果。结果61例挽救性治疗患者中位随访11个月(4~32个月),其中58例(95.1%)出现了奥西替尼再次耐药,24例(39.3%)死于肺癌进展。61例挽救治疗患者的中位无进展生存(PFS)时间为2.5个月(95%CI 2.1~3.0个月);中位总生存(OS)时间为19.0个月(95%CI 13.7~26.3个月),1、2年OS率分别为72.1%和41.7%。61例挽救治疗患者中,爆发性进展、缓慢进展及局部进展分别为8例(13.1%)、30例(49.2%)及23例(37.7%)。在接受适当的挽救治疗后,爆发性进展、缓慢进展及局部进展患者间PFS及OS差异均无统计学意义(均P>0.05)。进展后接受局部治疗(24例)与未接受局部治疗(37例)患者间PFS及OS差异均无统计学意义(均P>0.05)。58例挽救治疗后再次耐药患者中仅6例(10.3%)在挽救治疗后获得超过6个月的PFS,均为缓慢进展或局部进展患者。结论奥西替尼获得性耐药在临床类型上可以表现为爆发性进展、缓慢进展及局部进展,挽救治疗效果欠佳。     

肿瘤组织中B7-H4的表达及意义

B7-H4是共刺激分子B7家族的新成员,B7-H4通过抑制T细胞的增殖、细胞因子的产生和细胞周期的进行对T细胞免疫进行负调控.近期研究表明,B7-H4与肿瘤的发生发展有着密切关系,是肿瘤诊断和治疗的重要指标.