Radiographic and serologic response in patients with unresectable hepatocellular carcinoma receiving systemic antineoplastic treatments: A trial-level analysis.

BACKGROUND: In a disease like unresectable hepatocellular carcinoma, overall survival is an inadequate outcome measure for evaluating the effectiveness of treatments given the high risk of death from liver failure. There is an unmet need for reliable alternative end points for clinical trials and daily clinical practice. To evaluate treatment response in patients with unresectable or metastatic hepatocellular carcinoma (mHCC), imaging-related end points are often used, whereas serologic end points have been developed for patients with serum alpha-fetoprotein levels >20 ng/mL. The objective of this study was to evaluate clinical trials that report concomitant assessment of radiographic and serologic response in patients with mHCC. METHODS: After a systematic review, studies that evaluated response according to radiographic and serologic criteria were selected. A correlation between progression-free survival (PFS) and overall survival (OS) was performed, and a linear regression of each response-related outcome measure with OS was reported. Finally, the effect of eight baseline variables on OS and response-related measures was evaluated. RESULTS: Twenty-six studies were included, including 16 first-line studies and 10 second-line studies. PFS and response rates demonstrated a significant relationship with OS, whereas disease control rates did not. The responses were correlated with OS, particularly in the first-line setting, after targeted therapy, and whenever assessment was early. Among the baseline variables, only performance status had a prognostic role, whereas hepatitis B virus-related liver disease was associated with higher radiographic response rates. CONCLUSIONS: PFS and radiographic and serologic response rates appear to be reliable intermediate end points in patients with mHCC who are undergoing systemic antineoplastic therapy. However, the serologic response is available earlier.

Myocardial bridge in a patient with castration-resistant metastatic prostate cancer treated with enzalutamide.

INTRODUCTION: Myocardial bridge is a morphological anomaly of the heart characterised by the presence of a myocardial segment above a coronary artery, which results in a higher risk of cardiovascular events. In patients with prostate cancer treated with androgen receptor-targeted agents, a higher risk of cardiotoxicity was observed. CASE REPORT: An 88 years old man with metastatic castration-resistant prostate cancer in treatment with enzalutamide, denosumab, and triptorelin presented to our attention complaining dyspnoea and angina pectoris. MANAGEMENT AND OUTCOME: Blood examinations revealed normal Troponin I levels. Transthoracic echocardiography revealed no signs of acute myocardial ischaemia. The treadmill stress test revealed S-T tract under levelling in V4-V6 with a very slow resolution. Coronary angiography identified a myocardial bridge in the medium tract of the interventricular anterior artery. Due to these findings, ranolazine and simvastatin were started and, after multidisciplinary assessment, we decided to continue the treatment with enzalutamide. At the first follow-up visit echocardiography found out the cardiological reports stability and no therapy changes were performed. During follow-up visit cardiological revaluation showed reports stability and no therapy changes were performed. DISCUSSION: Due to the high prevalence of prostate cancer in elderly patients at high cardiovascular risk and the increasing use of androgen receptor-targeted agent, a multidisciplinary approach is highly recommended to weigh survival benefits on toxicities. This case report may support the use of androgen receptor-targeted agent in elderly patients with controlled cardiovascular diseases, a population that is often excluded from randomised trials.

Causes of deaths in long-term care and hospice care facilities during the first year of COVID-19 pandemic: a snapshot of Italy during 2020.

BACKGROUND: Older adults living in long-term care facilities (LTCF) have been severely affected by COVID-19. Hospice care (HC) facilities and palliative care are essential in treating patients dying from COVID-19. In Italy, little is known about the impact of COVID-19 on deaths in LTCF and the care provided in HC to COVID-19 patients. AIM: To assess overall and case-specific mortality in 2020 in LTC and HC facilities in comparison to the previous five years (2015-2019). METHODS: We performed a descriptive study using data derived from the Italian national "Cause of Death" registry-managed by the Italian National Institute of Statistics-on deaths occurred in LTC and HC facilities during 2020 and the period 2015-2019. RESULTS: Number of deaths significantly increased in 2020 compared with 2015-2019 in LTCF (83,062 deaths vs. 59,200) and slightly decreased in hospices (38,788 vs. 39,652). COVID-19 caused 12.5% of deaths in LTCF and only 2% in hospices. Other than COVID-19, in 2020, cancer accounted for 77% of all deaths that occurred in HC, while cardiovascular diseases (35.6%) and psychotic and behavioral disorders (10%) were the most common causes of death in LTCF. Overall, 22% of the excess mortality registered in Italy during 2020 is represented by the deaths that occurred in LTCF. DISCUSSION AND CONCLUSION: LTCF were disproportionally affected by COVID-19, while the response to the pandemic in HC was limited. These data can help plan strategies to limit the impact of future epidemics and to better understand residential care response to COVID-19 epidemic.

Contact skin radiotherapy (brachytherapy) for the treatment of non-melanoma skin cancers during COVID-19 pandemic.

In the context of the SARS-CoV-2 pandemic, it is important to ensure the quality of cancer treatment as well as patients and health professionals' safety. Individual-based treatment options should be considered in patients with advanced epithelial skin cancer, who are typically elderly and frail. Aim of this study was to assess feasibility and safety of Contact Skin Radiation Therapy (CSRT) to treat basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) during SARS-CoV-2 pandemic. Patients with advanced and difficult-to-treat BCC or SCC were discussed at skin multidisciplinary tumor board (S-MDTB) from February the 21st to May the 4th (phase 1 Italian Pandemic) and retrospectively analyzed. Patient's triage following internal recommendations was daily performed. CSRT was delivered in 8 fractions of 5 Gy each, twice a day. Beyond the clinical outcomes, treatment success indicators, such as the completion of CSRT without SARS-CoV-2 occurrence, were identified to evaluate the feasibility of CSRT during pandemic. A post-treatment psychological assessment regarding patient's safety perception was performed. Six male patients (median age 80 years; range 62-92) with histologically confirmed BCC or SCC were treated with CSRT. Complete clinical remission was achieved in 5/6 patients (83.4%). No high-grade acute toxicities occurred during treatment. No patients or healthcare personnel developed SARS-CoV-2 infection. All the treatment success indicators were achieved. CSRT represents a safe, and feasible treatment option even during the pandemic emergency period. Hypofractionation could be an option to reduce total number of fractions and, consequently, infective risk exposition.

Clinical impact of SARS-CoV-2 infection among patients with vulvar cancer: the Gemelli Vul.Can multidisciplinary team.

BACKGROUND: 'Severe acute respiratory syndrome coronavirus-2' (SARS-CoV-2) infection has dramatically affected the management of patients with cancer, who are most vulnerable to the consequences of the infection. Patients with vulvar cancer are frequently elderly and affected by multiple co-morbidities, thus representing a particularly frail population. OBJECTIVE: To assess the clinical impact of the SARS-CoV-2 infection among patients scheduled for treatment for active vulvar cancer. METHODS: Data on patients with vulvar tumors referred to Fondazione Policlinico Universitario Agostino Gemelli IRCCS between February 2020 and July 2021 were retrospectively analyzed. Patients with a positive reverse transcription polymerase chain reaction in nasopharyngeal swab were considered as positive for SARS-Cov-2. RESULTS: One hundred and ninety-one patients with vulvar cancer were evaluated and scheduled for treatment. The median age was 72 years (range 35-94). Seven (3.7%) patients were diagnosed with SARS-Cov-2 infection: three (42.9%) had their treatment delayed, with no apparent consequences, two (28.6%) had their treatment delayed and later abandoned because of clinical worsening due to oncologic disease progression, and two (28.6%) contracted the infection in the post-operative period and died due to respiratory complications. CONCLUSIONS: In most cases the infection had major clinical implications, being associated with significant delays in oncologic treatments and extremely high mortality when contracted in the post-operative period.

Characteristics of patients with cancer in European long-term care facilities.

PURPOSE: Up to 26% of residents in nursing homes (NHs) are affected by cancer. Their care represents a challenge, because NHs are not usually considered a setting focused on oncologic management and care. The aim of this paper is to describe socio-demographic and clinical features of patients with cancer residing in European NHs. METHODS: Cross-sectional study based on data from the Services and Health for Elderly in Long TERm care (SHELTER) study. Participants were assessed through the interRAI-LTCF, which includes cancer assessment. RESULTS: Among 4140 participants (mean age 83.4 years; female 73%), 442 (10.7%) had cancer. Patients with cancer had a higher prevalence of do-not-resuscitate directives compared to those without cancer (21.1% vs 16.5%, p = 0.019). Variables directly associated with cancer were male sex (adj OR 1.67, 95% CI 1.36-2.05), pain (adj OR 1.43, 95% CI 1.16-1.77), fatigue (adj OR 1.25, 95% CI 1.01-1.55), polypharmacy (adj OR 1.59, 95% CI 1.21-2.08) and falls (adj OR. 1.30, 95% CI 1.01-1.67). Dementia was inversely associated with cancer (adj OR 0.74, 95% CI 0.58-0.94). Symptomatic drugs such as opioids (23.5% vs 12.2, p < .001), NSAIDS (7.2% vs 3.9%, p = 0.001), antidepressants (39.1% vs 33.8%, p = 0.026) and benzodiazepines (40.3% vs 34.3, p = 0.012) were all prescribed more in participants with cancer compared to those without cancer. CONCLUSIONS: Cancer patients are prevalent in European NHs and they show peculiar characteristics. Studies are needed to evaluate the impact of a supportive care approach on the management of NHs residents with cancer throughout all its phases, until the end-of-life care.

Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG).

Breast cancer is increasingly prevalent in older adults and is a substantial part of routine oncology practice. However, management of breast cancer in this population is challenging because the disease is highly heterogeneous and there is insufficient evidence specific to older adults. Decision making should not be driven by age alone but should involve geriatric assessments plus careful consideration of life expectancy, competing risks of mortality, and patient preferences. A multidisciplinary taskforce, including members of the European Society of Breast Cancer Specialists and International Society of Geriatric Oncology, gathered to expand and update the previous 2012 evidence-based recommendations for the management of breast cancer in older individuals with the endorsement of the European Cancer Organisation. These guidelines were expanded to include chemotherapy toxicity prediction calculators, cultural and social considerations, surveillance imaging, genetic screening, gene expression profiles, neoadjuvant systemic treatment options, bone-modifying drugs, targeted therapies, and supportive care. Recommendations on geriatric assessment, ductal carcinoma in situ, screening, primary endocrine therapy, surgery, radiotherapy, adjuvant systemic therapy, and secondary breast cancer were updated.

Reduction of derived neutrophil-to-lymphocyte ratio after four weeks predicts the outcome of patients receiving second-line chemotherapy for metastatic colorectal cancer.

Systemic inflammation response (SIR) plays a role in predicting prognosis of patients with metastatic colorectal cancer (mCRC). Chemotherapy-induced neutropenia has been suggested as another evaluable prognostic and predictive factor. This is a retrospective analysis of derived neutrophil-to-lymphocyte ratio (dNLR) and its reduction > 10% after the first cycle of chemotherapy (R10) in a monoinstitutional series of patients with mCRC receiving a first-line and a second-line cytotoxic chemotherapy. The effects of the neutrophil-related variables on overall survival (OS) and on chemotherapy activity were analyzed. One hundred twenty-eight patients were selected. A relationship of dNLR with OS was evident at both time points, but disappeared after multivariate analysis, whereas R10 was independent prognostic factor only after second-line chemotherapy in multivariate analysis. A dNLR reduction > 10% before the second cycle predicts OS and disease control from second-line chemotherapy in patients with mCRC, in particular among patients with right-sided tumors and synchronous metastases.

Comprehensive geriatric assessment in older adults with cancer: Recommendations by the Italian Society of Geriatrics and Gerontology (SIGG).

INTRODUCTION: Optimizing the approach to older adults with cancer is now a priority given the increasing frequency of new cancer diagnoses that are made in the older population. The comprehensive geriatric assessment (CGA) represents the gold-standard for (1) defining prognosis and ability to withstand cancer treatments, (2) exploring the multiple aspects that define the complexity of frail older persons, and (3) designing person-tailored interventions. MATERIALS AND METHODS: In this document, based on a comprehensive revision of the literature, the Italian Society for Geriatrics and Gerontology proposes a CGA model (ONCOGER CGA) to be adopted by oncology centers for their routine approach to older patients with cancer. RESULTS AND DISCUSSION: A widespread use of this standardized CGA format will facilitate comparisons across institutions, promote studies based on a multidimensional patient assessment, and foster the inclusion of geriatric endpoints in oncological clinical trials. Furthermore, we predict that the use of a standardized CGA approach will increase the integration of geriatricians into oncology care teams with the final result of improving therapeutic choices and clinical outcomes.

Systemic Inflammation Scores Predict the Activity of First-Line Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma.

BACKGROUND: Systemic inflammation response (SIR)-related variables are controversial as predictive variables. METHODS: Patients with metastatic pancreatic adenocarcinoma (mPDAC) receiving chemotherapy were identified, three SIR-related variables and the relationships between each of them with overall survival (OS) were analysed. RESULTS: Of 129 patients receiving chemotherapy, 97 had metastases. A significant relationship between SIR and OS has been documented. Each of the SIR-related variables retained its independent prognostic role after multivariate analysis, whereas tri-linear peripheric blood-cell score (TRIS) appeared as the most reliable predictive parameter. CONCLUSIONS: Among patients with mPDAC receiving chemotherapy, SIR is prognostic and could predict the effectiveness of chemotherapy.

Psychological Aspects to Consider in Breast Cancer Diagnosis and Treatment.

PURPOSE OF REVIEW: Breast cancer (BC) is the most common cancer diagnosed in women in the West World. Coping with cancer is cause of extreme stress for patients and their family. The purpose of this review is to evaluate possible approaches to follow to control those situations that can impact on quality of life (QoL) and compliance to treatments. RECENT FINDINGS: Anxiety, distress, depression, and posttraumatic stress disorder are the most frequent psychological disorders in BC patients. Cognitive disorders and sexual dysfunction can also be important in affecting QoL both in younger and older patients. Younger and older patients show different characteristics of these disorders and different strategies of managing them. Several psychotherapeutic and supportive approaches have proven effective in managing psychological disorders in BC patients. Every BC patient should be supported with these techniques during her entire oncological history, in order to increase QoL and compliance to treatments.

Leukocyte kinetics during the first cycle of chemotherapy predicts the outcome of patients with metastatic colorectal cancer and previous resection of the primary tumor.

BACKGROUND: Many reports suggest more activity of cytotoxic chemotherapy among patients with metastatic colorectal cancer (mCRC) who experience neutropenia, but it is not clear whether this finding is related to drug effect alone. The aim of the study is to identify the characteristics of patients whose peripheral blood cell kinetics (PBCK) is related to the outcome. METHODS: The study is a retrospective analysis of patients with mCRC who had received first-line chemotherapy at Sanremo hospital from 2010 to 2015, evaluating seventeen baseline variables, six related to systemic inflammatory response activation (SIRA), and six to peripheral blood cell kinetics after one cycle. The relationship of peripheral blood cell kinetics variables was evaluated by tumor location, SIRA, and timing of metastases. RESULTS: Among 203 eligible patients, only four variables were able to independently predict survival (age, CA 19-9, number of drugs, chemotherapy-induced leukopenia after the first cycle or CIL-1). After stratification by tumor location or by SIRA, no relationship of PBCK variables with prognosis was present. On the contrary, after stratification by timing of metastasis, the prognostic role of CIL-1 was evident among patients with metachronous metastases, particularly among those with low SIRA and colon tumors, whereas the leukocyte reduction after the first cycle (WR) predicted longer survival of patients with synchronous metastases and a previous resection of the primary tumor (PTR). CONCLUSIONS: Absolute leukocyte reduction (CIL-1) predicts a better OS of patients with metachronous metastases, whereas relative leukocyte reduction (WR) could be prognostic among patients with synchronous metastases who have received PTR.

Perspectives and limits of cancer treatment in an oldest old population.

BACKGROUND: Population of oldest old will grow dramatically in the next future and cancer, physiologically related to aging, will be very prevalent among them. Lack of evidence is a huge problem to manage cancer in oldest old and will be more and more in the next years. AIMS: Our purpose was to investigate the characteristics of a population of oldest old patients with cancer treated in the Radiation Oncology Unit of Fondazione Policlinico A. Gemelli IRCCS. METHODS: We conducted a retrospective study. The primary outcome was to evaluate which characteristics of the population could influence the choice of oncological treatment (with radical or non-radical intent). RESULTS: We identified a total of 348 patients: 140 were on follow-up; 177 were under treatment; 31 were considered not eligible for treatments. Patients under treatment had a high comorbidity index (mean Charlson Comorbidity Index 5.4), and a high prevalence of polypharmacy (mean number of drugs 5.6). More than half (53.1%) was treated with radical intent. Patients treated with radical intent were 1 year younger (87.1 years old vs 88.1 years old), more performant (ECOG 0.7 vs 1.3), and had less prevalence of metastatic neoplasia (6.4% vs 34.9%); comorbidities and drugs did not show differences in the two groups. CONCLUSION: Oldest old, usually not considered in international guidelines, are treated for oncological disease, often with radical intent. The treatment seems not to be tailored considering comorbidities but on performance status.

Comorbidity assessment to determine prognosis in older adult patients with classical Hodgkin lymphoma.

The clinical management of older adult patients with Hodgkin lymphoma (HL) remains a major challenge. The aim of this study was to evaluate the impact of comorbidity assessment according to a standardized approach, the Cumulative Illness Rating Scale (CIRS), on prognosis in patients with classical HL aged 60 years and older. We studied 76 consecutive older adult patients with HL (median age 69 y, range 60-84) who had been treated in our institution between 1999 and 2018. Comorbidity was assessed at diagnosis according to CIRS. Anthracycline-containing chemotherapy with curative intent was administered in 59 (78%) patients. We identified 41 (54%) patients with at least one severe comorbidity rated on CIRS grade ≥ 3. Patients with severe comorbidity were more likely to have advanced-stage disease (P = .003), to have an International Prognostic Score (IPS) > 3 (P = .03), and to not receive anthracycline-containing chemotherapy (P = .008). The probability of overall survival (OS) at 3 years was 88% (95% CI, 71%-95%) in patients without severe comorbidities, while it was only 46% (95% CI, 29%-62%) in patients with a comorbidity CIRS grade ≥ 3 (P = .0001). The impact of comorbidity on prognosis was also evident when restricting the analysis to patients treated with anthracycline-containing therapy. The 3-year OS was 93% (95% CI, 76%-98%) (P = .004) in patients without severe comorbidity and 72% (95% CI, 47%-87%) in patients with severe comorbidity (P = .004). In a multivariate analysis, presence of comorbidity, but not age, was a significant factor for OS. Therefore, we conclude that a significant proportion of older adult patients with HL has severe comorbidity on the CIRS scale, which impacts more importantly than age on prognosis.

Tumor growth kinetics by CA 19-9 in patients with unresectable pancreatic cancer receiving chemotherapy: A retrospective analysis.

BACKGROUND: Recently, measures of tumor growth kinetics calculated by carbohydrate antigen 19-9 (CA 19-9) determinations after cytotoxic chemotherapy (CHT) have been reported as effective prognostic indicators in locally-advanced unresectable and metastatic pancreatic adenocarcinoma (mPDAC). The study aims to evaluate the prognostic role of tumor kinetics measured by CA 19-9 in patients with mPDAC, measuring it by three different ways. METHODS: Patients with mPDAC receiving a first-line CHT between 2009 and 2017 were identified, and those for whom CA 19-9 data were available were enrolled. Three CA 19-9-related variables were calculated: CA 19-9 related reduction rate (RR) and tumor growth rate (G), after 8 weeks of CHT, tumor growth and inflammation index (TGII), after 90 days of CHT. The relationships with the outcome were analysed, and a Cox model has been build with each of the three variables. RESULTS: Of 118 patients only 48 were eligible for the analysis. RR, G, or TGII appear as significant prognostic factors, and, after multivariate analysis, a reduction rate of 20% the baseline or more was associated with good survival (HR 0.321; CIs 0.156-0.661) as well as a G > -0.4%/day (HR 2.114; CIs 1.034-4.321), whereas TGII >190 was not correlated with the outcome (HR 1.788; CIs 0.789-4.055). CONCLUSIONS: In patients with mPDAC, after 8 weeks of first-line CHT, CA 19-9-related tumor reduction or growth rate appear as valuable prognostic factors.

Biological and Functional Biomarkers of Aging: Definition, Characteristics, and How They Can Impact Everyday Cancer Treatment.

PURPOSE OF REVIEW: Recognize which are the elements that predict why a person is aging faster or slower and which intervention we can arrange to slow down the process, which permits to prevent or delay the progression of multimorbidity and disability. RECENT FINDINGS: Aging is a complex process that leads to changes in all the systems of the body and all the functions of the person; however, aging develops at different rates in different people, and chronological age is not always consistent with biological age. Gerontologists are focused not only on finding the best theory able to explain aging but also on identifying one or more markers, which are able to describe aging processes. These biomarkers are necessary to better define the aging-related pathologies, manage multimorbidity, and improve the quality of life. The aim of this paper is to review the most recent evidence on aging biomarkers and the clusters related to them for personalization of treatments.

The Frailty Index in older women with gynecological cancer.

INTRODUCTION: Frailty is a key condition to be screened among elderly oncological patients. Aim of our work is to measure the functional and prognostic value for 1-year mortality of the Frailty Index (FI) in a cohort of older women with gynecological cancer. METHODS: The prognostic value of FI was tested in 200 older women with gynaecological cancer (mean age = 73.5 years). FI was retrospectively calculated following the Rockwood model. Spearman's rho test was used for correlations with other oncological scales: Eastern Cooperative Oncology Group Performance Status (ECOG); Karnofsky Performance Status (KPS); Vulnerable Elders Scale-13 (VES-13). Cox proportional hazard models and ROC curve were performed to estimate prognostic role of 1-year mortality. Sensitivity and specificity were also calculated. RESULTS: FI is normally distributed and descriptive statistics define our population as frail (mean = 0.25±0.11, range 0.08-0.51). 0.7 is confirmed as an upper limit compatible with life. FI does not significantly correlates with age, ECOG and KPS while it positively correlates with VES-13 (r = 0.7, p < 0.01). FI is the strongest predictor for 1-year mortality confirmed after all adjustments for confounders (OR 3.40; 95% CI 1.55-7.45, p < 0.01) and by ROC curve analyses (0.66, 95% CI 0.51-0.81, p = 0.01). CONCLUSIONS: Frailty Index is a useful tool to detect vulnerability in onco-geriatrics and it predicts 1-year mortality. Further studies are needed to confirm and extend these findings.

Carcinoembryonic antigen reduction after medical treatment in patients with metastatic colorectal cancer: a systematic review and meta-analysis.

PURPOSE: The introduction of new drugs and multimodal treatments for the management of patients with metastatic colorectal cancer (mCRC) has reduced the importance of time-to-event endpoints and reported the attention on the response-related endpoints. Furthermore, the prognostic role of the surgical scores before the resection of metastases has not been confirmed for multimodal treatments. The purpose of this research is to perform a meta-analysis of the studies that evaluated the relationship between carcinoembryonic antigen (CEA) response and outcome in patients with mCRC receiving systemic chemotherapy. METHODS: A systematic review of the literature on two databases and a selection of studies that evaluated the relationship between CEA response and outcome were performed according to predefined criteria. After, three meta-analyses were carried out on the selected studies, each for each outcome variable. RESULTS: Nineteen studies have been selected. Fourteen studies (1475 patients) have documented a close association between radiological response and CEA response (odds ratio (OR), 9.03; confidence intervals (CIs), 5.14-15.87; I2 statistic (I2), 72%). Four studies have reported a longer progression-free survival for patients with a CEA response (hazard ratio (HR), 0.73; CIs, 0.64-0.83; I2, 23%). Finally, 10 studies (13 study cohorts) have shown a strong relationship between CEA response and overall survival (OS) (HR, 0. 62; CIs, 0.55-0.70; I2, 35%). CONCLUSIONS: CEA response merits further investigation as a surrogate endpoint of clinical trials of first-line medical therapy of patients with mCRC, and should be studied as a prognostic factor for those patients who are candidates for multimodal treatment strategies.

Analysis of response-related endpoints in trials of first-line medical treatment of metastatic colorectal cancer.

BACKGROUND: Tumor radiologic response after systemic chemotherapy has been used as endpoint of trials of patients with metastatic colorectal cancer (mCRC), which can report the best overall response rate (ORR) and the disease control rate (DCR) by RECIST criteria as well as the early tumor shrinkage (ETS). The present study perform a trial-level analysis to verify whether such response-related endpoints are predictive of overall survival (OS). METHODS: After a systematic search, randomized clinical trials (RCTs) were selected each time they evaluated the three response endpoints and progression-free survival (PFS). Two arms per trial were selected, and the correlation between the difference in each endpoint and the difference in OS was calculated. The analysis then evaluated the effects of treatment on ∆ORR, or ∆DCR, ∆ETS, ∆PFS, and on ∆OS, using separate linear regressions for each of them, and the proportion of variability explained (R2trial) on OS for each of the four endpoints was calculated. RESULTS: The systematic review of the literature led to the selection of 12 RCTs, 7 phase-3 and 5 phase-2. ETS reported a different performance in the entire sample compared to phase-3 trials (R2trial = 0.172 vs. 0.842), differently from DCR (R2trial = 0.541 vs. 0.816) and ORR (R2trial = 0.349 vs. 0.740). Surprisingly, PFS predicted OS with a weak correlation, which was not significant in the subgroup of phase-3 studies (R2trial = 0.455 vs. 0.466). CONCLUSION: The results of the present trial-level analysis report a good performance of two response-related endpoints, DCR and ETS, and suggest that they could be differently used depending on the setting of disease and the type of medical treatment.

Early tumor shrinkage after first-line medical treatment of metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Early tumor shrinkage (ETS) is a response-related endpoint of clinical trials of chemotherapy (CHT) of patients with metastatic colorectal cancer (mCRC). It identifies a dimensional reduction of tumor size by at least 20-30% after 6-8 weeks of CHT. METHODS: A literature search of randomized trials of systemic treatment including CHT with or without antiangiogenics or anti-EGFR inhibitors in patients with mCRC has been conducted, and studies reporting the results of the relationship of ETS with overall survival (OS) and progression-free survival (PFS) were selected. RESULTS: Twelve trials, including 3117 patients, have been included; all data were retrospective and only 72% of the enrolled patients have been evaluated for ETS. Two meta-analyses, each including 20 study cohorts from the selected 12 trials, reported a strong relationship of ETS with OS (HR 0.62; CIs 0.55-0.69) and of ETS with PFS (HR 0.66; CIs 0.60-0.73). However, both meta-analyses displayed a high level of heterogeneity. Among nine possible moderators, three variables (median age, surgery of metastases, and publication year) were able to explain at least a part of this heterogeneity. CONCLUSION: ETS is a simple and interesting intermediate endpoint for clinical practice and future trials of medical treatments of patients with mCRC, but a large prospective analysis and validation are mandatory.