Chiara Baratelli

The Role of Lung Metastasis Resection in Improving Outcome of Colorectal Cancer Patients: Results From a Large Retrospective Study

BACKGROUND The role of surgery for lung metastases (LM) secondary to colorectal cancer (CRC) remains controversial. The bulk of evidence is derived from single surgical series, hampering any definitive conclusions. The aim of this study was to compare the outcomes of CRC patients with LM submitted to surgery with those who were not. PATIENTS AND METHODS Data from 409 patients with LM as the first evidence of advanced disease were extracted from a database of 1,411 patients. Patients were divided into three groups: G1, comprised of 155 patients with pulmonary and extrapulmonary metastases; G2, comprised of 104 patients with LM only and no surgery; G3, comprised of 50 patients with LM only and submitted to surgery. RESULTS No difference in response rates emerged between G1 and G2. Median progression-free survival (PFS) times were: 10.3 months, 10.5 months, and 26.2 months for G1, G2, and G3, respectively. No difference in PFS times was observed between G1 and G2, whereas there was a statistically significant difference between G2 and G3. Median overall survival times were 24.2 months, 31.5 months, and 72.4 months, respectively. Survival times were longer in resected patients: 17 survived >5 years and three survived >10 years. In patients with LM only and no surgery, four survived for 5 years and none survived >10 years. CONCLUSIONS Even though patients with resectable LM are more likely to be those with a better outcome, our study provides evidence suggesting an active role of surgery in improving survival outcomes in this patient subset.

Intermittent everolimus administration for malignant insulinoma

Summary Insulinoma is a rare form of insulin-secreting pancreatic islet cell neuroendocrine (NE) tumor. The medical treatment of the malignant NE disease of the pancreas deeply changed in the last years, thanks to the introduction of new target molecules, as everolimus. Even if the exact mechanism is not actually known, one of the side effects of everolimus, hyperglycemia, has been demonstrated to be useful to contrast the typical hypoglycemia of the insulinoma. We report the case of a patient with a metastatic malignant insulinoma treated with intermittent everolimus, obtaining an important improvement in the quality of life; this suggests the necessity of preclinical studies to analyze the cellular pathways involved in insulin-independent gluconeogenesis. Learning points Effect of somatostatin analogs is long-lasting in the control of functioning NE tumors. Persistent everolimus control of hypoglycemia despite serum insulin levels and disease progression. Open issue: are disease progression and the increase in serum markers the only valid criteria to reject a treatment?

Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: The PRESSING case-control study

Background Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. Patients and methods We conducted this multicentre, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. Results Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P < 0.001) and in right- (12 out of 29, 41.4%) than left-sided (13 out of 65, 20.0%) tumours (P = 0.03). The predictive accuracy of PRESSING panel and sidedness was 75.3% and 70.2%, respectively. Among hyper-selected patients, right-sidedness was still associated with resistance (P = 0.002). The predictive accuracy of the combined evaluation of PRESSING panel and sidedness was 80.4%. As a secondary analysis, 8 (17.0%) resistant and 0 sensitive patients showed microsatellite instability (P < 0.001). Conclusion The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.

Treatment of Patients With Metastatic Colorectal Cancer in a Real-World Scenario: Probability of Receiving Second and Further Lines of Therapy and Description of Clinical Benefit

Micro‐Abstract There are no prognostic variables indicating how many lines of therapy patients will receive and whether later lines could be effective. Among 420 subjects, joint probabilities for a patient submitted to first‐line therapy to receive further lines were: second line, 74.3%; third line, 47.0%; and fourth line, 21.6%. Moreover, 31% of the patients with early progression during first‐line therapy experienced a clinical benefit with later lines. Background The optimal therapeutic strategy for metastatic colorectal cancer patients is still a matter of debate. There are no prognostic variables indicating how many lines individual patients ought to receive, and whether later lines could be effective even when earlier ones were not. Patients and Methods We retrospectively collected data from 420 consecutive patients with metastatic colorectal cancer at our institution, describing the proportion of patients who received second or later lines of therapy and the chance of a line of treatment being active when the previous line was not. For each line of treatment, we defined clinical benefit as the probability of not having had evidence of disease progression 6 months after the start of chemotherapy. Results Of the 373 patients with disease progression after first‐line chemotherapy (1L), 277 received a second line (2L) (probability of being submitted to a 2L (P(2L)) = 74.3%): 143 (63.3%) of 226 received a 3L (P(3L)), and 56 (45.9%) of 122 were submitted to a 4L (P(4L)). Joint probabilities were: 2L 74.3%, 3L 47.0%, and 4L 21.6%. A total of 298 (71.5%) of 417 patients had a clinical benefit with 1L; 134 (48.6%) of 276 with 2L; 50 (35.2%) of 142 with 3L; and 12 (25.0%) of 48 with 4L. Taking all these data together, 31% of the patients who experienced early progression at 1L had the chance to have a clinical benefit with any further lines. Conclusion Our study demonstrated that of 4 patients submitted to a 1L, about 3 will receive a 2L, about 2 a 3L, and nearly 1 a 4L. Later lines could be beneficial even though earlier ones were not.

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis

Purpose The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). Materials and Methods A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson’s correlation coefficient (R) and the coefficient of determination (R2). Results Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, –2.4 to 3.4) for the median PFS and 0.7 months (range, –5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. Conclusion Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

Circannual variation of efficacy outcomes in patients with newly diagnosed metastatic colorectal cancer and treated with first-line chemotherapy

Seasonal variation of baseline diagnosis (or clinical suspect) of stage I–III colorectal cancer patients has been repeatedly reported as an independent variable influencing overall survival. However, data are conflicting and no information is available about such a rhythm in advanced stage patients. To test whether a circannual rhythm of efficacy outcomes can be detected in this setting, we collected data about response rate (RR), progression-free survival (PFS), and overall survival (OS) to first-line chemotherapy of 1610 newly diagnosed metastatic patients treated at four independent centers. Responses to first-line chemotherapy were available for 1495 patients. A strong circannual rhythm in RR was evident, with the higher proportion of responding patients in the subgroup diagnosed in January (acrophase). At the time of data cutoff, 1322 patients progressed and 986 died, with median PFS and OS of 11 and 25.6 months, respectively. A circannual rhythmicity of the proportion of patients progressing at 6 months and surviving at 1 year was demonstrated, with acrophases located both in winter (February and January, respectively), similar to what reported for RR. Several interpretations about the genesis of this cyclic variation could be claimed: the rhythm in sunlight exposure and, as a consequence, of vitamin D serum levels and folate degradation, the variability in toxic effect intensity of chemotherapy, and the rhythm in the biological behavior of tumor cells. This observation is worth of further investigation both in preclinical and in clinical settings in order to better elucidate the underlying mechanisms.

Efficacy of neurokinin-1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting in patients receiving carboplatin-based chemotherapy: A systematic review and meta-analysis

According to current ESMO - MASCC guidelines, a combination of a neurokinin-1 receptor antagonist (NK1RA), dexamethasone and a 5-HT3 receptor antagonist (5-HT3RA) is recommended to prevent carboplatin-induced emesis, albeit with moderate level of confidence and not unanimous consensus. We performed a meta-analysis of randomized trials (RCTs) comparing NK1RA + dexamethasone + 5-HT3RA vs. dexamethasone + 5-HT3RA in patients receiving the first cycle of carboplatin-based chemotherapy. Primary outcome was complete response (CR), defined as no emesis and no use of rescue medication. 9 trials were eligible, and data of CR were available from 8 trials (1598 patients). Addition of NK1RA improves CR in all phases: acute phase, 94.5% vs. 90.1%; delayed phase, 76.4% vs. 61.7%; overall period, 75.3% vs. 60.4%. There was no significant heterogeneity among trials. In patients receiving carboplatin-based chemotherapy, the addition of NK1RA to dexamethasone and 5-HT3RA is associated with a statistically significant and clinically relevant improvement in CR.

FOLFOX activity in a rare case of metastatic colonic adenocarcinoma of the tongue: a case report

BackgroundAdenocarcinomas of the oral cavity are rare neoplasms, and only four cases of primary colonic adenocarcinoma of the tongue have ever been described in literature. Very few information about chemotherapy sensitiveness of this type of neoplasia is available, with only one regimen that showed some activity in a metastatic patient.Case presentationWe describe the case of a patient bearing a metastatic colonic adenocarcinoma of the tongue submitted to a first-line chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen). After chemotherapy the patient obtained the complete disappearance of the primitive neoplasia located in the body of the tongue, and a tumor size reduction > 50% of liver and lung metastases.ConclusionsThis case demonstrated the activity of the combination of oxaliplatin and 5-fluorouracil in this very rare neoplasia. The FOLFOX regimen might be considered either in advanced and especially in the neoadjuvant setting, when the reduction of the primary tumor is highly needed.

Abstract LB-238: Dissecting primary resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) inRASandBRAFwild-type (wt) metastatic colorectal cancer (mCRC)

Patients with RAS and BRAF wt mCRC are regarded as the best candidates to receive anti-EGFRs. Nevertheless, almost half of these patients do not achieve response, so that a deeper refinement of candidates’ selection would be highly desirable. Different molecular alterations, supported by a strong and sound biologic rationale, have been suggested as predictors of primary resistance to anti-EGFRs, but up today their potential impact has been suggested only in preclinical experiences and retrospective series, and their low frequency makes difficult the validation of each single marker. The present case-control study was conducted to prospectively demonstrate the negative predictive impact of HER-2 amplification or mutations, MET amplification, NTRK/ROS1/ALK/RET rearrangements, and mutations activating MAPKs or PI3K/Akt axis. Patients with RAS and BRAF wt mCRC clearly resistant (cases) vs. clearly sensitive (controls) to single-agent anti-EGFRs were selected, their archival tissue samples were collected and the prevalence of above-mentioned alterations was prospectively assessed. HER-2 status was evaluated by immunohistochemistry (IHC) and silver in-situ hybridization (SISH); MET amplification was studied by SISH; gene rearrangements were screened by IHC followed by RNA-based NGS confirmation. Other candidate mutations were investigated by NGS (Hotspot Cancer Panel v2, Ion Torrent Personal Genome platform (Life Technologies®). Hypothesizing a prevalence of candidate alterations of 0% and 15% among controls and cases, respectively, we needed to include 47 cases and 47 controls to be able to reject the null hypothesis that the prevalence of alterations is equal, with α-error 0.05 and β-error 0.20. Moreover, we evaluated the predictive impact of microsatellite instability, since hypermutated tumors may hardly rely on a single pathway (i.e. EGFR) for their growth. Forty-six cases and 47 controls were included. The primary endpoint was met: above-mentioned alterations were reported in 19 (41.3%) cases and 1 (2.1%) control (p This is the first prospective demonstration that the combined assessment of these rare alterations allows to better select patients for treatment with anti-EGFRs, while opening the way to properly tailored therapies. Citation Format: Chiara Cremolini, Rosa Berenato, Federica Morano, Roberto Moretto, Federica Perrone, Elena Tamborini, Daniele Rossini, Annunziata Gloghini, Adele Busico, Giovanni Fuca, Chiara Baratelli, Emiliano Tamburini, Iolanda Capone, Chiara Costanza Volpi, Massimo Milione, Massimo Di Maio, Gabriella Fontanini, Filippo De Braud, Alfredo Falcone, Filippo Pietrantonio. Dissecting primary resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) in RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-238. doi:10.1158/1538-7445.AM2017-LB-238

A case of long-term survival after repeated response to oxaliplatin-based chemotherapy and repeated thermoablation of liver metastases from colorectal cancer. Should we introduce the concept of oxaliplatin-resistant tumors?

BACKGROUND The management of advanced colorectal cancer patients differs among cancer centers. International guidelines recommend offering all the recognized active regimens in order to obtain survival advantage, but little information is given about the sequence and combination in which such regimens should be administered. CASE REPORT We report the case of a man with multiple liver metastasis from colorectal cancer followed for more than 78 months at our Institution. Repeated response to the same oxaliplatin, 5-fluorouracil and folinic acid chemotherapy schedule was achieved, and repeated radiofrequency ablation of liver metastases was performed until progression of lung and brain disease at 50 and 72 months, respectively, after the diagnosis of advanced disease. Although the tumor became oxaliplatin and chemo-resistant after the onset of extra-hepatic disease, a more aggressive chemotherapy regimen, including a doublet with a biological, halted tumor growth. CONCLUSIONS The patient survived for more than 78 months without experiencing a major impact on his quality of life. This case reflects the importance of following tumor biology in the therapeutic decision-making process, reintroducing oxaliplatin whenever possible, and adopting a more aggressive strategy when the tumor becomes oxaliplatin-resistant.