Marco Russano

Immunotherapy for colorectal cancer: where are we heading?

ABSTRACT Introduction: In the last few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC). The development of new drugs that target the immune response to cancer cells seems very promising and has already been established for other tumor types. In particular, the use of immune checkpoint inhibitors seems to be an encouraging immunotherapeutic strategy. Areas covered: In this review, the authors provide an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC. To understand the key role of immunotherapy in CRC, the authors discuss the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment. Expert opinion: Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy. Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary. Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed. As expected, additional studies are required to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response.

Natural History of Non-Small-Cell Lung Cancer with Bone Metastases

We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival.

Optimal control of nausea and vomiting with a three-drug antiemetic regimen with aprepitant in metastatic pancreatic cancer patients treated with first-line modified FOLFIRINOX

To the Editor The 5-fluorouracil (5-FU)–leucovorin–irinotecan– oxaliplatin (FOLFIRINOX) regimen is increasingly being used for the first-line treatment of metastatic pancreatic cancer showing a consistent survival advantage over single-agent gemcitabine [1]. Along with the increased efficacy, this regimen showed a higher toxicity rate with grades 3–4 toxicities, suffered by more than 10 % of patients in the FOLFIRINOX arm, and consisting of neutropenia (45.7 %), fatigue (23.6 %), vomiting (14.5 %), and diarrhea (12.7 %). In both trial arms, the recommended antiemetic prophylaxis consisted of dexamethasone together with a 5-HT3 antagonist for the acute phase, and metochlopramide or a 5-HT3 antagonist or dexamethasone for the delayed phase. Aprepitant acts by blocking the binding of substance P at the NK-1 receptor in the central nervous system. This molecule has been shown to improve the antiemetic activity of 5HT3 receptor antagonists and dexamethasone, preventing both the acute and the delayed chemotherapy-induced emesis [2, 3]. It has been approved by the FDA and EMEA for the prevention of nausea and vomiting in patients receiving highly and moderately emetogenic chemotherapy [4]. In our institution, from February 2011 to September 2012, 28 consecutive pancreatic cancer patients (8 females and 20 males; median age 65 years) with good performance status were treated with a modified FOLFIRINOX regimen (oxaliplatin 85 mg/m plus irinotecan 150 mg/m and leucovorin 400mg/m on day 1, associated with fluorouracil 2,400 mg/m given as a 46-h continuous infusion, every 2 weeks). Antiemetic prophylaxis consisted of aprepitant (125 mg on day 1 and 80 mg on days 2 and 3), ondansetron (8 mg) or granisetron (3 mg), and dexamethasone (8 mg) on days 1 and 2. The median number of cycles was 7 (range 3–11). Patients were treated until progression or unacceptable toxicity. The first seven patients did not receive aprepitant during the first cycle and experienced grades 2–3 nausea and vomiting (five patients G2 and two patients G3); therefore, we decided to add aprepitant before the second cycle of chemotherapy in these seven patients and to administer it from the beginning in the following 21 patients treated with the same regimen. The degree of nausea and vomiting was recorded on a diary, delivered to each patient at the first chemotherapy cycle. After the addition of aprepitant (cycle 1 in 21 patients and cycle 2 in 7, respectively), we observed a complete response (no vomiting and no need for rescue therapy) in 27/28 (96 %) patients in the first 120 h from chemotherapy administration. Rate of no vomiting (0–120 h) was also 96 %, i.e., only one patient, who received aprepitant from the second cycle, experienced delayed vomiting G2. Persistent nausea (arising immediately after chemotherapy and lasting 24–48 h after its end) was reported by 2/28 patients (7 %); both received aprepitant from the first cycle. The persistent nausea, reported after the first cycle of chemotherapy from patients not treated with aprepitant, disappears after the inclusion of the drug during the second cycle of treatment. No increased toxicity to chemotherapy was observed despite that all our patients have received irinotecan, a drug metabolized by the cytochrome P450 3A4, for which aprepitant is a moderate inhibitor and inducer. In literature, there are scanty evidences on the potential interaction between N. Silvestris (*) Medical Oncology Unit, National Cancer Institute “Giovanni Paolo II”, Viale Orazio Flacco, 65, 70124 Bari, Italy e-mail: n.silvestris@oncologico.bari.it

Change from lung adenocarcinoma to small cell lung cancer as a mechanism of resistance to afatinib

We report the case of a patient affected by advanced EGFR mutation-positive lung who experienced resistance to therapy during treatment with Afatinib through the occurrence of a switch of tumor histotype to small cell lung cancer (SCLC) with features of a G3 neuroendocrine carcinoma. Unexpectedly, the switch to SCLC histotype occurred in the only site not responsive to afatinib and subsequently the most responsive to chemotherapy. Our case shows that occurrence of switch to SCLC is a possible mechanism of resistance during treatment with Afatinib.We report the case of a patient affected by advanced EGFR mutation-positive lung who experienced resistance to therapy during treatment with Afatinib through the occurrence of a switch of tumor histotype to small cell lung cancer (SCLC) with features of a G3 neuroendocrine carcinoma. Unexpectedly, the switch to SCLC histotype occurred in the only site not responsive to afatinib and subsequently the most responsive to chemotherapy. Our case shows that occurrence of switch to SCLC is a possible mechanism of resistance during treatment with Afatinib.

Treatment of Metastatic Colorectal Cancer Patients ≥75 Years Old in Clinical Practice: A Multicenter Analysis.

Background Colorectal cancer patients have a median age of incidence >65years although they are largely under-represented in phase-III trials. This large population contains patients unfit for treatment, those suitable for monotherapy or for doublets and the impact of chemotherapy outside clinical trial is unclear. The aim of the study was to retrospectively analyse Overall Survival(OS) of elderly metastatic colorectal cancer(mCRC) patients treated with chemotherapy in daily practice. Methods Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for differences between subgroups, Cox’s proportional hazard model to assess the impact of known prognostic factors and treatment. Results 751 patients with mCRC observed between January 2000 and January 2013 were collected. Median age was 79 year(75–93); Male/Female 61/39%, ECOG-PS 0-1/2 85/15%; colon/rectum 74/26%; multiple metastatic sites 34%, only liver metastasis in 41% of patients. KRAS status was studied in 35% of patients: 44% of them showed gene mutation. 20.5% of patients did not received any kind of treatment including surgery. Comorbidities observed: cardiovascular 34%, diabetes 14%, hypertension 50%. Primary tumor was resected in 80.6%; surgery of liver metastasis was done in 19% of patients (2.3% of patients >80years). 78% of patients underwent chemotherapy. Median follow up was 12 months(range 1–124). Median OS was 17 months (CI 95%15–19);median OS in no-treated patients was 5 months (4–6); mOS of patients with at least one treatment was 20 months (18–22). In KRAS mutated group median OS was 19months (15–23) while in KRAS wild type patients median OS was 25 months (20–30). At multivariate analysis sex(Female), age(<80y), performance status(0–1), chemotherapy, Surgery of metastasis, Surgery of primary tumor and Site of metastasis(liver) were prognostic factors for OS. Conclusion The results of our study show that in clinical practice treatment has a positive impact on OS of elderly patients, confirmed at multivariate analysis, included patients with age >80 years old or with a poor performance status (respectively p<0.0001 and p<0.0001). KRAS analysis deserve further evaluation.

Corrigendum: Natural History of Non-Small-Cell Lung Cancer with Bone Metastases.

Scientific Reports 5: Article number: 18670; published online: 22 December 2015; updated: 15 April 2016. The original version of this Article contained errors in the spelling of the authors Daniele Santini, Sandro Barni, Salvatore Intagliata, Alfredo Falcone, Francesco Ferrau, Domenico Galetta, LucaMoscetti, Nicla La Verde, Toni Ibrahim, Fausto Petrelli, Enrico Vasile, Laura Ginocchi, Davide Ottaviani, Flavia Longo, Cinzia Ortega, Antonio Russo, Giuseppe Badalamenti, Elena Collova, Gaetano Lanzetta, Giovanni Mansueto, Vincenzo Adamo, Filippo De Marinis, Flavia Cantile, Andrea Mancuso, Raffaele Addeo, Marco Russano, Michelle Sterpi, Francesco Pantano, Bruno Vincenzi and Giuseppe Tonini which were incorrectly given as Santini Daniele, Barni Sandro, Intagliata Salvatore, Falcone Alfredo, Ferrau Francesco, Galetta Domenico, Moscetti Luca, La Verde Nicla, Ibrahim Toni, Petrelli Fausto, Vasile Enrico, Ginocchi Laura, Ottaviani Davide, Longo Flavia, Ortega Cinzia, Russo Antonio, Badalamenti Giuseppe, Collova Elena, Lanzetta Gaetano, Mansueto Giovanni, Adamo Vincenzo, De Marinis Filippo, Cantile Flavia, Mancuso Andrea, Addeo Raffaele, Russano Marco, M Sterpi, Pantano Francesco, Vincenzi Bruno and Tonini Giuseppe respectively.

Outcomes of Advanced Gastric Cancer Patients Treated with at Least Three Lines of Systemic Chemotherapy

BACKGROUND Second-line therapy has consistently demonstrated survival benefit if compared with best supportive care; however, there is limited evidence whether further lines of treatment may improve the prognosis of advanced gastric cancer (AGC) patients. MATERIALS AND METHODS Starting from a real-world cohort of 868 AGC patients, we retrospectively analyzed baseline parameters, tumor characteristics, and treatment data of those treated with at least three lines. Categorical features were described through cross-tables and chi-square test. We explored the impact of treatment intensity and progression-free survival (PFS) experienced in previous lines on PFS and overall survival in third-line by uni- and multivariate Cox regression models and described by Kaplan-Meier estimator plot with log-rank test. RESULTS Overall, 300 patients were included in the analysis. The most common site of primary tumor was gastric body; 45.3% of cancers had an intestinal histotype, 14% were human epidermal growth receptor 2 positive. In third-line, 45.7% of patients received a single-agent chemotherapy, 49.7% a combination regimen. Patients who had experienced a first-line PFS ≥6.9 months had a better prognosis compared with those who had achieved a shorter one. Consistently, a second-line PFS ≥3.5 months positively influenced the prognosis. Patients receiving a third-line combination regimen had better outcomes compared with those treated with a single-agent chemotherapy. CONCLUSION Our real-world study confirms that selected AGC patients may receive third-line treatment. Longer PFS in previous lines or a more intense third-line treatment positively influenced prognosis. Further efforts are warranted to define the best therapeutic sequences, and to identify the optimal candidate for treatment beyond second-line. IMPLICATIONS FOR PRACTICE The benefit of third-line treatment to advanced gastric cancer patients is controversial. This study depicts a real scenario of the clinical practice in Italy, confirming that a non-negligible proportion of patients receive a third-line therapy. Longer progression-free survival in previous treatment lines or higher third-line treatment intensity positively influenced prognosis. Including a large number of real-world patients, this study provides information on third-line treatment from the daily clinical practice; moreover, its results help in defining the best therapeutic sequence and offer some hints to select the optimal candidate for treatment beyond second-line.

600PTREATMENT (T) OF METASTATIC COLORECTAL CANCER (MCRC) PATIENTS (PTS) ≥75 YEARS (Y) OLD IN CLINICAL PRACTICE: A MULTICENTER ANALYSIS

ABSTRACT Aim: CRC pts have a median age of incidence > 65y although they are largely under-represented in phase III trials. This large population contains pts unfit for T, those suitable for monotherapy or for doublets and the impact of chemotherapy (CHT) outside clinical trial is unclear. Aim of the study was to retrospectively analyse T of elderly mCRC pts. Methods: Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for diferences between subgroups, Coxs proportional hazard model to assess the impact of known prognostic factors and T. Results: 751 pts with mCRC observed from January 2000 to January 2013 were collected. Median age was 79y (75-93); Variables HR (CI95%) P value Sex 1.21 (1.01-1.46) 0.04 Age 1.75 (1.45-2.12) ECOG PS 2.51 (1.94-3.25) CT 2.14 (1.68-2.73) S of metastasis 2.48 (1.88-3.29) S of primary tumor 1.66 (1.31-2.11) Site of metastasis 1.33 (1.09-1.63) 0.006 Conclusions: These data show that in clinical practice treatment of metastatic disease has a positive effect on elderly pts OS, confirmed at multivariate analysis. KRAS analysis deserve further evaluation. Update results will be presented. Disclosure: All authors have declared no conflicts of interest.