An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer.

PURPOSE: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. EXPERIMENTAL DESIGN: Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg). RESULTS: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup. CONCLUSIONS: DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.

Current Therapeutic Strategies in BRAF-Mutant Metastatic Colorectal Cancer.

Around 8-12% of patients with advanced colon rectal cancer (CRC) present with BRAF alterations, in particular V600E mutation, which is associated with right-side, poorly differentiated and mucinous type tumors. The presence of BRAF mutation (BRAF-mt) has been identified as a hallmark of poor prognosis and treatment optimization in this patient subgroup is an important goal. Currently, the standard of care is an aggressive strategy involving triplet chemotherapy and anti-VEGF agents, but new therapeutic approaches are emerging. Very promising results have been obtained with targeted therapy combinations, such as anti-BRAF agents plus anti-EGFR agents. Furthermore, around 60% of BRAF-mt patients show a strong association with high microsatellite instability (MSI-H) and immune checkpoint inhibitors could represent the new standard of care for this subgroup. The focus of this review is to summarize current strategies for BRAF-mt CRC treatment and highlight new therapeutic options.

Alpha-fetoprotein surge following high-dose chemotherapy in germ cell tumours.

In patients with non-seminomatous germ cell tumours (NSGCTs) who receive chemotherapy and have residual disease, a persistently elevated serum marker level after induction chemotherapy indicates active and progressive disease. High-dose chemotherapy (HDCT) is the standard treatment for patients with relapsed NSGCT. We present a case of a patient with residual disease from NSGCT who showed an increase in serum alpha-fetoprotein levels after HDCT, mimicking progression. Resection of the mass did not show viable cells in the tumour specimen, thus suggesting that the elevated level of the marker was expression of hepatic reconstitution after drug-induced liver damage. HDCT is increasingly used in cases of relapsed NSGCT, and the possibility of treatment-induced alpha-fetoprotein elevation must be taken into account in patient management.

Gemcitabine and paclitaxel combination as second-line chemotherapy in patients with small-cell lung cancer: a phase II study.

BACKGROUND: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. PATIENTS AND METHODS: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m(2) days 1 and 8 immediately followed by gemcitabine at 1000 mg/m(2) every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. RESULTS: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. CONCLUSIONS: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic.

Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features.

OBJECTIVE: High-dose chemotherapy (HDCT) represents an option as salvage treatment for patients with resistant/refractory germ cell tumor (GCT). The objective of this retrospective analysis was to evaluate the long-term results of a single-center experience with salvage HDCT for GCT patients, and to validate the prognostic model proposed by Einhorn and colleagues [9]. MATERIALS AND METHODS: Between 1986 and 2003, 100 GCT patients received salvage HDCT consisting of high-doses of carboplatin, etoposide ± cyclophosphamide, or ifosfamide. Twenty-four patients underwent a second HDCT cycle, and in 1 case, a third cycle was given with a median interval time of 6 weeks (range, 5-10). RESULTS: With a median follow-up of 8 years (range, 3-17); 6 of 32 (19%) patients with resistant GCT and 1 of 19 (5%) patients with cisplatin-refractory disease have been continuously disease-free, while none of the 16 patients with absolutely cisplatin-refractory GCT were alive at 1 year from HDCT treatment. In the PBPC era, HDCT appeared to be inapplicable in 32% of patients, mainly due to progressive disease during the induction/mobilizing phase. The prognostic model by Einhorn et al. for tandem HDCT did categorize our patients treated with a single HDCT cycle or low-dose intensity regimens in a very similar manner, but with inferior overall results. CONCLUSIONS: Long-term results with a single HDCT cycle or a low dose-intensity multicycle HDCT regimen remained poor in patients with adverse prognostic features. The tandem HDCT regimen represents a major option for refractory GCTs and relapsed tumors in third-line or later therapy, while a single course of HDCT should be abandoned for these patients.

Weekly gemcitabine, paclitaxel, oxaliplatin combination chemotherapy in patients with Cisplatin-refractory germ cell tumor: preliminary experience.

Although the overall cure rate for advanced germ cell tumor (GCT) is high, the prognosis for patients with cisplatin-refractory GCT remains poor. Gemcitabine, paclitaxel, and oxaliplatin have shown significant activity as single agents in these patients. We investigated the activity and tolerance of a weekly gemcitabine, paclitaxel, oxaliplatin chemotherapy regimen. From September 2000 to February 2002, 9 patients with cisplatin-refractory GCT were treated with gemcitabine 800 mg/m2, paclitaxel 70 mg/m2, and oxaliplatin 50 mg/m2, days 1, 8, and 15, every 4 weeks. Only 1 patient stayed on schedule. In 7 patients, chemotherapy treatment was modified due to grade 3-4 hematological toxicity, whereas in another patient, who received high-dose chemotherapy 2 months before, chemotherapy was administered biweekly. In total, 21 cycles were administered with a median of 2 cycles for each patient. One patient achieved a partial remission lasting 5 months, 1 had disease stabilization for 5 months, whereas 7 had progressive disease. This chemotherapy regimen was not feasible in our patient population. Recently, oxaliplatin at full doses, but not as weekly administration, has appeared to possess activity in cisplatin-refractory GCT. Thus, we plan a phase II study protocol of the oxaliplatin and gemcitabine combination at full doses every 3 weeks.

Prevention and therapy of neutropenia in elderly patients.

Standard chemotherapy in elderly patients is still nowadays a difficult issue, due to the fact that marrow reserve decrease with age and the results might lead to higher toxicity of otherwise well tolerated regimen and schedule. In the literature, very few data exist of myelosuppression in patients with solid tumors, while more data have been published on non-Hodgkin's lymphoma. The burden of toxicity increase with age, leading to the fact that some patients with curable or sensitive disease do not receive appropriate treatment. One of the ways to try to circumvent neutropenia is the prophylactic use of haematopoietic growth factors with the double aim of maintaining dose-intensity and reducing toxicity. This paper will describe the patterns of marrow toxicity in treating elderly patients with cancer and the role of haematopoietic growth factors.

High-dose chemotherapy in adult patients with germ cell tumors.

BACKGROUND: Approximately 80% of patients with advanced germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. Patients with poor-prognosis disease have a cure rate of only 50%, whereas patients with first relapse have only a 25% chance of prolonged survival and potential cure following standard therapy. High-dose chemotherapy (HDC) is being investigated in patients with GCTs to improve the results of salvage treatment and in first-line setting for poor prognosis disease. METHODS: The authors review the results of the clinical trials that have evaluated the role of HDC in GCT patients. Data were obtained using a computer-assisted MEDLINE search, and meeting abstracts with clinical relevance in this field were hand-searched. Open randomized phase III studies are described and examined. RESULTS: Several phase II studies have shown a possible benefit for patients with recurrent disease, but the preliminary results of a phase III randomized trial did not demonstrate a survival advantage for HDC after three courses of standard-dose chemotherapy in the salvage therapy of patients in whom first-line treatment has failed. Three prospective, randomized trials are evaluating the role of HDC in a first-line setting. CONCLUSIONS: New HDC strategies are emerging, involving new drugs (eg, paclitaxel), intensive induction regimens, and upfront and/or multiple courses of HDC. The evaluation of mature data of randomized trials will better define the role of HDC in this disease.

Salvage high-dose chemotherapy in patients with germ cell tumors: an Italian experience with 84 patients.

BACKGROUND: High-dose chemotherapy (HDCT) followed by hematopoietic stem cell support (HSCS) potentially may be curative in patients with germ cell tumor (GCT) who develop recurrent tumors or who have an inadequate response after receiving standard-dose chemotherapy. The authors report their experience with HDCT as salvage therapy for patients with GCT. METHODS: Between 1986 and 2000, 84 patients with GCT, with a median age 29 years (range, 15-50 years), were treated with 105 courses of HDCT with HSCS. Patients were stratified into good, intermediate, and poor risk categories according to a validated prognostic index. RESULTS: Overall, 28 patients (33%) have been continuously disease free. In the good risk group, 24 patients (69%) have been continuously disease free compared with 4 patients (13%) in the intermediate risk group (P < 0.001) and 0 patients in the poor risk group (P < 0.001). Treatment-related mortality occurred only among patients in the poor risk (n = 6 patients) and the intermediate risk groups (n = 4 patients). CONCLUSIONS: In the authors' experience, HDCT induced impressive long-term remissions as salvage treatment among patients in the good risk group. Moreover, the use of validated prognostic classifications may contribute to a better definition of the role of HDCT other than improving the outcome of patients with GCT. The definitive statement on the possible role of HDCT in patients with GCT will derive from the ongoing Phase III randomized studies.

The status of high-dose chemotherapy with hematopoietic stem cell transplantation in germ cell tumor patients.

BACKGROUND AND OBJECTIVES: Germ cell tumors (GCTs) are very chemosensitive cancers, in which high-dose chemotherapy (HDCT) has been investigated as salvage therapy or as first-line treatment in poor prognosis patients. This paper presents an update of available information in order to define the status of HDCT in GCT patients. INFORMATION SOURCES: The authors have been working in this field, contributing to international clinical trials and to peer-reviewed journals with original papers. The material examined in this review includes articles published in journals covered by MedLine, reviews from journals with high impact factor, and unpublished data from the European Group for Blood and Marrow Transplantation (EBMT) registry. STATE OF THE ART AND PERSPECTIVES: The delineation of prognostic factors associated with a poor probability of survival after HDCT contributed to the selection of patients who are likely to get an advantage from HDCT and those who should be spared from dose-intensive treatment. HDCT as first-line therapy for poor prognosis GCT (IGCCCG classification), and in a salvage setting in good risk GCT (prognostic index from Beyer et al.77), has been associated with a very high rate of complete remissions and long-term disease-free survivors. However, it is important to wait for the results of ongoing randomized trials for the validation of these findings. Other strategies are required for patients with refractory GCTs. Several new treatment options are currently emerging for this subset of patients.