Rituximab in steroid-refractory immune-related pancreatitis: a case report.

The use of immune checkpoint inhibitors (ICIs) for treating several types of cancer is increasing, but they may be associated with immune-related adverse events (irAEs). Pancreatitis is a rare irAE, mostly responsive to steroid treatment. There are no published data on the management of steroid-refractory ICI-induced pancreatitis. Rituximab has shown efficacy in the setting of relapsing non-ICI-induced autoimmune pancreatitis. However, its use has not been tested for treating immunotherapy-related pancreatitis. Here, we present the case of a patient with steroid-refractory immune-related pancreatitis successfully treated with rituximab as a potential strategy for irAE management.

Total Neoadjuvant Treatment for Locally Advanced Rectal Cancer Patients: Where Do We Stand?

The therapeutic landscape in locally advanced rectal cancer (LARC) has undergone a significant paradigm shift in recent years with the rising adoption of total neoadjuvant treatment (TNT). This comprehensive approach entails administering chemotherapy and radiation therapy before surgery, followed by optional adjuvant chemotherapy. To establish and deliver the optimal tailored treatment regimen to the patient, it is crucial to foster collaboration among a multidisciplinary team comprising healthcare professionals from various specialties, including medical oncology, radiation oncology, surgical oncology, radiology, and pathology. This review aims to provide insights into the current state of TNT for LARC and new emerging strategies to identify potential directions for future research and clinical practice, such as circulating tumor-DNA, immunotherapy in mismatch-repair-deficient tumors, and nonoperative management.

Discontinuation of anti-PD1 in advanced melanoma: an observational retrospective study from the Italian Melanoma Intergroup.

BACKGROUND: Immunotherapy has improved the survival of patients with stage IV melanoma. In responders, clinical benefits may be long-lasting and persist even after treatment discontinuation. The optimal duration of anti-PD1 (anti-Programmed cell death-1) therapy in metastatic melanoma patients remains to be elucidated. Moreover, limited data are available on clinical outcomes of patients that discontinued anti-PD1 immunotherapy in a real-life setting. The aim of this study was to evaluate the progression-free survival (PFS) in patients with metastatic melanoma who interrupted anti-PD-1 treatment in the in the absence of disease progression. METHODS: We retrospectively reviewed patients with advanced/metastatic melanoma treated with anti-PD1 immunotherapy at 23 Italian Melanoma Intergroup (IMI) centres. The study investigated the risk of relapse in patients who stopped anti-PD1 therapy due to CR (Complete response), treatment-related toxicity, or by their own choice after a long period of treatment. Clinical and biological factors associated with or without recurrence were evaluated. RESULTS: The study population included 237 patients. The median age of patients was 68.9 years (standard deviation: 13; range 33-95). The median time on treatment was 33 months (standard deviation: 18, 7; range 1-98). Among the 237 patients, 128 (54%) interrupted the anti-PD1 for CR, 74 patients (31.2%) for adverse events (37 patients in CR, 27 patients in partial response (PR), ten patients in stable disease (SD), and 35 patients (14.8%) by their own choice (12 patients in CR, 17 patients in PR, and 6 patients in SD). After a mean follow-up of 21 months (range 1-81), PFS after anti-PD1 discontinuation was 85.7%. Thirty-four patients (14.3%) developed disease progression after a median of 12 months (range 1-35): ten patients (29.4%) after discontinuation in CR, 17 patients (50%) after discontinuation for treatment-related toxicity (seven in CR, five in PR, five in SD), and seven (20.6%) after discontinuation due to the patient's decision (two in CR, four in PR, one in SD). Only 7.8% of patients who interrupted in CR (10/128), along with 23% of patients who interrupted for limiting toxicity (17/74) and 20% of patients who interrupted by their own choice (7/35), developed recurrence. Regarding patients who discontinued therapy because of CR, we observed a negative association between recurrence and site of primary melanoma, especially mucosal sites (p = <0.05, HR (Hazard ratio) 15.57 IC (confidence interval) 95% 2.64-91.73). Moreover, M1b patients who achieved a CR showed a lower number of relapses (p = <0.05, HR 3.84 IC 95% 1.40-8.48). CONCLUSIONS: This study shows in a real-life setting that, with anti-PD-1 therapy, long-lasting responses, can be maintained after anti-PD1 interruption. In 70.6% of cases, recurrences were observed among patients who did not obtain a CR at treatment discontinuation.

A Case of Pulmonary Sarcoidosis during First-Line Targeted Therapy with Dabrafenib Plus Trametinib in BRAF V600E-Mutated Metastatic Melanoma.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) exert a cytotoxic and immune-mediated effect on metastatic melanoma. The immune-mediated mechanism can lead to some adverse events, including panniculitis, erythema, keratitis, vitiligo-like lesions, or, more rarely, sarcoid-like skin reactions. In particular, sarcoidosis-related manifestations during melanoma treatment are characterized mainly by skin involvement and are seldom associated with chest or lymph node lesions. Overall, managing these adverse events can be very challenging from the diagnostic and therapeutic points of view. We present a case of pulmonary sarcoidosis; it is the first without skin involvement and initially only with lung presentation, diagnosed during treatment with BRAFi and MEKi for metastatic cutaneous melanoma. After about 2 years of treatment, with an oncological complete response, a histologically confirmed form of pulmonary sarcoidosis was diagnosed and initially interpreted as tumor progression. Sarcoidosis has always remained asymptomatic. After progression in the thorax and supraclavicular lymph nodes, steroid therapy with prednisone was instituted with total remission of the signs of disease. The targeted therapy has never been interrupted, and the patient still shows a complete response. This clinical case suggests that rare immune-mediated events, such as pulmonary sarcoidosis, should be considered during targeted therapy for metastatic melanoma and not only during treatment with immune checkpoint inhibitors. It also suggests that the interruption of targeted treatment should be accurately considered based on the expected risks or benefits since such immune-mediated events may have low clinical impact.

Tailored Toxicity-Driven Administration of Vismodegib in Patients With Multiple or Locally Advanced Basal Cell Carcinoma: A Pilot Analysis.

In this pilot study, we describe our experience with vismodegib in the treatment of basal cell carcinoma (BCC) and evaluate the feasibility of a tailored toxicity-driven administration of vismodegib in patients with multiple or locally advanced BCC. We retrospectively analyzed the clinical charts of 17 consecutive patients with BCC who were treated with vismodegib. Therapy was started at the usual dosage of 150 mg per day per person, continuously; a rescheduled dosage of 150 mg per day for 4 weeks with a subsequent stop of 2 weeks was allowed during the treatment according to the standard practice of our institution. During treatment, 14 patients with responsive disease presented an adverse event (100% cramps and 20% dysgeusia), therefore, requiring a change in the treatment plan. Overall, in eight out of 17 patients (47% of the overall population), it was possible to re-schedule the treatment by postponing therapy for 2 weeks every 4 weeks. These patients were all still alive at the time of the present analysis and were showing complete response. Adverse events resolved during the first interruption of therapy. The intermittent vismodegib schedule assessed in this pilot series could be beneficial in improving duration of treatment, allowing to maintain a long-term treatment response, even in an elderly and fragile population. Based on these preliminary findings, dedicated studies may be planned to further evaluate an intermittent schedule of vismodegib administration.

An Italian Retrospective Survey on Bone Metastasis in Melanoma: Impact of Immunotherapy and Radiotherapy on Survival.

BACKGROUND: We performed a multicenter retrospective observational study to investigate the impact of clinical-pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma. PATIENTS AND METHODS: A total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician's practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs. RESULTS: Eighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT. CONCLUSION: Based on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation.

Regorafenib in patients with refractory metastatic pancreatic cancer: a Phase II study (RESOUND).

Aim: Regorafenib may be active in different cancer types. This Phase II trial included patients with various refractory cancer types treated with regorafenib. Here, we report the results of the pancreatic adenocarcinoma cohort. Methods: The primary end point was progression-free survival (PFS) rate at 8 weeks; further investigation of regorafenib would be warranted with a PFS rate ≥50%. Results: A total of 20 patients were enrolled. The best response was stable disease in four patients (20%). The 8-week PFS rate was 25% with a median PFS of 1.7 months (95% CI: 1.5-2.0). A total of 13 patients (65%) experienced grade 3-4 treatment-related adverse events. Conclusion: The study did not meet its primary end point. Further investigation of regorafenib monotherapy in this setting is not recommended. Clinical Trial Registration: NCT02307500.

Phase II Study of Tivantinib and Cetuximab in Patients With KRAS Wild-type Metastatic Colorectal Cancer With Acquired Resistance to EGFR Inhibitors and Emergence of MET Overexpression: Lesson Learned for Future Trials With EGFR/MET Dual Inhibition.

BACKGROUND: MET overexpression/amplification has been associated with resistance to anti- epidermal growth factor receptor therapies in patients with metastatic colorectal cancer (mCRC). Combining tivantinib, an inhibitor of the MET receptor tyrosine kinase, and cetuximab may be effective in patients with epidermal growth factor receptor-resistant MET-high mCRC. PATIENTS AND METHODS: This multicenter, single-arm, Simon 2-stage, phase II study enrolled patients with MET-high, KRAS wild-type mCRC, who were treated with ≥ 1 prior systemic therapy, with at least stable disease on the last treatment regimen containing cetuximab or panitumumab. Patients were enrolled if they presented tumor progression on cetuximab or panitumumab within 3 months before enrollment. Patients received tivantinib (360 mg twice daily) plus cetuximab (500 mg intravenously every 2 weeks). The primary endpoint was objective response rate; secondary endpoints included progression-free survival, overall survival, and safety. The treatment would be considered effective if ≥ 5 confirmed partial responses were observed among 41 patients. RESULTS: In total, 41 patients were evaluated, 4 patients (9.8%) achieved an objective response, the median progression-free survival was 2.6 months (95% confidence interval, 1.9-4.2 months), and the median overall survival was 9.2 months (95% confidence interval, 7.1-15.1 months). Among 13 patients with tested MET amplification, 2 responding patients had MET amplification compared with none of the nonresponding patients. The most common grade ≥ 3 treatment-emergent adverse events were neutropenia (14.6%), skin toxicity (12.2%), and fatigue (9.8%). CONCLUSION: Although the study did not meet its primary endpoint, efficacy results suggest some activity of the tested combination, with almost 10% of patients achieving objective response in a difficult-to-treat setting. Treatment-emergent adverse events were consistent with the known safety profile of tivantinib and cetuximab.

Effect of Comorbidities in Stage II/III Colorectal Cancer Patients Treated With Surgery and Neoadjuvant/Adjuvant Chemotherapy: A Single-Center, Observational Study.

BACKGROUND: Comorbidity has a detrimental effect on cancer survival, however, it is difficult to disentangle its direct effect from its influence on treatment choice. In this study we assessed the effect of comorbidity on survival in patients who received standard treatment for resected stage II and III colorectal cancer (CRC). PATIENTS AND METHODS: In total, 230 CRC patients, 68 rectal (29.6%) and 162 colon cancer (70.4%) treated with surgical resection and neoadjuvant/adjuvant chemotherapy from December 2002 to December 2009 at Humanitas Cancer Center were retrospectively reviewed. The key independent variable was the Charlson Comorbidity Index (CCI) score, measured as a continuous variable. The differences between groups for categorical data were tested using the χ2 test. Actuarial survival curves were generated using the Kaplan-Meier method. RESULTS: Median follow-up was 113 (range, 8.2-145.0) months. Median age was 63 (range, 37-78) years. In univariate analysis CCI score was significantly associated with poorer disease-free survival (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.52-1.80; P < .001), and overall survival (OS; HR, 1.55; 95% CI, 1.41-1.71; P < .001). Factors associated with poorer outcome also included (stage III vs. stage II, P < .029) and age (age >70 vs. ≤70 years, P < .001). After adjusting for these factors, a significant negative prognostic role of CCI score was still observed (adjusted HR for OS, 1.59; 95% CI, 1.43-1.76; P < .001). CONCLUSION: Among CRC patients who underwent surgical resection and chemotherapy, a higher CCI score was associated with poorer outcome and might predict long-term survival.

Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications.

BACKGROUND: HER2 and topoisomerase 2 alpha (TOP2A) genomic status was previously reported to predict benefit from anthracyclines in breast cancer. We sought to define the prognostic impact and possible pitfalls related to these biomarkers in resectable gastroesophageal adenocarcinoma. METHODS: HER2 and TOP2A gene amplification by fluorescent in situ hybridization and HER2 protein expression by immunohistochemistry (IHC) were assessed on whole tissue sections from 101 patients receiving peri- or postoperative epirubicin-based chemotherapy. In a subgroup of patients, at least two matched tumor blocks, originating either from surgical procedures (n = 88) or diagnostic biopsies (n = 32), were available for HER2 analyses by IHC. RESULTS: Eighteen of 101 patients (17.8 %) were HER2 positive, whereas TOP2A was amplified in 4 of 84 patients (4.7 %). HER2 positivity was significantly associated with improved disease-free survival [HR = 0.47 (95 % CI 0.22-0.99), P = 0.046] and overall survival [HR = 0.33 (95 % CI 0.13-0.83), P < 0.018], independent of clinical-pathologic features. HER2 expression in matched tumor blocks from the same resection specimen was discordant in up to 11.8 % of pairs, while this rate increased up to 27.2 % when diagnostic biopsies and paired surgical samples were compared. CONCLUSIONS: HER2 status is an independent prognostic biomarker in gastroesophageal adenocarcinomas receiving epirubicin-based chemotherapy. Compared to diagnostic biopsies, HER2 assessment in multiple resection specimens might lower the risk of sampling errors. These findings have several implications with respect to the optimal choice of the sample to be submitted to IHC testing of HER2.

KRAS mutation in lung metastases from colorectal cancer: prognostic implications.

KRAS mutant colorectal cancer (CRC) patients develop lung and brain metastases more frequently than KRAS wild-type (WT) counterpart. We retrospectively investigated the prognostic role of KRAS, BRAF, and PIK3CA (exon 20) mutations and loss of phosphatase and tensin homolog (PTEN) in surgically resected lung metastases. Lung specimens from 75 metastatic CRC (mCRC) patients treated with one or more metastasectomies with curative intent were analyzed. Sixty-four percent of patients had KRAS WT lung metastases. PTEN loss-of-function was found in 75%. BRAF and PIK3CA exon 20 mutations were not found. Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation. In univariate analysis, median overall survival (OS) for KRAS WT patients was longer, compared to KRAS mutant patients (median 60.9 vs. 36.6 months, P = 0.035). In addition, both progression-free survival (PFS) and lung disease-free survival (LDFS) between lung surgery and relapse were not associated with KRAS and PTEN status. In multivariate analysis, the risk of death was significantly increased by KRAS mutational status (OS Hazard ratio (HR) 2.17, 95% IC 1.19-3.96, P = 0.012) and lack of adjuvant chemotherapy (OS HR 0.10, 95% IC 0.01-0.74, P = 0.024). The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors. Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis. Moreover, administration of adjuvant chemotherapy after lung metastasectomy (LM) significantly improved both PFS and OS. KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM. Further larger and prospective studies are necessary to confirm these findings.

FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study.

BACKGROUND: Retrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression. PATIENTS AND METHODS: Originally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab. CONCLUSION: Although prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.

Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma.

PURPOSE: Preclinical studies show that sorafenib, a multitarget kinase inhibitor, displays anti-proliferative, anti-angiogenic, and pro-apoptotic properties in hepatocellular carcinoma (HCC). However, the determinants of sorafenib sensitivity in vivo remain largely unknown. METHODS: We assessed the expression of Mcl-1, activated/phosphorylated extracellular signal-regulated kinase (pERK) 1/2, and activated/phosphorylated AKT (pAKT) in pretreatment tumor specimens from 44 patients with advanced HCC who received sorafenib. Furthermore, we assessed MYC and MET gene copy numbers (GCN) by fluorescence in situ hybridization. RESULTS: Poorer overall survival (OS) times were correlated with pERK expression [hazard ratio (HR) 1.013; 95 % CI 1.003-1.035] and Mcl-1 expression (HR 1.016; 95 % CI 1.002-1.030) in pretreatment tumor samples. Expression levels of pERK and Mcl-1, however, were not correlated with time to tumor progression (TTP). Increased pERK expression was positively associated with higher Cancer of Liver Italian Program scores (P = 0.012) and was prognostic in patients with scores 2-6 but not in those with scores 0-1. pERK expression was significantly less frequent in specimens sourced from previous surgical procedures compared to biopsy samples (9.6 vs. 92.3 %, respectively; P < 0.0001). Analysis of pAKT expression, MET and MYC GCN, did not indicate any prognostic nor predictive values for these biomarkers in terms of survival. CONCLUSIONS: Expression levels of Mcl-1 and pERK are associated with reduced OS in HCC patients treated with sorafenib and might be useful markers for risk stratification. However, in contrast to previous findings, pERK expression levels, as well as other biomarkers tested, did not affect TTP.

Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Tumor shrinkage has been considered a fundamental surrogate efficacy measure for new cancer treatments. However, in patients treated with sorafenib for advanced hepatocellular carcinoma (HCC), tumor shrinkage rarely accompanies increased survival, thereby questioning the prognostic value of imaging-based Response Evaluation Criteria in Solid Tumors (RECIST). We investigated the prognostic usefulness of a decrease in serum alpha-fetoprotein (AFP) and compared it to RECIST. METHODS: In HCC patients treated with sorafenib with baseline AFP >20 ng/ml, AFP response was defined as a >20% decrease in AFP during 8weeks of treatment. Patients were also assessed by RECIST and were categorized as having radiologically proven progressive disease or disease control (consisting of complete or partial responses and stable disease). Comparisons of survival by RECIST and AFP response were corrected for guarantee-time bias by the landmark method. RESULTS: We evaluated 85 patients for AFP response, among them, 82 were also evaluated by RECIST. In the analysis of AFP response, 32 out of 85 patients (37.6%) were responders, whereas 58 out of 82 patients (70.7%) achieved disease control. In landmark analysis, the hazard ratios (HR) for survival according to AFP response and disease control were 0.59 (p=0.040) and 1.03 (p=0.913), respectively. In multivariate analysis, only AFP response (HR=0.52; p=0.009) and Cancer of the Liver Italian Program dichotomized stage (HR=0.42; p=0.002) were prognostic factors of survival. CONCLUSIONS: Assessment of AFP response may be considered as an alternative to RECIST to capture sorafenib activity in HCC.

Adjuvant PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) or gemcitabine followed by chemoradiation in pancreatic cancer: a randomized phase II trial.

BACKGROUND: Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. METHODS: Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS)>60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and ß=.10, the study was to enroll 51 patients per arm. RESULTS: A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS>80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. CONCLUSIONS: The 4-drug regimen deserves further assessment in resectable pancreatic cancer.

Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial.

PURPOSE: To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. PATIENTS AND METHODS: Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. RESULTS: Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). CONCLUSION: Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

Clinical outcome of hypofractionated stereotactic radiotherapy for abdominal lymph node metastases.

PURPOSE: We report the medium-term clinical outcome of hypofractionated stereotactic body radiotherapy (SBRT) in a series of patients with either a solitary metastasis or oligometastases from different tumors to abdominal lymph nodes. METHODS AND MATERIALS: Between January 2006 and June 2009, 19 patients with unresectable nodal metastases in the abdominal retroperitoneal region were treated with SBRT. Of the patients, 11 had a solitary nodal metastasis and 8 had a dominant nodal lesion as part of oligometastatic disease, defined as up to five metastases. The dose prescription was 45 Gy to the clinical target volume in six fractions. The prescription had to be downscaled by 10% to 20% in 6 of 19 cases to keep within dose/volume constraints. The first 11 patients were treated with three-dimensional conformal techniques and the last 8 by volumetric intensity-modulated arc therapy. Median follow-up was 1 year. RESULTS: Of 19 patients, 2 had a local progression at the site of SBRT; both also showed concomitant tumor growth at distant sites. The actuarial rate of freedom from local progression was 77.8% ± 13.9% at both 12 and 24 months. Eleven patients showed progressive local and/or distant disease at follow-up. The 12- and 24-month progression-free survival rates were 29.5% ± 13.4% and 19.7% ± 12.0%, respectively. The number of metastases (solitary vs. nonsolitary oligometastases) emerged as the only significant variable affecting progression-free survival (p < 0.0004). Both acute and chronic toxicities were minimal. CONCLUSIONS: Stereotactic body radiotherapy for metastases to abdominal lymph nodes was shown to be feasible with good clinical results in terms of medium-term local control and toxicity rates. Even if most patients eventually show progressive disease at other sites, local control achieved by SBRT may be potentially significant for preserving quality of life and delaying further chemotherapy.

Treatment trends in metastatic pancreatic cancer patients: Is it time to change?

BACKGROUND: Since gemcitabine became the standard treatment for metastatic pancreatic adenocarcinoma, combination chemotherapy obtained conflicting impact on survival (OS). AIMS: To evaluate Italian treatment trends in metastatic pancreatic cancer. METHODS: Data on treatment outcome of 943 chemo-naive patients with pathological diagnosis of stage IV pancreatic adenocarcinoma treated between 1997 and 2007 in Italian centres were analysed. RESULTS: Four treatment groups could be identified: (1) single agent gemcitabine (N=529); (2) gemcitabine-platinating agent doublets (N=105); (3) gemcitabine-free three-drug intraarterial combination (N=75); (4) four-drug gemcitabine-cisplatin-fluoropyrimidine based combinations (N=170). Median and actuarial 1 y OS of the whole population were 6.2 months and 20%, respectively. Gemcitabine (median OS 5.1 months) appeared significantly inferior to gemcitabine-free triplets (median OS 6.0 months; p=.04), gemcitabine-platinating agent doublets (median OS 7.4 months; p=.00001), or gemcitabine-based four drug combinations (median OS 9.1 months; p<.00001). CONCLUSION: These data mirror the Italian clinical practice in the therapeutic management of pancreatic cancer and suggest that four-drug combination chemotherapy may be included amongst the candidate regimens for phase III testing.

Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy.

BACKGROUND: NGR-hTNF consists of human tumour necrosis factor (hTNF) fused with the tumour-homing peptide Asp-Gly-Arg (NGR), which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Preclinical antitumour activity was observed even at low doses. We evaluated the activity and safety of low-dose NGR-hTNF in colorectal cancer (CRC) patients failing standard therapies. PATIENTS AND METHODS: Thirty-three patients with progressive disease at study entry received NGR-hTNF 0.8 µg/m(2) given intravenously every 3 weeks. The median number of prior treatment regimens was three (range, 2-5). One-quarter of patients had previously received four or more regimens and two-thirds targeted agents. Progression-free survival (PFS) was the primary study objective. RESULTS: NGR-hTNF was well tolerated. No treatment-related grade 3 to 4 toxicities were detected, most common grade 1 to 2 adverse events being short-lived, infusion-time related chills (50.0%). One partial response and 12 stable diseases were observed, yielding a disease control rate of 39.4% (95% CI, 22.9-57.8%). Median PFS and overall survival were 2.5 months (95% CI, 2.1-2.8) and 13.1 months (95% CI, 8.9-17.3), respectively; whereas in patients who achieved disease control the median PFS and overall survival were 3.8 and 15.4 months, respectively. In an additional cohort of 13 patients treated at same dose with a weekly schedule, there was no increased toxicity and 2 patients experienced PFS longer than 10 months. CONCLUSION: Based on tolerability and preliminary evidence of disease control in heavily pretreated CRC patients, NGR-hTNF deserves further evaluation in combination with standard chemotherapy.