S. Giaquinta

Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study)

Background:The conventional treatment options for advanced gastric patients remain unsatisfactory in terms of response rate, response duration, toxicity, and overall survival benefit. The purpose of this phase II study was to evaluate the activity and safety of cetuximab combined with cisplatin and docetaxel as a first-line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma.Methods:Untreated patients with histologically confirmed advanced gastric or gastro-oesophageal adenocarcinoma received cetuximab at an initial dose of 400 mg m−2 i.v. followed by weekly doses of 250 mg m−2, cisplatin 75 mg m−2 i.v. on day 1, docetaxel 75 mg m−2 i.v. on day 1, every 3 weeks, for a maximum of 6 cycles, and then cetuximab maintenance treatment was allowed in patients with a complete response, partial response, or stable disease.Results:Seventy-two patients (stomach 81.9% and gastro-oesophageal junction 18.1%; locally advanced disease 4.2%; and metastatic disease 95.8%) were enrolled. The ORR was 41.2% (95% CI, 29.5–52.9). Median time to progression was 5 months (95% CI, 3.7–5.4). Median survival time was 9 months (95% CI, 7–11). The most frequent grades 3–4 toxicity was neutropenia (44.4%). No toxic death was observed.Conclusions:The addition of cetuximab to the cisplatin/docetaxel regimen improved the ORR of the cisplatin/docetaxel doublet in the first-line treatment of advanced gastric and gastro-oesophageal junction adenocarcinoma, but this combination did not improve the TTP and OS. The toxicity of cisplatin/docetaxel chemotherapy was not affected by the addition of cetuximab.

Prospective study on the FDG–PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer

BACKGROUND 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was carried out before and after neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery for locally advanced rectal cancer (LARC). The aim of this study was to define its predictive and prognostic values. PATIENTS AND METHODS Patients with cT3-T4 N-/+ carcinoma of medium/low rectum received daily 5-fluorouracil-based chemotherapy infusion and radiation therapy on 6-week period followed by surgery 7-8 weeks later. Tumour metabolic activity, expressed as maximum standardised uptake value (SUV-1 = at baseline and SUV-2 = pre-surgery), was calculated in the most active tumour site. Predictive and prognostic values of SUV-1, SUV-2 and Δ-SUV (percentage change of SUV-1 - SUV-2) were analysed towards pathological response (pR) in the surgical specimen and disease recurrence, respectively. RESULTS Eighty consecutive patients entered the study. SUV-1, SUV-2 and Δ-SUV appeared singly correlated with pR, but not one of them resulted an independent predictive factor at multivariate analysis. After a median follow-up of 44 months, 13 patients (16.2%) presented local and/or distant recurrence. SUV-2 ≤5 was associated with lower incidence of disease recurrence and resulted prognostic factor at multivariate analysis. CONCLUSIONS Dual-time FDG-PET/CT in patients with LARC treated with NCRT and radical surgery supplies limited predictive information. However, an optimal metabolic response appears associated with a favourable patient outcome.

Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study)

BACKGROUND The aim of this phase II study was to assess the activity of panitumumab in combination with oxaliplatin, 5-fluorouracil, and external radiotherapy (RT) as preoperative treatment in locally advanced rectal cancer patients. PATIENTS AND METHODS Patients had rectal adenocarcinoma, cT3N+ or cT4N-/+ stage, located <12 cm from the anal margin. Panitumumab was administered before the start of chemo-RT, and every 2 weeks in combination with 5-fluorouracil-oxaliplatin with concurrent RT. Rectal surgery was carried out 7-8 weeks after the end of neoadjuvant treatment. The primary end point was a pathological complete response rate of 25%. RESULTS Sixty patients were enrolled from February 2007 to October 2009. Fifty-five (91.7%) patients underwent surgery. Rate of pathological complete response was 21.1% (95% confidence interval 10.4% to 31.6%). Pathological downstaging occurred in 33 of 57 (57.9%) patients. Grade 3-4 toxicity during neoadjuvant treatment was diarrhea (38.9%), cutaneous reactions (18.6%), nausea (5.1%), asthenia (3.4%), anorexia (3.4%), and neutropenia (1.7%). One toxic death was observed for diarrhea. CONCLUSIONS In our study, the primary end point is not reached and panitumumab combination treatment was associated with high incidence of grade 3-4 diarrhea. The higher pathological complete response rate in comparison with the results of previous neoadjuvant rectal cancer trials with anti-epidermal growth factor receptor monoclonal antibodies supports further studies necessary to understand the possibility of optimal regimens and sequences with chemo-RT.

The predictive value of 18F-FDG-PET early evaluation in patients with metastatic gastric adenocarcinoma treated with chemotherapy plus cetuximab

BackgroundThe aim of the study was to evaluate whether the therapy-induced reduction of the 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) maximum standardized uptake value in patients with advanced gastric adenocarcinoma treated with chemotherapy plus cetuximab could predict the objective response and outcome early during the treatment.MethodsThe study was performed as a part of a phase II trial evaluating cetuximab plus the leucovorin/5-fluorouracil/irinotecan (FOLFIRI) regimen. The objective response was evaluated according to the response evaluation criteria in solid tumors (RECIST) every 6 weeks. The early metabolic response evaluated by 18F-FDG-PET was assessed according to our own evaluated cutoff value (<35%) after receiver operating characteristic (ROC) analysis.ResultsTwenty of 22 patients had positive baseline 18F-FDG-PET. The best RECIST response was: complete response (CR), 3; partial response (PR), 9; stable disease (SD), 8. Twelve patients (60%) were classified as metabolic responders and 8 (40%) as nonresponders. At the median follow-up time of 11 months, median time to disease progression (TTP) and overall survival (OS) for early metabolic responders versus nonresponders were 11 versus 5 months (P = 0.0016) and 16 versus 6 months (P = 0.1493), respectively.ConclusionThe early metabolic response evaluated by 18F-FDG-PET predicted the clinical outcome in this series of patients with advanced gastric cancer treated with chemotherapy plus cetuximab.

Treatment Strategy for Rectal Cancer with Synchronous Metastasis: 65 Consecutive Italian Cases from the Bologna Multidisciplinary Rectal Cancer Group

Background: Twenty percent of rectal cancer patients have synchronous distant metastasis at diagnosis. At present, the treatment strategy in this patient setting is not well defined. This study in one institution evaluates the treatment strategy of three different patient groups. Patients and Methods: Between January 2000 and July 2011, 65 patients with M1 rectal cancer were evaluated. Three different groups were defined: rectal cancer with resectable metastatic disease (group A); rectal cancer with potentially resectable metastatic disease (group B), and rectal cancer with unresectable metastatic disease (group C). Results: Group A included 11 patients (16.9%), group B 28 patients (43.1%) and group C 26 patients (40%). Forty-three (66.2%) patients underwent surgery for primary rectal cancer, and 30 (46.2%) patients for metastasis resection (23 liver, 4 lung and 3 ovary). Median overall survival (OS) by group was: 51 (5-86; group A), 32 (24-40; group B) and 16 (7-26; group C) months. Patients undergoing metastasis resection have higher median OS than unresected patients (44 vs. 15 months; p < 0.001). Conclusions: The treatment strategy in synchronous metastatic rectal cancer must consider the possibility of distant metastasis resection. Long-term survival can be achieved using an integrated approach.

Phase II Study of Preoperative Treatment with External Radiotherapy Plus Panitumumab in Low‐Risk, Locally Advanced Rectal Cancer (RaP Study/STAR‐03)

BACKGROUND Treatment with fluoropyrimidines and concomitant long-course external radiotherapy (RTE) is the standard of care in locally advanced rectal cancer (LARC) preoperative chemoradiation. A randomized phase II study (RaP/STAR-03) was conducted that aimed to evaluate the activity and safety of the monoclonal antibody anti-epidermal growth factor receptor panitumumab as a single agent in combination with radiotherapy in low-risk LARC preoperative treatment. MATERIALS AND METHODS Patients had adenocarcinoma of the mid-low rectum, cT3N- or cT2-T3N+, KRAS wild-type status, and negative circumferential radial margin. Panitumumab was administered concomitant to RTE. Rectal surgery was performed 6-8 weeks after the end of preoperative treatment. The adjuvant chemotherapy regimen was FOLFOX. The primary endpoint was the pathologic complete response (pCR) rate. The sample size was calculated using Simons two-stage design. A pCR of 16% was considered to qualify the experimental treatment for further testing. RESULTS Ninety-eight patients were enrolled in 13 Italian centers from October 2012 to October 2015. Three panitumumab infusions were administered in 92 (93.4%) patients. The RTE compliance was median dose 50.4 Gy; ≥28 fractions in 82 (83.7%) patients. Surgical treatment was performed in 92 (93.9%) patients, and no severe intraoperative complications were observed. A pCR was observed in 10 (10.9%) patients (95% confidence interval, 4.72%-17.07%). Pathological downstaging occurred in 45 (45.9%) patients. Grade 3 toxicities were observed in 22 (22.3%) patients, and the common adverse events were skin rash in 16 (16.3%) patients. No grade 4 toxicities were reported. CONCLUSION The pCR rate (our primary endpoint), at only 10.9%, did not reach the specified level considered suitable for further testing. However, the analysis showed a good toxicity profile and compliance to concomitant administration of panitumumab and RTE in preoperative treatment of LARC. The pCR evaluation in all wild-type RAS is ongoing. IMPLICATIONS FOR PRACTICE The aim of the RaP/STAR-03 study was to evaluate the activity and safety of monoclonal antibody anti-epidermal growth factor receptor (EGFR) panitumumab as a single agent without chemotherapy in low-risk, locally advanced rectal cancer (LARC) preoperative treatment. Nevertheless, the use of panitumumab in combination with radiotherapy in preoperative treatment in patients with KRAS wild type and low-risk LARC did not reach the pathologic complete response primary endpoint. This study showed a good toxicity profile and compliance to combination treatment. Further analysis of NRAS and BRAF on tissue and circulating levels of the EGFR ligands and vascular factors (soluble vascular endothelial growth factor, E-selectin) may provide insight on the potential molecular pathways involved in the anti-EGFR response.

Analysis of predictive and prognostic value of clinical and pathological factors in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT): Bologna multidisciplinary rectal cancer group study (BMRG-B01-Study).

421 Background: Preoperative fluoropyrimidine based CRT is standard treatment in LARC patients. The aim of this study was to evaluate prognostic and predictive role of clinical and pathological factors in this setting Methods: Between December 2001 and January 2012 we evaluated 149 pts with cT3-T4 N-/+ rectal adenocarcinoma located ≤12 cm from the anal margin. Preoperative CRT consisted of radiotherapy 50.4 Gy in 28 daily fractions + 5-fluorouracil or capecitabine +/- oxaliplatin. Rectal surgery with total mesorectal excision was performed 6-8 weeks after the end of neoadjuvant treatment. Pathological examination of surgical specimens included TRG according to the Dworak criteria. TS, EGFR, Ki-67, p53, Bcl-2, MLH1 and MSH2 were immunohistochemically determined in pre-treatment biopsies and surgical specimens. For immunohistochemistry evaluation serial sections of formalin-fixed, paraffin-embedded tissues were stained with specific antibodies using a biotin-free ready-to-use amplification system Results: A...

Long-term results of a pilot study on an intensive induction regimen for unresectable stage III non-small-cell lung cancer

BACKGROUND In 1995, we designed and carried out a pilot study on the combination of cisplatin + high dose epirubicin + vinorelbine with granulocyte-colony-stimulating factor support for the induction treatment of unresectable stage IIIAN2 and wet IIIB non-small-cell lung cancer. The present report concerns the long-term results. METHOD Eligible patients received cisplatin, 75 mg/m(2), and epirubicin, 120 mg/m(2), on day 1, vinorelbine, 25 mg/m(2), on days 1 and 15, and granulocyte-colony-stimulating factor, 300 microg s.c., from days 3 to 12. The cycle was repeated every 3 weeks for 3 times. Subsequently, all the patients were re-evaluated for surgical resection. RESULTS Twenty-six patients were enrolled: 21 males and 5 females; median age, 55 years (range, 31-64); median performance status, 90% (range, 80-100); 16 stage IIIA and 10 IIIB. After the 3 cycles, objective response was as follows: 2 complete (8%), 18 partial (69%), 5 no change (19%) and 1 progressive disease (4%). Ten patients were not operated (9 unresectable and 1 refusal) and received radiotherapy. Sixteen patients (61%) underwent surgery and 14 were completely resected (54%). After a median follow-up of 84 months (range, 12-120), the median overall progression-free survival was 17 months (range, 2-104+): 47 months for resected and 8 months for nonresected patients. The median overall survival was 40 months (range, 4-123+): 87 months for resected and 13 months for nonresected patients. One-year, 3-year and 5-year survival rates were 73%, 42% and 37%, respectively. CONCLUSIONS These intensive cytotoxic regimen enabled us to obtain favorable long-term results in a selected series of inoperable stage III non-small-cell lung cancer patients.