Giuseppe Fanetti

FOLFOX-4 chemotherapy for patients with unresectable or relapsed peritoneal pseudomyxoma.

PURPOSE The standard treatment of peritoneal pseudomyxoma is based on cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The establishment of newer systemic treatments is an unmet clinical need for unresectable or relapsed peritoneal pseudomyxoma. The aim of our study was to assess the activity of chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX-4 regimen) in terms of response rate in this subset of patients. MATERIALS AND METHODS Patients were included in a single-center, observational study and treated with FOLFOX-4 administered every 2 weeks for up to 12 cycles or until progressive disease or unacceptable toxicity. RESULTS Twenty consecutive patients were reviewed from July 2011 to September 2013. Only partial responses were observed, with an objective response rate of 20%. Median progression-free survival and overall survival were 8 months and 26 months, respectively. Two patients were able to undergo laparotomy with complete cytoreduction and HIPEC in one case. Safety data for FOLFOX-4 were consistent with the literature. By means of a mutant enriched polymerase chain reaction, KRAS mutation was found in 16 of 19 cases (84%), and MGMT promoter methylation was found in 8 (42%, all KRAS mutant). CONCLUSION FOLFOX-4 chemotherapy is tolerable and active in patients with peritoneal pseudomyxoma when disease is deemed unresectable or relapsed after peritonectomy and HIPEC. The identification of predictive biomarkers, such as KRAS for resistance to anti-epidermal growth factor receptor monoclonal antibodies and MGMT for response to temozolomide, is a priority for the development of evidence-based treatment strategies for peritoneal pseudomyxoma.

Salvage Stereotactic Body Radiotherapy for Isolated Lymph Node Recurrent Prostate Cancer: Single Institution Series of 94 Consecutive Patients and 124 Lymph Nodes

Background The purpose of the study was to evaluate the prostate serum antigen (PSA) response, local control, progression‐free survival (PFS), and toxicity of stereotactic body radiotherapy (SBRT) for lymph node (LN) oligorecurrent prostate cancer. Patients and Methods Between May 2012 and October 2015, 124 lesions were treated in 94 patients with a median dose of 24 Gy in 3 fractions. Seventy patients were treated for a single lesion and 25 for > 1 lesion. In 34 patients androgen deprivation (AD) was combined with SBRT. We evaluated biochemical response according to PSA level every 3 months after SBRT: a 3‐month PSA decrease from pre‐SBRT PSA of more than 10% identified responder patients. In case of PSA level increase, imaging was performed to evaluate clinical progression. Toxicity was assessed every 6 to 9 months after SBRT. Results Median follow‐up was 18.5 months. In 13 patients (14%) Grade 1 to 2 toxicity was reported without any Grade 3 to 4 toxicity. Biochemical response, stabilization, and progression were observed in 64 (68%), 10 (11%), and 20 (21%) of 94 evaluable patients. Clinical progression was observed in 31 patients (33%) after a median time of 8.1 months. In‐field progression occurred in 12 lesions (9.7%). Two‐year local control and PFS rates were 84% and 30%, respectively. Age older than 75 years correlated with better biochemical response rate. Age older than 75 years, concomitant AD administered up to 12 months, and pelvic LN involvement correlated with longer PFS. Conclusion SBRT is safe and offers good in‐field control. At 2 years after SBRT, 1 of 3 patients is progression‐free. Further investigation is warranted to identify patients who benefit most from SBRT and to define the optimal combination with AD. Micro‐Abstract Stereotactic body radiotherapy is being investigated in nodal oligometastatic prostate cancer recurrences as an alternative to systemic treatment. This approach yields excellent in‐field control and a low toxicity profile. In selected cases, this approach might also defer palliative androgen deprivation therapy.

Role of MGMT as biomarker in colorectal cancer.

O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.

Role of BAX for outcome prediction in gastrointestinal malignancies

Our group and numerous others have shown in both preclinical and clinical studies that the proapoptotic mediator BAX may be deregulated through gene mutation or loss of protein expression, affecting resistance to chemotherapy and radiotherapy in several cancer types. However, BAX is also involved in cancer development and may related to prognosis, independently of treatment outcome. The clinical impact of BAX status in gastrointestinal malignancies remains controversial, although it is generally hypothesized that high expression may be a positive prognostic factor and predict increased efficacy of chemotherapy (with particular regard to platinum derivatives). The present review aims to provide updated information on BAX as potential prognostic and/or predictive biomarker in gastroesophageal and colorectal cancers, as well as in other less studied gastrointestinal malignancies.

No increase in toxicity of pelvic irradiation when intensity modulation is employed: clinical and dosimetric data of 208 patients treated with post-prostatectomy radiotherapy.

OBJECTIVE To compare the toxicity of image-guided intensity-modulated radiotherapy (IG-IMRT) to the pelvis or prostate bed (PB) only. To test the hypothesis that the potentially injurious effect of pelvic irradiation can be counterbalanced by reduced irradiated normal tissue volume using IG-IMRT. METHODS Between February 2010 and February 2012, 208 patients with prostate cancer were treated with adjuvant or salvage IG-IMRT to the PB (102 patients, Group PB) or the pelvis and prostate bed (P) (106 patients, Group P). The Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria were used to evaluate toxicity. RESULTS Median follow-up was 27 months. Toxicity G ≥ 2 in Group PB: in the bowel acute and late toxicities were 11.8% and 10%, respectively; urinary acute and late toxicities were 10.8% and 15%, respectively. Toxicity G ≥ 2 in Group P: in the bowel acute and late toxicities were both 13.2%; urinary acute and late toxicities were 13.2% and 15.1%, respectively. No statistical difference in acute or late toxicity between the groups was found (bowel: p = 0.23 and p = 0.89 for acute and late toxicity, respectively; urinary: p = 0.39 and p = 0.66 for acute and late toxicity, respectively). Of the clinical variables, only previous abdominal surgery was correlated with acute bowel toxicity. Dosimetric parameters that correlated with bowel toxicity were identified. CONCLUSION The toxicity rates were low and similar in both groups, suggesting that IG-IMRT allows for a safe post-operative irradiation of larger volumes. Further investigation is warranted to exclude bias owing to non-randomized character of the study. ADVANCES IN KNOWLEDGE Our report shows that modern radiotherapy technology and careful planning allow maintaining the toxicity of pelvic lymph node treatment at the acceptable level, as it is in the case of PB radiotherapy.

Are antineoplastic drug acute hypersensitive reactions a submerged or an emergent problem? Experience of the Medical Day Hospital of the Fondazione IRCCS Istituto Nazionale Tumori

Background Acute hypersensitivity reactions are adverse events potentially associated with antineoplastic drug infusions. Their occurrence can be particularly relevant in an outpatient environment where time of administration and subsequent observation is limited to a short period of time. In addition, concern about the onset of more severe hypersensitivity reactions can limit subsequent use of crucial drugs. Methods During a 3-year observational period, we collected a total of 240 infusional acute hypersensitivity reactions out of 56,120 administrations performed, with an overall incidence of 0.4%. Results In order of frequency, platinum derivatives, taxanes and monoclonal antibodies accounted for the highest incidences. Their relative frequency was: oxaliplatin, 2.5%; carboplatin, 0.4%; paclitaxel, 1.2%; docetaxel, 1.2%; trastuzumab, 1.2%, and rituximab, 1.2%. Conclusions Since the number of chemotherapeutic agents is steadily increasing, much attention should be paid to such reactions, particularly when several administrations are performed daily, and where management of the potential risk associated with specific drugs is mandatory. Their occurrence represents an unpredictable, unexpected and often hard to manage contingency, and our opinion is that observation and consciousness of this issue are fundamental for its appropriate management. We describe our experience, emphasizing the role of this toxicity and explaining how this awareness allowed us to define some empirical rules to handle acute hypersensitivity reactions.

Nutritional Intervention for Nonsurgical Head and Neck Cancer Patients Treated with Radiation Therapy: Results from a Prospective Stepped-Wedge Clinical Protocol

Abstract Aim: To evaluate the impact on weight loss (WL) of a standardized nutritional stepped-wedge protocol on consecutive head and neck cancer (HNC) patients treated with curative radiotherapy (RT). Methods: We prospectively collected data of patients followed by a trained dietitian and treated according to a pre-defined stepped-wedge protocol. Patients with swallowing defect at the baseline and WL >10% 3 months prior to the beginning of RT were excluded from the analysis. Nutritional status was assessed at the baseline and weekly during the course of RT. Fluid and caloric intake were assessed through a 24-h recall. Results: Between May 2010 and March 2011, 42 patients treated were evaluated. Median overall treatment time was 52.5 days. WL per CTCAE 4.03 was G0, G1 and G2 in 23 (55%), 14 (33%) and 5 (12%) patients, respectively. Thirty-five (83%) patients did not require enteral nutrition. About 90% of patients completed RT without interruption of oral feeding. Conclusions: Despite the high toxicity profile of curative RT in HN, we proposed a standardized stepped-wedge protocol allowing to prevent severe WL in most of our patients. Further larger prospective studies are warranted to validate our approach and to achieve consensus on nutritional intervention in this subset of patients.