Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer:A multicenter retrospective observational comparative study

BACKGROUND Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy(CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electrohyperthermia(mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer.AIM To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer.METHODS This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer(stage Ⅲ and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128(59%) of them were treated with CHT(no-mEHT) and 89(41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT.RESULTS Median patients’ age was 67 years(range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group(20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses(45% vs 24%, P = 0.0018) and a lower number of progressions(4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions.CONCLUSION mEHT seems safe and has beneficial effects on survival and tumor response of stage Ⅲ-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

Polyethylene glycol microspheres loaded with irinotecan for arterially directed embolic therapy of metastatic liver cancer

AIM To study tumor response, and tolerability of arterially directed embolic therapy(ADET) with polyethylene glycol embolics loaded with irinotecan for the treatment of colorectal cancer liver metastases(CRC-LM). Secondary objectives were to monitor quality of life, time to progression and survival of patients.METHODS Patients were included in the study if they were affected by CRC-LM, refractory to systemic chemotherapy, treated with ADET using polyethylene glycol embolics, and had liver involvement < 50%. Tumor response, performance status(PS), tumor marker antigens, and quality of life(QoL) were monitored at 1, 3 and 6 mo after ADET. QoL was assessed with the Palliative Performance Scale(PPS).RESULTS We treated 50 consecutive CRC-LM patients with ADET using polyethylene glycol embolics. Their tumor response one month after ADET was: 28% of complete response(CR), 48% of partial response(PR), 8% stable disease(SD), and 16% of progression. Tumor response 3 mo after ADET was CR 24%, PR 38%, SD 19% and progression disease(PD) 19%. Tumor response 6 mo after ADET was CR 18%, PR 44%, SD 21% and PD 18%. QoL was 90% PPS at each time point. Median time to progression for patients who progressed was 2.5 mo(range 0.8-6). Median follow-up was 14 mo(0.8-25 range). ADETs were performed with no complications. Observed side effects(mild or moderate intensity) were: Pain in 32% of patients, increase of transaminase levels in 20% and fever in 14%, whereas 30% of patients did not complain any adverse event. CONCLUSION The treatment of unresectable CRC-LM with ADET using polyethylene glycol microspheres loaded with irinotecan was effective in tumor response and resulted in mild toxicity, and good QoL.

Multidisciplinary approach of colorectal cancer liver metastases

Large bowel cancer is a worldwide public health challenge.More than one third of patients present an advanced stage of disease at diagnosis and the liver is the most common site of metastases.Selection criteria for early diagnosis,chemotherapy and surgery have been recently expanded.The definition of resectability remains unclear.The presence of metastases is the most significant prognostic factor.For this reason the surgical resection of hepatic metastases is the leading treatment.The most appropriate resection approach remains to be defined.The two step and simultaneous resection processes of both primary and metastases have comparable survival long-term outcomes.The advent of targeted biological chemotherapeutic agents and the development of loco-regional therapies(chemoembolization,thermal ablation,arterial infusion chemotherapy) contribute to extend favorable results.Standardized evidence-based protocols are missing,hence optimal management of hepatic metastases should be single patient tailored and decided by a multidisciplinary team.This article reviews the outcomes of resection,systemic and loco-regional therapies of liver metastases originating from large bowel cancer.

Isolated limb infusion chemotherapy with or without hemofiltration for recurrent limb melanoma

AIM: To better define the efficacy and the safety of intra-arterial infusion performed with or without hemofiltration for recurrent limb melanoma. METHODS: Patients with the following characteristics were included in the study: recurrent limb melanoma not indicated for surgical resection, measurable disease in the extremity, > 18 years, performances status(Eastern Cooperative Oncology Group) was 0-1 and life expectancy of at least 6 mo. Twenty nine consecutive patients were enrolled in the study. Patients underwent fluoroscopic placement of angiographic arterial and venous catheters to infuse the drug in the artery [isolated limb infusion(ILI)], and to stop the out flow(venous). Melphalan was rapidly infused into the isolated limb via the arterial catheter after the inflation of venous balloon catheter. Then the circulation of the limb was completely blocked with a pneumatic cuff at the root of the limb. Haemofiltration(HF) was available only in the main center, and was performed with an extracorporeal perfusion system, in order to reduce high systemic toxic peaks of drug.RESULTS: Thirty seven ILI were done in 29 cases(31 ILI-HF and 6 ILI) between 2001 and 2014 at Ancona and Pesaro Hospitals, Italy. Clinical outcomes were monitored 30 d after treatment. Eleven patients(38%) received infusion of melphalan alone, 7(24%) melphalan associated to mitomicin C and 7(24%) melphalan associated to cisplatin, the remaining 4 were treated with cisplatin, melphalan and epirubicin or cisplatin and mitomicin C. The overall response rate was 66%, in particular, 3 patients(10%) were complete responders and 16(56%) were partial responders; whereas 7 patients(24%) had stable disease, and 3(10%) showed progressive disease. Limb toxicity was assessed adopting Wieberdink scale, with evidence of 90% of low grade(I and II) toxicity.CONCLUSION: ILI-HF and ILI are effective and safe treatments for recurrent non-resectable limb melanoma. They present evidence of favorable clinical benefit and is effective in delaying progression.

Immune response activation following hyperthermic intraperitoneal chemotherapy for peritoneal metastases:A pilot study

BACKGROUND Hyperthermic intraperitoneal chemotherapy(HIPEC)for peritoneal metastases(PM)is considered to be feasible,safe and to improve survival.AIM To investigate whether an immune response is activated following HIPEC for PM.METHODS Six patients were enrolled in this study.Peripheral blood samples were obtained from each patient prior to(day 0)and post-procedure(day 30),and used to evaluate the number of CD3+total,CD3+/CD4+T-Helper,CD3+/CD8+cytotoxic T,CD3+/CD56+natural killer and CD19+B lymphocyte numbers,and CD4+:CD8+T lymphocyte ratios.RESULTS The total numbers of CD3+,CD3+/CD4+T-Helper,CD3+/CD8+cytotoxic T,CD3+/CD56+natural killer and CD19+B lymphocytes,and CD4+:CD8+lymphocyte ratios were increased in all but one patient 30 d following the cytoreductive surgery-HIPEC procedure,and these increases were significant(P≤0.05)for CD3+/CD4+T Helper and CD3+/CD8+cytotoxic T lymphocyte numbers.CONCLUSION This report provides the first evidence that HIPEC exhibits immunomodulating activity in PM patients,resulting in generalized activation of the adaptive immune response.Moreover,the majority of lymphocyte populations increased following HIPEC and continued to be elevated several weeks following the procedure,consistent with a potential authentic immunomodulating effect rather than a normal inflammatory response,to be fully characterised in future studies.

Locoregional therapy and systemic cetuximab to treat colorectal liver metastases

AIM: To investigate efficacy and safety of second-line treatment with irinotecan-loaded drug-eluting beads(DEBIRI) and cetuximab(DEBIRITUX) of unresectable colorectal liver metastases.METHODS: Patients with the following characteristics were included in the study: unresectable hepatic metastases from colorectal carcinoma(CRC-LM), progression after first line chemotherapy(any type of chemotherapeutic drug and combination was allowed), second line treatment(mandatory), which included for each patient(unregarding the KRas status) two cycles of DEBIRI(using 100-300 μm beads loaded with irinotecan at a total dose 200 mg) followed by 12 cycles of cetuximab that was administered weekly at a first dose of 400 mg/m2 and then 250 mg/m2; good performance status(0-2) and liver functionality(alanine aminotransferase and gamma-glutamyl transferase not exceeding three times the upper limit of normal, total bilirubin not exceeding 2.5 mg/m L). Data were collected retrospectively and included: tumor response(evaluated monthly for 6 mo then every 3 mo), overall response rate(ORR), KRas status, type and intensity of adverse events(G according to the Common Terminology Criteria for Adverse Events v3.0, CTCAE), overall survival(OS) and progression free survival(PFS).RESULTS: Forty consecutive cases of CRC hepatic metastases were included in the study. Median duration of DEBIRITUX was 4.4 mo(range, 4.0-6.5). Sixteen patients(40%) received the planned 2 cycles of DEBIRI and an average of 10 cetuximab cycles. ORR of the whole sample was 50%, in particular 4 patients were complete responders(10%) and 16(40%) partial responders. The most observed side effects(G2) were: post-embolization syndrome(30%), diarrhea(25%), skin rushes(38%) and asthenia(35%). The retrospective evaluation of KRas status(24 wild type, 16 mutated) showed that the group of patients with wild type KRas had ORR significantly higher than mutant KRas. Median follow-up was 29 mo(8-48 range); median PFS was 9.8 mo and OS was 20.4 mo. Future randomized trials are required in this setting to establish a role for DEBIRITUX compared with systemic chemotherapy.CONCLUSION: DEBIRITUX seems to be efficacious after first line chemotherapy for the treatment of unresectable CRC-LM.

Modulated electro-hyperthermia in stage III and IV pancreatic cancer:Results of an observational study on 158 patients

BACKGROUND An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy(CHT)and radiotherapy for the treatment of pancreatic cancer;in particular,the use of modulated electrohyperthermia(mEHT)results in increased survival and tumor response.AIM To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer.METHODS This was an observational retrospective study;data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019.A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals;58(37%)of these received CHT+mEHT and 100(63%)CHT.CHT was mainly gemcitabine-based regimens in both groups.RESULTS Overall(19.5 mo vs 11.02 mo,P<0.001)and progression-free(12 mo vs 3 mo,P<0.001)survival were better for the CHT+mEHT group compared to the CHT group.The association of mEHT resulted also in an improvement of tumor response with disease control rate 95%vs 58%(P<0.001)at 3 mo.Toxicity was comparable in the two study groups,and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns.CONCLUSION The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity.