Joon-Oh Park

Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum.

Background:Docetaxel is widely used as a chemotherapeutic agent for gastric cancer treatment. A combined regimen with sunitinib demonstrated a synergistic antitumour effect in a preclinical model. The aim of this study was to evaluate the efficacy and safety of this combination in patients with unresectable or metastatic advanced gastric cancer following failure of treatment with a fluoropyrimidine and platinum combination.Methods:This open-label, phase II, randomised trial enrolled patients with unresectable or metastatic gastric cancer. Patients were assigned to either a docetaxel monotherapy arm (D only arm: 60 mg m−2, every 3 weeks) or a combination arm (DS arm: docetaxel+sunitinib 37.5 mg every day). The primary end point of the study was time to progression and the secondary end points were overall response rate, disease control rate, overall survival, and toxicity profile. A pharmacokinetic study was also performed.Results:A total of 107 patients were entered into the study. The TTP was not significantly prolonged in the DS arm when compared with the D only arm (DS vs D only arm: 3.9 months (95% confidence interval (CI) 2.9–4.9) vs 2.6 months (95% CI 1.8–3.5) (P=0.206). The hazard ratio for TTP was 0.77 (95% CI 0.52–1.16). However, the objective response rate was significantly higher in the DS arm (41.1% vs 14.3%, P=0.002). Patients in the DS arm experienced stomatitis, diarrhoea, and hand–foot syndrome more frequently.Conclusion:The addition of sunitinib to docetaxel did not significantly prolong TTP, although it significantly increased response.

Patterns of failure in gastric carcinoma after D2 gastrectomy and chemoradiotherapy: a radiation oncologist's view

The risk of locoregional recurrence in resected gastric adenocarcinoma is high, but the benefit of adjuvant treatment remains controversial. In particular, after extended lymph node dissection, the role of radiotherapy is questionable. Since 1995, we started a clinical protocol of adjuvant chemoradiotherapy after D2 gastrectomy and analysed the patterns of failure for 291 patients. Adjuvant chemotherapy consisted of five cycles of fluorouracil and leucovorin, and concurrent radiotherapy was given with 4500 cGy from the second cycle of chemotherapy. With a median follow-up of 48 months, 114 patients (39%) showed any type of failure, and the local and regional failures were seen in 7% (20 out of 291) and 12% (35 out of 291), respectively. When the recurrent site was analysed with respect to the radiation field, in-field recurrence was 16% and represented 35% of all recurrences. Our results suggest that adjuvant chemoradiotherapy has a potential effect on reducing locoregional recurrence. Moreover, low locoregional recurrence rates could give a clue as to which subset of patients could be helped by radiotherapy after D2 gastrectomy. However, in order to draw a conclusion on the role of adjuvant radiotherapy, a randomised study is needed.

Salvage chemotherapy with irinotecan, 5-fluorouracil and leucovorin for taxane- and cisplatin-refractory, metastatic gastric cancer.

We performed a phase II study of combination chemotherapy with irinotecan, 5-fluorouracil (5-FU) and leucovorin in metastatic gastric cancer patients who were previously treated with taxane and cisplatin, to evaluate the antitumour activity and toxicity of the combination chemotherapy. The metastatic gastric adenocarcinoma patients who were previously treated with taxane and cisplatin combination as first line, and had at least one measurable lesion, 0–2 ECOG performance status and adequate organ functions, were considered eligible. They received irinotecan (150 mg m−2, day 1) and leucovorin (100 mg m−2, day 1), followed by continuous infusion of 5-FU (1000 mg m−2 day−1, days 1 and 2) every 2 weeks. Treatment was continued until progression of disease was observed. In all, 64 patients were treated with this combination chemotherapy. The median age of the patients was 55 years (range, 33–74 years), and the median ECOG performance status was 1 (0–1, 61 (95%)). Out of 64 patients, 57 were assessable for response. Among 57 assessable patients, no complete response and 12 partial responses were observed (overall response rate, 21%; 95% confidence interval (CI), 10–32%). Stable disease was observed in 14 patients (25%) and progressive disease in 31 patients (54%). The median time to progression was 2.5 months (95% CI, 1.6–3.4) and the median overall survival since the start of the second-line modified FOLFIRI was 7.6 months (95% CI, 6.5–8.7). Grade 3–4 haematologic toxicities included neutropenia in seven patients (11%) and thrombocytopenia in five patients (8%). Grade 3–4 nonhaematologic toxicities included diarrhoea in two patients (3%) and vomiting in two patients (3%). There were no treatment-related deaths. The combination of irinotecan, 5-FU and leucovorin showed moderate activity and favourable toxicity profile as a second-line treatment in metastatic gastric cancer patients, who were previously treated with taxane and cisplatin.

Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours

Background:Treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs) are still limited. We investigated the antitumour activity and safety profile of pazopanib – a multitarget drug with anti-angiogenic activity in patients with metastatic GEP NETs.Methods:This was a nonrandomised, open-labeled, single-center phase II study. Pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The primary end point was an objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety. An independent review of objective response was planned. The trial is registered with ClinicalTrials.gov, NCT number 01099540. Correlative biomarker analyses were performed.Results:Between April 2010 and February 2012, a total of 37 patients were enrolled. Thirty-two percent of the enrolled patients had pancreatic primary and 22% of the patients had colorectal primary NETs. This phase II study demonstrated an objective response rate of 18.9% (7 of the 37, 95% CI 8.0–35.2) and a disease control rate (CR+confirmed PR+stable disease) of 75.7% (28 of the 37, 95% CI, 58.8–88.2) in metastatic GEP NETs. The independent review demonstrated a higher overall response rate of 24.3% (95% CI, 11.8–41.2%) with nine confirmed PRs.Conclusion:Pazopanib showed a comparable efficacy to other targeted agents not only in pancreatic NETs but also in NETs originating from gastrointestinal (GI) tract.

Combination chemotherapy with epirubicin, docetaxel and cisplatin (EDP) in metastatic or recurrent, unresectable gastric cancer

Based on single agent activities and the additive or synergistic effects of three individual drugs in gastric cancer, we performed a phase II study of a new regimen combining epirubicin, docetaxel and cisplatin (EDP) for unresectable gastric cancer. The patients with histologically confirmed metastatic or recurrent, unresectable gastric cancer and no history of palliative chemotherapy were eligible for this trial. In total, 40 mg m−2 epirubicin (reduced to 30 mg m−2 due to high incidence of febrile neutropaenia; 75%) intravenously (i.v.) over 30 min, followed by 60 mg m−2 docetaxel i.v. over 1 h, then 75 mg m−2 cisplatin i.v. over 1 h was administered every 3 weeks. Between January 2002 and February 2003, 30 patients (epirubicin 40 mg m−2, eight; 30 mg m−2, 22) were enrolled. The median age was 52 years (range, 33–68). The patients received a median of four cycles (range, 1–8). One patient (3%) achieved a complete response, 13 (43%) showed partial responses, 13 (43%) had stable diseases and three (10%) progressed. The overall response rate was 47% (95% CI, 28–66%), and the median duration of response was 5.0 months (95% CI, 3.0–7.0). The median time to progression was 4.1 months (95% CI, 2.4–5.9), and the median overall survival was 11.0 months (95% CI, 9.5–12.4). Grade 4 neutropaenia were observed in 41%, and febrile neutropaenia in 32%, out of the patients receiving 30 mg m−2 of epirubicin. Grade 3 nonhaematological toxicities included nausea, vomiting, anorexia and peripheral neuropathy. In conclusion, EDP is active in gastric cancer, with a manageable and predictable toxicity profile.

Genetic polymorphisms associated with 5-Fluorouracil-induced neurotoxicity.

Background: Encephalopathy is a rare drug toxicity of fluorouracil therapy. Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes, thymidylate synthase and dihydropyrimidine dehydrogenase. Methods: Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5-fluorouracil-based chemotherapy presented with acute mental change and hyperammonemia. To evaluate the genetic background of the fluorouracil-associated hyperammonemic encephalopathy, analysis of the polymorphisms of the TYMS, DPYD and MTHFR genes was performed. Results: The patients revealed to be TYMS suppressors showing homogenous deletion of 6 bp in the 3′-UTR and 3RC/3RC genotype in the promoter enhancer region (TSER), respectively. Conclusion: Genetic polymorphisms of the TYMS gene would contribute to the 5-fluorouracil-associated hyperammonemic encephalopathy. The prospective validation of the clinical implication of TYMS gene polymorphisms is warranted.

A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer

Background:The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer.Methods:We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1 : 1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m−2 as a 90-min infusion, leucovorin at 200 mg m−2 as a 2-h infusion, and a bolus injection of 5-FU 400 mg m−2 followed by a 46-h continuous infusion of 5-FU at 2400 mg m−2. The XELIRI regimen consisted of irinotecan at 250 mg m−2 as a 90-min infusion with capecitabine 1000 mg m−2 twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity.Results:Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5–7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4–8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade ⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively).Conclusions:The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.

A phase II trial of concurrent chemoradiation therapy followed by consolidation chemotherapy with oral etoposide and cisplatin for locally advanced inoperable non-small cell lung cancers

We report a phase II study to evaluate the survival rate, response rate and toxicity of concurrent chemoradiation therapy (CCRT) followed by consolidation chemotherapy (CT) with oral etoposide and cisplatin for patients with locally advanced inoperable non-small cell lung cancer (NSCLC). Fifty-four patients with locally advanced inoperable NSCLC who had received no prior therapy were enrolled into this trial between May 1995 and December 2000. Treatment consisted of two cycles of concurrent CT and four cycles of consolidation CT with oral etoposide (50 mg/m2) on days 1-14 during the CCRT courses and on days 1-21 during the consolidation CT courses, plus cisplatin (75 mg/m2 i.v.) on day 1 of a 28-day cycle. Conventional radiotherapy (1.8 Gy/fraction, 63 Gy over 7 weeks) was delivered from day 1 of the CT. Fifty-two patients were evaluable for response. Twelve patients (22%) achieved complete responses, and 32 patients (60%) achieved partial responses, for an overall response rate of 82% with a median duration of response of 9.1 months. Forty-three per cent developed grade 4 haematological toxicity, 11% grade 3 or 4 oesophagitis and 7% grade 3 or 4 lung toxicity. There were two treatment-related deaths, one from radiation pneumonitis and the other from sepsis. After a median follow-up duration of 50 months (range 20-85), the median overall survival time was 15.3 months (95% CI, 9.7-20.8), and the 1-, 2-, 3-, and 5 year overall survival rates were 62, 40, 30 and 16%, respectively. The duration of median progression-free survival was 12.3 months (95% CI, 7.4-17.3), and the 1-, 2-, 3-, and 5-year progression-free survival rates were 47, 40, 29 and 23%, respectively. Thus, concurrent conventional chest radiotherapy with oral etoposide plus cisplatin followed by consolidation CT led to an encouraging survival rate and prolongation of the time to progression, with moderate toxicity in patients with locally advanced inoperable NSCLC.

Esophageal Squamous Cell Carcinoma Recurring as a Solitary Renal Mass

Herein, a case of solitary, unilateral renal metastasis in a patient with curatively resected thoracic esophageal carcinoma, who achieved a pathological complete remission after neoadjuvant concurrent chemoradiotherapy, is reported. The kidney is the 4(th) or 5(th) most common visceral metastasis site of a primary esophageal carcinoma. More than 50% of renal metastases typically show bilateral involvement. Solitary, unilateral renal metastasis is extremely rare. Renal metastases from a primary esophageal carcinoma are usually latent and its diagnosis is very unusual in a live patient. The solitary renal metastasis in this case was not accompanied by metastases to other sites. The value of a nephrectomy in solitary renal metastasis of esophageal cancer is not known due to the rarity of such cases. A nephrectomy could be justified in limited situations, such as with uncertainty of histological diagnosis, severe life-threatening hematuria, which cannot be controlled by embolization, or solitary renal metastasis with a long disease-free interval.

IMVP-16/Pd followed by high-dose chemotherapy and autologous stem cell transplantation as a salvage therapy for refractory or relapsed peripheral T-cell lymphomas

The present study aimed to analyse the treatment outcome of IMVP-16/Pd (ifosfamide, methotrexate, etoposide and prednisone) followed by high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with peripheral T-cell lymphomas (PTCLs) who were previously treated with CHOP. Since 1995, 32 PTCL patients were treated with IMPV-16/Pd. Nine of 32 patients achieved a response (5 demonstrating complete response (CR) and 4 partial response), with an overall response rate of 28.1% (95% onfidence interval 0.12–0.45). Considering histopathologic subtypes, 3 of 4 relapsed natural killer (NK)/T-cell lymphoma patients (75%) achieved CR, but only 1 of 6 in non-NK/T-cell lymphoma patients (16.7%) achieved CR (P = 0.19). Six of 9 IMVP-16/Pd sensitive patients underwent HDC/ASCT. Three of them relapsed after 3, 4 and 15 months, respectively, of HDC/ASCT. Estimated 3-year overall survival and progression-free survival rates were 14.2% and 12.2%, respectively. Multivariate analysis revealed that responsiveness to first-line CHOP was a significant prognostic factor (P < 0.05). These results indicate that IMVP-16/Pd followed by HDC/ASCT appears to be an effective salvage regimen, especially for NK/T-cell lymphoma.