Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer were updated and published online in 2023, and adapted, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with early breast cancer. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with breast cancer representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and KSMO. The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with early breast cancer across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling, as well as the age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

The efficacy of immune checkpoint inhibitors in elderly patients: a meta-analysis and meta-regression.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has improved patient survival in advanced cancers; however, the efficacy of ICIs in elderly patients is still elusive. This study assessed the efficacy of ICIs in elderly patients with advanced cancer in terms of overall survival (OS) and progression-free survival (PFS). MATERIALS AND METHODS: We carried out a systematic review and identified 30 head-to-head phase II/III randomized controlled trials that compared immunotherapy with the standard of care in advanced solid tumor patients. The data on patients younger or over 65 years of age were indexed from PubMed-Medline, Embase, and Scopus and obtained for meta-analysis. The subgroup analyses were stratified by primary tumor type, line of treatment, or type of immunotherapy, and a meta-regression analysis was carried out after adjusting for all other variables. RESULTS: The study included 17 476 patients, comprising 58% (10 119) younger (<65 years old) and 42% (7357) elderly (≥65 years old) patients. The hazard ratio (HR) for OS was 0.77 [95% confidence interval (CI) 0.70-0.85] and 0.77 (95% CI 0.70-0.85) in the younger and elderly groups, respectively, suggesting similar efficacies of ICIs in these two age groups. The subgroup analyses revealed no significant relationship between age and treatment outcomes, except for the PFS benefit in younger patients with melanoma than in elderly patients (HR 0.44 in younger patients versus 0.65 in elderly patients, P = 0.04). These results were further supported by meta-regression analysis, which showed no statistically significant difference in OS (P = 0.954) and PFS (P = 0.555) between the two age groups. CONCLUSIONS: The findings suggest that age-associated impairments of the immune system did not affect the efficacy of ICIs in elderly patients compared to younger patients. Therefore, the choice of ICIs for elderly patients can be considered, regardless of chronological age.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Association of the ABCB1 gene polymorphisms 2677G>T/A and 3435C>T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients.

BACKGROUND: ABCB1 is responsible for multidrug resistance, the principal mechanism by which many cancers develop resistance to chemotherapeutic drugs. There is a controversy whether ABCB1 gene polymorphisms correlate with survival and response in cancer patients treated with chemotherapy. We evaluated the association between clinical outcome (safety and efficacy) of paclitaxel monotherapy in metastatic breast cancer patients with ABCB1 gene polymorphisms 2677G>T/A or 3435C>T. PATIENTS AND METHODS: Patients with metastatic breast cancer were treated with 175 mg/m(2) paclitaxel per 3-week cycle. Peripheral blood mononuclear cells from patients were used to genotype ABCB1 2677G>T/A and 3435C>T polymorphisms. Genotypes were investigated for their association with tumor response, survival, toxicity, and chemoresistance. RESULTS: ABCB1 3435 CT showed a significantly lower disease control rate than the CC genotype (P = 0.025). ABCB1 3435 CT was correlated with shorter overall survival (OS) in Cox regression analysis (P = 0.026). The 2677 GG genotype showed a significant association with chemoresistance to paclitaxel and anthracycline (P = 0.04 and 0.04, respectively). None of the ABCB1 genotypes correlated with toxicity. CONCLUSIONS: ABCB1 genotypes may be a predictor of paclitaxel activity as well as a prognostic factor in metastatic breast cancer patients.

Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer.

BACKGROUND: This phase II study describes the efficacy and safety of combination chemotherapy of 5-fluorouracil (5-FU), low-dose leucovorin, and oxaliplatin (FLOX regimen) for pretreated advanced gastric cancer. PATIENTS AND METHODS: Patients who had been previously treated with greater than or equal to one regimen were enrolled. Patients received an oxaliplatin 75 mg/m(2) on day 1, 5-FU 1000 mg/m(2) on days 1-3, and leucovorin 20 mg/m(2) on days 1-3, every 3 weeks. The primary end point was overall survival (OS). RESULTS: Among the 52 patients enrolled, 26 patients were treated as second line, and the remaining 26 patients were enrolled as third- or fourth line. A total of 203 cycles of chemotherapy were administered with the median being three cycles (range 1-15) per patient. The median OS was 6.6 months [95% confidence interval (CI) 4.5-8.8] and the median progression-free survival was 2.5 months (95% CI 1.9-3.0). The response rate was 4% (95% CI 0-9%), and the disease control rate was 48% (95% CI 34-62%). The most common toxic effects of grade 3/4 were neutropenia (16%) and vomiting (6%). CONCLUSIONS: The FLOX regimen showed modest activity as a salvage treatment in pretreated advanced gastric cancer with a favorable compliance.

Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases.

BACKGROUND: The benefit of surgical resection of liver metastases from gastric cancer has not been well established. The aim of this study was to evaluate the rationale for hepatic resection in patients with hepatic metastases from gastric cancer. METHODS: Among 10 259 patients diagnosed with gastric adenocarcinoma in the Yonsei University Health System from 1995 to 2005, we reviewed the records of 58 patients with liver-only metastases from gastric cancer who underwent gastric resection regardless of hepatic surgery. RESULTS: The overall 1-year, 3-year, and 5-year survival rates of 41 patients who underwent hepatic resection with curative intent were 75.3%, 31.7%, and 20.8%, respectively, and three patients survived >7 years. Of the 41 patients, 22 had complete resection and 19 had palliative resection. Between the curative and palliative resections, survival rates after curative intent were not different. The number of liver metastasis (solitary or multiple) was a marginally significant prognostic factor for survival. CONCLUSIONS: Surgery for liver metastases arising from gastric adenocarcinoma is reasonable if complete resection seems feasible after careful preoperative staging, even if complete resection is not actually achieved. Hepatic resection should be considered as an option for gastric cancer patients with hepatic metastases.

A phase II study of S-1 monotherapy administered for 2 weeks of a 3-week cycle in advanced gastric cancer patients with poor performance status.

Systemic chemotherapy for gastric cancer is often associated with treatment-related toxicity, which is particularly severe in patients with a poor performance status. In this paper, we describe the first study to evaluate S-1 monotherapy as an option for advanced gastric cancer patients who are not candidates for combination chemotherapy due to poor clinical condition. Fifty-two patients with Eastern Cooperative Oncology Group (ECOG) performance scale 2-3, whose general condition had made use of combination chemotherapy impossible, were enrolled. S-1 was administered to 30 patients as second- or third-line therapy. The initial dose of S-1 was 35 mg m(-2), administered b.i.d for 14 days every 3 weeks. With a median follow-up period of 33 weeks, the median progression-free survival, and overall survival were 11 weeks (95% CI, 8-14) and 33 weeks (95% CI, 19-47), respectively. The overall 1-year survival rate was 29% by intent-to-treat analysis. The overall response rate was 12% (95% CI, 3-21), and the percentage of stable disease was 35%, resulting in the disease control rate of 47% (95% CI, 32-60). Significant drug-related toxicity included grade 3 diarrhoea (14%), anorexia (14%), fatigue (10%), neutropenia (10%), and leucopenia (6%). In conclusion, this study indicated the modest activity of S-1 in gastric cancer patients with poor performance status.

A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens.

This is the first phase II study of S-1 monotherapy for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. The initial dose of S-1 was 35 mg m-2, administered twice daily for 14 days every 3 weeks. Treatment was repeated until the occurrence of disease progression. Twenty-eight patients were enrolled. S-1 was administered to 21 patients as third-line therapy and to the remaining seven patients as fourth-line therapy. Of 26 evaluable patients, the overall response rate was 14.3% (95% CI, 0.4-28.1), and the disease control rate was 42.9% (95% CI, 23.3-62.4). With a median follow-up period of 227 days, median time to progression and overall survival duration were 91 and 414 days, respectively. The 1-year survival rate of all patients was 60.7%. There was no grade 4 toxicity. Grade 3 haematological toxicities were documented only in two patients. In conclusion, S-1 shows potential as a salvage regimen in heavily pretreated colorectal cancer patients. The twice-daily dose of 35 mg m-2 was well tolerated and can be used in designing further combination chemotherapy.

Identification of human astrovirus infections from stool samples with diarrhea in Korea.

Human astrovirus (HAstV) infections were confirmed in 17 (1.5%) of 1153 children and adults with diarrhea, from different regions of Korea, by testing their stool samples by reverse transcription-polymerase chain reaction using primers targeted to partial ORF 1a. Genotypes of isolates were determined by sequencing the 289-bp PCR products. The predominant genotype was HAstV type 1, with intragenotypic variation of 0.7%. Unlike Norwalk-like viruses (NLVs), rotavirus and enteric adenovirus, no data on HAstV have been reported in association with diarrhea in Korea. The incidence of HAstV infection reported in this study indicates that HAstV is one of the viral agents causing gastroenteritis in Korea, and that a continuous molecular epidemiological study of HAstV infection is required.

Monthly 5-days 5-fluorouracil and low-dose leucovorin for adjuvant chemotherapy in colon cancer.

We investigated the dose-related effect of the 5-fluorouracil (5-FU)/leucovorin regimen on survival in 139 colon cancer patients with Dukes' B2 and C2 stage disease. Chemotherapy consisted of 400 mg/m(2) of 5-FU and 20 mg/m(2) of leucovorin injected daily for 5 days in every 4 weeks for a maximum of 12 cycles. The total dose of 5-FU administered per body surface area had a significant effect on the 5-year disease-free survival and 5-year overall survival in stage B2 and C2 colon cancer patients (P=0.0018, P=0.0011). Analysis with reference to the median DSDI demonstrated that there was a significant difference in 5-year survival in Dukes' C2 (P=0.0016), but survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administered per surface area affected the 5-year disease-free survival and 5-year overall survival (P=0.0016, P=0.0007, respectively). It can be concluded that the total dose of 5-FU administered is important in planned dosage schedule of adjuvant chemotherapy in colon cancer.

Effect of vinorelbine, ifosfamide, and cisplatin combination chemotherapy in advanced non-small-cell lung cancer.

Cisplatin-based chemotherapy is being tried in the treatment of nonoperable cases of non-small-cell lung cancer (NSCLC). However, the prognosis is unfavorable and to improve survival, clinical studies using various combinations of a variety of drugs as well as experimental material are in progress. We compared the efficacy and toxicities of combination chemotherapy using different doses of vinorelbine and ifosfamide with a constant dose of cisplatin in this study. Patients diagnosed with inoperable stage III or IV NSCLC between June 1997 and December 1998 were included. Cisplatin was administered at a constant dose of 80 mg/m2 on day 5, whereas vinorelbine on days 1 and 5 and ifosfamide on day 5 were administered in one of two different doses. In arm A, vinorelbine 25 mg/m2 and ifosfamide 3.0 g/m2 were administered. In arm B, vinorelbine 20 mg/m2 and ifosfamide 2.5 g/m2 were administered. Also, we reviewed for phase II and III studies that test 1) cisplatin, 2) vinorelbine monotherapy, and 3) vinorelbine/cisplatin/ifosfamide combination chemotherapy for stage IIIb-IV non-SCLC. Summation dose intensity (SDI) was calculated in each published and current study. Twenty patients in arm A and 35 patients in arm B were available for evaluation. There was no difference in patient activity, pathologic diagnosis, and differentiation or stage between the two arms. The median number of cycles was four in both arms. The response rate was 50% in arm A and 30% in arm B. The median survival times for arm A and B were 40 and 42 weeks, respectively, whereas the SDI was 1.94 and 1.7, respectively. More than grade III leukopenia was observed in 28.9% in arm A, which is more frequent than the 17.2% in arm B. There was a significant correlation between the SDIs and response rates and median survival (r2 = 0.629, p = 0.001; r2 = 0.453, p = 0.001, respectively). Although the follow-up period is relatively short, the survival time was similar in both arms. Because a high response rate may not be followed by a high survival time in combination chemotherapy of NSCLC, further studies on the appropriate dose of individual agents with regard to the relationship between response rate, severity, and incidence of toxicities and survival rate should be carried out.

Combined pre-operative chemotherapy with intra-arterial cisplatin and continuous intravenous adriamycin for high grade osteosarcoma.

Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment (pre-operative chemotherapy + limb salvage surgery + adjuvant therapy) improved the patients' overall survival and quality of life. We evaluated the efficacy and feasibility of pre-operative chemotherapy with intra-arterial (IA) cisplatin plus continuous intravenous infusion (CI) of adriamycin. We assessed the rate of limb salvage, recurrence pattern and the survival impact based on the histologic response of pre-operative chemotherapy. Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1995. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72 h CI was administered every 3 weeks for 3 cycles, followed by limb salvage surgery if possible or by amputation. According to the histologic tumor response, if the tumor necrosis was >90%, the same regimen was administered for 3 cycles as an adjuvant therapy. A salvage regimen (Ifosfamide 7.5 gm/m2/5 d IV + high dose MTX 10 gm/m2 IV+VP-16 360 mg/m2/3 d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%. Of 41 patients, 37 patients were evaluable for efficacy and toxicities, because 4 patients refused chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 were female with median age of 16 years (range 8-41). The tumor locations were: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (grade III 10; 27.8%, grade IV 17; 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lung. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive cares. Pre-operative chemotherapy with IA DDP+CI ADR followed by surgery showed 75% histologic tumor response rate, 83% limb salvage rate and 54.7% 3-year disease-free survival rate with tolerable side effects. To improve the survival rate, the possible role of good salvage chemotherapy with a non-cross resistance regimen in poor responders should be evaluated.

Menstrual state should be considered in determining sero-positivity of soluble angiogenic factors in breast cancer.

We investigated whether blood angiogenic factor (vascular endothelial growth factor, VEGF; angiogenin; basic fibroblast growth factor, bFGF; platelet-derived growth factor-AB, PDGF-AB) levels change during menstrual cycle of healthy premenopausal females or after menopause. We also measured the serum angiogenic factor levels in 34 operable breast cancer patients and compared them to those of healthy volunteer controls. No differences in the four angiogenic factor levels were found between the follicular and luteal phases of normal menstruation. However, angiogenin and bFGF levels were higher in pre-menopausal females than post-menopausal female and young male healthy volunteers. In cancer patients, the sero-positivity rate of the bFGF was 8.8% with menstrual-state-unmatched cut-off points, which increased to 36.4% with menstrual-state-matched cut-off points. This discrepancy was especially high in post-menopausal cancer patients. In conclusion, physiological elevation of the bFGF during normal menstruation can influence the precise interpretation of the pathological elevation of the bFGF in pre-menopausal breast cancer patients.

Alpha-fetoprotein-producing gastric cancer.

We measured the sero-positivity rate of serum alpha-fetoprotein (alphaFP) of gastric cancer patients by ELISA assay; forty-two curatively resected patients, 14 palliatively resected patients, 8 who received explo-laparotomy or bypass surgery and 18 patients with systemic metastasis. The sero-positive rate was 9.8% (8/82) and the positivity increased with cancer progression. Sex, age and pathological type were similar between alphaFP-positive and -negative patients. The overall synchronous hepatic metastasis rates in alphaFP-positive and alphaFP-negative groups were 37.5% (3/8) and 12.2% (9/74), respectively (p=0.08). The predictability of synchronous liver metastasis in eight alphaFP-positive patients were as follows: 37. 5% of total patients (3/8), 50.0% (3/6) of unresectable patients, and 60.0% (3/5) of patients with systemic metastasis. In three alphaFP-positive patient with liver metastasis, all the hepatic lesions were intrahepatic and multiple, while in alphaFP-negative patients, 67% (6/9) of the hepatic lesions was single intrahepatic lesion or surface nodule. The predictability of both synchronous and metachronous liver metastasis in alphaFP-positive gastric cancer patients was 75%. These findings suggested that, in advanced stomach cancer patients, especially in stage IV, alphaFP can be used in predicting liver metastasis during follow-up.

Overexpression of c-ErbB-2 protein in gastric cancer by immunohistochemical stain.

An immunohistochemical stain to the c-ErbB-2 protein was performed in 225 paraffin-embedded tissue blocks from patients with locally advanced gastric cancer who underwent curative resection. The overexpression of the c-ErbB-2 protein was observed in 27.4% of the patients. The c-ErbB-2 positivity showed a statistically significant correlation with nodal status and stage. The patients with an overexpression of the c-ErbB-2 protein had a tendency to a shorter survival than those without, but it was not statistically significant (p = 0.08). The 5-year survival rate after surgery was 54% in the negative staining group to the c-ErbB-2 protein and 49% in the positive staining group. This suggests that the c-ErbB-2 protein has a possible role in lymph node metastasis. Therefore overexpression of the c-ErbB-2 protein is a useful indicator of disease progression in gastric carcinoma patients who received curative surgery.