FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

Current diagnostic approaches in tumor-induced bone disease.

PURPOSE: To assess the role of the current imaging methods in the diagnosis, staging and post-therapeutic monitoring of cancer-induced bone disease. PATIENTS AND METHODS: 183 cancer patients underwent baseline whole body bone scintigraphy (WBBS) with 555- 740 MBq (99m)Tc-MDP. Computed tomography (CT) was carried out in 43 patients, and magnetic resonance imaging (MRI) in 26 patients with abnormal uptake on the bone scan in order to differentiate metastatic or degenerative skeletal lesions with similar scintigraphic appearance. Sixty-four patients with established tumor-induced bone disease were followed-up after their anticancer treatment. RESULTS: WBBS was positive for metastatic disease in 54 patients and normal skeletal scan was obtained in 28 patients. Comparative analysis of the sensitivity and specificity of WBBS in relation to CT for diagnosis of metastatic spots in the examined group of 43 patients showed: for WBBS 93.3% (28/30) and 92.8% (13/14), respectively; for CT 90% (27/30) and 100% (13/13), respectively. Sensitivity and specificity of WBBS in relation to MRI in the examined group of 26 patients showed: for WBBS 86.6% (13/15) and 77.7% (7/9), respectively/ for MRI 100% (15/15) and 88% (8/9), respectively. Scintigraphic follow-up examinations of 64 patients after appropriate therapy showed partial response (PR) in 28 cases, stable disease (SD) in 12, progressive disease (PD) in 10, pathological fractures in 11 and "flare phenomenon) in 3 cases. CONCLUSION: In most cases WBBS is suffi cient to find and locate osseous metastases. Because of the lower specificity of WBBS, patients with spots of increased mineral metabolism of unclear character and persisting pain in the spine necessitate target CT or MRI to evaluate the characteristics of the detected scintigraphic changes.

Quality of life is improved in breast cancer patients by Standardised Mistletoe Extract PS76A2 during chemotherapy and follow-up: a randomised, placebo-controlled, double-blind, multicentre clinical trial.

The objective of this randomised, multicentre, double-blind clinical trial was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to mistletoe lectins, on quality of life (QoL) in breast cancer patients. A total of 352 patients were randomly allocated to 2 groups receiving PS76A2 (15 ng mistletoe lectin/0.5 ml) or matching placebo twice weekly for 4 to 6 cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy followed by 2 months follow-up. The primary efficacy end-point was the change from baseline of 3 FACT-G subscales (physical, emotional and functional well-being) during the fourth CMF cycle. Secondary measures included GLQ-8 (8 linear analogue self-assessment scales), Spitzer's uniscale and haematological variables. The main variables of safety analysis were adverse events, including injection site reactions and clinical laboratory tests. The results showed that physical, emotional and functional well-being improved upon PS76A2, but deteriorated following placebo. The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G, which was analysed as O'Brien's rank sum of its 3 subscales: The total score increased by 4.40 +/- 11.28, indicating a higher QoL after PS76A2, but decreased by 5.11 +/- 11.77 with placebo (p<0.0001). The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 (sum of item nos. 1, 5, 6, 7, 8) and GLQ-3 (sum of item nos. 2, 3, 4). GLQ-5 characterises typical aspects of QoL, while GLQ-3 consists of 3 side-effects of CMF (feeling sick, numbness or pins and needles, loss of hair). GLQ-5 decreased by 42.9 +/- 125.0 upon PS76A2, indicating an improvement in QoL, but increased by 60.3 +/- 94.0 upon placebo (p<0.0001). GLQ-3 deteriorated in both groups (PS76A2: 13.9 +/- 52.4; placebo: 34.5 +/- 57.0), but the differences in favour of PS76A2 were, nevertheless, statistically significant (p=0.0007). The total score GLQ-8 improved by 28.9 +/- 154.6 after PS76A2 and deteriorated by 94.8 +/- 141.1 after placebo (p<0.0001). Spitzer's uniscale improved by 12.2 +/- 30.7 upon PS76A2 and deteriorated by 10.8 +/- 26.1 with placebo (p<0.0001). After follow-up without chemotherapy, a significant treatment difference in favour of PS76A2 was determined by means of FACT-G, GLQ-8 and Spitzer's uniscale. PS76A2 was well tolerated in this trial, with the exception of slight local reactions in 17.6% of the PS76A2 group. In conclusion, PS76A2 (15 ng mistletoe lectin/0.5 ml twice weekly) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up.

Nuclear medicine approaches in the monitoring of thyroid cancer patients.

PURPOSE: To evaluate the role of some nuclear medicine approaches such as (99m)Tc-MIBI scan and (131)I whole-body scintigraphy (WBS) in the monitoring of patients with differentiated thyroid cancer (DTC). PATIENTS AND METHODS: 95 patients (69F/26M) aged 17-74 years (mean 44.2) with DTC (56 cases with papillary, 20 with follicular and 19 with papillary-follicular carcinoma) were assessed. All of them had undergone total or near-total thyroidectomy and received radioiodine treatment for ablation of post-surgical residual thyroid tissue. They were examined after 4 weeks of L-thyroxin withdrawal in the follow-up of DTC. Planar and whole-body images were acquired at 15 and 180 min after i.v. administration of (99m)Tc-MIBI (555-740 MBq) and at 48 h after p.o. administration of(131)I(111-185 MBq) on Toshiba GCA gamma camera. Serum thyroglobulin (Tg) estimations were performed to clarify the presence of residual normal tissue or recurrent malignancy. RESULTS: (131)I scan was positive in 63 patients showing thyroid remnants in 31 cases, lymph node metastases in 24 cases (17 to the neck, 7 to the neck/mediastinum), pulmonary metastases in 6 cases, bone and brain lesions in 2 cases. In 15 patients (131)I scan was negative, Tg was undetectable, so patients were considered tumor-free. In 17 patients (131)I scan was negative while serum Tg was increased. These false negative results were observed predominantly in cases with less differentiated metastatic disease, especially after several courses of high-dose (131)I therapy. (99m)Tc-MIBI scan revealed the presence of lymph node and/or lung metastases (non-functioning metastases) in 14 of them, false negative results were obtained in 2 cases, and one false positive in 1 case. Serum Tg was increased in all patients with local lymph node and distant metastases, visualized by (131)I or by (99m)Tc-MIBI, but also in 18 patients with thyroid remnants only. CONCLUSION: (99m)Tc-MIBI scan has been reported to be a highly sensitive technique for the detection of DTC metastases that have lost the capability to uptake (131)I; the combined (99m)Tc-MIBI scintigraphy and serum Tg estimation appear to be an alternative method of radioiodine imaging in cases with DTC and elevated Tg.

The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial.

Patients with breast cancer receiving adjuvant chemotherapy frequently suffer from a restricted quality of life (QoL) due to the side-effects of chemotherapy and the consequences of coping with the diagnosis. Therefore, the objective of this clinical study was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to the galactoside-specific mistletoe lectin, on QoL by performing a placebo-controlled trial. Overall, 272 patients with breast cancer receiving adjuvant CMF chemotherapy (cyclophosphamide-methotrexate-fluorouracil) were enrolled and randomised to groups receiving placebo or PS76A2 at concentrations of 10, 30 or 70 ng mistletoe lectin (ML) per ml. The patients received 0.5 ml study medication twice weekly subcutaneously for 15 consecutive weeks (4 CMF cycles). Primary variables were the self-assessment QoL scores GLQ-8 (Global Life Quality) and Spitzer's uniscale. As a result, statistically significant effects on QoL were obtained with the medium dose (15 ng ML/0.5 ml). The treatment difference between the medium dose and placebo with regard to the GLQ-8 sum was 60.8 mm (95% confidence interval: 19.3 to 102.0 mm). The treatment effect for Spitzer's uniscale between the medium dose and placebo was 16.4 mm (95% confidence interval: 6.3 to 26.6 mm). The results on QoL were supported by an increase of T helper lymphocytes (CD4+) and the CD4+/CD8+ ratio (p<0.05). Overall, PS76A2 was well tolerated. Local reactions at the injection sites occurred dose-dependently, but were mild at the low and medium dose levels.