Paragon (ANZGOG-0903): Phase 2 Study of Anastrozole in Women With Estrogen or Progesterone Receptor-Positive Platinum-Resistant or -Refractory Recurrent Ovarian Cancer.

BACKGROUND: There is some evidence that a subset of patients with recurrent ovarian cancer may benefit from antiestrogen therapy. The Paragon study is a basket protocol that includes a series of phase 2 trials investigating the activity of anastrozole in patients with estrogen or progesterone receptor-positive recurrent gynecological cancers. We report the results of treatment in patients with platinum-resistant or -refractory recurrent epithelial ovarian cancer. METHODS: Postmenopausal women who had estrogen and/or progesterone receptor-positive platinum-resistant or platinum-refractory recurrent ovarian cancer and disease measurable by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or GCIG (Gynecologic Cancer InterGroup) CA-125 criteria were eligible. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. The study was prospectively registered (ACTRN12610000796088). RESULTS: There were 49 evaluable patients, and clinical benefit was observed in 13 (27%; 95% confidence interval [CI], 16%-40%). There were no complete or partial RECIST version 1.1 responses. Clinical benefit was associated with higher global quality-of-life scores. Median progression-free survival was 2.7 months (95% CI, 2.0-2.8 months). The median duration of clinical benefit was 2.8 months (95% CI, 2.6-5.7 months). Most patients (83%) progressed within 6 months. Seven patients continued on treatment for longer than 6 months. Anastrozole was well tolerated in most patients. Subgroup analysis suggested greater clinical benefit in patients with tumors with estrogen-receptor histoscore of more than 200, but this difference was not statistically significant. CONCLUSIONS: A subset of patients with estrogen- or progesterone-positive platinum-resistant or platinum-refractory recurrent epithelial ovarian cancers derives clinical benefit from anastrozole, with acceptable toxicity. The challenge remains how to identify them.

A phase III randomized trial of high-dose CEOP + filgrastim versus standard-dose CEOP in patients with non-Hodgkin lymphoma: 10-year follow-up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial.

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

Phase I trial of hypofractionated chemoradiotherapy in the palliative management of esophageal and gastro-esophageal cancer.

BACKGROUND: Many patients with incurable esophageal cancer (ECa) present with dysphagia as their predominant symptom. Currently there is no consensus on how best to initially manage this scenario with multiple therapeutic options available. We aimed to assess the safety and efficacy of using hypofractionated radiotherapy given over a progressively shorter timeframe with concurrent carboplatin and paclitaxel in the management of patients with ECa and dysphagia. METHODS: In this phase I trial we enrolled patients with histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or the gastro-esophageal junction with symptomatic dysphagia from local disease and not for curative treatment. Patients needed to be 18 years or older, have an ECOG performance status of 0-2 and be suitable to receive carboplatin and paclitaxel chemotherapy. Patients were placed in four progressively shorter radiation schedules culminating in 30 Gy in 10 fractions in a step wise manner, all with concurrent carboplatin AUC 2 and paclitaxel 50 mg/m2 chemotherapy delivered weekly with the radiation therapy. The primary endpoint was the development of the dose limiting toxicities (DLTs) esophageal perforation or febrile neutropenia. Secondary endpoints were relief of dysphagia, time to improvement of dysphagia, dysphagia progression free survival and overall survival. RESULTS: Eighteen patients were enrolled in the study between October 2014 and March 2019. There were no DLTs experienced during the trial. The most common grade 3 + acute toxicity experienced by patients were nausea and vomiting (both in 4/18 patients). The most common radiation specific acute toxicity experienced was esophagitis with 67% of patients experiencing grade 1-2 symptoms. All patients experienced improvement in dysphagia. The median time to dysphagia improvement was 3 weeks from the start of chemoradiotherapy (CTRT) (range 2-10 weeks). The median dysphagia free survival was 5.8 months with a median overall survival of 8.9 months. CONCLUSION: Hypofractionated palliative CTRT with 30 Gy/10# of radiation therapy with concurrent weekly carboplatin and paclitaxel chemotherapy is well tolerated and provides a good response in improvement of dysphagia. Further studies need to be undertaken which provide both symptomatic improvement in the primary tumor but also control of the metastatic burden in these patients. CLINICAL TRIAL REGISTRATION: This trial was prospectively registered with www.anzctr.org.au Identifier: ACTRN12614000821695.

Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: the ELSIE study.

AIM: To evaluate the efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia. METHODS: In this open-label, phase II study, the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially, then 250 mg/m2 every week, with the same regimen of irinotecan on which the patients had progressed (4 pre-defined regimens allowed). The primary objective was evaluation of progression-free survival (PFS) at 12 wk. Secondary objectives included a further investigation of PFS, and an assessment of the overall response rate (ORR), duration of response, time to treatment failure (TTF), overall survival and the safety profile. RESULTS: One hundred and twenty nine patients were enrolled from 25 centers in the Asia-Pacific region and of these 123 received cetuximab plus irinotecan. The most common recent irinotecan regimen used was 180 mg/m2 every 2 wk which had been used in 93 patients (75.6%). The PFS rate at 12 wk was 50% (95% confidence interval (CI, 41-59) and median PFS time was 12.1 wk (95% CI: 9.7-17.7). The ORR was 13.8% (95% CI: 8.3-21.2) and disease control rate was 49.6% (95% CI: 40.5-58.8). Median duration of response was 31.1 wk (95% CI: 18.0-42.6) and median overall survival was 9.5 mo (95% CI, 7.5-11.7). The median TTF was 11.7 wk (95% CI: 9.1-17.4). Treatment was generally well tolerated. The most common grade 3/4 adverse events were diarrhea (13.8%), neutropenia (8.9%), rash (5.7%) and vomiting (5.7%). CONCLUSION: In patients from Asia and Australia, this study confirms the activity and safety of cetuximab plus irinotecan observed in previous studies in Europe and South America.