Quality of life and treatment response among women with platinum-resistant versus platinum-sensitive ovarian cancer treated for progression: a prospective analysis.

OBJECTIVE: Most women with ovarian cancer relapse and undergo further chemotherapy however evidence regarding the benefits of this for women with platinum-resistant disease is limited. Our objective was to determine whether there was a quality of life improvement or treatment response among women treated for platinum-resistant recurrent ovarian cancer. METHODS: We combined data from 2 studies where women treated with chemotherapy for recurrent ovarian cancer (n=172) completed a quality of life questionnaire every 3 months. Cancers were classified as platinum-resistant if they progressed within 6 months of completing first-line chemotherapy. Mixed effects models were used to analyze change in quality of life during the first 6 months after second-line chemotherapy. RESULTS: One-quarter of women (n=44) were classified as having platinum-resistant disease. Overall, their quality of life did not significantly increase or decrease, following commencement of second-line chemotherapy (least square mean scores=107, 105, 103 at chemotherapy start, 3 and 6 months later, respectively), although 26% of these women reported a meaningful increase and 31% reported a meaningful decline. One-third of the platinum-resistant group responded (11% complete and 21% partial response) to second-line chemotherapy, and this figure increased to 54% among the subset (36%) re-treated with platinum-based agents with or without other agents. Preliminary analyses suggest that quality of life may be higher at chemotherapy initiation in women whose disease responded (median score 121 vs 110). CONCLUSIONS: Overall, quality of life appears to be maintained in women with platinum-resistant ovarian cancer who receive further chemotherapy and some women respond to re-treatment.

A case of IVIg responsive paraneoplastic SOX1 peripheral neuropathy in a male with breast carcinoma.

BACKGROUND AND AIMS: SOX1 antibodies are generally associated with small cell lung cancer and anti-Hu antibody overlap is common. This case demonstrates isolated anti-SOX1 antibodies with an uncommon tumor type, and relapse of a paraneoplastic syndrome with recurrence of tumor. METHODS: We describe a case of a 65-year-old male with a paraneoplastic peripheral neuropathy and anti-SOX1 antibody positivity in the context of a prior male breast Grade 2 ductal carcinoma, in remission at the time of the initial neurological presentation. RESULTS: Treatment response to intravenous immunoglobulin (IVIg) was demonstrated. After period of clinical stability on IVIg in the context of remission of breast carcinoma, the patient experienced a relapse of his neuropathy. This was associated with tumor recurrence and again responded to tumor excision, radiotherapy and IVIg. INTERPRETATION: Male breast carcinoma has not previously been associated with anti-SOX1 antibody positive paraneoplastic neuropathy.

Renal Cell Carcinoma Metastasis to Meckel's Cave Treated With Repeat Stereotactic Radiosurgery: A Case Report and Review of the Literature.

Renal cell carcinoma (RCC) metastases to Meckel's cave (MC) are a rare condition. To the best of our knowledge, we present the first case of an RCC metastasis to MC successfully treated on two consecutive occasions with stereotactic radiosurgery (SRS). A 57-year-old man presented with new-onset facial pain and numbness. Magnetic resonance imaging (MRI) revealed a lesion invading MC. He was treated with Gamma Knife SRS successfully, resulting in both symptomatic improvement and radiologic tumour regression. Thirteen months after treatment, he presented with a recurrence of trigeminal nerve symptoms. He was treated with hypofractionated SRS successfully, with a follow-up MRI revealing resolution of the disease. While RCC metastases to MC are a rare phenomenon, published literature to date recommends surgical resection in combination with radiotherapy and systemic therapy. Metastatic disease to MC has only been treated once before with radiosurgery alone. Our case demonstrates that repeat SRS is feasible and efficacious. This approach may be favourable in patients wishing to avoid risks of surgical resection, or for those with unresectable disease. Metastases of RCC to MC are a rare occurrence and typically present with facial pain and/or hypoesthesia. This case demonstrates that repeat radiosurgery may be an effective alternative to surgical resection.

Ranked importance of outcomes of first-line versus repeated chemotherapy among ovarian cancer patients.

PURPOSE: To examine the importance of possible outcomes of first-line versus repeated chemotherapy to ovarian cancer patients and to compare doctors' treatment intentions with patients' beliefs about cure. METHODS: Women with newly diagnosed (74) or relapsed (48) ovarian cancer were prospectively followed over 2 years. The level of importance they ascribed to four chemotherapy outcomes and their beliefs about cure were assessed. Their doctors independently specified intent of successive treatments. RESULTS: Approximately half (54%) of newly diagnosed ovarian cancer patients (65% with residual disease >2 cm and 49% with no or < or =2 cm residual disease) ranked 'tumour shrinkage (or decrease in blood levels of CA125)' as 'most important' during first-line chemotherapy. Approximately two thirds (65-70%) of all women whose disease had relapsed also ranked 'tumour shrinkage' as 'most important' during repeated chemotherapy. Few women (<8%) rated symptom relief or absence of side-effects as most important. While both patients' and doctors' belief about cure decreased over successive treatments, patients grew more optimistic relative to doctors over time. Women's reports of advice by doctors about cure were consistent with doctors' stated intent for repeat chemotherapy. However, discordance between doctors' actual treatment intent and patients' beliefs about cure increased from 24% at first-line to 83% by fourth-line chemotherapy. CONCLUSIONS: Women prioritise tumour response as the most important outcome of chemotherapy for ovarian cancer. This priority predominates in women with residual and relapsed disease despite declining likelihood of cure. Women may still hope for a cure while acknowledging their doctor's advice that their disease is incurable.

Australian recommendations for EGFR T790M testing in advanced non-small cell lung cancer.

First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line therapy in patients with non-small cell lung cancer (NSCLC) harboring a sensitizing mutation in the EGFR gene. Unfortunately, resistance to these therapies often occurs within 10 months of commencing treatment and is mostly commonly due to the development of the EGFR T790M mutation. Treatment with the third-generation EGFR TKI, osimertinib can prolong progression free survival in patients with the T790M mutation, so it is important to determine the resistance mechanism in order to plan ongoing therapeutic strategies. Here we review the evidence and make recommendations for the timing of T790M mutation testing, the most appropriate specimens to test and the available testing methods in patients progressing during treatment with first line EGFR TKIs for NSCLC.

Concurrent chemoradiation with cisplatin and vinorelbine followed by consolidation with oral vinorelbine in locally advanced non-small cell lung cancer (NSCLC): the phase II CONCAVE study.

AIM: Despite recent advances, outcomes for patients with stage III non-small cell lung cancer (NSCLC) with concurrent chemoradiotherapy (CRT) remain poor. We evaluated the combination of ciplatin/vinorelbine and concurrent thoracic radiotherapy followed by consolidation oral vinorelbine in this phase II study. METHODS: Eligible patients with unresectable stage III NSCLC received cisplatin intravenous (IV) 40 mg/m2 and vinorelbine IV 20 mg/m2 on days 1, 8, 22 and 29 concurrent with thoracic radiotherapy of 60 Gy in 30 fractions. Four to eight weeks later, oral vinorelbine 60 mg/m2 day 1 and 8 every 3 weeks was given for 3 cycles. The primary end point was overall response rate (ORR). Secondary end points were safety, quality of life, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-seven eligible patients were enrolled from December 2007 to June 2010 before the trial was prematurely closed due to toxicity concerns. The median age was 63 years (range, 42-71), 56% were male, 52% ECOG 0 and 52% stage IIIa. The ORR was 81% (including 37% complete response rate) and disease control rate of 93%. The median PFS was 11 months and median OS was 26 months. Consolidation vinorelbine was associated with significant grade 3/4 toxicity (68%) including grade 3-5 febrile neutropenia (27%) and respiratory infections (36%) including two deaths in the consolidation phase (9%). CONCLUSIONS: Consolidation oral vinorelbine after CRT was associated with significant toxicity. Overall, this regimen achieved a high ORR and survival results comparable to other CRT protocols but the significant toxicity precludes further evaluation of this approach.

Outcomes treating stage III non-small cell lung carcinoma with curative-intent radiotherapy and concurrent carboplatin-paclitaxel chemotherapy.

BACKGROUND AND AIM: Thoracic radiotherapy administered concurrently with chemotherapy is the standard of care for patients with inoperable stage III non-small cell lung cancer, but the optimal chemotherapy regimen is not clearly established. The objective of this study was to assess outcomes in a large cohort of patients treated with curative-intent using carboplatin and paclitaxel. METHODS: Consecutive patients undergoing curative-intent radiotherapy to 60-66 Gy in 30-33 daily fractions with concurrent weekly carboplatin (AUC = 2) and paclitaxel (45 mg/m(2) /week) between March 2004 and May 2012 were identified from a prospective database and reviewed individually. A minimum follow-up of 3 months was required unless death occurred sooner. Response to treatment was defined according to established guidelines on re-staging computed tomography scan at 3 months. Toxicities were assessed using a standardised scoring system. RESULTS: One hundred and seven patients were analysed. The median follow-up was 43.5 months. Three months after treatment, a complete or partial response was observed in 72 patients (68%), and nine patients (8%) had already died. The overall locoregional failure rate was 47%, and failure eventually occurred at any site in 75 patients (70%). Median progression-free survival, and median survival were 15 and 22 months, respectively. Grade 3-4 neutropaenia, thrombocytopaenia, nephrotoxicity, oesophagitis and pneumonitis were observed in 15%, 1%, 3%, 11% and 9% of patients during treatment, respectively. There was one episode of fatal radiation pneumonitis. CONCLUSION: Treatment with thoracic radiotherapy and concurrent carboplatin and paclitaxel chemotherapy is feasible. Survival and toxicity outcomes compare favorably to those reported using cisplatin-based regimens.

Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma.

OBJECTIVES: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage. MATERIALS AND METHODS: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated. RESULTS AND CONCLUSION: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.

Efficacy of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC): analysis of the Australian subpopulation of the TRUST study.

AIMS: The efficacy of erlotinib (Tarceva, Roche Products, Dee Why, Australia) has been demonstrated in patients with advanced non-small-cell lung cancer (NSCLC). Tarceva lung cancer survival treatment (TRUST) is an open-label, single-arm, phase IV global trial which investigated erlotinib in advanced NSCLC patients who had failed prior therapy or were unsuitable for chemo/radiotherapy. The aim of this analysis was to report the safety and efficacy of erlotinib in the Australian patient subpopulation. METHODS: Patients with stage IIIB/IV NSCLC progressing after standard systemic chemotherapy or unsuitable to receive chemo/radiotherapy were eligible for the study. The patients were treated with erlotinib at 150 mg/day orally, until disease progression or unacceptable toxicity. RESULTS: In Australia, 460 patients were recruited. Erlotinib was given as first-line (16%), second-line (49%) or third-line (35%) treatment. In the intent-to-treat population (N = 460), the median progression-free survival was 2.7 months (95% CI 2.3-3.4), 1-year survival was 35% (95% CI 30-39%) and median overall survival was 6.9 months (95% CI 5.7-8.0). Tumor response rates were available for 363 patients, with a disease control rate of 58%. Of the 460 patients included in the safety analysis, 24% had one or more erlotinib-related adverse event (AE). Rash was reported in 77% of patients, most commonly grade 1/2 (63%). Treatment-related serious AE were reported in 7% of patients; most commonly diarrhea (2%). Dose modifications were required in 18% of patients. CONCLUSIONS: Outcomes for Australian patients confirmed the efficacy and tolerability of erlotinib for the treatment of advanced NSCLC in routine clinical practice.

Second-line erlotinib in patients with advanced non-small-cell lung cancer: subgroup analyses from the TRUST study.

Erlotinib is a highly potent inhibitor of epidermal growth factor receptor tyrosine-kinase activity that significantly prolongs overall survival in patients with non-small-cell lung cancer (NSCLC), and improves symptom control and quality of life compared with placebo. The safety and efficacy of erlotinib has been investigated in a large, international, phase IV, open-label study (TRUST) in patients (n=6665) with advanced stage IIIB/IV NSCLC. An analysis of efficacy and safety outcomes is reported for patients receiving erlotinib as second-line therapy in TRUST (n=3224). Best response data were available for all 3224 patients. Complete response, partial response and stable disease were achieved in 25 (<1%), 368 (14%) and 1444 (54%) patients, respectively, for a disease control rate of 68%. Median progression-free and overall survivals were 13.6 weeks and 8.6 months, respectively; 1-year survival was 39.4%. Safety data were available for all patients. Of these, 389 patients (12%) had an erlotinib-related adverse event (AE) other than pre-specified AEs defined in the protocol; only 96 patients (3%) had an erlotinib-related AE ≥ grade 3. Of 1376 patients (43%) with serious AEs (SAEs), only 122 (4%) had treatment-related SAEs and most were gastrointestinal disorders (mainly diarrhoea and nausea). No treatment-related SAE occurred in ≥ 1% of patients. Data on the incidence of erlotinib-related rash were collected for all patients, 2302 (71%) of whom experienced rash. Of these rash events, 83% were of grade 1/2. These data confirm the good efficacy and tolerability of second-line erlotinib in a broad range of patients with NSCLC.

A randomized phase II trial of two regimens of moderate dose chemoradiation therapy for patients with non-small cell lung cancer not suitable for curative therapy: Trans Tasman Radiation Oncology Study TROG 03.07.

BACKGROUND: There are patients with stage I-III non-small cell lung cancer (NSCLC) who are not suitable for curative radical chemoradiation therapy. There are patients with an isolated solitary extracranial metastasis who have improved outcomes compared with those with cranial or multiple metastases. Patients of good performance status receiving moderate dose radiation therapy have improved survival. Two regimens of moderate dose chemoradiation therapy for such patients were compared in a randomized phase II trial. METHODS: Patients were eligible if they had stage I-IIIB NSCLC, unsuitable for curative therapy, or stage IV with a PET-detected extracranial solitary metastasis. Patients were randomized to the following groups-arm A: 40 Gy/20 fractions/4 weeks with concurrent weekly vinorelbine 25 mg/m + cisplatin 20 mg/m or arm B: 30 Gy/15 fractions/3 weeks with concurrent weekly gemcitabine 200 mg. Primary end points were feasibility, response rates, and toxicity. Secondary end points were progression-free survival, overall survival, and quality of life. RESULTS: Eighty-four patients were randomized. Compliance was above 90% for both arms. The overall response rate was 51% in arm A and 38% in arm B (p = 0.147). Grade 3/4 toxicity in both arms was acceptable. There was no difference in median progression-free survival between the two arms (5.5 versus 5.0 months, p = 0.19). Patients in arm A had longer median survival but this did not reach statistical significance (13.1 versus 8.3 months, p = 0.25). No difference in quality of life was observed. CONCLUSIONS: Arm A was chosen for a future phase II comparison with radiation therapy alone as it demonstrated a response rate greater than 50%, and data suggested that arm A had superior survival to arm B.