Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006.

BACKGROUND: Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized. PATIENTS AND METHODS: In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. RESULTS: At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi + MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR). CONCLUSIONS: Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.

Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Validation of a frailty index in older cancer patients with solid tumours.

BACKGROUND: Frailty is an indicator of physiological reserve in older people. In non-cancer settings, frailty indices are reliable predictors of adverse health outcomes. The aims of this study were to 1) derive and validate a frailty index (FI) from comprehensive geriatric assessment (CGA) data obtained in the solid tumour chemotherapy setting, and 2) to explore whether the FI-CGA could predict chemotherapy decisions and survival in older cancer patients with solid tumours. METHODS: Prospective cohort study of a consecutive series sample of 175 cancer patients aged 65 and older with solid tumours. A frailty index was calculated using an accumulated deficits model, coding items from the comprehensive geriatric assessment tool administered prior to chemotherapy decision-making. The domains of physical and cognitive functioning, nutrition, mood, basic and instrumental activities of daily living, and comorbidities were incorporated as deficits into the model. RESULTS: The FI-CGA had a right-skewed distribution, with median (interquartile range) of 0.27 (0.21-0.39). The 99% limit to deficit accumulation was below the theoretical maximum of 1.0, at 0.75. The FI-CGA was significantly related (p < 0.001) to vulnerability as assessed by the Vulnerable Elders Survey-13 and to medical oncologists' assessments of fitness or vulnerability to treatment. Baseline frailty as determined by the FI-CGA was also associated with treatment decisions (Treatment Terminated, Treatment Completed, No Planned Treatment) (p < 0.001), with the No Planned Treatment group significantly frailer than the other two groups. CONCLUSION: The FI-CGA is a potentially useful adjunct to cancer clinical decision-making that could predict chemotherapy outcomes in older patients with solid tumours.

Lessons learned from a pilot study of an Indigenous patient navigator intervention in Queensland, Australia.

Indigenous patient navigator (IPN) programmes show promise in addressing barriers to cancer care and facilitation of patient self-efficacy. The purpose of this paper is to describe and reflect upon the experience of training an IPN and implementation of the intervention in the Australian context with Indigenous cancer patients. Randomised clinical trial might provide the best available evaluation measure of an intervention but caution should be taken in the implementation process. Socio-cultural aspects and training can affect the conduct of this type of intervention. We report here five issues needing consideration prior to implementing such intervention. Specifically: (1) recognition of the collective bonds within Indigenous community and understanding by IPN of the degree of personal assistance perceived as not intrusive by the patient; (2) conduct ongoing evaluation of the different role of an IPN involved in this intervention care provider vs. researcher. (3) meaningful engagement develops from a trusting/collaborative relationship between research team and study site staff which may not occur in the study time frame; (4) existing skills as well as training provided may not translate in the IPN understanding and aligning with the study objectives/research values; (5) recruitment of participants requires innovative and highly flexible strategies to be successful.

Follow-up cancer care: perspectives of Aboriginal and Torres Strait Islander cancer survivors.

PURPOSE: The purpose of this study was to explore Indigenous Australian cancer survivors' perspectives of follow-up cancer care and management.. METHODS: This is a qualitative study employing individual interviews with 21 Indigenous cancer survivors (13 females, 8 males) recruited from a rural primary health service and large tertiary hospital in Brisbane, Queensland. Yarning methods were used to conduct semi-structured interviews. Yarning is a culturally appropriate, informal conversational process emphasising the importance of storytelling. RESULTS: Findings describe a range of ways in which follow-up cancer care is experienced with four major categories elucidated, namely: links to tertiary health services, links to primary health services, communication between tertiary and primary health services, and lost in transition. Both positive and negative experiences were described; however, the importance of timely and informative discharge information, continuity of care, good communication between tertiary and primary health services, and strong therapeutic relationships were salient issues raised by participants. CONCLUSIONS: These findings highlight the importance of establishing strong therapeutic relationships between patients and tertiary and primary health professionals. Also important for survivorship is provision of discharge summaries or care plans at discharge for survivors and general practitioners as well as access to a range of allied health services. Alternative means for follow-up could be investigated for regional and rural survivors to facilitate convenient and cost-effective follow-up care. Finally, provision of responsive and flexible follow-up care to cater for the diverse range of needs and preferences of cancer survivors is required. A patient navigator available across the cancer continuum could go some way to addressing this.

Health professional's perspectives of the barriers and enablers to cancer care for Indigenous Australians.

To investigate health professionals' perspectives about factors that impede or facilitate cancer care for Indigenous people. Semi-structured interviews with 22 health professionals involved in Indigenous cancer care. Data were interpreted using an inductive thematic analysis approach. Participants presented their perspectives on a number of barriers and enablers to Indigenous cancer care. Barriers were related to challenges with communication, the health system and coordination of care, issues around individual and community priorities and views of cancer treatment and health professional judgement. Enablers to cancer care were related to the importance of trust and rapport as well as health care system and support factors. The findings highlighted the need for recording of Indigenous status in medical records and a coordinated approach to the provision of evidence-based and culturally appropriate cancer care. This could go some way to improving Indigenous patient's engagement with tertiary cancer care services.

IgE sequences in individuals living in an area of endemic parasitism show little mutational evidence of antigen selection.

Patterns of somatic mutation in IgE genes from allergic individuals have been a focus of study for many years, but IgE sequences have never been reported from parasitized individuals. To study the role of antigen selection in the evolution of the anti-parasite response, we therefore generated 118 IgE sequences from donors living in Papua New Guinea (PNG), an area of endemic parasitism. For comparison, we also generated IgG1, IgG2, IgG3 and IgG4 sequences from these donors, as well as IgG1 sequences from Australian donors. IgE sequences had, on average, 23.0 mutations. PNG IgG sequences had average mutation levels that varied from 17.7 (IgG3) to 27.1 (IgG4). Mean mutation levels correlated significantly with the position of their genes in the constant region gene locus (IgG3 < IgG1 < IgG2 < IgG4). Interestingly, given the heavy, life-long antigen burden experienced by PNG villagers, average mutation levels in IgG sequences were little different to that seen in Australian IgG1 sequences (19.2). Patterns of mutation provide clear evidence of antigen selection in many IgG sequences. The percentage of IgG sequences that showed significant accumulations of replacement mutations in the complementarity determining regions ranged from 22% of IgG3 sequences to 39% of IgG2 sequences. By contrast, only 12% of IgE sequences had such evidence of antigen selection, and this was significantly less than in PNG IgG1, IgG2 and IgG4 subclass sequences (P < 0.01). The anti-parasite IgE response therefore has the reduced evidence of antigen selection that has previously been reported in studies of IgE sequences from allergic individuals.

Lung cancer patients in Queensland suffer delays in receiving radiation therapy--but not as a result of distance.

AIM: To determine whether lung cancer radiation therapy waiting times in Queensland public hospitals are associated with distance of residence from the nearest treatment facility. METHODS: Retrospective analysis of radiation therapy waiting times of 1535 Queensland residents who were diagnosed with lung cancer from 2000 to 2004 and received radiation therapy as initial treatment at a public hospital. The effect of distance of residence from treatment centre on median waiting time was analysed by quantile regression controlling for sex, age, lung cancer histology, stage and therapeutic intent. RESULTS: The median waiting time from diagnosis to start of radiation therapy was 33 days for all patients. There was no significant difference (P = 0.141) in median waiting times in relation to distance of residence from a treatment centre. However, in most patients, waiting times were significantly longer than recommended by the Royal Australian and New Zealand College of Radiologists. Curative patients waited longer than palliative patients, while patients with earlier stage cancer waited longer than those with more advanced disease. CONCLUSION: Waiting times for radiation therapy among lung cancer patients in Queensland was not associated with distance from place of residence to the nearest public treatment facility. However, delays overall are excessive and are likely to worsen unless radiation treatment capabilities are enhanced to keep pace with population growth in Queensland.

Completeness of histopathology reporting of melanoma in a high-incidence geographical region.

BACKGROUND: Appropriate histopathology reporting helps to ensure effective therapy and prognosis. OBJECTIVE: To examine compliance with clinical practice guidelines for histopathology reports of melanomas. METHODS: A sample of melanoma histopathology reports in Queensland was audited for inclusion of recommended information. The quality of documentation was constructed and multivariate analysis used to determine factors affecting the quality of reporting practices. RESULTS: Documentation of the most important features of melanoma was high: clear diagnosis (99.8%; 95% CI 98.6-100), thickness (99.8%; 95% CI 98.6-100), comment on adequacy of excision (87.9%; 95% CI 84.9-91.0) and measurement of margins (91.9%; 95% CI 88.8-91.4). Overall reporting of ulceration and regression was of lesser completeness (83.0 and 77.8%, respectively) and these features were more likely to be reported by high-volume laboratories (p < 0.001 and p = 0.037, respectively). This trend was not apparent for other features. Fewer than 50% of reports documented mitotic rate per square millimetre, predominant cell type, microsatellites, growth phase and desmoplasia. CONCLUSION: Awareness of current reporting practices and identification of areas in which insufficiencies exist enable the revision of systems and potential improvements to the transfer of information to treating clinicians.

Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus.

Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was -56.8% (SD 29) and in the non-responders -27.8% (SD 32.1) (P = 0.035). The mean percentage change in TLR was -49.1% (SD 44.8) in the responders and in the non-responders -27.3% (SD 31.3) (P = 0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3-6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear.

Phase II study of IV vinflunine in patients with chemotherapy naive metastatic malignant melanoma.

This phase II study evaluated vinflunine in chemotherapy naive patients with metastatic melanoma. Vinflunine was administered at 350 mg/m(2) every 3 weeks, but after 9 patients this was reduced to 320 mg/m(2) based on interim analyses of all phase II trials. A partial response was observed in 1 of the first 9 patients (11.1%) treated at 350 mg/m(2), which gives a 3.0% [95% confidence interval (CI): 0.08-15.8] response rate in 33 patients. No change was the best response in 13 patients (39.4%) with progressive disease in 16 (48.5%) and 3 were not evaluable for response. The time to response was 1.4 months and duration was 6 months. At 350 mg/m(2) grade 4 neutropaenia occurred in 3 patients (33.3%) and grade 3 in 2 patients (22.2%) while at 320 mg/m(2) grade 4 neutropaenia occurred in 6 patients (25%) and grade 3 in 3 patients (12.5%) with 2 episodes of grade 3 febrile neutropaenia. Two patients (8.3%) had grade 3 anaemia. These results do not show activity at this dose and schedule for vinflunine in patients with chemotherapy naive metastatic melanoma.

Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer.

PURPOSE: To determine the place of single-agent paclitaxel compared with nonanthracycline combination chemotherapy as front-line therapy in metastatic breast cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic breast cancer were randomized to receive either paclitaxel 200 mg/m(2) intravenously (IV) over 3 hours for eight cycles (24 weeks) or standard cyclophosphamide 100 mg/m(2)/d orally on days 1 to 14, methotrexate 40 mg/m(2) IV on days 1 and 8, fluorouracil 600 mg/m(2) IV on days 1 and 8, and prednisone 40 mg/m(2)/d orally on days 1 to 14 (CMFP) for six cycles (24 weeks) with epirubicin recommended as second-line therapy. RESULTS: A total of 209 eligible patients were randomized with a median survival duration of 17.3 months for paclitaxel and 13.9 months for CMFP. Multivariate analysis showed that patients who received paclitaxel survived significantly longer than those who received CMFP (P =.025). Paclitaxel produced significantly less severe leukopenia, thrombocytopenia, mucositis, documented infections (all P <.001), nausea or vomiting (P =.003), and fever without documented infection (P =.007), and less hospitalization for febrile neutropenia than did CMFP (P =.001). Alopecia, peripheral neuropathy, and myalgia or arthralgia were more severe with paclitaxel (all P <.0001). Overall, quality of life was similar for both treatments (P > = .07). CONCLUSION: Initial paclitaxel was associated with significantly less myelosuppression and fewer infections, with longer survival and similar quality of life and control of metastatic breast cancer compared with CMFP.

Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer.

PURPOSE: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m(2) or doxorubicin 75 mg/m(2) every 3 weeks for a maximum of seven treatment cycles. RESULTS: A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P =.008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel. CONCLUSION: The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.

A phase I study of moderate-dose radiation therapy and weekly gemcitabine in patients with locally advanced non-small cell lung cancer not suitable for radical chemoradiation therapy.

AIMS: To describe the toxicity and response seen in patients receiving moderate-dose radiation therapy with concurrent weekly low-dose gemcitabine in the management of locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighteen patients with confirmed NSCLC were enrolled over a 17-month period from August 2000 until January 2002. All had localised disease but were considered unsuitable for curative therapy. Radiation therapy was given to a dose of 30 Gy in 15 fractions over 3 weeks. Gemcitabine was given weekly before and within 3 h of fractions 1, 6 and 11. The study was designed as a dose-escalation study, commencing at 100 mg/m2 and increasing at levels of 50 mg/m2, until the maximum tolerated dose (MTD) was reached. RESULTS: The MTD was regarded as being 150 mg/m2. The major acute toxicity observed was oesophagitis. Skin reactions were also reported. The overall response rate in all patients was 88%, with 44% achieving a complete response. CONCLUSION: The combination of gemcitabine and moderate-dose radiation therapy is feasible, and offers low toxicity and excellent response rates in patients with localised NSCLC not suitable for high-dose therapy.

Prognostic value of quality of life scores in a trial of chemotherapy with or without interferon in patients with metastatic malignant melanoma.

In a multi-centre randomised clinical trial comparing dacarbazine (DTIC) plus recombinant interferon-alfa2a (IFN) versus DTIC alone for patients with metastatic malignant melanoma, aspects of quality of life (QL) were measured prospectively by patients using linear analogue self assessment (LASA) scales including the GLQ-8 and by doctors using Spitzer's QL Index. QL scores and performance status at the time of randomisation were available for 152 of 170 eligible patients. These scores carried significant prognostic information. In univariate analyses, Spitzer QL Index assessed by the doctor and LASA scores for physical wellbeing (PWB), mood, pain, appetite, nausea and vomiting, GLQ-8 total and overall QL were significant (P < 0.01) predictors of subsequent survival. QL Index and LASA scales for mood, appetite, and overall QL remained independently significant (all P < 0.05) in multivariate models allowing for significant prognostic factors other than QL (liver metastases and performance status). These findings closely parallel those in patients with metastatic breast cancer. They add further validity to the QL Index and LASA scores, provide the first evidence of the prognostic significance of the GLQ-8, and argue strongly for the routine assessment of QL in future therapy trials.

A randomised trial of dexamethasone, lorazepam and prochlorperazine for emesis in patients receiving chemotherapy.

To define further the place of dexamethasone in antiemetic combinations, lorazepam, prochlorperazine and placebo (LP) were compared with lorazepam, prochlorperazine and dexamethasone (DLP) in a randomised, double-blind, crossover study. Both patient and observer assessments were documented in 84 patients receiving both cisplatin and non-cisplatin chemotherapy. The addition of dexamethasone significantly reduced the severity of nausea (P = 0.002) and vomiting (P less than 0.0001), duration of nausea (P = 0.01) and vomiting (P = 0.002) and the number of vomiting episodes (P = 0.003). DLP was the superior regimen in subsets of patients receiving cisplatin and the non-cisplatin chemotherapy. The improvements produced by the dexamethasone regimen were large and of major benefit to our patients. Patients documented significantly improved tolerance to chemotherapy with DLP courses (P = 0.0006). Overall, significantly more patients preferred DLP (P less than 0.0001). Patient assessments produced results similar to observer assessments but gave a broader understanding of their experience. The addition of dexamethasone to prochlorperazine and lorazepam significantly improved our patients' experience while receiving chemotherapy.

Causes for increased myelosuppression with increasing age in patients with oesophageal cancer treated by chemoradiotherapy.

The aim of this study was to identify why increasing myelosuppression accompanies increasing age in patients treated for oesophageal cancer by chemoradiation. Weekly neutrophil and platelet counts were obtained throughout treatment in 86 patients undergoing chemoradiation without surgery for oesophageal cancer. One or two cycles of cisplatin 80 mg/m2/day followed by 5-fluorouracil 800 mg/m2/day for 4-5 days were administered during the first and fourth or fifth week of radiotherapy using 2 Gy daily fractions. 44 of the patients underwent 5-fluorouracil pharmacokinetic studies. Multiple regression procedures were used to determine the strength of factors that contribute to initial and nadir neutrophil and platelet counts. The kinetics of myeloid response were evaluated from the rates of disappearance and re-appearance of neutrophils and platelets during treatment. Age, fluorouracil dose (or AUC), baseline body weight and neutrophil (or platelet) count were found to be powerfully and independently predictive of both first neutrophil and platelet nadir count. Baseline neutrophil and platelet counts were also found to correlate negatively with advancing age independently of other factors. The rate of descent of both indices, however, was independent of age, baseline count and fluorouracil dose suggesting that variations in the size of the myeloproliferative compartment prior to treatment were responsible for interpatient variations. In addition, the rate of recovery of both indices was not influenced by age amongst patients in whom data was assessable suggesting that proliferation of surviving marrow elements is not compromised by age. These data are compatible with the hypothesis that a progressive depletion of the myeloid stem cell compartment accompanies advancing age, and that this is responsible for increasing myelotoxicity.

A randomized study of paclitaxel versus cyclophosphamide/methotrexate/5-fluorouracil/prednisone in previously untreated patients with advanced breast cancer: preliminary results. Taxol Investigational Trials Group, Australia/New Zealand.

When administered as a single agent to previously treated patients with advanced breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has good activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line treatment for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive either paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles over 24 weeks or standard treatment with oral cyclophosphamide 100 mg/m2/d days 1 to 14, intravenous methotrexate 40 mg/m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisone 40 mg/m2 daily days 1 to 14 (CMFP) for six cycles over 24 weeks. Patients whose disease progressed or relapsed were recommended for second-line therapy with epirubicin. Accrual has been completed with 209 patients randomized, and an interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by the linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP, with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months with paclitaxel and 6.4 months with CMFP, with a median survival of 17.3 months for patients treated with paclitaxel and 11.3 months for those given CMFP. Grades 3 and 4 neutropenia occurred in 64% of patients with paclitaxel and 63% with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% with CMFP. Major infections (World Health Organization grade 4) were seen in 7% of patients treated with CMFP, but in none of those given paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel and 27% of CMFP patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results for those treated with paclitaxel compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides control of metastatic cancer comparable to that of CMFP combination therapy when used as front-line therapy in an outpatient setting.

Analysis of toxicity of Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group study.

PURPOSE: The acute and late toxicities of synchronous carboplatin, etoposide, and radiation therapy were prospectively assessed in a group of patients with high-risk Merkel cell carcinoma of the skin. PATIENTS AND METHODS: Forty patients from six different centers throughout Australia were entered into a Phase II study under the auspices of the Trans-Tasman Radiation Oncology Group. The trial was activated in 1996 and continues to accrue. Patients are eligible if they have disease localized to the primary site and nodes and are required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (area under curve [AUC] 4.5) and etoposide (80 mg/M(2) i.v.) were given on days 1-3 during weeks 1, 4, 7, and 10. The median age of the group was 67 years (43-78). RESULTS: The median duration of follow-up was 22 months (2-45). There were no treatment-related deaths. Grade 3 or 4 skin toxicity occurred in 63% of patients (95% CI 48, 78). The most serious acute effect was on neutrophils with Grade 3 or 4 (neutrophils < 1 x 10(9)/L), occurring in 60% (95% CI 45, 75) of cases. Complications from neutropenia (fever and sepsis) occurred in 16 patients (40% of cases). The median time for neutropenic complications was 27 days (9-35), and 10/16 (62%) cases of neutropenic fever occurred after the second cycle of chemotherapy. The probability of Grade 3 or 4 late effects on platelets (<50 x 10(9)/L) and hemoglobin (<8 g/dl) was 10% (95% CI 1, 20) and 6% (95% CI 2, 15), respectively. Of the 40 patients, 35 were able to complete 4 cycles of chemotherapy. There were no factors predictive for neutropenic toxicity at a p value < 0.05. CONCLUSIONS: The protocol has acceptable toxicity, and the treatment has been deliverable in a multi-institutional trial setting. Neutropenia is likely to occur with synchronous carboplatin/etoposide and radiation in this population of patients. The risk of a febrile neutropenia was greatest at the time of the second cycle of chemotherapy, when there was moist desquamation of skin or mucosal membranes that provided a portal for infection. This should be considered in the design of subsequent protocols with chemoradiotherapy.