Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2 + /HR + metastatic breast cancer.

PURPOSE: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. METHODS: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). RESULTS: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37-0.89, p = 0.014) and OS (HR 0.52, CI 0.31-0.90, p = 0.018), with no increase in adverse events noted. CONCLUSION: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors.

Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive, HER2-Negative Metastatic Breast Cancer.

BACKGROUND: International guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported. MATERIALS AND METHODS: KARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2. RESULTS: Data from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2. CONCLUSION: The ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.

Real-World Outcomes in Patients With Brain Metastases Secondary to HER2-Positive Breast Cancer: An Australian Multi-centre Registry-based Study.

BACKGROUND: The development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC. MATERIALS & METHODS: Data was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes. RESULTS: A total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02). CONCLUSION: Real-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.

Assessing the accuracy of 68 Ga-PSMA PET/CT compared with MRI in the initial diagnosis of prostate malignancy: A cohort analysis of 114 consecutive patients.

INTRODUCTION: Prostate cancer diagnosis is shifting towards a minimally invasive approach, maintaining accuracy and efficacy while reducing morbidity. We aimed to assess if PSMA-Ga68 PET/CT can accurately grade and localise prostatic malignancy using objective methods, compared with pathology and MRI. METHODS: Retrospective analysis on 114 consecutive patients undergoing staging PSMA PET/CT scans over 12 months was carried out. The SUVmax and site of highest PSMA activity within the prostate gland were recorded. Pathology/biopsy review assessed maximum Gleason score (and location). MRI analysis assessed the highest PIRADS score and location. The grade, location and size of malignant tissue on biopsy, and PSA, were correlated with the SUVmax and the PIRADS score. RESULTS: SUVmax was significantly elevated in cases with PSA ≥10 (P = 0.003) and Gleason score ≥8 (P = 0.0002). SUVmax demonstrated equivalent sensitivity to MRI-PIRADS in predicting Gleason ≥8 disease, with higher specificity when tested under a high-specificity regime (SUVmax ≥10, PIRADS = 5, P = 0.002). Furthermore, the region of highest SUVmax was superior to MRI-PIRADS for localising the highest grade tumour region, correctly identifying 71% of highest grade regions compared to 54% with MRI (P = 0.015). CONCLUSION: PSMA PET/CT is as effective as MRI in identifying high-grade prostate malignancy. Our findings also support previous studies in showing a significant relationship between SUVmax and Gleason grade. These benefits, along with the known advantage in identifying distant metastases and the reduced cost, further support the argument that PSMA PET/CT should be offered as an initial investigation in the workup of prostate cancer.

Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.

BACKGROUND: International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. AIM: To describe real-world practice of Australian breast oncologists. METHODS: Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. RESULTS: Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. CONCLUSION: Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.

A prospective study investigating the efficacy and toxicity of definitive ChemoRadiation and ImmunOtherapy (CRIO) in locally and/or regionally advanced unresectable cutaneous squamous cell carcinoma.

BACKGROUND: Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort. METHODS: Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC (stage III-IVa) deemed fit for CRIO by consensus of the Multidisciplinary meeting will be eligible. In the first stage of a two-stage minimax design, we aim to recruit a total of 15 patients. If fewer than 7 patients achieved a complete response in the first stage, we will conclude the treatment is not more effective than standard treatment. The co-primary endpoints of CRIO are the safety of treatment (acute and late toxicities) and the rate of complete response. Secondary endpoints would include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers (CD73, CD39, PD-1, PD-L1) will also be explored utilising multiplex immunohistochemistry on tumour biopsy samples obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET/CT scan will be explored. DISCUSSION: CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent and adjuvant durvalumab for patients with unresectable stage III-IVa cSCC. TRIAL REGISTRATION: Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246).

Impact of prior (neo)adjuvant trastuzumab (NAT) exposure on the efficacy of HER2-targeted therapy for metastatic breast cancer.

PURPOSE: Trastuzumab, pertuzumab, and docetaxel are the standard first-line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC). However, only 10% of patients received neoadjuvant and/or adjuvant trastuzumab (NAT) in the registration trial (NCT00567190). In contemporary practice, the majority of recurrent HER2+ MBC patients had prior NAT. We explore any impact of prior therapy on the efficacy of dual HER2-targeted antibody with taxane therapy for metastatic disease. METHODS: Utilising a prospective national registry, clinico-pathological, treatment, and outcome data for HER2+ MBC patients diagnosed between October 2006 and January 2019 were collected. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. RESULTS: Of 287 HER2+ MBC patients, 222 (77%) received first-line trastuzumab, pertuzumab, and taxane therapy. There were 130 (45%) with de novo MBC. Of the recurrent MBC patients 107/157 (68%) had received NAT. The median progression-free survival (PFS) among patients who received NAT was 15.8 months compared with 24.3 months without prior NAT (hazard ratio [HR] 1.45, 95% CI 1.05-2.03, p = 0.03). The median overall survival (OS) was 42.7 months in patients who had NAT, and was not reached in those who did not (HR 1.80, 95% CI 1.12-2.90, p = 0.02). However, when excluding de novo MBC patients, prior NAT exposure was no longer significantly associated with survival (p = 0.11). De novo MBC patients had the longest median PFS (25.2 months) and OS (91.2 months). CONCLUSIONS: Prior receipt of NAT was associated with inferior median PFS following first-line HER2-based therapy in the metastatic setting. However, prior NAT exposure did not significantly impact OS, supporting the efficacy of taxane, trastuzumab, pertuzumab combination for first-line HER2+ MBC regardless of prior NAT exposure. Patients with de novo MBC had the longest survival, suggesting stratification for synchronous versus metachronous disease in prospective clinical trials of MBC should be considered.

Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.

BACKGROUND: Conventional imaging using CT and bone scan has insufficient sensitivity when staging men with high-risk localised prostate cancer. We aimed to investigate whether novel imaging using prostate-specific membrane antigen (PSMA) PET-CT might improve accuracy and affect management. METHODS: In this multicentre, two-arm, randomised study, we recruited men with biopsy-proven prostate cancer and high-risk features at ten hospitals in Australia. Patients were randomly assigned to conventional imaging with CT and bone scanning or gallium-68 PSMA-11 PET-CT. First-line imaging was done within 21 days following randomisation. Patients crossed over unless three or more distant metastases were identified. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358. FINDINGS: From March 22, 2017 to Nov 02, 2018, 339 men were assessed for eligibility and 302 men were randomly assigned. 152 (50%) men were randomly assigned to conventional imaging and 150 (50%) to PSMA PET-CT. Of 295 (98%) men with follow-up, 87 (30%) had pelvic nodal or distant metastatic disease. PSMA PET-CT had a 27% (95% CI 23-31) greater accuracy than that of conventional imaging (92% [88-95] vs 65% [60-69]; p<0·0001). We found a lower sensitivity (38% [24-52] vs 85% [74-96]) and specificity (91% [85-97] vs 98% [95-100]) for conventional imaging compared with PSMA PET-CT. Subgroup analyses also showed the superiority of PSMA PET-CT (area under the curve of the receiver operating characteristic curve 91% vs 59% [32% absolute difference; 28-35] for patients with pelvic nodal metastases, and 95% vs 74% [22% absolute difference; 18-26] for patients with distant metastases). First-line conventional imaging conferred management change less frequently (23 [15%] men [10-22] vs 41 [28%] men [21-36]; p=0·008) and had more equivocal findings (23% [17-31] vs 7% [4-13]) than PSMA PET-CT did. Radiation exposure was 10·9 mSv (95% CI 9·8-12·0) higher for conventional imaging than for PSMA PET-CT (19·2 mSv vs 8·4 mSv; p<0·001). We found high reporter agreement for PSMA PET-CT (κ=0·87 for nodal and κ=0·88 for distant metastases). In patients who underwent second-line image, management change occurred in seven (5%) of 136 patients following conventional imaging, and in 39 (27%) of 146 following PSMA PET-CT. INTERPRETATION: PSMA PET-CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning. FUNDING: Movember and Prostate Cancer Foundation of Australia. VIDEO ABSTRACT.

Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer.

INTRODUCTION: The management of prostate cancer has undergone significant advances since the introduction of 68 Ga-prostate-specific membrane antigen (68 Ga-PSMA) positron emission tomography (PET) scans. Data on the use of 68 Ga-PSMA PET scans in the setting of biochemical recurrence is widely available. Data on the use of 68 Ga-PSMA PET as an initial staging modality, however, is limited. The aim of this retrospective study was to compare the staging of patients with newly diagnosed prostate cancer between 68 Ga-PSMA PET and current conventional imaging modalities. The potential impact of any change in stage will be analysed. METHODS: Details of all patients who underwent 68 Ga-PSMA PET in South Australia between March 2016 and March 2017 were obtained. One hundred and thirty-one patients with newly diagnosed prostate cancer who had 68 Ga-PSMA PET prior to consideration of definitive treatment were included in this study. The stage pre-68 Ga-PSMA PET (based on conventional imaging) and post-68 Ga-PSMA PET was recorded. The stage was classified as A - localised disease, B - presence of regional lymphadenopathy, C - oligometastatic disease (up to three metastases) and D - widespread metastases. Management plans were recorded. RESULTS: This study showed that the use of 68 Ga-PSMA PET resulted in a change of stage in 37 (28%) patients with an upstage in 17 (13%) patients and a downstage in 20 (15%) patients (P < 0.001). 68 Ga-PSMA PET excluded oligometastatic disease in 11 (8%) patients who had suspicious oligometastatic disease based on a single conventional imaging modality. These 68 Ga-PSMA PET findings impacted on management in at least 24 (18%) patients. CONCLUSION: The use of 68 Ga-PSMA PET scans in initial staging can have a significant impact on staging and management when compared to current conventional imaging modalities.

Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials.

Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.

Prospective study of definitive chemoradiation in locally or regionally advanced squamous cell carcinoma of the skin.

BACKGROUND: The purpose of this study was to present our evaluation of the outcomes of concurrent chemoradiotherapy (CRT) in patients with locally advanced cutaneous squamous cell carcinoma (SCC). METHODS: This was a prospective phase II study. The primary endpoint was complete response (CR). Patients with locally/regionally advanced cutaneous SCC deemed unsuitable for surgery received definitive radiotherapy (RT; 70 Gy in 35fractions) and concurrent weekly platinum-based chemotherapy (cisplatin 40 mg/m2 or carboplatin area under the curve 2). RESULTS: Twenty-one patients were enrolled in this study. Eighteen patients had a locally advanced primary or nodal disease in the head and neck region with 66% having stage IV nonmetastatic disease. Of 19 evaluable patients, 10 achieved a CR to definitive CRT with 2 further patients rendered disease-free by salvage surgery for an overall CR of 63%. CONCLUSION: This is the only prospective series of CRT for cutaneous SCC. A high CR rate was documented in patients with locoregional advanced disease who were unable to undergo surgery. © 2016 Wiley Periodicals, Inc. Head Neck 39: 679-683, 2017.

Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study.

INTRODUCTION: This study had three aims: to establish the incidence of ipsilateral breast tumour recurrence (IBTR) in a community treatment setting, to evaluate known factors--in particular younger age (< 40 years)--predictive for local recurrence, and to assess the impact of local recurrence on disease-specific survival (DSS). METHODS: A consecutive series of 1,540 women with node-negative breast cancer, diagnosed between the ages of 18-75 years, were prospectively accrued between September 1987 and September 1999. All had undergone a resection of the primary breast cancer with clear margins, an axillary lymph node dissection with a minimum of four sampled nodes, and breast-conserving surgery (of any type). RESULTS: During the study follow-up period, 98 (6.4%) IBTRs and 117 (7.6%) deaths from or with breast cancer were observed. The median time to IBTR was 3.1 years and to death from or with disease was 4.3 years. In the multivariate Cox proportional hazards (PH) regression model for IBTR with adjuvant therapy factors, independent risk factors included age < 40 years (relative risk (RR) = 1.89, 95% confidence interval (CI) of 1.00 - 3.58), presence of intraductal disease (RR = 1.81, 95% CI = 1.15-2.85) and histological grade ('G2' or G3 versus G1: RR = 1.59, 95% CI = 0.87-2.94). In the multivariate Cox PH regression model for DSS with adjuvant therapy factors, independent risk factors included previous IBTR (RR = 2.58, 95% CI = 1.41-4.72), tumor size (1-2 cm versus < 1 cm: RR = 1.95, 95% CI = 1.05-3.64, > 2 cm versus < 1 cm: RR = 2.94, 95% CI = 1.56-5.56), progesterone receptor status (negative or equivocal versus positive or unknown: RR = 2.15, 95% CI = 1.36-3.39), lymphatic invasion (RR = 1.78, 95% CI = 1.17-2.72), and histological grade ('G2' or G3 versus G1: RR = 8.59, 95% CI = 2.09-35.36). The effects of competing risks could be ignored. CONCLUSION: The Cox PH analyses confirmed the importance of known risk factors for IBTR and DSS in a community treatment setting. This study also revealed that the early occurrence of an IBTR is associated with a relatively poor five-year survival rate.

Phase I trial of gemcitabine, doxorubicin and cisplatin (GAP) in patients with advanced solid tumors.

A phase I study was conducted to determine the recommended phase II dose, safety profile and anti-tumor activity of a combination regimen of gemcitabine, doxorubicin and cisplatin (GAP). Gemcitabine (G) and doxorubicin (A) were administered on days 1 and 8 at increasing doses (starting level 800 and 15 mg/m, respectively). Cisplatin (P) was given at a fixed dose of 50 mg/m2 (day 1). Treatment cycles were repeated every 3 weeks. Nineteen patients received 76 cycles of treatment. A and G were escalated up to 20 and 1000 mg/m2, and finally de-escalated to 15 and 800 mg/m2. The dose-limiting toxicity was neutropenic fever that was observed in 21% of the patients. Non-hematological toxicities included mild/moderate nausea, vomiting, diarrhea and fatigue, observed in 58, 37, 21 and 95% of the patients, respectively. Of 19 patients with evaluable disease, six patients had a partial response yielding an overall response rate of 31.6 % (95% confidence interval 12.6-56.6%) by intention-to-treat. We conclude that GAP is an active and tolerable treatment combination, with minimal visceral organ toxicities.

Sucralfate mouthwash for prevention and treatment of 5-fluorouracil-induced mucositis: a randomized, placebo-controlled trial.

A randomized, double-blind, placebo-controlled trial was conducted to evaluate the effectiveness of a sucralfate mouthwash in preventing and alleviating oral mucositis induced by 5-fluorouracil (5FU). A total of 81 patients with colorectal cancer were enrolled. Patients were studied during their first cycle of chemotherapy with 5FU and leucovorin (LV) daily for 5 days every 4 weeks (Mayo Clinic schedule). Patients were randomly allocated to receive either a sucralfate suspension or a placebo suspension that was identical in appearance. Patients were instructed to use the suspension as a mouthwash four times daily from the beginning of the chemotherapy cycle. All patients received oral cryotherapy. Patients graded the severity of their own symptoms on a daily basis, and this was the primary outcome measure. There was no difference in the frequency or severity of oral mucositis between the sucralfate- and the placebo-treated group. Some mucositis was reported by 79% of the patient group. Assessment of mucositis by trial staff underestimated the incidence of this problem. Results of this trial do not support the hypothesis that a sucralfate mouthwash can prevent or alleviate oral mucositis induced by 5FU. Patient reporting of mucositis is a more sensitive instrument for assessment of mucositis than review by medical staff.

Rationale for Ras and raf-kinase as a target for cancer therapeutics.

Improvements in our understanding of the intrinsic aberrancies in cancer cells have enabled the design and development of novel therapeutics that specifically target these changes. Among the many complex cellular pathways and mechanisms which have been unveiled by new molecular techniques, RAS-mediated signal transduction is one met with tremendous research interests. Activation of RAS initiates several signaling cascades, of which the RAS-RAF-MEK-ERK pathway is among the better delineated, and is the main focus of this review. Other cellular consequences of RAS activation including interactions with the RHO-family proteins, the PI3-kinase pathway, and other mitogen activated protein kinase cascades, will be discussed. The intricate balance and coordination of multiple RAS-mediated signals lead to ultimate effects on cell growth, differentiation, cycling and survival. Pharmacological strategies such as analog development, synthesis of small molecule inhibitors, antisense technology, and vaccine therapy have been utilized to intervene with key RAS-signaling proteins, in an attempt to provide rational therapeutic solutions in malignant diseases.