Survival outcomes for patients with colorectal cancer with synchronous liver only metastasis.

BACKGROUND: Colorectal cancer with synchronous liver-only metastasis is managed with a multimodal approach, however, optimal sequencing of modalities remains unclear. METHODS: A retrospective review of all consecutive rectal or colon cancer cases with synchronous liver-only metastasis was conducted from the South Australian Colorectal Cancer Registry from 2006 to 2021. This study aimed to investigate how order and type of treatment modality affects overall survival. RESULTS: Data of over 5000 cases were analysed (n = 5244), 1420 cases had liver-only metastasis. There were a greater number of colon than rectal primaries (N = 1056 versus 364). Colonic resection was the preferred initial treatment for the colon cohort (60%). In the rectal cohort, 30% had upfront resection followed by 27% that had chemo-radiotherapy as 1st line therapy. For the colon cohort, there was an improved 5-year survival with surgical resection as initial treatment compared to chemotherapy (25% versus 9%, P < 0.001). In the rectal cohort, chemo-radiotherapy as the initial treatment was associated with an improved 5-year survival compared to surgery or chemotherapy (40% versus 26% versus 19%, P = 0.0015). Patients who were able to have liver resection had improved survival, with 50% surviving over 5 years compared to 12 months in the non-resected group (P < 0.001). Primary rectal KRAS wildtype patients who underwent liver resection and received Cetuximab had significantly worse outcomes compared to KRAS wildtype patients who did not (P = 0.0007). CONCLUSIONS: Where surgery is possible, resection of liver metastasis and primary tumour improved overall survival. Further research is required on the use of targeted treatments in patients undergoing liver resection.

Can sarcopenia predict complete response after total neoadjuvant therapy in advanced rectal cancer? A multicentre observational cohort study.

BACKGROUND: The association between sarcopenia and response to neoadjuvant treatment remains unclear. This study investigates sarcopenia as a predictor of overall complete response (oCR) after Total Neoadjuvant Therapy (TNT) for advanced rectal cancer. METHOD: A prospective observational study was performed of patients with rectal cancer undergoing TNT at three South Australian hospitals between 2019 and 2022. Sarcopenia was diagnosed by pretreatment computed tomography measurement of psoas muscle cross-sectional area at the third lumbar vertebra level, normalised for patient height. The primary endpoint was oCR rate defined as the proportion of patients who achieved either clinical complete response (cCR) or pathological complete response. RESULTS: This study included 118 rectal cancer patients with an average age of 59.5 years, 83 (70.3%) of whom formed the non-sarcopenic group (NSG) and 35 (29.7%) the sarcopenic group (SG). The oCR rate was significantly higher in NSG compared with the SG (p < 0.001). cCR rate was significantly greater in NSG compared with the SG (p = 0.001). Multivariate analysis revealed sarcopenia (p = 0.029) and hypoalbuminemia (p = 0.040) were risk factors for cCR and sarcopenia was an independent risk factor for oCR (p = 0.020). CONCLUSION: Sarcopenia and hypoalbuminemia were negatively associated with tumour response following TNT in advanced rectal cancer patients.

Personalized total neoadjuvant therapy (pTNT) for advanced rectal cancer with tailored treatment sequencing based on clinical stage at presentation.

BACKGROUND: This study aimed to assess short-term outcomes of a personalized total neoadjuvant treatment (pTNT) protocol, with treatment sequencing based on clinical stage at presentation. METHODS: A multidisciplinary pTNT protocol was implemented across two metropolitan hospitals. This consists of two-schema based on clinical stage: patients with distant failure risk were offered induction chemotherapy before chemoradiation (nCRT), and patients with locoregional failure risk received nCRT followed by consolidation chemotherapy. Patients underwent surgical resection unless a complete clinical response (cCR) was achieved, in which case non-operative management (NOM) was offered. A prospective cohort analysis of all patients with rectal cancer who underwent pTNT with curative intent between Jan 2019 and Aug 2022 was performed. RESULTS: Of 270 patients referred with rectal cancer, 102 received pTNT with curative intent and 79 have completed their treatment thus far. Thirty-three patients (41.8%) received induction chemotherapy and 46 (58.2%) received consolidation chemotherapy per protocol. The percentage of patients with EMVI, resectable M1 disease, cT4 disease, and positive lateral lymph nodes were 54.4%, 36.7%, 27.8% and 15.2%, respectively. Overall, 32 (40.5%) patients had cCR and 4 (5.1%) pCR, and 40 (50.6%) patients had non-operative management. Grade 3 toxicity was reported in 10.1% of patients and only three patients (3.8%) experienced Grade 4 chemotherapy-related toxicity, with no treatment related mortality. CONCLUSION: Early results with a defined two-schema pTNT protocol are encouraging and suggest that tailoring sequencing to disease risk at presentation may represent the optimal balance between local and distant disease control, as well as treatment toxicity.

Regorafenib outcomes from the population based South Australian Metastatic Colorectal Cancer Registry.

AIM: Reviewing outcomes of regorafenib use in metastatic colorectal cancer using real-world data from the South Australian Metastatic Colorectal Cancer Registry. METHODS: A retrospective review of the characteristics and outcomes of patients who received regorafenib in the Registry up to December 2018. The registry started in February 2006. RESULTS: Fifty-three patients received regorafenib therapy since approved by the therapeutic goods administration in November 2013. The median age was 66 (range 34-82). 66% were male, 66% had stage IV disease at diagnosis, 53% had liver only involvement, whereas 13% had liver and lung disease and 6% had lung only involvement. 75% had left-sided primary. KRAS was available in 35/53 patients with 49% of them being WT. BRAF status was known in 8/53 with 25% of them having a mutated variant. MSI testing was known in 14 patients in whom 21% of them had MSI-High tumors. Prior lines of treatment received: one line 4%, two 9%, three 23%, four 26%, >four 37%. Prior biological use: bevacizumab 72%, anti-EGFR 100% (for RAS WT). Median survival from diagnosis was 3.3 years (95% CI, 2.8-3.8 years). Median survival from the start of regorafenib was 7.1 months (95% CI, 4.8-9.4 months) and the 12-month survival rate was 28%. CONCLUSION: The survival outcome for those patients from our population-based registry who access regorafenib is in keeping with reports from large, randomized trials. Thus, clinicians can quote local real world data when discussing efficacy and access to regorafenib therapy for mCRC patients.

Efficacy of topical Calendula officinalis on prevalence of radiation-induced dermatitis: A randomised controlled trial.

OBJECTIVES: A randomised controlled trial was undertaken to compare the efficacy of topical Calendula officinalis (Calendula) versus standard of care (Sorbolene: 10% glycerine in cetomacragol cream) in reducing the prevalence of radiation-induced dermatitis in women undergoing breast cancer radiotherapy. METHODS: A total of 271 women were screened and 82 were randomised. The primary outcome was prevalence of acute radiation-induced dermatitis (RTOG grade 2+) assessed at multiple skin sites. A chi-squared test was conducted for the primary outcome with a worst-case scenario imputation. RESULTS: The recruitment target (n = 178) was not achieved. A total of n = 81 participants were analysed (n = 40 Calendula; n = 41 Sorbolene). There was no detectable difference in prevalence of radiation-induced dermatitis grade 2+ between the Calendula (53%) and Sorbolene (62%) groups (primary analysis OR = 0.87, 95% CI: [0.36, 2.09], P = 0.92; covariate adjusted complete case analysis OR 0.40, 95% CI: [0.13, 1.20], P = 0.10). CONCLUSION: This randomised controlled trial showed no difference between Calendula and standard of care (Sorbolene) for the prevention of radiation-induced dermatitis. However, the study was underpowered (limited recruitment) for the primary comparison.

Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer.

BACKGROUND: Resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether the benefit is consistent for BRAF V600E mutant (MT) and wild type (WT) mCRC. This retrospective analysis explores the influence of BRAF MT on survival after metastasectomy. METHODS: Overall survival (OS) and recurrence-free survival (RFS) for BRAF MT and WT mCRC were evaluated. Survival was also analyzed in the cohort of BRAF MT with or without metastasectomy. RESULTS: Five hundred and thirteen patients who had undergone metastasectomy were identified, 6% were BRAF-MT. Median age 63. Median OS in BRAF MT vs WT: 25.7 vs 48.5 months (hazard ratio [HR] 1.95; 1.18-3.22). However, difference was not significant in a multivariate model. Right primary tumor, intact primary, >1 metastatic site, non-R0 resection, peritoneal metastasis, and synchronous metastasis were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 vs 19 months, p=0.09). In another cohort of 158 BRAF-MT patients, OS was significantly better after metastasectomy compared to "no metastasectomy" (HR 0.34; 0.18-0.65, P= 0.001). Proficient mismatch repair status showed a trend toward worse survival after metastasectomy in BRAF MT (HR 1.71, P = 0.08). CONCLUSION: OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Median OS was >2 years in this study after metastasectomy among BRAFV600E MT patients suggesting a survival benefit of metastasectomy in this group where systemic therapeutic options are limited. Metastasectomy may be considered in carefully selected BRAF-MT patients.

Measuring (and narrowing) the gap: The experience with attendance of Indigenous cancer patients for Radiation Therapy in the Northern Territory.

INTRODUCTION: Barriers exist for both Indigenous and remote patients attending cancer care facilities. We sought to measure clinical attendance of all patients referred for consideration of radiation therapy (RT) at the single radiation therapy centre in the Northern Territory (NT), with particular attention to a comparison of Indigenous and non-Indigenous patients, and to analyse methods introduced to address the attendance of patients. METHODS: Patients referred for radiation therapy over a 5 year period from the commencement of the Alan Walker Cancer Care Centre (AWCCC), NT, were analysed for attendance, and for possible improvement over time. RESULTS: Multivariate analysis of non-attendance prior to RT (pre-RT) showed significance for Indigenous status (P < 0.001), and female gender (P < 0.001), and during RT showed significance for Indigenous status (P < 0.001) and curative intent RT (P = 0.012). Attendance during RT over the 5 years showed significant improvement over time for Indigenous patients from 70.6% to 81.6% (P = 0.038). There was no significant improvement with pre-RT attendance for either the Indigenous or non-Indigenous cohort. CONCLUSION: Indigenous patients experienced a lower level of attendance during RT, but this has significantly improved over the first 5 years of operation at AWCCC, as recognition and management of contributing factors has improved.

Brain metastasis in advanced colorectal cancer: results from the South Australian metastatic colorectal cancer (SAmCRC) registry.

OBJECTIVE: Brain metastasis is considered rare in metastatic colorectal cancer (mCRC); thus, surveillance imaging does not routinely include the brain. The reported incidence of brain metastases ranges from 0.6% to 3.2%. METHODS: The South Australian mCRC Registry (SAmCRC) was analyzed to assess the number of patients presenting with brain metastasis during their lifetime. Due to small numbers, a descriptive analysis is presented. RESULTS: Only 59 patients of 4,100 on the registry at the time of analysis had developed brain metastasis (1.4%). The clinical characteristics of those with brain metastasis were as follows: the median age was 65.3 years and 51% were female. Where the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status of the tumor was known, the majority harbored a KRAS mutation (55%); 31 (53%) underwent craniotomy and 55 (93%) underwent whole-brain radiotherapy. The median survival time from diagnosis of brain metastasis was 4.2 months (95% confidence interval 2.9-5.5). Patients who underwent craniotomy and radiotherapy had superior survival compared to those who underwent whole-brain radiotherapy (8.5 months vs. 2.2 months, respectively). Data from the SAmCRC (a population-based registry) confirm that brain metastases are rare and the median time to development is approximately 2 years. CONCLUSIONS: Brain metastasis is a rare outcome in advanced CRC. Patients within the registry tended to be female, young in age, and harbored with higher rates of KRAS mutations. Whether routine surveillance brain scanning should be considered remains controversial given the relative rarity of developing brain metastases in mCRC and ultimately, most patients with central nervous system involvement die from their extracranial disease.

Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial.

BACKGROUND: Adjuvant radiotherapy is recommended for patients with melanoma after lymphadenectomy. We previously showed this treatment reduced risk of repeat lymph-node field cancer in patients with a high risk of recurrence but had no effect on overall survival. Here, we aim to update the relapse and survival data from that trial and assess quality of life and toxic effects. METHODS: In the ANZMTG 01.02/TROG 02.01 randomised controlled trial, we enrolled patients who had undergone lymphadenectomy for a palpable lymph-node field relapse and were at high risk of recurrence at 16 hospitals (11 in Australia, three in New Zealand, one in Netherlands, and one in Brazil). We randomly assigned patients (1:1) to adjuvant radiotherapy (48 Gy in 20 fractions, given over a maximum of 30 days) or observation, stratified by institution, areas of lymph-node field (parotid and cervical, axilla, or groin), number of involved nodes (≤3 vs >3), maximum involved node diameter (≤4 cm vs >4 cm), and extent of extracapsular extension (none, limited, or extensive). Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation, but participants were unaware of each other's treatment allocation. In this follow-up, we assessed outcomes every 3 months from randomisation for the first 2 years, then every 6 months up to 5 years, then annually. The primary endpoint was lymph-node field relapse as a first relapse, assessed in patients without major eligibility infringements (determined by an independent data monitoring committee). We assessed late adverse effects (occurring >90 days after surgery or start of radiotherapy) with standard criteria in the as-treated population. This study is registered with ClinicalTrials.gov, number NCT00287196. FINDINGS: Between March 21, 2003, and Nov 15, 2007, we randomly assigned 123 patients to adjuvant radiotherapy (109 eligible for efficacy assessments) and 127 to observation (108 eligible). The final follow-up date was Nov 15, 2011. Median follow-up was 73 months (IQR 61-91). 23 (21%) relapses occurred in the adjuvant radiotherapy group compared with 39 (36%) in the observation group (adjusted hazard ratio [HR] 0·52 [95% CI 0·31-0·88], p=0·023). Overall survival (HR 1·27 [95% CI 0·89-1·79], p=0·21) and relapse-free survival (0·89 [0·65-1·22], p=0·51) did not differ between groups. Minor, long-term toxic effects from radiotherapy (predominantly pain, and fibrosis of the skin or subcutaneous tissue) were common, and 20 (22%) of 90 patients receiving adjuvant radiotherapy developed grade 3-4 toxic effects. 18 (20%) of 90 patients had grade 3 toxic effects, mainly affecting skin (nine [10%] patients) and subcutaneous tissue (six [7%] patients). Over 5 years, a significant increase in lower limb volumes was noted after adjuvant radiotherapy (mean volume ratio 15·0%) compared with observation (7·7%; difference 7·3% [95% CI 1·5-13·1], p=0·014). No significant differences in upper limb volume were noted between groups. INTERPRETATION: Long-term follow-up supports our previous findings. Adjuvant radiotherapy could be useful for patients for whom lymph-node field control is a major issue, but entry to an adjuvant systemic therapy trial might be a preferable first option. Alternatively, observation, reserving surgery and radiotherapy for a further recurrence, might be an acceptable strategy. FUNDING: National Health and Medical Research Council of Australia, Cancer Council Australia, Melanoma Institute Australia, and the Cancer Council South Australia.

External evaluation of the Radiation Therapy Oncology Group brachial plexus contouring protocol: several issues identified.

INTRODUCTION: The aims of the study were to evaluate interobserver variability in contouring the brachial plexus (BP) using the Radiation Therapy Oncology Group (RTOG)-approved protocol and to analyse BP dosimetries. METHODS: Seven outliners independently contoured the BPs of 15 consecutive patients. Interobserver variability was reviewed qualitatively (visually by using planning axial computed-tomography images and anteroposterior digitally reconstructed radiographs) and quantitatively (by volumetric and statistical analyses). Dose-volume histograms of BPs were calculated and compared. RESULTS: We found significant interobserver variability among outliners in both qualitative and quantitative analyses. These were most pronounced for the T1 nerve roots on visual inspection and for the BP volume on statistical analysis. The BP volumes were smaller than those described in the RTOG atlas paper, with a mean volume of 20.8 cc (range 11-40.7 cc) compared with 33 ± 4 cc (25.1-39.4 cc). The average values of mean dose, maximum dose, V60Gy, V66Gy and V70Gy for patients treated with conventional radiotherapy and IMRT were 42.2 Gy versus 44.8 Gy, 64.5 Gy versus 68.5 Gy, 6.1% versus 7.6%, 2.9% versus 2.4% and 0.6% versus 0.3%, respectively. CONCLUSION: This is the first independent external evaluation of the published protocol. We have identified several issues, including significant interobserver variation. Although radiation oncologists should contour BPs to avoid dose dumping, especially when using IMRT, the RTOG atlas should be used with caution. Because BPs are largely radiologically occult on CT, we propose the term brachial-plexus regions (BPRs) to represent regions where BPs are likely to be present. Consequently, BPRs should in principle be contoured generously.

Radiation treatment compliance in the Indigenous population: the pilot Northern Territory experience and future directions.

INTRODUCTION: There is a perception that Indigenous patients are less likely to attend radiotherapy treatment. This study sought to determine if a difference in radiotherapy treatment compliance rates exists between Indigenous and non-Indigenous patients. Secondly, we aimed to ascertain which patient, disease and treatment factors affect compliance in Indigenous patients. METHODS: All patients treated with radiotherapy at the Alan Walker Cancer Care Centre between March and October 2010 were analysed. Data regarding compliance rates (defined as those who chose and completed the recommended course of treatment), patient, disease and treatment factors were collected, and chi-squared and Fisher's exact tests were applied. RESULTS: A total of 41 courses were delivered to Indigenous patients and 224 courses delivered to non-Indigenous patients in this period. There was no difference in compliance between Indigenous and non-Indigenous patients (83% vs. 81%, P = 0.75). Of the factors assessed, it was found that there was an association between toxicity grade and compliance (P = 0.048). CONCLUSIONS: From this cohort, we cannot support the perception that Indigenous patients have overall poorer compliance with recommended radiation treatment courses. In this study, the only factor which correlated significantly with compliance was toxicity grade. It is felt that a number of factors, which negatively impact on compliance, can potentially be counteracted by a culturally sensitive model of care.

Survival differences in patients with metastatic colorectal cancer and with single site metastatic disease at initial presentation: results from South Australian clinical registry for advanced colorectal cancer.

BACKGROUND: Colorectal cancer is the third most common cancer in Australia. The median overall survival for metastatic colorectal cancer is nearly 2 years. However, there may be survival differences based on site of metastatic disease. METHODS: Data was collected from the South Australian Registry for Advanced Colorectal Cancer. A total of 1207 patients with single site metastatic disease at initial diagnosis were subclassified into 6 subgroups: liver only (n = 780), pelvic only (n = 148), lung only (n = 142), lymph node only (n = 95), bone only (n = 32), and brain only (n = 10). Univariate and multivariate parametric survival analyses were performed. RESULTS: Median overall survival was 20.3 months for the whole group. The overall survival for lung-only metastases group was 41.1 months followed by liver- and pelvic-only disease groups (22.8 and 23.8 months, respectively). Patients with isolated bone-only and brain-only metastases had poor overall survival (5.1 and 5.7 months, respectively). On multivariate analysis, prognosis was superior for the lung-only group. CONCLUSIONS: Lung only group had the longest median overall survival. Bone and brain sites had a poor outlook. Site of metastatic disease at initial presentation may be prognostic.

Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.

BACKGROUND: The use of radiotherapy after therapeutic lymphadenectomy for patients with melanoma at high risk of further lymph-node field and distant recurrence is controversial. Decisions for radiotherapy in this setting are made on the basis of retrospective, non-randomised studies. We did this randomised trial to assess the effect of adjuvant radiotherapy on lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes. METHODS: This randomised controlled trial included patients from 16 hospitals in Australia, New Zealand, the Netherlands, and Brazil. To be eligible for this trial, patients had to be at high risk of lymph-node field relapse, judged on the basis of number of nodes involved, extranodal spread, and maximum size of involved nodes. After lymphadenectomy, randomisation was done centrally by computer and patients assigned by telephone in a ratio of 1:1 to receive adjuvant radiotherapy of 48 Gy in 20 fractions or observation, with institution, lymph-node field, number of involved nodes, maximum node diameter, and extent of extranodal spread as minimisation factors. Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation. The primary endpoint was lymph-node field relapse (as a first relapse), analysed for all eligible patients. The study is registered at ClinicalTrials.gov, number NCT00287196. The trial is now closed and follow-up discontinued. FINDINGS: 123 patients were randomly allocated to the adjuvant radiotherapy group and 127 to the observation group between March 20, 2002, and Sept 21, 2007. Two patients withdrew consent and 31 had a major eligibility infringement as decided by the independent data monitoring committee, resulting in 217 eligible for the primary analysis (109 in the adjuvant radiotherapy group and 108 in the observation group). Median follow-up was 40 months (IQR 27-55). Risk of lymph-node field relapse was significantly reduced in the adjuvant radiotherapy group compared with the observation group (20 relapses in the radiotherapy group vs 34 in the observation group, hazard ratio [HR] 0·56, 95% CI 0·32-0·98; p=0·041), but no differences were noted for relapse-free survival (70 vs 73 events, HR 0·91, 95% CI 0·65-1·26; p=0·56) or overall survival (59 vs 47 deaths, HR 1·37, 95% CI 0·94-2·01; p=0·12). The most common grade 3 and 4 adverse events were seroma (nine in the radiotherapy group vs 11 in the observation group), radiation dermatitis (19 in the radiotherapy group), and wound infection (three in the radiotherapy group vs seven in the observation group). INTERPRETATION: Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy. FUNDING: National Health and Medical Research Council of Australia, Cancer Australia, Melanoma Institute Australia, Cancer Council of South Australia.