Adam Pawinski

Colorectal Cancer Metastatic to the Brain: Time Trends in Presentation and Outcome

Objective: It was the aim of this study to compare differences in disease pattern, patient characteristics and survival in patient cohorts treated during different decades. Methods: We conducted a retrospective analysis of all patients with brain metastases from colorectal cancer treated between 1983 and June 2008 in Northern Norway. The patients were assigned to 3 different groups, based on the decade of treatment. Results: The time interval between first cancer diagnosis and brain metastases has significantly increased over time. The use of chemotherapy before development of brain metastases has also increased. Only few patients did not harbour extracranial metastases. Chemotherapy after diagnosis of brain metastases has been used exclusively in the present decade, but in only 3 patients. Combined surgical resection or radiosurgery plus whole-brain radiotherapy has increasingly been utilized, but whole-brain radiotherapy alone remained the cornerstone. Neither survival from first cancer diagnosis nor from brain metastasis treatment has improved significantly; however, with up to 17 patients, the groups were small. Three factors were significantly associated with better survival: good performance status, limited number of brain metastases (1 vs. 2–3 vs. 4 or more) and absence of extracranial metastases. The prognostic impact of the recursive partitioning analysis classes was confirmed, while the new graded prognostic assessment index performed less well. Conclusions: Median survival was maximum 6 months in all decades, despite the increasing use of more aggressive treatment. As most patients harbour extracranial metastases that threaten their lives, systemic treatment might theoretically play a role in the management of these patients, but more data need to be collected to confirm the clinical impact of this approach.

Continuous controversy about radiation oncologists’ choice of treatment regimens for bone metastases: should we blame doctors, cancer-related features, or design of previous clinical studies?

Recent studies from Italy, Japan and Norway have confirmed previous reports, which found that a large variety of palliative radiotherapy regimens are used for painful bone metastases. Routine use of single fraction treatment might or might not be the preferred institutional approach. It is not entirely clear why inter-physician and inter-institution differences continue to persist despite numerous randomized trials, meta-analyses and guidelines, which recommend against more costly and inconvenient multi-fraction regimens delivering total doses of 30 Gy or more in a large number of clinical scenarios. In the present mini-review we discuss the questions of whether doctors are ignoring evidence-based medicine or whether we need additional studies targeting specifically those patient populations where recent surveys identified inconsistent treatment recommendations, e.g. because of challenging disease extent. We identify open questions and provide research suggestions, which might contribute to making radiation oncology practitioners more confident in selecting the right treatment for the right patient.

Anaemia and thrombocytopenia in patients with prostate cancer and bone metastases

BackgroundThe purpose of this study was to determine the incidence, risk factors and prognostic impact of anaemia and thrombocytopenia in patients with bone metastases (BM) from prostate cancer.MethodsRetrospective cohort study including 51 consecutive patients treated at a community hospital. Twenty-nine patients (57%) received taxotere after diagnosis of BM.ResultsHaemoglobin (Hb) ≤ 12.0 g/dL at BM detection was associated with shorter overall survival. During follow-up, 25 patients (49%) experienced episodes with Hb < 10 g/dL unrelated to side effects of cancer therapy. Fifteen patients required red blood cell transfusion. Median time from diagnosis of BM to Hb < 10 g/dL was 23 months. Median survival from Hb < 10 g/dL was 5.4 months. There was no factor predicting for Hb < 10 g/dL. Five patients (10%) developed thrombocyte (Trc) count <50 × 109/L. All of these had previously received blood transfusion. Median interval from Hb < 10 g/dL to Trc < 50 × 109/L was 2.5 months. Survival after thrombocytopenia was short (3 weeks to 4 months). Haematuria and subdural haematoma were among the causes of death.ConclusionsWe found high rates of significant bone marrow failure in treatment-refractory patients. Both Hb < 10 g/dL and Trc < 50 × 109/L predict for unfavourable survival.

A review of clinical trials of cetuximab combined with radiotherapy for non-small cell lung cancer

Treatment of non-small cell lung cancer (NSCLC) is challenging in many ways. One of the problems is disappointing local control rates in larger volume disease. Moreover, the likelihood of both nodal and distant spread increases with primary tumour (T-) stage. Many patients are elderly and have considerable comorbidity. Therefore, aggressive combined modality treatment might be contraindicated or poorly tolerated. In many cases with larger tumour volume, sufficiently high radiation doses can not be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents, which increase tumour cell kill, might improve the therapeutic ratio. If such agents have a favourable toxicity profile, even elderly patients might tolerate concomitant treatment. Based on sound preclinical evidence, several relatively small studies have examined radiotherapy (RT) with cetuximab in stage III NSCLC. Three different strategies were pursued: 1) RT plus cetuximab (2 studies), 2) induction chemotherapy followed by RT plus cetuximab (2 studies) and 3) concomitant RT and chemotherapy plus cetuximab (2 studies). Radiation doses were limited to 60-70 Gy. As a result of study design, in particular lack of randomised comparison between cetuximab and no cetuximab, the efficacy results are difficult to interpret. However, strategy 1) and 3) appear more promising than induction chemotherapy followed by RT and cetuximab. Toxicity and adverse events were more common when concomitant chemotherapy was given. Nevertheless, combined treatment appears feasible. The role of consolidation cetuximab after RT is uncertain. A large randomised phase III study of combined RT, chemotherapy and cetuximab has been initiated.

Estimating Need for Palliative External Beam Radiotherapy in Adult Cancer Patients

PURPOSE Older surveys and benchmark data from different sources have suggested that 46-53% of all radiotherapy courses were administered with palliative intent. In Sweden, 87 annual palliative treatment courses per 100,000 inhabitants were registered in 2001, mainly for the treatment of bone and brain metastases (95% confidence interval [CI] 85-89). The corresponding number for Norway was 95 (95% CI 93-98) in 2004. New data are lacking, although new systemic treatment options might alter this number. METHODS AND MATERIALS We collected prospective data on the use of palliative external beam radiotherapy for adult cancer patients during a 12-month period between 2007 and 2008. All patients (median age 69 years) were treated in one Norwegian county and had unlimited, rapid access to treatment. Efforts were made to account for potential overuse. RESULTS Most irradiated patients had skeletal target volumes, followed by nonbony thoracic targets and brain metastases. In the present population, 133 annual treatments per 100,000 inhabitants were registered (after correction for overuse, but not accounting for radiosurgery of brain metastases and emerging treatment options; e.g., stereotactic radiotherapy for lung and liver metastases; 95% CI 119-149). Because some patients received simultaneous treatment to different target volumes, the annual number of target volumes amounted to 175 per 100,000 inhabitants (95% CI 161-191). CONCLUSION The need for palliative radiotherapy has not decreased and might be greater than previously estimated. In regions with a significantly different cancer incidence, age structure, and other socioeconomic factors than northern Europe, separate analyses should be conducted.

Prognostic Models Predicting Survival of Patients with Brain Metastases: Integration of Lactate Dehydrogenase, Albumin and Extracranial Organ Involvement

AIMS To explore the role of expanded assessment of metastatic extracranial organ involvement, as well as albumin and lactate dehydrogenase (LDH), i.e. surrogates of disease extent, in survival prediction models for patients with brain metastases. MATERIALS AND METHODS A retrospective analysis of 189 patients treated with whole brain radiotherapy was carried out. Uni- and multivariate analyses included recursive partitioning analysis classes, basic score for brain metastases and diagnosis-specific graded prognostic assessment (DS-GPA). RESULTS Elevated LDH correlated significantly with extracranial organ involvement, low albumin with primary tumour type and primary tumour control. Elevated LDH, low albumin and a combination of both correlated significantly with overall survival. LDH, albumin and the number of extracranial organs involved (none, one, two or more harbouring metastases) were independent prognostic factors in multivariate analyses (if added to the three established scores mentioned above and also if added to individual parameters such as age, performance status, etc.). A combination of these three new prognostic factors predicted very short survival (median 0.7 months if all three were present). CONCLUSION We have previously defined patient groups in whom foregoing radiotherapy was unlikely to compromise survival. These were patients with a DS-GPA score of 0-1.5 points and age ≥75 years or Karnofsky performance status ≤50 or uncontrolled primary tumour with extracranial metastases to at least two organs. Patients with a combination of three new adverse features (elevated LDH plus low albumin plus extracranial metastases to at least two organs) might also be considered for best supportive care. Furthermore, it appears warranted to study whether scores such as DS-GPA can be optimised by integrating information on these three parameters.

Survival Prediction Score: A Simple but Age-Dependent Method Predicting Prognosis in Patients Undergoing Palliative Radiotherapy

Purpose. Validation of a Canadian three-tiered prognostic model (survival prediction score, SPS) in Norwegian cancer patients referred for palliative radiotherapy (PRT), and evaluation of age-dependent performance of the model. Patients and Methods. We analyzed all 579 PRT courses administered at a dedicated PRT facility between 20.06.07 and 31.12.2009. SPS was assigned as originally described, That is, by taking into consideration three variables: primary cancer type, site of metastases, and performance status. Results. Patients with poor prognosis (non-breast cancer, metastases other than bone, and Karnofsky performance status (KPS) ≤ 60) had median survival of 13 weeks. Those with intermediate prognosis (two of these parameters) survived for a median of 29 weeks, and patients with good prognosis for a median of 114 weeks, P < 0.001. While this model performed well in patients who were 60 years or older, it was less satisfactory in younger patients (no significant difference between the good and intermediate prognosis groups). Conclusion. SPS should mainly be used to predict survival of elderly cancer patients. However, even in this group accuracy is limited because the good prognosis group contained patients with short survival, while the poor prognosis group contained long-term survivors. Thus, improved models should be developed.

Can prophylactic breast irradiation contribute to cardiac toxicity in patients with prostate cancer receiving androgen suppressing drugs

BackgroundAndrogen suppression treatment (AST) might increase the risk of cardiac morbidity in prostate cancer patients. Possible explanations were provided, however, they disregard the potential contribution of prophylactic radiotherapy to the mamillary regions (PMRT, prescribed to avoid gynecomastia).MethodsWe studied the exposure of the heart in a typical electron beam PMRT setting by evaluating computed tomography (CT) scans in 40 non-cancer patients (age 65 and 75 years in 50% each) and 17 prostate cancer patients. Five of the younger, 7 of the older and 4 of the cancer patients had significant cardiac disease.ResultsThe median distance between skin and outer heart contour decreased with age. In all three groups, patients with cardiac morbidity had smaller distances. When using the CT-determined PMRT beam energy, 10% of the younger, 15% of the older and none of the prostate cancer patients would receive approximately 50% of the prescription dose to a part of the heart (2 had no history of cardiac disease). When using the clinically rather than CT-determined beam energy, as often done in daily practice, an additional 12.5% of the non-cancer and 12% of the prostate cancer patients would be exposed to comparably high doses.ConclusionThe present data provide preliminary evidence that PMRT might be a factor that contributes to cardiac side effects. Previous studies that established a relationship between AST and cardiac morbidity did not include information on delivery of PMRT.

Pathologic fracture and metastatic spinal cord compression in patients with prostate cancer and bone metastases

BackgroundThe purpose of this study was to determine the risk factors for and incidence as well as prognostic impact of pathologic fracture (PF) and metastatic spinal cord compression (MSCC) in patients with bone metastases (BM) from prostate cancer.MethodsRetrospective cohort study including 61 consecutive patients seen at Nordland hospitals department of oncology between 2007 and 2009. The initial diagnosis of BM might have been made earlier. Twenty-nine patients (48%) received taxotere and 72% zoledronic acid after diagnosis of BM.ResultsMedian actuarial survival after diagnosis of BM was 23 months. Six patients (10%) were alive at 5 years. Bone pain at baseline was present in 49% of patients. Eighty-nine percent required external beam radiotherapy and/or radioisotopes after diagnosis of BM. Seventeen patients (28%) developed at least one major skeletal complication, i.e. MSCC or PF (4 of them developed more than one). The actuarial risk was 44% at 4 and 5 years. Most events developed before treatment with zoledronic acid and/or taxotere. Median survival from diagnosis of either MSCC or PF was 11 months (5 months from MSCC). We did not identify statistically significant risk factors for development of major skeletal complications. Serum alkaline phosphatase above median value and age less than or equal to 70 years were the only risk factors approaching significance.ConclusionsWe found high rates of major skeletal complications in this unselected contemporary group of patients. Identification of risk factors might guide the development of early interventions aiming at prevention of MSCC and PF.

Comorbidity, Use of Common Medications, and Risk of Early Death in Patients with Localized or Locally Advanced Prostate Cancer

In this paper, we analyze predictive factors for early death from comorbidity (defined as death within 3 years from diagnosis and unrelated to prostate cancer) in patients with localized or locally advanced prostate cancer. Such information may guide individually tailored treatment or observation strategies, and help to avoid overtreatment. We retrospectively analyzed baseline parameters including information on comorbidity and medication use among 177 patients (median age at diagnosis 70 years). Actuarial survival analyses were performed. During the first 3 years, two patients (1.1%) died from progressive prostate cancer after they had developed distant metastases. The risk of dying from other causes (3.4%) was numerically higher, although not to a statistically significant degree. Six patients who died from other causes had age-adjusted Charlson comorbidity index (CCI) scores ≥5 (CCI is a sum score where each comorbid condition is assigned with a score depending on the risk of dying associated with this condition). The main comorbidity was cardiovascular disease. The two statistically significant predictive factors were medication use and age-adjusted CCI score ≥5 (univariate analysis). However, medication use was not an independent factor as all patients with age-adjusted CCI score ≥5 also used at least one class of medication. Median survival was 30 months in patients with age-adjusted CCI score ≥5. Prediction of non-prostate cancer death may be important to prevent overtreatment in patients who are more threatened by comorbidity. Our data suggest that simple parameters such as use of medications vs. none, or presence of serious cardiac disease vs. none, are not sufficient, and that age-adjusted CCI scores outperform the other factors included in our analysis.