Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway.

BACKGROUND: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. METHODS: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. DISCUSSION: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.

Prospective case series of neuropathic cancer pain in patients treated with an EGFR-inhibitor.

BACKGROUND: Novel treatments of neuropathic pain are urgently needed. Rapid relief of neuropathic cancer pain in patients treated with epidermal growth factor receptor (EGFR) inhibitors have been reported. Experiments in rodent models confirm the pain relief and reveal novel mechanisms critically involving the EGFR. Clinical pain research is complicated and patients with advanced cancer are heterogeneous, often with complex, deteriorating clinical pictures, hampering feasibility of drug-trial procedures. ACTUAL CASE: Prospective case series exploring the EGFR inhibition/neuropathic cancer pain association in order to inform planning clinical trials. POSSIBLE COURSES OF ACTION: Symptom assessment method was tailored to what was ethical, feasible, and clinically relevant for each patient. FORMULATION OF A PLAN: Patients with neuropathic cancer pain treated off-label with the monoclonal antibody panitumumab were studied to assess feasibility of different measurement tools. OUTCOME: Fourteen of 20 patients (70%) experienced clinically significant pain relief. There was good concordance in patient and physician-reported outcomes. LESSONS: Results support panitumumab's potential to be of significant benefit to patients with refractory neuropathic cancer pain. Findings also reinforce the difficulty of using conventional drug trial endpoints and designs in this population. VIEW: Innovative research methods must be considered for much needed pivotal trials.

Palliative pelvic radiotherapy of symptomatic incurable rectal cancer - a systematic review.

BACKGROUND: Locally advanced and recurrent rectal cancers frequently cause pelvic morbidity including pain, bleeding and mass effect. Palliative pelvic radiotherapy is used to relieve these symptoms and delay local progression. There is no established optimal radiotherapy regimen and clinical practices vary. Our aim was to review the efficacy and toxicity of palliative pelvic radiotherapy of symptomatic rectal cancer and to evaluate different fractionation schedules, based on published literature. MATERIAL AND METHODS: Systematic literature searches of Medline, Embase and Cochrane databases were performed through 2011. Studies reporting symptomatic response or quality of life (QOL) after palliative radiotherapy for rectal or rectosigmoid cancer were eligible. Results. Twenty-seven studies were included, of which 23 were retrospective reviews. There were no patient-reported outcomes or QOL assessments. There were large variations in applied radiotherapy regimens. Pooled overall symptom response rate was 75% and positive responses were reported for pain (78%), bleeding and discharge (81%), mass effect (71%) and other pelvic symptoms (72%). Toxicity results were not evaluable. CONCLUSION: Palliative pelvic radiotherapy for symptomatic rectal cancer appears to provide relief of a variety of pelvic symptoms, although there is no documented optimal radiotherapy regimen in this context. There is inadequate evidence regarding onset, duration and degree of symptom palliation, QOL and associated toxicity with this treatment and prospective studies are therefore needed.

WITHDRAWN: Neuropathic Cancer Pain in Patients Treated With an EGFR-Inhibitor

This article has been withdrawn because of a publisher error. It should not have been posted.

Differential effects of epidermal growth factor receptor inhibitors in a single patient with neuropathic pain.

Neuropathic pain (NP) represents an unmet medical need, where analgesic responses to different epidermal growth factor receptor inhibitors (EGFR-Is) have been described. The human EGFR family of receptors consists of four members (human epidermal growth factor receptor, HER 1-4), signalling via different homodimer and heterodimer combinations. A 52-year-old man was treated with the EGFR-I cetuximab in a trial of severe NP. Pain scores decreased dramatically after blinded cetuximab, but not after placebo. On pain recurrence after the trial, he was prescribed the oral EGFR-Is erlotinib, gefitinib, and lapatinib without relief. However, treatment with the pan-HER-inhibitor afatinib was effective. After 4 years on afatinib, pain control remains excellent with manageable side effects. This is the first reported observation of differential effects of EGFR-Is on NP in the same patient and the first report describing NP relief with afatinib. Further understanding of the underlying pathophysiology could lead to development of EGFR-Is specifically targeting NP.

Palliative pelvic radiotherapy for symptomatic incurable prostate cancer ­ A prospective multicenter study.

BACKGROUND AND PURPOSE: Radiotherapy is used to palliate pelvic symptoms of castration resistant prostate cancer (CRPC). However, magnitude and time course of effects and toxicities are poorly documented. Study aims were to evaluate changes in patient-reported target symptoms (TS), health-related quality of life (HRQOL) and toxicity following palliative pelvic radiotherapy (PPRT) of CRPC. MATERIAL AND METHODS: 47 patients with CRPC and a symptomatic pelvic mass prescribed PPRT with 30-39 Gy were prospectively included. Primary endpoint was patient-reported improvement or complete resolution of the TS twelve weeks after PPRT. HRQOL changes were explored. Toxicity was physician-evaluated. RESULTS: Lower urinary tract symptoms (LUTS) (45%), hematuria (26%) and pain (19%) were the most common TS. In the 40 evaluable patients, overall TS response twelve weeks after PPRT was 70%. TS responses were 8/18 for LUTS, 11/12 for hematuria, and 7/9 for pain. Global HRQOL improved transiently. The most common toxicity was grade 1 or 2 diarrhea (50%). There was no grade 4 toxicity. CONCLUSIONS: In the majority of patients with CRPC and a symptomatic pelvic tumor, PPRT with 30-39 Gy contributes to relief of hematuria, pain and other pelvic symptoms, with acceptable toxicity. Future studies should investigate whether PPRT regimens can be simplified.

Palliative pelvic radiotherapy of symptomatic incurable prostate cancer - a systematic review.

BACKGROUND AND PURPOSE: Patients with prostate cancer (PC) and a symptomatic pelvic tumor may be treated with palliative pelvic radiotherapy for symptom relief or to delay symptom progression. Radiotherapy dose and fractionation regimens vary. We aimed to provide an overview of the literature and to evaluate palliative pelvic radiotherapy of PC focusing on symptomatic effect, quality of life (QOL), and toxicity, and to determine the optimal radiotherapy schedule. MATERIAL AND METHODS: Systematic literature searches of Medline, Embase and Cochrane databases were performed through 2011. Studies reporting symptom and QOL responses were eligible. RESULTS: Nine studies were included, all retrospective chart reviews. There were large variations in radiotherapy dose and fractionation. Overall symptom response rate was 75% and positive responses were reported for hemorrhage (73%), pain (80%), bladder outlet obstruction (63%), rectal symptoms (78%) and ureteric obstruction (62%). Toxicity results were not evaluable. CONCLUSIONS: Despite limitations in the review process and the included studies, we conclude that pelvic radiotherapy for symptomatic PC appears to provide effective palliation of a variety of symptoms. There is currently no valid documentation regarding onset or duration of palliation. No recommendations can be provided regarding target dose or fractionation schedule in this context.

Epithelial growth factor receptor (EGFR)-inhibition for relief of neuropathic pain-A case series.

Background Neuropathic pain remains a significant challenge with unsatisfactory therapeutic options. Its pathogenesis may involve the neuropathic triad of neuronal, glial and immune cells. Communication between these cells is possibly perpetuated by mitogen-activated protein kinase (MAPK)-signaling. For several years, we successfully treated a rectal cancer patient with the epithelial growth factor receptor (EGFR)-inhibitor cetuximab, for debilitating neuropathic pain due to progressive malignant invasion of the sacral plexus. Here, we report the effect of treatment with various EGFR-inhibitors in five additional patients with severe and long-standing, therapy-resistant neuropathic pain. Methods All patients had well-documented neuropathic pain syndromes with the following etiologies: inflammatory polyneuropathy, complex regional pain syndrome type 1, radiculopathy after failed back surgery, malignant invasion of the sacral plexus by bladder cancer, and phantom limb pain. All patients were given intravenous (extracellular) EGFR-inhibitors (cetuximab, panitumumab) initially, and switched to oral (intracellular) agents (gefitinib, erlotinib) after an analgesic effect was obtained. Results Four of the five patients responded, all within 24h of intravenous administration, with a mean decrease in worst pain from 9 to 1 on a 10-point scale. All four EGFR-inhibitors were effective. The clinical courses, including patient-reported pain relief, are prospectively documented with 78-219 days follow-up for those who responded to treatment. Toxicities were transient and manageable. Conclusions/implications EGFR-inhibition resulted in dramatic relief of neuropathic pain. A plausible biological explanation involves the interruption of MAPK-signaling. The role of EGFR-inhibition as a target for the treatment of neuropathic pain appears promising and warrants investigation.

Cetuximab alleviates neuropathic pain despite tumour progression.

The authors present the case of a 68-year-old male patient with metastatic rectal cancer. A pelvic recurrence resulted in neuropathic pain, radiating down his left leg. The pain was resistant to standard treatments. However, after nearly 3 years of debilitating pain, the patient experienced dramatic relief just hours after an infusion of the antiepidermal growth factor receptor antibody cetuximab. The analgesic effect lasted for 10-12 days and was repeated roughly every 12 days for three and a half years. To test for placebo effect, the patient received (unknown to him) 20% of his usual cetuximab dose and experienced no pain relief. The dramatic analgesic effect was documented in clinical notes, medication lists and in numeric rating scales even while his cancer was in radiological progression. Mitogen-activated protein kinase (MAPK)-signalling is believed to be an important driver of neuropathic pain and therefore, the authors hypothesise a direct inhibition of MAPK-signalling by cetuximab in neuronal or glial cells.