Systemic Therapy and Chemoradiation in Advanced Localised Pancreatic Cancer - 2

Pancreatic cancer has a poor outcome. Approximately 8000 cases are diagnosed in the UK each year and approximately 8000 patients die from the disease \[1\]. 20% of the patients are operable at diagnosis, 30-40% have locally advanced inoperable disease \[LANPC\] and another 40-50% have metastatic disease. Patients with LANPC have a relatively better prognosis compared to patients with metastatic disease (median overall survival 10-12 months and 5-6 months respectively). Currently, treatment options for LANPC include: 1. Primary chemotherapy 2. Primary chemoradiation (CRT) followed by adjuvant chemotherapy 3. Induction chemotherapy followed by CRT Studies investigating primary chemotherapy vs. primary CRT have reported overall survival between ten to 12 months and there are conflicting reports as to whether chemotherapy alone or primary CRT is superior \[2, 3\]. More recently, there has been a shift to using induction chemotherapy to pre-select patients who are suitable for CRT. The LAP07 trial \[4\] compared chemotherapy alone (gemcitabine with/without erlotinib) versus same chemotherapy for 4 months followed by consolidation capecitabine-based CRT. The study aimed to recruit over 700 patients but closed early on recommendation of IDMC following a planned interim analysis after 442 patients. This study failed to show superiority of consolidation CRT over continuing chemotherapy alone (median overall survival 15.2 months vs. 16.4 months, log rank p=0.8) but confirmed good tolerance of CRT in multi-institutional setting (Grade 3/4 gastro-intestinal toxicity 5.9%; Grade 3/4 neutropenia 3.1%) \[4\]. The investigators concluded that both chemotherapy alone and consolidation CRT are options for this group of patients and further trials should investigate intensifying both radiotherapy (RT) and chemotherapy strategies. In the UK, the recently reported SCALOP trial randomised patients to gemcitabine or capecitabine based CRT following 4 months of induction GEMCAP chemotherapy \[5\]. 114 patients were recruited from 28 centres over 2 years, and 74 non-progressive patients were randomised to CRT. This study demonstrated UK's feasibility to recruit to CRT trials in pancreatic cancer and deliver high quality RT within a well-controlled Radiotherapy Trials Quality Assurance programme coordinated by the NCRI RTTQA Group. SCALOP suggested superiority of capecitabine-based CRT over gemcitabine based-CRT in terms of overall survival (median overall survival 15.2 vs. 13.4 months, HR 0.39, p=0.012) and treatment related Grade 3/4 toxicity (haematological 0% vs. 18%, p=0.008; non-haematological 12% vs. 26%, p=0·12). The outcome/toxicity in the cape-RT arm was very similar to that reported in LAP07 study, and capecitabine could now be considered as the preferred radio-sensitizer in the context of pancreatic CRT. The importance of local control in LANPC Although LANPC and metastatic pancreatic cancer have been traditionally treated similarly with chemotherapy under the premise that this is largely a systemic disease, recent developments in molecular and genetic aspects of pancreatic cancer would suggest that this disease is heterogeneous with different genetic subtypes and the systemic nature of the disease can no longer be assumed. Studies have shown that nearly a third of patients with LANPC die as a result of local progression of their disease rather than systemic spread; the loss of Dpc4 gene has been correlated with systemic spread of the disease whereas patients with intact Dpc4 have local tumour predominance \[6, 7\]. Local progression occurs in more than half the cases after conventional CRT (SCALOP unpublished data) and one study has shown that local failure may be a predictor of early mortality (HR 2.15; p=0.0074, \[8\]). One meta-analysis of 4,394 patients suggests that one-third of initially unresectable tumours may become operable following neo-adjuvant therapy \[9\], and improving local control is likely to become more relevant in the face of improved systemic treatment like GEMABX (gemcitabine + nab-paclitaxel) and FOLFIRINOX, as patients are likely to live long enough to develop local symptoms. Radiotherapy dose escalation It is widely accepted that adenocarcinoma is a radio-resistant tumour and radiation doses of less than 60-70Gy are unlikely to eradicate the disease. However current pancreatic CRT schedules (45-54Gy in 25-30 fractions) are limited by the tolerance dose of the surrounding organs at risk (OARs), i.e., small bowel, duodenum, stomach, liver and kidneys. Using current dose schedules, local failure occurs in 40-60% cases despite CRT \[8, 10, 11\] and \<5% of patients show radiological or pathological complete response following treatment \[9, 12\]. A small retrospective study has shown that RT dose ≥ 54Gy was associated with a trend towards improved overall survival (11.3 mo. vs. 6.8 mo., p=0.089) \[13\]. Another Phase I dose intensification study explored the role of escalating dose per fraction, and a higher Biological Equivalent Dose (BED) of RT was delivered (dose escalated from 50 to 60 Gy in 25 fractions, concurrent with gemcitabine 1000mg/m2 weekly) \[14\]. The recommended phase II dose was 55Gy in 25 fractions, at which the DLT (Dose Limiting toxicity) probability was 0.24; of the 50 patients recruited to the study, the median OS was 14.8 months with a 2-year OS of 30%; 12 underwent resection (R0=10) with a median OS of 32 months in resected patients. The promising outcome and acceptable toxicity seen in this study suggests that role of RT dose escalation should be further investigated in a randomised trial. Although concerns about safe radiation doses to the surrounding critical organs has previously discouraged dose escalation studies, modern day technical advancement with Intensity Modulated radiotherapy (IMRT) and Image Guided RT (IGRT) allows precise delivery of radiotherapy while reducing dose to OARs \[14-16\]. A dose of 59.4Gy/33 fractions has been safely delivered in combination with gemcitabine, cisplatin and RT in the ARC I and the ARC II studies \[17\](see below ). A hypothetical planning study from the MD Anderson group has demonstrated that dose to the pancreas can be escalated to 72Gy/36 fractions based on relationship of GTV to the gastro intestinal-OARs, using IMRT or proton therapy \[18\]. Taken together, these studies indicate that radiation dose in the region of 60Gy using conventional fractionation and conservative radiation volumes could be investigated as a component of dose escalation in a multi-centre 'trial, within constraints of a rigorous Radiotherapy Quality Assurance programme. Nelfinavir in pancreatic cancer CRT Pancreatic cancer remains refractory to most conventional therapies and is driven by multiple oncogenic mutations including KRAS mutation and PTEN loss. EGFR (Epidermal Growth Factor Receptor), KRAS and PIK3CA signalling are mediated in part through PI3K (Phospho-Inositol-3 Kinase) and Akt signalling. Preclinical data suggest that PI3K-inhibition using HIV protease inhibitors including nelfinavir reduce radioresistance \[19, 20\] and downregulates phosphorylation of Akt at Ser473 leading to radiosensitization \[21, 22\]. As Akt pathway is overactive in tumours but not normal tissue, it causes selective radiosensitization without aggravating RT mediated normal tissue damage. This radiosensitization effect is seen even in KRAS mutant pancreatic cell lines \[19\], which is highly relevant in clinical practice as \>90% of pancreatic tumours are KRAS mutant. The inhibition of this pathway has also been shown to normalise tumour vasculature, increase vascular flow and perfusion and reduce hypoxia in tumour xenografts \[23, 24\], all of which may also contribute to the radiosensitizing effect seen with this class of drugs. As nelfinavir has been widely used as an anti-retroviral agent, there is a wealth of safety data on this agent \[25\] and a retrospective study has shown no increase in radiation related acute toxicity compared to control \[26\]. The ARC-I trial, a phase I study which tested the toxicity of nelfinavir-based CRT in LANPC. Twelve patients were treated with a RT dose of 59.4Gy radiation in 33 fractions in combination with nelfinavir (1250mg bd, starting 3 days before start of RT, until final day of RT), gemcitabine (Dose level 1: 200mg/m2; Dose level 2: 300mg/m2) and cisplatin 30mg/m2 with the chemotherapy being delivered on days 1, 8, 22, 29 \[17\]. Grade 3 /4 non-haematological toxicity was reported in 16.7%; complete radiological response on FDG-PET was seen in 50% of the cases and R0 resection was achieved in 6 patients. Median OS was 18 months. A subsequent phase II study, ARC II (35), tested the efficacy and toxicity of the combination at the higher dose of Gemcitabine (300mg/m2) in 23 patients. Although upfront CRT (without induction chemotherapy) was used, median and 1-year overall survival were 17.4 months and 73.4% respectively, which compares well historic studies of primary CRT. Key Grade 3/4 toxicities (nausea/vomiting 21.7%; diarrhoea 21.7%; fatigue 17.4%; neutropenia 8.7%; thrombocytopenia 39.1%) is likely to have been contributed by the gemcitabine/cisplatin chemotherapy and large RT fields which included prophylactic nodal irradiation. In addition to this study, a recently reported phase I study combining radical CRT with nelfinavir in stage IIIA and B non-small cell lung cancer showed minimal toxicity with five out of nine complete responses \[27\]. Nelfinavir has demonstrated promising radio-sensitizing effects and therefore merits further investigation in a phase II trial. Systemic therapy in pancreatic cancer Both FOLFIRINOX (5FU, Folinic Acid, Irinotecan, Oxaliplatin) \[28\] and GEMABX \[29\] are treatment options for patients with good performance status advanced pancreatic cancer. The MPACT study \[29\] compared gemcitabine alone with a combination of gemcitabine and nab-paclitaxel in 861 patients with metastatic pancreatic cancer. The OS (8.5 vs. 6.7 months, p\<0.001), PFS (5.5 vs. 3.7 months, p\<0.001) and overall response rate (23% vs. 7%, p\<0.001) favoured the combination therapy. Although Grade 3/4 neutropenia was seen in 38% of patients (cf 27% on gemcitabine alone), incidence of febrile neutropenia was low (3%) and other toxicities were manageable (Grade 3/4 fatigue 17% vs. 7%; Grade 3/4 neuropathy 17% vs. 1%, improved to Grade 0/1 in 29 days). Relative protocol doses of gemcitabine and nab-paclitaxel were 75% and 81% respectively (cf 85% in the gemcitabine arm) and suggested that the regimen is well tolerated. Moreover, the relative lack of non-overlapping toxicity with capecitabine-RT, most importantly gastro-intestinal toxicity, makes it an attractive regimen to use prior to consolidation CRT. 2.3 Rationale Local control is important in pancreatic cancer but current CRT schedules could be refined. Improving local control through RT dose escalation or enhanced radiosensitization may improve local control and overall survival in pancreatic cancer. We wish to test this hypothesis in the SCALOP-2 trial.

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