NACF 2017: News in Respirology

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CYSTIC FIBROSIS

NACF 2017. P247. Efficacy and Safety of Tezacaftor/Ivacaftor in Patients Aged ≥12 Years with CF Homozygous for F508del-CFTR: A Randomized Placebo-Controlled Phase 3 Trial

 J. Taylor-Cousar, et al.

Results:

509 pts received ≥1 dose of tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (n=251) or placebo (PBO) (n=258). Baseline (BL) characteristics were well balanced between groups. There was a significant treatment effect favouring TEZ/IVA in absolute change in ppFEV1 (4.0 percentage points; 95% CI 3.1, 4.8; P<0.0001); a similar effect was seen in pts with ppFEV1 <40 at BL (TEZ/IVA [n=23] vs PBO [n=24]: 3.5 percentage points; 95% CI 1.0, 6.1; P=0.0070). Treatment differences for relative change in ppFEV1 and pulmonary exacerbations (Pex) (event rate, 0.64 vs 0.99; P=0.0054 [negative binomial regression]) met statistical significance while the comparison for change in BMI did not. Effects favouring TEZ/ IVA in CFQ-R and sweat chloride were nominally significant. In pts who had treatment-emergent adverse events (AEs), the majority were mild (TEZ/IVA 45.4% vs PBO 38.4%) or moderate (TEZ/IVA 36.3% vs PBO 45.3%); the most common were infective PEx (TEZ/IVA 29.9% vs PBO 37.2%), cough (26.3% vs 32.6%), headache (17.5% vs 14.3%), nasopharyngitis (16.7% vs 15.1%), and sputum increased (14.3% vs 16.3%). Predefined respiratory events occurred in 13.1% of pts in the TEZ/IVA arm and 15.9% in the PBO arm. Discontinuations due to AEs occurred in 2.8% (TEZ/IVA) and 3.1% (PBO) of pts; none were due to respiratory events. Serious AEs were reported in 12.4% (TEZ/IVA) and 18.2% (PBO) of pts, and no deaths were reported.

Conclusions:

Significant improvements in ppFEV1, PEx rate, CFQ-R score (nominal), and sweat chloride (nominal) were observed with 24 wks of TEZ/IVA vs PBO. Treatment was well tolerated with few discontinuations due to AEs. Incidence of respiratory events was similar between PBO and TEZ/IVA, and none resulted in treatment discontinuation. These study results support the safety and efficacy of TEZ/IVA in pts with CF homozygous for F508del-CFTR.

 

NACF 2017. P273. Efficacy and Safety of Tezacaftor/Ivacaftor and Ivacaftor in Patients Aged ≥12 Years with CF Heterozygous for F508del and a Residual Function Mutation: A Randomized, Double blind, Placebo-Controlled, Crossover Phase 3 Study

 S. Rowe, et al.

Results:

Pts received tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (TEZ/ IVA) (n=161), IVA monotherapy (n=156), or placebo (PBO) (n=161). Study baseline characteristics were balanced between groups (mean [SD] ages (y), 35.6 [13.5], 36.3 [15.2], and 32.6 [13.9] and mean [SD] baseline ppFEV1, 61.8 [14.9], 62.8 [14.6], and 62.1 [14.0] percentage points for TEZ/IVA, IVA, and PBO). Significant treatment effects were observed for TEZ/IVA and IVA in absolute ppFEV1 and CFQ-R respiratory domain score vs PBO. In addition, the treatment difference of absolute ppFEV1 between TEZ/IVA and IVA was statistically significant in favour of TEZ/ IVA. The majority of adverse events (AEs) were mild (TEZ/IVA 35.8%; IVA 35.0%; PBO 38.9%) or moderate (34.0%; 32.5%; 33.3%). The most common AEs (>10%) were infective pulmonary exacerbation of CF, cough, headache, and haemoptysis. No increase in respiration abnormal with TEZ/IVA was observed. No treatment discontinuations due to AEs were reported in the TEZ/IVA group vs 1.3% IVA and 0.6% PBO. Serious AEs were reported (TEZ/IVA 4.9%; IVA 6.4%; PBO 8.6%). No deaths occurred during the study.

Conclusions:

Significant improvements in ppFEV1 and CFQ-R respiratory domain were seen with TEZ/IVA and IVA treatment vs PBO. Significant improvement in ppFEV1 was also seen with TEZ/IVA vs IVA. Treatments were well tolerated with no (TEZ/IVA) or few (IVA) discontinuations due to AEs. These findings support safety and efficacy of TEZ/IVA and IVA in pts with CF heterozygous for F508del and a second mutation resulting in CFTR residual function.

CARE FACULTY PERSPECTIVE:

The two studies on tezacaftor-ivacaftor show that this combination therapy improves lung function (FEV1) and reduces exacerbation rate in CF patients with the most common genotype (Phe508del/ Phe508del) similar to lumacaftor-ivacaftor (OrkambiTM) but with better tolerability, and also improves lung function in patients with a residual function mutation, to a similar degree as ivacaftor monotherapy. Whether the combination of improved FEV1 and reduced exacerbation rate will result in greater treatment effects over time is unclear at this point though conceivable, as exacerbations contribute to a more rapid pulmonary function decline. Results from the open-label extension studies in which the majority of the study subjects were enrolled, may help clarify this in the near future.

While these studies demonstrate that CFTR modulating therapies have beneficial effects on some aspects of the disease, the clinical benefit of the current combination therapies for CF patients with the most common CFTR genotype (Phe508del/ Phe508del) falls within the range of established symptomatic therapies such as nebulized inhaled hypertonic saline or recombinant human DNAse. There is still an unmet need for truly effective new therapies to be developed for all individuals with CF. The complete study results on tezacaftor-ivacaftor combination therapy were recently published in the New England Journal of Medicine (Taylor-Cousar JL, et al., and Rowe SM, et al., N Engl J Med. 2017 Nov 3. [Epub ahead of print]), with an accompanying Editorial (Grasemann H, N Engl J Med. 2017 Nov 3. [Epub ahead of print]).

Whether new CFTR targeting combination therapies that are in the drug development pipeline, will ultimately result in clinically meaningful improvement of lung function and clinical status needs to be seen. Preliminary results presented by Dr. E. Tullis from Toronto suggest that the addition of a second corrector to corrector/potentiator combination regimens can result in improved efficacy of CFTR modulator therapy.

EHA 2017: News in Hematology

Multiple Myeloma

EHA 2017. LB2236. Daratumumab, Bortezomib and Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma (RRMM): Efficacy and Safety Update (CASTOR)

Antonio Palumbo et al.

Results: PFS Data

Conclusions: Daratumumab significantly improved PFS, TTP, and ORR in combination with Vd versus Vd alone. DVd doubled rates of both VGPR or better and stringent CR/CR versus Vd alone. Safety of DVd is consistent with the known safety profile of daratumumab and Vd. The addition of daratumumab to Vd should be considered a new standard of care for patients with RRMM currently receiving Vd alone.


ASCO 2017. 8006. Efficacy of Daratumumab in Combination with Lenalidomide Plus Dexamethasone (DRd) or Bortezomib Plus Dexamethasone (DVd) in Relapsed or Refractory Multiple Myeloma (RRMM) Based on Cytogenetic Risk Status

Katja Weisel et al.

Results: Samples from 311/569 pts in POLLUX and 353/498 pts in CASTOR were assessed via NGS. In POLLUX, the median duration of follow-up was 17.3 months. Significantly longer median PFS and numerically higher ORR were observed with DRd vs Rd among high-risk patients, and significant improvements in these outcomes were observed in std-risk patients. In CASTOR, the median duration of follow-up was 13.0 months. Significantly longer median PFS and higher ORR were observed with DVd vs Vd among both high- and std-risk pts. Concordance rates for t(4;14), t(14;16), and del17p were high (88%-98%) between NGS and FISH. Updated data, including subgroup analyses, will be presented. 

Conclusions: In RRMM pts, the addition of D to standard-of-care regimens improved outcomes regardless of cytogenetic risk status. Targeting CD38 by combining D with Rd or Vd appears to improve the poor outcomes associated with high-risk cytogenetic status. Clinical trial information: NCT02136134 and NCT02076009

CARE Faculty Perspective: These data (LB2236 & 8006) reinforce the benefit of daratumumab and dexamethasone in combination with bortezomib or lenalidomide for patients who have received at least one prior therapy. These regimens were approved by Health Canada in April 2017.

The combination of daratumumab with pomalidomide and dexamethasone received FDA approval in June 2017, for patients who have received at least two prior therapies including lenalidomide or a proteasome inhibitor. This was based on clinical trial results from the phase 1 EQUULEUSstudy, which showed an overall response rate of 59.2 percent with the daratumumab triplet. We wait on approval in Canada.

This designation reinforces the versatility of daratumumab with a range of treatment regimens and provides an urgently needed option for this patient sub-group. Daratumumab is also being investigated as a front-line therapy for patients with multiple myeloma in Phase 3 clinical trials.

 

ASCO 2017: News in Hematology

Multiple Myeloma: CAR-T Cell Therapy

ASCO 2017. LBA3001. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma

Frank (Xiaohu) Fan et al.

Results: Among the 19 patients who completed the infusion, 7 patients were monitored for a period of more than 6 months. Six out of the 7 achieved complete remission (CR) and minimal residual disease (MRD)-negative status. The 12 patients who were followed up for less than 6 months met near CR criteria of modified EBMT criteria for various degrees of positive immunofixation. All these effects were observed with a progressive decrease of M-protein and thus expected to eventually meet CR criteria. In the most recent follow-up examination, all 18 survived patients were determined to be free of myeloma-related biochemical and hematologic abnormalities. One of the most common adverse event of CAR-T therapy is acute cytokine release syndrome (CRS). This was observed in 14 (74%) patients who received treatment. Among these 14 patients there were 9 cases of grade 1, 2 cases of grade 2, 1 case of grade 3, and 1 case of grade 4 patient who recovered after treatments. 

Conclusions: A 100% objective response rate (ORR) to LCAR-B38M CAR-T cells was observed in refractory/relapsed myeloma patients. 18 out of 19 (95%) patients reached CR or near CR status without a single event of relapse in a median follow-up of 6 months. The majority (14) of the patients experienced mild or manageable CRS, and the rest (5) were even free of diagnosable CRS. Based on the encouraging safety and efficacy outcomes, we believe that our LCAR-B38M CAR-T cell therapy is an innovative and highly effective treatment for multiple myeloma.

CARE Faculty Perspective: CAR-T cells are being explored in MM, however, they are further developed in acute lymphocytic leukemia and lymphoma. While these data are still early, the results demonstrate proof of concept, as well as safety and efficacy of CAR T-cell therapy in MM. Toxicities appear common and like many CAR-T cell trials, patients were highly selected.
We await more data.

EHA 2017: News in Hematology

Chronic Lymphocytic Leukemia: Ibrutinib Monotherapy

EHA 2017. S769. Long-term Efficacy and Safety with Ibrutinib in Previously Treated CLL: Up to Four Years Follow-up of the RESONATE Study

Byrd, John C et al.

Results: A total of 391 patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). The median age was 67 years, with 40% age ≥70 years, and Rai stage III/IV in 57% of patients. At a median follow-up of 44 months (maximum 53 months) for the ibrutinib arm, PFS was significantly longer for ibrutinib vs ofatumumab (median NR vs 8 months, [HR 0.133; P<0.0001]). The 3-year PFS was 59% for ibrutinib vs 3% for ofatumumab. A significant PFS benefit was observed across baseline subgroups. In the ibrutinib arm, PFS for the del11q subgroup trended to have the most favorable outcome; however, PFS outcomes were not statistically different for patients with del17p or del11q or patients without these FISH abnormalities. At time of analysis, with the majority of patients randomized to ofatumumab (68%) crossing over to receive ibrutinib therapy, OS was longer for ibrutinib vs ofatumumab (median OS NR for either arm). The 3-year OS rate for ibrutinib was 74%. The ORR for ibrutinib was 91% with a CR/CRi rate that increased over time (currently 9%). Baseline cytopenias improved with extended ibrutinib therapy for hemoglobin (85% of patients), platelet (95% of patients), and absolute neutrophil counts (95% of patients). The adverse event (AE) profile of ibrutinib was consistent with previous reports. During a follow-up of up to 4 years, major hemorrhage occurred in 6%, grade ≥3 atrial fibrillation occurred in 6%, and grade ≥3 hypertension occurred in 8% of patients. The incidence of most grade ≥3 AEs decreased from year 1 vs year 2-3: neutropenia: 18% vs 8%; pneumonia: 11% vs 4%; atrial fibrillation: 4% vs 2%, respectively. The most frequent reasons for treatment discontinuation were progressive disease (27%) and AEs (12%). At analysis, 90 patients randomized to ibrutinib (46%) continue to receive ibrutinib.

Conclusion: In this international phase 3 RESONATE study with median follow-up of up to 4 years, long-term treatment with ibrutinib showed a favorable tolerability profile with sustained PFS and OS benefit regardless of high-risk cytogenetics. The results in relapsed del17p and del11q patients compared favorably to those previously reported in phase 2 studies.

Clinical trial information: NCT01578707

CARE Faculty Perspective: Ibrutinib improves long-term survival outcomes, especially in patients with relapsed/refractory CLL who are not eligible for chemotherapy approaches.

This phase 3 RESONATE trial confirmed these positive survival effects in terms of PFS and OS, while maintaining a favourable tolerability profile.  Furthermore, at the recent International Workshop on Chronic Lymphocytic Leukemia, pooled data from the RESONATE, RESONATE-2, and HELIOS trials were presented. Ibrutinib achieved higher CR rates, ORR rates, PFS, and OS when compared with other agents. This pooled analysis confirms the data from the original studies and highlights the efficacy of ibrutinib as monotherapy or as part of a combination.

Access & Innovation Considerations - The main concerns with ibrutinib use relate to toxicities that may limit its use or lead to the introduction of alternative therapies. Ibrutinib resistance is another clinical challenge. A better understanding of the mechanisms of resistance to monotherapy and combination strategies as well more in depth understanding of the effects of ibrutinib on immune effectors will be of benefit for practicing clinicians.

ASCO 2017: News in Genitourinary Cancer - High Risk Prostate Cancer

ASCO 2017. LBA 3. LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.

Karim Fizazi et al.

Results:

 

Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. 


ASCO 2017. LBA 5003. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE

Nicholas D. James et al.

Results: 1,917 pts were contemporaneously randomized to these arms (Nov 2011- Jan 2014). Groups were balanced: median age 67yrs; 52% metastatic, 20% N+/X M0, 28% N0M0; 95% newly-diagnosed; median PSA 53ng/ml. Median follow-up was 40m. There were 262 control arm deaths (82% PCa). The adjusted HR = 0.63 (95% CI 0.52-0.76; p=0.115x10-7; 184 deaths) for SOC+Abi vs SOC, with 3yr OS improved from 76% to 83%. There were 535 control arm FFS events; the adjusted HR = 0.29 (95% CI 0.25-0.34; p = 0.377x10-63, 248 FFS events) for SOC+Abi vs SOC. Grade 3 & 4 adverse events were seen in 29% & 3% SOC, 41% & 5% SOC+Abi; Grade 5: 3 & 9 (1 & 2 related). 

Conclusions: The results show a clinically & statistically significant effect on overall survival & failure-free survival from adding abiraterone at start of ADT with a manageable increase in toxicity. ADT (+/- RT) + abiraterone is a new standard of care for this group. Clinical trial information: NCT00268476

CARE Faculty Perspective:

Abiraterone has established a survival benefit for patients with advanced prostate cancer. The combination of abiraterone, prednisone, and androgen deprivation therapy (ADT) is able to stop the production of hormones directly at the testicular level and through inhibition of CYP17, an enzyme that convers cholesterol in androgens.

The STAMPEDE and LATITUDE trials support the use of upfront treatment of abiraterone with prednisone and ADT for advanced prostate cancer. The STAMPEDE trial investigated almost 2000 patients.  Patients were eligible if they had metastatic disease, or if they had local/locoregional disease with high risk features.  For all comers, the 3-year survival rate when adding abiraterone and prednisone to ADT was 83% compared to 76% when using ADT alone. The LATITUDE trial concluded that when abiraterone (with prednisone) is added to ADT therapy, a 38% improvement in OS was noted and PFS was 33 months compared with 14.8 months with ADT alone. These results could change the treatment paradigm of patients with advanced but castrate sensitive disease moving forward.

There is still much to be learned about the optimal treatment combination or sequence. We still do not know how abiraterone compares to docetaxel, and whether combination of the two is better than either agent alone. It will be interesting to see the results of trials looking at these types of combinations that are currently underway, such as the PEACE 1 & 2 trials and the ENZAMET study (although patients were randomized to enzalutamide or bicalutamide, roughly 50% of patients in either arms also received docetaxel as part of standard of care). This will give us an idea of the impact of abiraterone and docetaxel with ADT, and how the standard-of-care may be impacted.

Whether abiraterone is better than docetaxel, at least in patients with metastatic disease, remains untested in head to head randomized trials.  However, as eloquently shown by Eric Small during his discussion of the two studies, the results observed in LATITUDE seem to quite closely mirror the results of CHAARTED – given the cost and toxicity differences in these two treatment approaches, deciding on an optimal regimen in these patients may require a personalized approach and payers may potentially end up taking some the decisions away from the prescriber and patient. 

Treatment efforts do not end with this combination. It is also important to consider treatment sequencing after a patient [inevitably] progresses. Recent retrospective trials focused on sequencing have suggested that post- ADT, chemotherapeutic options (docetaxel followed by cabazitaxel) may extend OS. It is therefore important to monitor patients closely with PSA and regular imaging and not wait until symptomatic progression to consider further treatment. Otherwise, the opportunity to maximize subsequent lines of therapy may be less effective and/or not valid.

With the number of specialists involved in the management of prostate cancer (i.e. medical oncologists, urologists, radiation oncologists), collaboration and education on the entire course of therapy is of value, along with considerations for referral to another specialist if the patient’s current management approach is no longer working.

 

ATS 2017: News in Respirology - Cystic Fibrosis Case Study

Male CF Patient Homozygous For The CFTR Mutation, f508del

Adolescent pancreatic insufficient male CF patient homozygous for the most common CFTR mutation (F508del) with conserved pulmonary function (obtained by conventional pulmonary function testing), but poor nutritional status, chronic rhinosinusitis, chronic airway infection with P. aeruginosa and frequent hospital admissions (3-5/year) for IV antibiotic treatment of pulmonary exacerbations. Standard of care with daily treatments including inhaled rhDNase, inhaled antibiotics, hypertonic saline and chest physiotherapy with good adherence but no clinical improvement. 

 

Considerations: 

  • Are there guidelines which would influence your treatment of this patient?
  • Does drug cost/reimbursement influence your treatment of this patient?  
  • What would you like to use/ what would you use to treat this patient? 
  • Would you recommend initiation with Ivacaftor/Lumacaftor (Orkambi TM) therapy for this patient? 
    • How long would you treat before reassessing? 
    • Which parameters would you use to assess potential therapeutic benefit?

 

Dr. Grasemann’s Recommendations:

  • There is no “definitive solution” for this Case Study. Currently, there are no established guidelines on the use of CFTR targeting therapy in CF patients homozygous for the F508del mutation.

  • Ivacaftor/Lumacaftor (Orkambi™) is a valid treatment choice. This combination therapy is approved in Canada, and stands as a “proof of concept” for the effectiveness of combination (corrector/potentiator) CFTR targeting therapies in CF.   
  • The efficacy of Ivacaftor/Lumacaftor was demonstrated in adolescents and adults homozygous for F508del, and a recent Canadian-lead phase 3 clinical trial by Felix Ratjen et al., also suggests improvement in lung function in treated CF children 6-10 years of age. This study used change in the lung clearance index (LCI) as primary endpoint.
  • The degree of clinical improvement experienced by CF patients using Orkambi™ therapy may vary, however the fact that it is both effective (to some degree) and safe, seems consistent.     
  • Due to its proven capacity to reducing pulmonary exacerbation rate, I would consider OrkambiTM BUT cost and reimbursement can be limiting factors. Drug costs/reimbursement does influence the treatment of individual CF patients.  
  • I would like to use Ivacaftor/Lumacaftor therapy in this patient, however I am based in Toronto and Ontario’s provincial drug plan does not cover OrkambiTM. 
  • Reimbursement in Ontario is only available through private programs, which limits access. 
  • Once OrkambiTM therapy is initiated, the efficacy of the treatment should be reviewed, however
    • what is a reasonable treatment period to monitor effects on exacerbation rate?
    • what other parameters should be used to demonstrate therapeutic benefits in an individual patient?     
  • The Case Study illustrates how a lack of guidance and availability can impact treatment. 

 

Moving Forward:

This case study illustrates that Ivacaftor/Lumacaftor combination therapy can be a treatment choice in CF patients homozygous for the most common CFTR mutation F508del; but can we access it, and how should we?  

Current CFTR targeting therapies offer the opportunity of treating CF at the “source” i.e. the protein that causes the disease, and early treatment may help prevent the natural progression of the disease.  

However, defining meaningful clinical endpoints to demonstrate efficacy of these therapies can be problematic in patients with early CF lung disease and minimal symptoms.

The lung clearance index (LCI), a measure of lung function obtained by multiple breath washout (MBW), is more sensitive to changes than conventional spirometry, but is a test that requires equipment not currently available in many CF centers.  Thus, while LCI may help to demonstrate effects of therapy on lung function in patients with CF, it’s accessibility is limited. Forced expiratory volume in 1 second (FEV1), which is broadly used to monitor CF lung disease however, is not sensitive enough to detect early changes, such as peripheral mucus plugging of airways, or subtle responses to therapies. Therefore, there is an ongoing need to develop easily administered, cost and time efficient tools to monitor disease progression in CFTR related respiratory diseases. 

Though “innovation” is often associated with the development of novel therapies, the use of pre-existing treatments in new, more effective ways (or in different combinations) is also considered innovative.  There is concern that new beneficial agents will be inaccessible due to costs.  Cost is always a major factor in treatment initiation in Canada, with individual provinces and territories having different rules on reimbursement/funding.  CF treatment in Canada must remain both innovative and accessible.  There is a need to develop a guidance for the use of new therapies in CF patients.  The guidance would be developed by experts, based on experience and considering clinical trial data, helping to make CF treatment consistent in centers and provinces across Canada.  

Insights Provided by Dr. Hartmutt Grasemann
CARE Respirology Faculty
The Hospital for Sick Children
Professor, University of Toronto

ASCO 2017: Case Study - The Impact of Early Diagnosis

The Impact of Early Diagnosis

Case Study: A 62-year-old man presented with a 4-month history of fatigue, vague abdominal discomfort and a 30 lbs unintentional weight loss.  His past history was significant for ethanol abuse, hypertension, high cholesterol and type 2 diabetes and his medications included hydrochlorothiazide, rosuvastatin, metformin and ramipril.  Bloodwork including CBC, lytes, creatinine and LFTs were all normal. U/S of the abdomen revealed a nonspecific gas pattern with no obvious significant abnormalities.  Due to persistent symptoms, a CT abd/pelvis was arranged that identified subtle soft tissue changes in the region of the celiac axis.  An MRI was performed to specifically evaluate the pancreas which confirmed a primary pancreatic lesion that might represent the sequelae of chronic inflammation although pancreatic cancer couldn’t be excluded.  CA 19-9 was 87.  He was referred to gastroenterology who performed upper and lower endoscopy and took brushings and washings of the pancreatic duct.  All results were either insufficient for interpretation or negative for malignancy.  His case was discussed at a GI multidisciplinary case conference and it was felt that the lesion could be consistent with a pancreatic cancer and that due to the presence of vessel involvement, would not be a surgical candidate.  It was also deemed that the lesion could not be safely biopsied percutaneously and so he was referred for an endoscopic ultrasound and biopsy for diagnosis.  This was ultimately performed but the sample demonstrated very little cellular material with some inflammatory cells and signs of atypia but no confirmation of adenocarcinoma or malignancy.  During this time, his weight loss continued and his pain worsened. 

Discussion: Pancreatic cancer continues to be a challenging tumour site.  Early diagnosis is key to management as the only curative strategy involves surgical resection of the primary tumour.  However, patients often have very few symptoms or have those that mimic more common, less dangerous conditions thus leading to a potential delay in the time to appropriate investigations and diagnosis.  At present, there are no screening programs for pancreatic cancer due to the relatively low prevalence of the disease, challenging imaging characteristics and lack of a reliable identifiable biomarker. 

As highlighted by the case example, making a diagnosis can be very challenging as patients often present with nonspecific symptoms and are already at a point where the disease has become too advanced for surgery.  Imaging tests may not be able to reliably distinguish between chronic pancreatitis and malignancy and although the CA 19-9 is sometimes helpful, it can be elevated for both benign and malignant reasons and may even be normal in the setting of malignancy.  Acquiring appropriate tissue sampling is also often a challenge particularly in the locally advanced setting as the primary site may be difficult to access for biopsy.  This may lead to repeated attempts at biopsy and a delay in initiating treatment.

Patients with advanced disease are often managed in multidisciplinary settings with supportive care and palliative care forming a significant element of co-managed care from the outset.  For motivated patients with good PS, multi-agent chemotherapy with FOLFIRINOX or Gemcitabine and nab-paclitaxel or enrollment on clinical trials if available are good options for initial therapy.  Single agent gemcitabine still remains an option for some patients or those with poorer PS. While newer therapies such as the immuno-oncology agents have yet to show significant benefit, other agents that attempt to improve drug delivery and/or drug penetration into the tumour are showing promise.  Examples include nanoliposomal irinotecan and PEGPH20.  In addition, there is evidence from retrospective series now showing that effective use of first-line treatment leads to a greater likelihood of receiving second line therapy and a longer overall duration of treatment with improved OS.  This highlights the importance of careful patient selection and treatment individualization to maximize outcomes. 

Insights provided by: 
Dr. Robert El-Maraghi, MD, FRCPC
Simcoe Muskoka Regional Cancer Centre