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Seed and soil: the challenges of MDS treatment

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Dr. Rena Buckstein

17 May 2018

Typical case:

  • An 82 year old patient is referred to you for the consideration of AZACITIDINE chemotherapy for high risk myelodysplastic syndromes. 
  • He has a past medical history of prostate cancer 2 years ago treated with radiation therapy and (current) hormone blockade and a coronary artery bypass graft 5 years ago for double vessel disease. 
  • He is a past cigarette smoker of 1 pack per day x 30 years, and has mild chronic obstructive pulmonary disease for which he is on inhaled puffers.
  • He is dependent on red blood cells, 2 units every 3 weeks and gets short of breath and very tired for 3-4 days before his scheduled transfusion at a hemoglobin threshold of 80 g/L.
  • Three times per week, he is able to walk 3 level blocks slowly outside with the help of a cane and he does all his own activities of daily living. He lives with his wife, still drives and is active socially. 

Is he a good candidate for AZACITIDINE chemotherapy?

What should be considered by a physician and patient before starting anti-MDS therapy?

Treatment of MDS patients can be divided into supportive care (growth factors, iron chelation therapy, antibiotics) and disease modifying (lenalidomide, hypomethylating agents, chemotherapy, allogeneic stem cell transplants and many clinical trial agents). Before commencing therapies associated with significant toxicities, the physician needs to thoroughly explore the wishes and goals of care with their patient. Is quality of life more important than quantity? What is their current quality of life? How could their quality of life be improved? What is their prognosis and likelihood of responding? Do they understand and are they prepared for the risks of disease modifying therapies? What are their home support and transportation needs? Are they being met? Is the patient ‘fit enough’ to withstand an adequate trial of a disease modifying therapy? The focus of this column is on the latter question. 

How should patient related factors be incorporated into the overall assessment of ‘fitness’ to tolerate disease modifying therapy?

Performance status assessed by Eastern Cooperative Oncology Group (ECOG) scoring is a quick, easy and validated way to assess this but this is a relatively insensitive and crude tool to assess fitness. In the Canadian experience, 85-90% of MDS patients have an assigned ECOG score of 0-1, yet have moderate disability and comorbidity assessed by other tools that may impact a patient’s fitness. Other elements of ‘fitness’ include the assessment of comorbidity (co-existing health problems at present or in the past), physical fitness using a variety of tests (including grip strength, 4 metre walk test, get up and go test, stand sit and balance tests etc.), assessment of disability (inability to perform activities of daily living), depression, concurrent medications and nutrition. These tests are typically conducted as part of complete geriatric assessments but may be very time consuming to perform in total in the clinic. Identifying without great delay the patients who are vulnerable or frail and more likely to experience complications, dose delays, need dose reductions or drug cancellation is of significant importance.

How does one define frailty and how is it different from comorbidity?

Frailty is a state of high vulnerability for adverse health outcomes, including disability, dependency, falls, need for long-term care, and mortality. Frailty is common in older patients with cancer and has been associated with treatment-related toxicity, poor response to therapy, and worse overall survival. There are a number of methods to determine frailty in the clinic. Using a schema developed by Rockwood and associates, known as the Clinical Frailty Scale (CFS), we assigned 445 patients scores of 1 to 9. A score 1 indicates very fit, 4 indicates vulnerable, and 8 indicates very severely frail. The median age of enrolled patients was 73. Frailty was found to correlate only modestly with ECOG performance status, less with and MDS specific comorbidity index and minimally with MDS specific prognostic scoring (IPSS-R). Frailty improved the prognostication of the IPSS-R in all but the highest-risk group. In a multivariate analysis that included IPSS-R and comorbidity scores, frailty was independently associated with survival. Most notably, incorporation of frailty improved MDS risk stratification by 30%.

Patients with MDS are often of advanced age at diagnosis such that the majority have at least one additional comorbid condition. Common comorbidities reported include cardiovascular disease (28%), diabetes (12%) and a history of other solid tumours (10%).  Comorbidity is overlapping with but still distinct from frailty. A patient may have several important comorbidities but not be frail or be frail with few comorbidities. One explanation is that much of the frailty seen in patients with a syndrome such as MDS may be due to the disease itself and cannot be attributed to additional medical diagnoses. Thus, a patient with MDS and with no comorbid conditions—or several comorbidities that are well-managed—may still be considered frail due to the effects of MDS alone (such as advanced anemia and/or recurrent infections).

In the case of the patient discussed above, his CFS would be ‘4- vulnerable’ and his MDS comorbidity score would be 3 (high risk, by virtue of the history of cardiac disease (weighted 2) and recent prostate cancer (weighted 1).  

Does this mean he will suffer a higher rate of complications while on AZACITIDINE, have a lower probability of completing 4-6 cycles, or have a shorter survival? Should he be denied this therapy?

While our previous prognostic models and the models of others incorporating comorbidity have demonstrated a lower survival of MDS patients with higher degrees of frailty or comorbidity, there are currently no guidelines regarding the incorporation of frailty assessment into MDS clinical practice, and consensus recommendations are needed. In Ontario, 1/3 of MDS patients with higher risk disease failed to receive 4 cycles of AZACITIDINE and had greatly reduced survivals compared with those that did.  What is not known is why they did not receive 4+ cycles. Did they have high rates of hospitalization, dose delays, dose reductions, dose cancellations? Did they have higher rates of treatment related death? Were there any baseline patient related clues that could have earmarked them for this? This research is currently underway in Ontario. The goal will be to have easy to deploy tests in the clinic that will allow the physician to better identify their ‘higher risk’ patients for toxicities. These tests may permit more informed decision making by patients and their physicians. It is increasingly apparent that not all patients should be offered ‘potentially-toxic’ therapies in MDS since they may not tolerate them for the necessary durations and quality of life may be worsened without the upside benefits of improved survival or transfusion independence.

Is it possible for a frail or pre-frail patient to become less frail?

Even less is known about this. Exercise studies are underway in many cancer clinical trials.  Some have shown a reduction in side effects and an improvement in quality of life. No studies to improve exercise tolerance, or reduce frailty have been initiated in MDS to the best of my knowledge. This would be an excellent focus for a research project. 

Back to the case….

I would counsel my patient that his comorbidity and frailty scores worsen the overall prognosis of his disease and possibly place him at increased risk of AZACITIDINE related complications like fevers, infections, hospitalization and even death. I would ensure that his comorbidities were optimally managed by touching base with his other specialists. I would target a hemoglobin threshold for transfusion that was closer to 85-90 than 80 g/L. I would recommend that he continue to walk but target daily exercise instead of just three times per week. After informed decision making, I would offer the patient AZACITIDINE at recommended dosing if he wished to receive it, but re-evaluate after every cycle the benefits/risks based on their tolerance and quality of life on drug. 

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