The Narrow Path of Personalized Cancer Medicine

Since I’m not directly involved in oncology care, I have a limited perspective on how quickly molecular medicine may transform cancer care.  A recent commentary (IF Tannock, JA Hickman. NEJM 2016; 1289-94) explains the “Limits to Personalized Cancer Medicine.”

While the idea of careful molecular characterization of tumors that lead to targeted therapy with better survival and better patient quality of life has been proven effective in several circumstances, there are a number of reasons why this approach will not be useful for most cancers.

Key points:

  • Examples of current personalized cancer Rx: trastuzumab for HER2-expressing breast cancer and vemurafenib for BRAF-mutated-expressing melanomas.
  • Very few studies have shown feasibility/effectiveness of targeted drug treatment
  • There has been limited success with targeted drugs within and outside studies
  • Though proponents of targeted therapy expect further advances, tumors typically have heterogeneity which allows a Darwinian evolution to evade these new therapies. “Cancer cells have an almost universal capacity to develop resistance to a single molecular targeted agent by means of upregulation of the partially inhibited pathway, mutation of the target, or activation of alternative pathways.”
  • Targeted therapies are usually limited by only partial inhibition of the signaling pathways and by toxicity when used in combination therapy.
  • In some cases, a clonal driver mutation may be present which would be present in all cell lines –however the authors note that success from this approach is likely to be rare.
  • Cost: “new drugs to treat cancer are marketed at ever-increasing prices…unrelated to value (i.e. to clinical effectiveness)….but the development and marketing of expensive drugs with marginal effectiveness diverts resources from the development of more effective therapies.”

My take (borrowed from authors): “The concept of personalized medicine is so appealing…[but] there should also be a clear message to patients that personalized cancer medicine has not led to gains in survival…and is an appropriate strategy only within well-designed clinical trials.”

Related blog post:

University of Virginia

The Lawn, University of Virginia

Cancers Complicating Inflammatory Bowel Disease

In several prior posts, the issue of cancer and inflammatory bowel disease (IBD) has been discussed.  In my view, even the word “cancer” is so scary that it can make people make bad choices (related: Facts, “Misfearing” and Women’s Health | gutsandgrowth).  An up-to-date succinct summary (Laurent Beaugerie, M.D., Ph.D., and Steven H. Itzkowitz, M.D. N Engl J Med 2015; 372:1441-1452) provides a fairly good overview of “Cancers Complicating Inflammatory Bowel Disease.”

Key points:

  • “Smokers are overrepresented among the patients with Crohn’s disease…results in an excess rate of smoking related cancers.” (Smoking also is associated with more aggressive Crohn’s)
  • Colorectal cancers risk factors (Table 1), specific to IBD, include coexisting primary sclerosing cholangitis (PSC), and increasing duration & extent of colonic IBD.
  • A “progressive decrease in the excess risk of colorectal cancer in patients with IBD has been noted over time.”  This may be due to better control of inflammation, surveillance, and colectomy.  Still, the risk of colorectal cancer in patients with IBD is 1.5 to 2 times greater than the general population risk.
  • Small-bowel adenocarcinoma –risk is 20-30 times that of the general population, typically arises more than 8 years after diagnosis.  Absolute risk in those with disease more than 8 years is estimated at “0.5 per 1000 patient-years.”
  • Intestinal lymphomas –absolute risk is about 0.1 per 1000 patient-years.
  • Cholangiocarcinoma (CCA)–absolute risk is approximately “0.08 per 1000 patient-years.” CCA is mainly evident in patients with PSC who have a risk ~160 times the general population and lifelong risk of 5-10%.
  • Non-Hodgkin’s lymphoma –“whether TNF-alpha antagonists promote lymphomas by themselves in patients with IBD is difficult to assess…” A recent study found no excess risk in patients receiving TNF-alpha antagonists after adjustments for cotreatments.
  • Skin Cancers –nonmelanoma skin cancer, though not life-threatening, occur more often in those with current thiopurine usage.
  • HPV-Related Cervical Cancer –“it is still unclear whether the risk of HPV-related cervical cancer is intrinsically increased in woman with IBD or independently worsened by exposure to an immunosuppressant.”
  • Thiopurines: “after adjustment for confounders, current use of thiopurines for IBD has been shown to be associated with an overall relative risk of cancer of 1.3 to 1.7.”
  • TNF-alpha antagonists: “There is no overall excess risk of cancer in patients treated with TNF-alpha antagonists for IBD.”  However, more long-term data are needed.

Recommendations:

  • Figure 2 provides recommendations for colorectal cancer surveillance based on the American Gastroenterological Association (AGA), British Society of Gastroenterology (BSG) and European Crohn’s and Colitis Organisation (ECCO) recommendations. Typically, 8-10 years after diagnosis of colitis, starting surveillance (with chromoendoscopy if available) is recommended.  In patients with Crohn’s disease, “the excess risk appears when more than 30 to 50% of the colonic surface is ever involved.” However, with PSC, the excess risk of colorectal cancer is significant at the time of diagnosis.
  • For cholangiocarcinoma screening in those with PSC, “most experts recommend noninvasive annual imaging of the biliary tract (MRCP or ultrasound) and serum CA 19-9.”
  • For HPV, vaccination is recommended and regular Papanicolaou tests

Take-home message: Some cancers are increased in association with IBD.  However, the medications, particularly immunosuppressants, may reduce the incidence of inflammation-related cancers…or promote immunosuppression-related cancers.

Related blog posts:

Sandy Springs

Sandy Springs

Inequality in Pediatric Health Care

“Of all the forms of inequality, injustice in health care is the most shocking and inhuman.”

-Martin Luther King, Jr

This quote is part of an editorial (Flores G, “Dead Wrong: The Growing List of Racial/Ethnic Disparities in Childhood Mortality” J Pediatr 2015; 166: 790-3). The author discusses the disparities among African-American (AA) and Latino children in comparison to white children.

Key points:

  • AA children and young adults had ~6 times the death rate for drowning in swimming pools, 4 times more likely of dying after liver transplant, and about twice the likelihood of dying due to acute lymphoblastic leukemia.
  • Latino children have higher cancer death rates with about twice the likelihood of dying due to acute lymphoblastic leukemia and increased drowning death rate as well.
  • One new study (pages 812-8) shows that black children have increased in-hospital mortality (OR 1.66) after complications following congenital heart surgery and that hispanic children have an increased complication rate following surgery (OR 1.13). This was a retrospective study using the Kids’ Inpatient Database with approximately 3 million discharge abstracts for three separate years.
  • A second study (pages 819-26) with a data set of 98,833 children shows that birth defects resulted in higher 8-year adjusted hazards of death for black, latino, and Asian/Pacific Islander children.

Recognizing these disparities inevitable leads to the question of why. Dr. Flores postulates several factors.

  • Genetic differences.  For example, some ethnicities have more difficult to treat cancers, either due to genetic mutations or due to metabolism of medications.
  • Delays in diagnosis and treatment.  Patients who present at a later stage of diagnosis often have lower cure/response rates. The author notes that black children receive a diagnosis of autism a mean of 1.4 years later than white children.
  • Barriers to specialty care.  Specialty care can result in improved outcomes.
  • Bias in healthcare delivery, both conscious and unintentional.

Bottomline: The problems of racial inequality is not just a matter of relationships between the police and the community.  It is clear that more needs to be done to improve outcomes in healthcare as well.

Related blog posts:

Unrelated Link: Surgeon General Tells Elmo to Get His Vaccines

Monotherapy or Combination Therapy with Adalimumab?

Since the introduction of anti-tumor necrosis factor therapies (anti-TNFs), the benefit of using these agents in combination with immunomodulators or as monotherapy has shifted a few times based on the latest studies.  The most influential recent studies had been SONIC and UC Success which indicated that combination therapy for Crohn’s and Ulcerative Colitis, respectively, was more effective and without more adverse effects than monotherapy. A recent study may create some additional uncertainty in this line of thought (Gastroenterol 2014; 146: 941-49).

The author performed a pooled analysis of data from 1594 patients with Crohn’s disease (CD).  Studies included CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE.  In total, these studies provided 3050 patient-years of exposure. For individual patients, the median followup period was 1.5 years.

Key findings:

  • “Those patients receiving combination therapy had an increased risk of malignancy (other than non melanoma skin cancer [NMSC])” with a relative risk of 2.82.
  • Adalimumab monotherapy was not associated with an increased risk of malignancy other than NMSC
  • Combination therapy was associated with relative risk of NMSC of 3.46

In the discussion, the authors state “the data suggest that the increased risk likely is attributed to the immunomodulator therapy.”

A related editorial (884-86) helps dissect the articles strengths/limitations as well as implications.

Strengths:

  • the study captured data from randomized controlled trials.

Limitations:

  • median followup of 1.5 years –may not be long enough to detect a malignancy signal from anti-TNF therapy
  • unclear how many adalimumab monotherapy patients had been on a thiopurine previously

Implications:

  • “Even if Osterman et al are correct, is this information clinically meaningful enough to swing the mono-combo pendulum back to mono therapy?”
  • “The clinical relevance of the increase in absolute cancer risk from 4 in 1000 with adalimumab monotherapy to 10 in 1000 with combination therapy for cancers other than NMSC is unclear”
  • This difference of 6 in 1000 “translates to 167 patients who are treated before seeing 1 excess cancer”
  • “Most (if not all) of the cancer risk is associated with thiopurine exposure…induction therapy is more effective with combination treatment–>”we propose that we should induce patients into remission with combination therapy, and then consider withdrawing thiopurines at some point.
  • “Consider treating younger males with thiopurines short term, or alternatively with methotrexate.”  Though the authors note that data from rheumatology brings some concern to methotrexate cancer risk (Semin Arthritis Rheum 2014; 43: 489-97). Source Article: Methotrexate Safety | gutsandgrowth
  • “Consider treating elderly patients with anti-TNF monotherapy to decrease their risk of serious infections”

Also noted: “Risk of Cancer in Patients with Inflammatory Bowel Diseases: A Nationwide Population-based Cohort Study with 30 Years of Follow-up Evaluation” (Clin Gastroenterol Hepatol 2014; 13: 265-73). n=13,756 patients with CD and 35,152 with UC. Key findings –among CD patients, the excess risk was largely due to extra-intestinal cancers such as hematological malignancies (SIR 1.9) and smoking-related malignancies (SIR 1.5).  Associations between UC and gastrointestinal/extraintestinal cancers were weaker (both SIRs were 1.1); the risk of gastrointestinal cancers decreased over the course of the study.

Related blog posts: