VOLUME 34 • NUMBER 30 • OCTOBER 20,
JOURNAL OF CLINICAL ONCOLOGY
Challenge of Prognostic Uncertainty in the Modern
Era of Cancer Therapeutics
Jennifer S. Temel, Alice T. Shaw, and Joseph A. Greer, Massachusetts General Hospital, Boston, MA
Patients with advanced cancer often fail to understand their
prognosis and goals of treatment.1,2 Such misperceptions are as-
sociated with poor patient outcomes, including aggressive care
at the end of life, as well as increased health care costs.3,4 Re-
cently, advances in cancer therapeutics have resulted in signifi-
cantly prolonged survival for some patients with advanced cancer,
further complicating clinicians’ capacity to estimate prognosis and
counsel patients about their end-of-life care options. Little has been
written about how these discoveries are challenging the ability of
clinicians to communicate effectively with patients regarding the
likely trajectory of illness and options for care. Although such novel
cancer therapies are affecting the care of patients with many cancer
types, recent advances in non–small-cell lung cancer (NSCLC)
nicely exemplify the changing climate of cancer care.
A 2002 study published in the New England Journal of
Medicine comparing four chemotherapy regimens for metastatic
NSCLC was noteworthy not only because the survival curves
were overlapping but also because the median survival was a mere
7.9 months.5 This therapeutic nihilism began to change 2 years
later, when Lynch et al6 reported activating mutations in the
epidermal growth factor receptor (EGFR) in patients responding to
a tyrosine kinase inhibitor. Over the ensuing years, the pendu-
lum continued to swing toward therapeutic optimism, as multiple
US Food and Drug Administration–approved agents were in-
troduced for patients with EGFR mutations and, subsequently,
anaplastic lymphoma kinase gene (ALK) translocations.7-12 While
still basking in the excitement of these discoveries in genotype-
directed therapy, data on the benefits of immunotherapy emerged
and again altered the landscape of treatment of metastatic
NSCLC.13-15 Similar phenomena have occurred in other cancers,
such as melanoma, with therapies targeting BRAF and MEK and
the myriad of immunotherapy drugs.16-21
Although any potential downside to these changes in can-
cer therapeutics is difficult to discern, we have observed some
unintended consequences for clinician-patient communication.
Conversations with patients about prognosis and end-of-life
care have always been challenging for clinicians, partially because
of uncertainty in estimating patient survival.22 However, when
a study of all available first-line chemotherapies for metastatic
NSCLC showed a median survival of 7.9 months, clinicians had
accurate data on which to base these discussions. In the current
environment, clinicians are confronted with much more complex
discussions about prognosis and end-of-life care in patients with
targetable mutations and in those responding to immunotherapy,
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2016
COMMENTS AND CONTROVERSIES
who can survive years with metastatic disease. Although clinicians
often rely on clinical assessment, such as performance status, to
evaluate patients’ ability to tolerate cytotoxic chemotherapy, it
is unclear whether guidelines recommending that oncologists
should not administer treatment to patients with a poor performance
status apply to these novel and often less-toxic therapies.23-25 Despite
such challenges, providing patients with evidence-based infor-
mation about their prognosis and end-of-life care options remains
an essential aspect of quality cancer care.
Importance of Communication About Prognosis and
End-of-Life Care
Effective patient-clinician communication about prognosis
and end-of-life care preferences has many important benefits for
patients, their families, and the health care system. Patients who are
aware that their life expectancy is likely short are empowered to
make informed decisions about how they want to spend their
remaining time.26 Understanding that their prognosis is poor also
allows patients to acknowledge that they will potentially miss
future events and ensures they have time to communicate their
wishes, address unresolved concerns, and leave a legacy for loved
ones, such as through letters or videos.27 Importantly, patients who
have communicated with their clinicians about their end-of-life
care options are more likely to receive care that is concordant with
their goals and preferences.28
Patients who discuss their care preferences with their clini-
cians are also less likely to receive intensive medical interventions
near the end of life, such as cardiopulmonary resuscitation or
chemotherapy administration.3 Thus, communication about end-
of-life care options allows patients to spend less time in the hospital
and intensive care unit and more time receiving hospice services.
Moreover, family and professional caregivers of patients who re-
ceive less intensive medical care near the end of life rate the pa-
tient’s quality of death to be better than those who received more
intensive medical interventions.3 These caregivers also have better
outcomes themselves, including lower rates of depression and
improved quality of life. Importantly, patients who engage in
discussions about their preferences for care at the end of life use
fewer health care resources than patients who have not participated
in these conversations.4
Although learning that one’s life expectancy is limited can
be quite upsetting, patients do recognize the importance of these
conversations.29 Both patients and their families want to know
© 2016 by American Society of Clinical Oncology 3605
 Temel, Shaw, and Greer
what to expect regarding the likely disease trajectory to be prepared
for death.30 Patients with advanced cancer prefer their oncologist
to be realistic about their future and to discuss prognosis early in
the course of illness.31 Despite the stated preferences of patients to
receive prognostic information and to prepare for the end of life,
the majority of patients actually fail to understand their prognosis
or engage in conversations about their care preferences.32,33 For
example, Weeks et al2 showed that more than two thirds of patients
with metastatic lung or colorectal cancer reported believing that
chemotherapy was likely to cure their cancer. Most conversations
with patients about their end-of-life care preferences take place
within weeks of their death.34 Unfortunately, conversations about
prognosis and end-of-life care options are not well integrated into
cancer care, especially given clinicians’ difficulty in estimating and
communicating patients’ prognoses.35
Prognostic Uncertainty in the Modern Era
With the rapidly evolving fields of genotype-directed treat-
ment and immunotherapy, prognostic uncertainty in oncology is
quite prevalent. Assessing mutation status at the time of diagnosis
is now standard of care for cancer populations in which this in-
formation has implications for prognosis and treatment re-
sponse.36 The widespread availability of genetic testing has allowed
patients to receive more accurate information about their specific
prognosis early in the course of illness.37 Nonetheless, uncertainties
about therapeutic benefit make decision making challenging. For
example, consider Martha, a 93-year-old never-smoker with ra-
diographs consistent with metastatic NSCLC. Might it be worth
subjecting her to a biopsy and consideration of EGFR-directed
therapy if she does harbor a mutation? If such treatment could
potentially extend her life and offer symptom relief, should the
oncologist recommend that the family consider an invasive pro-
cedure? Thus, the rapidly evolving options for care, including the
increased availability of targeted therapies with fewer toxicities,
undeniably complicate discussions about treatment planning.
Patients and their families also seek accurate information from
their care team about their likely disease course and expected
length of life. However, it is difficult to estimate patients’ prognoses
when the landscape of their options for cancer therapy changes
during their illness, as exemplified in the following case. Jane was
diagnosed with metastatic NSCLC with brain metastases at age
42 years and initially responded to chemotherapy and brain ra-
diation. Three years after diagnosis, genetic testing revealed an ALK
translocation, and she started crizotinib, with excellent disease
control for 5 years. She ultimately experienced progression with
leptomeningeal involvement, but fortunately we had availability of
a clinical trial with alectinib. At the time of enrollment, Jane was
rapidly declining, with deteriorating mental status and inability to
ambulate. Within days of initiating alectinib, she markedly im-
proved and continues to have excellent disease control and quality
of life now 2 years later.
Far from the previous expected 7.9-month median survival,
Jane’s experience underscores how novel therapies can dramatically
alter patients’ prognosis and clinicians’ perceptions of medically
appropriate therapy, as she has now lived a decade with advanced
cancer. Yet, most patients diagnosed with metastatic NSCLC will
not have Jane’s experience. How then should clinicians provide
3606 © 2016 by American Society of Clinical Oncology
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
patients and their families with accurate information about prog-
nosis given the tremendous variability in clinical outcomes?
Expert clinicians, and more recently the Institute of Medicine,
recommend that patient-clinician communication about prog-
nosis and end-of-life care begin at diagnosis and continue over
time as the patient’s health status evolves.38,39 The integration of
such conversations into the longitudinal care of patients enables
clinicians to incorporate new information and assist patients with
treatment decision making. On diagnosis, Jane’s oncologist esti-
mated her life expectancy to be approximately 1 year. When genetic
testing revealed her cancer harbored an ALK translocation, her
oncologist revised her prognosis, with the understanding that Jane
would likely live several years. However, when she became resistant
to therapy and arrived at the clinic unable to walk, it seemed likely
that she would die within days. Although none of the estimates her
oncologist communicated to Jane regarding life expectancy were
accurate, these conversations nonetheless helped her appreciate the
uncertainty about her prognosis and facilitated salient discussions
about her care preferences at the end of life.
New Psychosocial Challenges for Patients in the
Modern Era
Even with effective communication strategies, such pronounced
prognostic uncertainty poses complex challenges for patients
and their clinicians. Like Jane, Susan was a young woman di-
agnosed with metastatic NSCLC harboring an ALK translocation.
Her cancer responded to initial treatments with ALK-directed
therapy. However, 2 years after her diagnosis, her cancer progressed
and she became seriously ill, requiring hospitalization. Her clinicians
communicated their concern that she could soon die, but they
administered intravenous chemotherapy with the hope she might
sufficiently improve to return home. However, Susan experienced
a dramatic recovery with chemotherapy and was even able to
resume work. Later, when her cancer progressed again, she en-
rolled in yet another clinical trial with an ALK inhibitor. After
8 months, she developed rapidly progressive disease, once again
resulting in hospitalization. A biopsy of her tumor revealed that
her new resistance mutation predicted response to crizotinib, which
she started during her hospitalization. After reinitiating crizotinib,
Susan experienced another remarkable response and return to her
excellent health status.
This discovery of the re-emergence of a mutation with sen-
sitivity to crizotinib was published in New England Journal of
Medicine.40 Yet, the scientific aspects of her tumor genetics and
response to ALK-directed therapy tell only half of Susan’s story. As
her health status was rapidly improving on crizotinib, Susan
expressed to her family and clinicians that she did not feel she could
cope with becoming ill and facing death again, only to return to
good health. The distress of being on the verge of death yet sur-
viving so many times nearly led Susan to discontinue crizotinib,
despite its positive effect on her health status. Ultimately, when her
cancer progressed on crizotinib, a repeat biopsy suggested that she
might again respond to lorlatinib. However, she opted to defer
treatment. The emotional toll of preparing for death and saying
goodbye to her family and friends, only to survive and confront the
same scenario again, was overwhelming, and Susan worried about
its impact on her loved ones. This compelling story not only
JOURNAL OF CLINICAL ONCOLOGY
 Challenge of Prognostic Uncertainty in the Modern Era
highlights the immense importance of readdressing patients’ prog-
nosis and goals of care over the course of illness but also calls clinicians
to understand and attend to the psychosocial impact of such treat-
ment decisions.
In summary, with each passing year, new cancer therapies are
altering the paradigm of cancer care. Despite the promise of these
novel treatments to extend life, most patients with an advanced
cancer diagnosis still face an incurable illness. What has not
changed is that patients with incurable cancer deserve and prefer to
have accurate information about their prognosis and to engage in
timely discussions about their end-of-life care options. Although
many obstacles discourage clinicians from engaging in these
conversations, the worry that we may provide patients with in-
accurate information about their life expectancy is a notable
barrier. Advances in cancer therapy make it significantly more
challenging for clinicians to provide an accurate prognosis, es-
pecially if we approach prognostic disclosure as a one-time event.
Describing the nature of this uncertainty to patients and revisiting
discussions about prognosis over time are essential strategies for
overcoming challenges in communicating prognosis in the modern
era. In addition, data show that the integration of palliative care
early in the course of illness enables patients to understand their
prognosis more accurately and improves clinician-patient com-
munication about end-of-life care preferences.41-43 Future research
is needed to determine how best to provide patients and their
families with support as they navigate the psychosocial sequelae and
uncertainties inherent to these innovations in cancer therapeutics.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Provision of study materials or patients: Jennifer S. Temel, Alice T. Shaw
Manuscript writing: All authors
Final approval of manuscript: All authors
REFERENCES
1. Weeks JC, Cook EF, O’Day SJ, et al: Relationship between cancer patients’
predictions of prognosis and their treatment preferences. JAMA 279:1709-1714,
1998
2. Weeks JC, Catalano PJ, Cronin A, et al: Patients’ expectations about effects
of chemotherapy for advanced cancer. N Engl J Med 367:1616-1625, 2012
3. Wright AA, Zhang B, Ray A, et al: Associations between end-of-life dis-
cussions, patient mental health, medical care near death, and caregiver be-
reavement adjustment. JAMA 300:1665-1673, 2008
4. Zhang B, Wright AA, Huskamp HA, et al: Health care costs in the last week
of life: Associations with end-of-life conversations. Arch Intern Med 169:480-488,
2009
5. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemo-
therapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:
92-98, 2002
6. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal
growth factor receptor underlying responsiveness of non-small-cell lung cancer to
gefitinib. N Engl J Med 350:2129-2139, 2004
7. Shaw AT, Engelman JA: Ceritinib in ALK-rearranged non-small-cell lung
cancer. N Engl J Med 370:2537-2539, 2014
8. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in
advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013
9. Shaw AT, Gandhi L, Gadgeel S, et al: Alectinib in ALK-positive, crizotinib-
resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial.
Lancet Oncol 17:234-242, 2016
10. Zhou C, Wu YL, Chen G, et al: Erlotinib versus chemotherapy as first-line
treatment for patients with advanced EGFR mutation-positive non-small-cell lung
www.jco.org
Downloaded from ascopubs.org by University Colorado Health Science Center on December 11, 2018 from 140.226.057.056
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3
study. Lancet Oncol 12:735-742, 2011
11. Jänne PA, Yang JC, Kim DW, et al: AZD9291 in EGFR inhibitor-resistant non-
small-cell lung cancer. N Engl J Med 372:1689-1699, 2015
12. Sequist LV, Yang JC, Yamamoto N, et al: Phase III study of afatinib or
cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with
EGFR mutations. J Clin Oncol 31:3327-3334, 2013
13. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-
small-cell lung cancer. N Engl J Med 372:2018-2028, 2015
14. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in ad-
vanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627-1639,
2015
15. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in
advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123-135,
2015
16. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated
melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015
17. Robert C, Karaszewska B, Schachter J, et al: Improved overall survival in
melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30-39,
2015
18. Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK in-
hibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877-1888,
2014
19. Chapman PB, Hauschild A, Robert C, et al: Improved survival with
vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:
2507-2516, 2011
20. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined nivolumab and
ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015
21. Postow MA, Chesney J, Pavlick AC, et al: Nivolumab and ipilimumab versus
ipilimumab in untreated melanoma. N Engl J Med 372:2006-2017, 2015
22. Christakis NA, Lamont EB: Extent and determinants of error in doctors’
prognoses in terminally ill patients: Prospective cohort study. BMJ 320:469-472,
2000
23. Gripp S, Moeller S, Bölke E, et al: Survival prediction in terminally ill cancer
patients by clinical estimates, laboratory tests, and self-rated anxiety and de-
pression. J Clin Oncol 25:3313-3320, 2007
24. Maltoni M, Caraceni A, Brunelli C, et al: Prognostic factors in advanced
cancer patients: Evidence-based clinical recommendations—A study by the
Steering Committee of the European Association for Palliative Care. J Clin Oncol
23:6240-6248, 2005
25. Schnipper LE, Smith TJ, Raghavan D, et al: American Society of Clinical
Oncology identifies five key opportunities to improve care and reduce costs: The
top five list for oncology. J Clin Oncol 30:1715-1724, 2012
26. Chochinov HM, Kristjanson LJ, Breitbart W, et al: Effect of dignity therapy
on distress and end-of-life experience in terminally ill patients: A randomised
controlled trial. Lancet Oncol 12:753-762, 2011
27. Yun YH, Lee CG, Kim SY, et al: The attitudes of cancer patients and their
families toward the disclosure of terminal illness. J Clin Oncol 22:307-314,
2004
28. Mack JW, Weeks JC, Wright AA, et al: End-of-life discussions, goal at-
tainment, and distress at the end of life: Predictors and outcomes of receipt of care
consistent with preferences. J Clin Oncol 28:1203-1208, 2010
29. El-Jawahri A, Traeger L, Park ER, et al: Associations among prognostic
understanding, quality of life, and mood in patients with advanced cancer. Cancer
120:278-285, 2014
30. Steinhauser KE, Christakis NA, Clipp EC, et al: Factors considered important
at the end of life by patients, family, physicians, and other care providers. JAMA
284:2476-2482, 2000
31. Hagerty RG, Butow PN, Ellis PA, et al: Cancer patient preferences for
communication of prognosis in the metastatic setting. J Clin Oncol 22:1721-1730,
2004
32. Temel JS, Greer JA, Admane S, et al: Illness understanding in patients with
advanced lung cancer. J Clin Oncol 27, 2009 (suppl; abstr 9515)
33. Temel JS, Greer JA, Admane S, et al: Code status documentation in the
outpatient electronic medical records of patients with metastatic cancer. J Gen
Intern Med 25:150-153, 2010
34. Mack JW, Cronin A, Taback N, et al: End-of-life care discussions among
patients with advanced cancer: A cohort study. Ann Intern Med 156:204-210, 2012
35. Keating NL, Landrum MB, Rogers SO Jr, et al: Physician factors associated
with discussions about end-of-life care. Cancer 116:998-1006, 2010
36. Moran T, Sequist LV: Timing of epidermal growth factor receptor tyrosine
kinase inhibitor therapy in patients with lung cancer with EGFR mutations. J Clin
Oncol 30:3330-3336, 2012
© 2016 by American Society of Clinical Oncology 3607
 Temel, Shaw, and Greer

37. Lindeman NI, Cagle PT, Beasley MB, et al: Molecular testing guideline for
selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors:
Guideline from the College of American Pathologists, International Association for
the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol
8:823-859, 2013
38. Jackson VA, Jacobsen J, Greer JA, et al: The cultivation of prognostic
awareness through the provision of early palliative care in the ambulatory setting: A
communication guide. J Palliat Med 16:894-900, 2013
39. Institute of Medicine: Dying in America: Improving Quality and Honoring
Individual Preferences Near the End of Life. Washington, DC, The National
Academies Press, 2015
40. Shaw AT, Friboulet L, Leshchiner I, et al: Resensitization to crizotinib by the
lorlatinib ALK resistance mutation L1198F. N Engl J Med 374:54-61, 2016
41. Temel J, El Jawahri A, Greer J, et al: Randomized trial of early integrated
palliative and oncology care. J Clin Oncol 34, 2016 (suppl; abstr 10003)
42. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for pa-
tients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742,
2010
43. Temel JS, Greer JA, Admane S, et al: Longitudinal perceptions of prog-
nosis and goals of therapy in patients with metastatic non–small-cell lung cancer:
Results of a randomized study of early palliative care. J Clin Oncol 29:2319-2236,
2011
DOI: 10.1200/JCO.2016.67.8573; published online ahead of print at
www.jco.org on August 22, 2016.

n n n

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 Challenge of Prognostic Uncertainty in the Modern Era

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Challenge of Prognostic Uncertainty in the Modern Era of Cancer Therapeutics
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Jennifer S. Temel Joseph A. Greer
Research Funding: Helsinn Therapeutics (Inst), Pfizer (Inst) No relationship to disclose
Travel, Accommodations, Expenses: Helsinn Therapeutics
Alice T. Shaw
Honoraria: Pfizer, Novartis, Genentech
Consulting or Advisory Role: Pfizer, Novartis, Genentech, Roche, ARIAD
Pharmaceuticals, Ignyta, Blueprint Medicines, Daiichi Sankyo, EMD
Serono, Taiho Pharmaceutical, Loxo Oncology
Research Funding: Pfizer (Inst), Novartis (Inst), Genentech (Inst), Daiichi
Sankyo (Inst)

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