Home Forums Melanoma: Stage III Comprehensive article of decision making for interferon

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  • #21170
    Catherine Poole
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    PubMed

    PubMed Citation

    Articles by Hurley, K. E.

    Articles by Chapman, P. B.

    Helping Melanoma Patients Decide Whether to Choose Adjuvant High-Dose Interferon-2b

    Karen E. Hurley, Paul B. Chapman

    Department of Psychiatry and Behavioral Sciences, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    High-dose interferon-2b is a U.S. Food and Drug Administration–approved adjuvant treatment for stage III melanoma, and yet, because of its limited efficacy and well-known toxicity, it is not universally accepted by patients and oncologists. In this paper, we evaluate the benefits and risks of adjuvant high-dose interferon-2b and try to provide a framework to help oncologists guide patients trying to decide whether to undergo adjuvant high-dose interferon therapy.

    The value of a year of high-dose interferon-2b (HD IFN) for the adjuvant treatment of stage III melanoma remains a source of controversy among oncologists and patients. Since it is a U.S. Food and Drug Administration–approved treatment and is administered on an outpatient basis, some oncologists recommend it to all stage III melanoma patients after complete surgical resection. However, a substantial proportion of oncologists feel that the benefits of adjuvant HD IFN treatment do not justify the toxicities. Initially, some of this controversy arose from the lack of mature results from the two randomized phase III trials comparing adjuvant HD IFN with observation [1, 2]. Over the past few years, however, these data have matured, and an updated pooled analysis has recently been published [3]. These data, which are reviewed below, can be considered to represent the final word on the value of HD IFN, and as a result, it seems timely to consider how oncologists can help patients weigh the risks and benefits of adjuvant HD IFN treatment and so come to an informed decision on whether to undergo this treatment.

    The two randomized trials, in which a total of 713 patients received either adjuvant HD IFN or observation, both showed similar results [1, 2]. To be eligible for these trials, melanoma patients had to have had either deep primaries (>4 mm) or regional lymph node involvement. They were started on the trials within 70 days after complete surgical excision. With follow-up now complete in the first trial (median of 12.6 years of follow-up of survivors) and a median follow-up of 6.6 years in the second trial, neither showed an overall survival benefit associated with adjuvant HD IFN treatment. This is reflected in the pooled analysis of these two studies, which was recently published [3]. This pooled analysis showed that the survival curves were virtually superimposable (p = .42). Both treatment arms show an approximately 50% survival rate at 5 years, and there was no effect on the “tail of the survival curve,” meaning that HD IFN did not increase the chance of cure. On the other hand, HD IFN was associated with longer recurrence-free survival in both trials. However, in the pooled analysis [3], the median time to relapse was longer in the HD IFN group by less than 1 year.

    What does all this mean to the patient? It means that, among patients destined to recur, a year’s worth of HD IFN treatment can delay the time of recurrence in a small subset, although for half of these patients this delay will be less than 1 year. However, the overall chance of recurrence and the overall survival is not improved. This means that, if the patient is destined to relapse and die of melanoma, HD IFN does not affect this nor does it significantly delay the time of death.

    HD IFN is associated with toxicities that result in decreased performance status in virtually all patients. In the most recent HD IFN trials, severe toxicities (grade 3–4) were frequently reported for fatigue, myalgias, and hepatotoxicity (Table 1). Although toxicities such as fatigue, fever, and flu-like symptoms are universal, they are under-reported in publications since generally only grade 3 or worse toxicities are reported. Depression appears to be very common, occurring in 40% of patients if patients are assessed carefully [4]. Patients reporting a depressed mood or insomnia before starting HD IFN have been shown to be at a higher risk for worsening of depression during treatment, particularly if they also have low levels of social support [5]. In some patients, serious cardiac, hepatic, and bone marrow toxicities are also seen, and because of the need to screen for and manage these toxicities, frequent follow-up and blood tests are necessary in patients on HD IFN. This represents both a financial cost as well as a further cost in quality of life (QoL).

    View this table:

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    Table 1. Benefits and risks of high-dose interferon-2b therapy

    Data on QoL during HD IFN therapy can be presented to patients as part of informed decision-making. Trask and colleagues [6] conducted a longitudinal study of QoL in stage III melanoma patients receiving HD IFN after surgical resection. Patients reported increased depression, fatigue, and somatic complaints and decreased physical well-being over the course of 6 months of HD IFN treatment. Similarly, data from the E1684 trial show that up to 70% of patients on HD IFN experienced grade 3 toxicities or higher and that the mean length of time spent experiencing these symptoms was 7.4 months out of the 12 months of treatment [7].

    In oncology, we often offer toxic, noncurative treatment to our patients with metastatic cancer. However, in the setting of evaluable metastatic disease, the oncologist and patient can frequently evaluate the risk–benefit ratio by weighing the antitumor effects in the patient against the side effects being experienced. Even if the treatment is not curative, individual patients could elect to continue treatment if the risk–benefit ratio is sufficiently high. For example, in the setting of stable disease and no toxicity, the patient might reasonably choose to continue treatment. Alternatively, some patients may experience tumor regression and, as a result, might tolerate more toxicity. If the risk–benefit ratio becomes too low, treatment would be stopped.

    In the adjuvant setting, it is impossible to assess the ongoing benefits in an individual patient because there is no tumor to evaluate. Although the toxicities are evident, the individual patient cannot gauge the benefit in an individual case; this must be inferred from previous phase III trials. For many adjuvant treatments, data are not available regarding the magnitude or likelihood of the potential benefits, and the risk–benefit ratio must be estimated based on scientific rationale. In the case of HD IFN, however, mature data defining the benefit are available (as noted above), and a more precise risk–benefit analysis is possible.

    Now that the benefits and risks of HD IFN have been well defined (Table 1), it is possible to examine how oncologists and patients might weigh the risks against the benefit of longer relapse-free survival to decide on the advisability of adjuvant HD IFN.

    In the case of HD IFN, the question is: How much risk is a median improvement in progression-free survival of less than a year worth to the patient, knowing that there is no improvement in overall survival? Each patient has a sense of what risk–benefit ratio is acceptable. In some cases, it may be reasonable to accept a higher risk–benefit ratio (e.g., when potential benefits are greater). No matter what risk–benefit ratio the patient feels comfortable with, the physician can help the patient come to a treat/no-treat decision by discussing both the benefits (longer progression-free survival but no improvement in survival) and the risks (toxicities, frequent injections, office visits, blood tests). As an example, we may consider a stage IIIB patient with a single, palpable regional lymph node involved with melanoma. This patient has an approximately 50% chance of dying from melanoma over 5 years [8], a risk that is not improved by HD IFN according to the published data [3]. This means that if the patient chooses to receive HD IFN, he runs a 50% risk that he will spend at least 20% of his remaining time (presumably the best 20%, because it is the year immediately after surgery) on HD IFN.

    Psychosocial studies of patient preferences for HDIFN show large standard deviations [7, 9], suggesting that patients may differ in their subjective valuation of the risk–benefit ratio and that factors other than outcome data are influencing patient decisions [10]. Research on decision making among patients with other types of cancer has shown that patients are less likely to experience regret when they feel the decision was their own rather than undergoing the specific treatment because the doctor told them to [11, 12]. In discussing HD IFN, the oncologist can facilitate this process by exploring the meaning of disease-free survival for the patient, as well as expectations about side effects, to reach a decision that addresses both the patient’s physical and mental well-being. This approach can help maintain the doctor–patient relationship in the long run and facilitate patient acceptance of recommendations in case of toxicities or recurrence.

    Some patients may be willing to risk the toxicity of HD IFN because they perceive the advent of recurrence as synonymous with death, whereas the disease-free period allows them to cling to hope that they might achieve long-term survival. For other patients, recurrence in the absence of action may trigger thoughts that they missed an opportunity to stave off death [7]. In this instance, taking HD IFN may represent a form of “regret management” in which patients seek to avoid the scenario that would trigger the most regret and self-blame. Feeling that one has done everything possible may make the possibility of recurrence more bearable; if the disease returns despite HD IFN, the patient may interpret this as meaning that it was meant to be and that he or she is blameless. Paradoxically, severe side effects can be construed as concrete evidence that one’s efforts to survive were sincere and that no stone was left unturned.

    Kilbridge and colleagues [9] developed a decision rule consisting of two screening questions that allow identification of patients who would clearly benefit from HD IFN. These questions were based on the assumption that adjuvant HD IFN is associated with an improvement in overall survival. However, since subsequent data no longer support the primary assumption that adjuvant HD IFN is associated with improved overall survival (as discussed above), these specific screening questions appear to be no longer valid. However, the findings do suggest that, for most patients, a discussion of expectations about HD IFN can be accomplished in a brief, focused fashion and that the key elements of assessing patient readiness for HD IFN include a realistic understanding of the probability and nature of the side effects, a clear willingness to tolerate side effects for the possibility of modifying the course of one’s disease, and a realistic understanding of the nature and probability of any benefits of HD IFN.

    If the patient (or oncologist) is convinced that the risks of HD IFN are not reasonable for the potential benefits, it is rational to explore alternative options. In the past, adjuvant chemotherapy has been explored, but, aside from one trial assessing the role of adjuvant dacarbazine (DTIC-Dome®; BayerPharmaceuticals Corporation, WestHaven, CT, http://www.bayerpharma-na.com/), all the other randomized trials were either significantly underpowered or tested drugs that we no longer believe are active in melanoma. As a result, the question of the role of adjuvant chemotherapy in melanoma remains an open one. Currently, an intercooperative group study is testing the efficacy of biochemotherapy as an adjuvant treatment compared with HD IFN, a trial in which both treatment arms are associated with significant toxicity and a high risk–benefit ratio. The European Organization for Research and Treatment of Cancer is evaluating the role of prolonged (5-year) treatment with low-dose pegylated interferon- as an adjuvant treatment. Other adjuvant strategies focus on vaccine approaches. Although the benefits are not yet defined, the risks are generally minimal, and patients may view these as having lower risk–benefit ratios.

    In most situations in melanoma, patients are faced with trying to make a rational decision in the setting of incomplete information. For the issue of adjuvant HD IFN, however, the information is remarkably complete, and oncologists can help patients to quantitate the risks and benefits that will help them come to a decision.

    DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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    Learning objectives

    Abstract

    Introduction

    The benefits and risks…

    How do we determine…

    Patient decision-making about hd…

    Subjective benefits of hd…

    Decision rules for discussing…

    Other options for adjuvant…

    Disclosure of potential…

    References

    Dr. Chapman has acted as a consultant for Schering-Plough.

    ACKNOWLEDGMENT

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    Learning objectives

    Abstract

    Introduction

    The benefits and risks…

    How do we determine…

    Patient decision-making about hd…

    Subjective benefits of hd…

    Decision rules for discussing…

    Other options for adjuvant…

    Disclosure of potential…

    References

    The authors thank Courtney Hudson, CEO and founder of EmergingMed, for valuable discussions and ideas. We also thank Sabrina Jhanwar, M.A., and Erin Schweers, Ed.M., for technical assistance with the manuscript.

    REFERENCES

    Top

    Learning objectives

    Abstract

    Introduction

    The benefits and risks…

    How do we determine…

    Patient decision-making about hd…

    Subjective benefits of hd…

    Decision rules for discussing…

    Other options for adjuvant…

    Disclosure of potential…

    References

    Kirkwood JM, Ibrahim JG, Sondak VK et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000;18:2444–2458.[Abstract/Free Full Text]

    Kirkwood JM, Strawderman MH, Ernstoff MS et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.[Abstract]

    Kirkwood JM, Manola J, Ibrahim J et al. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004;10:1670–1677.[Abstract/Free Full Text]

    Musselman DL, Lawson DH, Gumnick JF et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344:961–966.[Abstract/Free Full Text]

    Capuron L, Ravaud A, Miller AH et al. Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. Brain Behav Immun 2004;18:205–213.[Medline]

    Trask PC, Paterson AG, Esper P et al. Longitudinal course of depression, fatigue, and quality of life in patients with high risk melanoma receiving adjuvant interferon. Psychooncology 2004;13:526–536.[CrossRef][Medline]

    Kilbridge KL, Weeks JC, Sober AJ et al. Patient preferences for adjuvant interferon alfa-2b treatment. J Clin Oncol 2001;19:812–823.[Abstract/Free Full Text]

    Balch CM, Buzaid AC, Soong SJ et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635–3648.[Abstract/Free Full Text]

    Kilbridge KL, Cole BF, Kirkwood JM et al. Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data. J Clin Oncol 2002;20:1311–1318.[Abstract/Free Full Text]

    Jansen SJ, Otten W, Stiggelbout AM. Review of determinants of patients’ preferences for adjuvant therapy in cancer. J Clin Oncol 2004;22: 3181–3190.[Abstract/Free Full Text]

    Borgen PI, Hill AD, Tran KN et al. Patient regrets after bilateral prophylactic mastectomy. Ann Surg Oncol 1998;5:603–606.[Abstract]

    Frost MH, Schaid DJ, Sellers TA et al. Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy. JAMA 2000;284:319–324.[Abstract/Free Full Text]

    Capuron L, Gumnick JF, Musselman DL et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002;26:643–652.[CrossRef][Medline]

    This article has been cited by other articles:

    A. A. Tarhini, J. Shipe-Spotloe, M. DeMark, S. S. Agarwala, and J. M. Kirkwood

    Response to “Helping Melanoma Patients Decide Whether to Choose Adjuvant High-Dose Interferon-{alpha}2b”.

    Oncologist, May 1, 2006; 11(5): 538 – 539.

    [Full Text] [PDF]

    #59988
    johnbil
    Participant

    There is also a response to this article…which changes things a bit maybe?

    http://theoncologist.alphamedpress.org/content/11/5/538.full

    #59989
    Catherine Poole
    Keymaster

    Except for one major issue, the authors do not disclose any conflict of interest, which they clearly have. Kirkwood’s institution, UPMC runs or used to run a hotline/website for interferon (melanoma.com) and is well known as the greatest proponent of interferon in the land. Even Chapman admited doing some work for Schering Plough. So the studies too have been slanted with funding by the pharma and authored by proponents. Don’t think it changes anything. There is no profit motive to disclosing a drug simply doesn’t prolong overall survival or prevent recurrence.

    #59990
    ncdaniel
    Participant

    I wish more people and oncologist would see and read this. In 2011 my wife and I made the decision not to doInterferion after her removal of her 11.5mm deep melanoma. Our descision was based on a U of M Surgon and oncologist who told us at that time that it was less than 10% effective and stated lastest information believed it was less than 2%. On returning home to NC our local oncologist told my wife she should start interferion. We did not, and have never looked back even though today she is stage four with mets on her lungs. Interferion would have only been another year of pain with nno results.

    Again all I can say to any readers who see this is see a Melanoma oncologist not a general cancer oncologlist. We were fortunate enough that while my wifes first tumor was removed by a general doctor upon results he reccomended that we immeadiatley go to A melanoma clinic for treatment and helped arrange things with the U of M.

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