Rodger J. Winn

What are the most important symptom targets when treating advanced cancer? A survey of providers in the National Comprehensive Cancer Network (NCCN).

We derived a set of brief, clinically relevant symptom indices for assessing symptomatic response to chemotherapy for advanced bladder, brain, breast, colorectal, head and neck, hepatobiliary/pancreas, lung, ovarian, and prostate cancers. Questions were extracted from a multidimensional cancer quality of life (QOL) measurement system, the Functional Assessment of Cancer Therapy (FACT). Surveys of disease-related symptoms were presented to expert physicians and nurses at 17 National Comprehensive Cancer Network (NCCN) member institutions. In a two-step procedure, each expert narrowed the list to no more than five of the very most important to attend to when assessing the value of drug treatment for advanced disease. Symptoms endorsed at a frequency greater than chance probability were retained for the nine symptom indices. The resulting NCCN/FACT symptom indices are comprised of 6–15 items, depending on disease. Fatigue, pain, nausea, weight loss, worry about worsening condition, and contentment with current QOL were consistently selected by experts as priority symptoms across tumor sites. These nine tumor-specific symptom indices indicate the most important clinician-rated targets of chemotherapy for many advanced cancers. These results await validation in patient populations and examination of the extent to which changes in symptomatology translate into meaningful improvement to the patient.

Ongoing care of patients after primary treatment for their cancer.

Nearly nine million people living in the United States have had a diagnosis of cancer. As the population ages, this number will increase. Most of these people will need follow‐up care to deal with problems related to their cancer. Depending on the cancer, they may or may not benefit from surveillance to detect recurrence. Most will be more likely than average to develop a second primary cancer. Some will be genetically susceptible to another type of cancer. Many will have complications from their treatment that need attention. Also, their treatment may have altered certain physiologic functions. Finally, many will have suffered psychosocial difficulties either as a result of their cancer or its treatment. This article deals with these issues for the most commonly encountered cancers. Its major goal is to alert physicians to be aware of and help them to deal with these issues. Clearly, such an ambitious goal can only be partly achieved in a single journal article. Hopefully, the references included will allow physicians to proceed further if they wish.

Myeloid Growth Factor Guidelines: Moving Toward a Societal Perspective

The Myeloid Growth Factors guidelines in this month’s issue are in some ways a paradigm for successful guidelines—guidelines that support clinical decision-making. The algorithm comes down to the level of actual administration, with specific thresholds for beginning, dosages, and stopping. This granularity is possible, of course, because of the extraordinary number of trials meticulously designed to answer specific drug-related questions. For example, Frankfurt and Tallman’s article on using these agents in leukemia describes trials that have investigated not only the efficacy of these stimulating factors but also their potential deleterious effects. I’m reassured to learn from Lyman and Kleiner of the consistency found across 3 well-known guidelines for these agents. A major recommendation in all 3 guidelines is that growth factors be initiated for primary prophylaxis if the expected rate of febrile neutropenia is 20%. This new threshold varies considerably from the initial American Society of Clinical Oncology (ASCO) guidelines in 1994, which used a 40% threshold. The new mark is based on results from several randomized clinical trials and meta-analyses that confirm the efficacy of these agents in significantly diminishing the incidence of febrile neutropenia at this level. In what will likely become a major issue for guidelines developers in the future, economic considerations emerged in these discussions. Although NCCN and ASCO state that decisions were based on proven clinical benefit, both groups acknowledge the potentially large economic impact that using these agents may have—both their capacity to save in-hospital expenses and the financial burden they could impose if large numbers of patients are treated with them. This is especially concerning when only a minority of patients may actually benefit. One of the major goals of clinical practice guidelines is improving the quality of care. In formulating goals of quality care, the Institute of Medicine proposed that quality be based not only on effectiveness but also on the efficiency of care. Many professional groups, such as the National Quality Forum and the Ambulatory Quality Alliance, now focus considerable resources on developing a framework for how these economic issues will be defined and integrated into value-based systems of health care. The concept is not new, and our hospitals have been operating under a Diagnostic Related Groups (DRG) system that is designed to promote efficiency. Efficiency relates to the provision of optimal quality care with the optimal use of resources. ASCO guidelines recognize this in the statement that if alternative chemotherapy regimens are available that produce the same result without the need for growth factors, they should be used. That we now face a tremendous explosion of healthcare costs from new agents that significantly improve patient care or outcomes but carry costs that must be borne by the entire system is well-publicized. How to meld this societal perspective into guidelines will undoubtedly become a serious challenge to tomorrow’s panels. Bringing the dimension of cost into guidelines—an action not only appropriate but also necessary—will require new research and methodologies. The science of costeffectiveness, at least as it translates to the clinician, is still abstruse and fraught with multiple interpretations. We need newly trained oncology minds who understand not only the intricacies of the cell cycle but also the arcana of indirect costs. The bottom line, however, is that in the end we will have better guidelines, ones in which clinical decision-making includes the full range of factors that affect our daily lives. By Rodger J. Winn, MD

Lobular Neoplasia of the Breast: Rethinking the Known

One of the strengths of clinical practice guidelines is their dynamic nature. Rather than representing absolute truths, they reflect the best evidence available when they are produced. Periodic review is, therefore, mandatory. Given the prodigious outpouring of new data in oncology, NCCN has determined that guidelines must be reviewed at least annually to remain valid, with interim modifications for important information emerging within the cycle. This pursuit of change is at the core of guidelines utility: to provide a basis for physician and patient decision-making, they must be as up-to-date as the data. For the most part, innovations—new technology advances, either in the diagnostic or therapeutic realms—lead to changes. Often these changes are incremental, such as replacing previously recommended adjuvant regimens with new combinations reported in well-conducted randomized trials. In some instances, new technologies can change the entire approach to a disease, as seen in how GIST tumors are managed now that responsiveness to imatinib mesylate and subsequent agents was demonstrated. In this case, GIST was separated from a group of sarcomas for which relatively similar care had been recommended. In this issue, Andersen et al. address the current management of lobular neoplasia of the breast. As they note, for the past 20 years, lobular carcinoma in situ (LCIS) was considered a risk marker for subsequent breast cancer but not a malignant lesion itself. The therapeutic implications of this idea were that no further treatment other than biopsy was required, even if margins were positive. What Anderson et al. elegantly outline is that the basic concept of the disease is changing. The demonstration of a variant form of LCIS called pleiomorphic LCIS, the finding that pleiomorphic LCIS may be associated with the development of invasive lobular carcinoma, and the finding that some LCIS had previously been called DCIS (but now could be differentiated by E-cadherin expression) have all been reported in the past 10 to 15 years. In effect, these discoveries force us, and eventually guidelines developers, to re-conceptualize lobular neoplasia and examine how these new facets alter the basic approach to managing the disease. The lymphatic oncologists made similar adjustments as mantle cell lymphoma split off as a unique entity. Our understanding of a specific tumor is made by conjoining diverse but re-enforcing observations so that we see a coherent picture of the natural history of the neoplastic process and can form a rational plan for intervening. The essence of science is the continued re-examination of our concepts in light of new data. When these new observations point to possible deficiencies in the underlying disease concept, new hypotheses can be generated and new studies launched to determine if the old paradigm must be modified. In some instances, this new orientation could lead to simplifying the approach. However, given the availability of ever more sophisticated laboratory technology in genetics and molecular chemistry, the odds are that we will be expanding our concepts of disease and the resultant approaches will entail increasing complexity in our scientific scaffolding. For guidelines developers, Einstein’s dictum, “Everything should be made as simple as possible, but not simpler” must be a guiding principle. 431

Expanding the Oncology Team: Welcome the Cancer Geneticist

Although it is certainly true that each step in any NCCN algorithm must receive due consideration, sometimes it is the most obvious things that need restating, lest the eye skip over something that might, on superficial reading, appear perfunctory. A case in point is the carefully worded Genetics/Familial High Risk Assessment Clinical Practice Guideline. In keeping with the formula for NCCN supportive care guidelines, the algorithm proposes screening as the first step, followed by a detailed risk assessment if the screening result is positive. What must not be glossed over, however, is the important recommendation joining these clinical decision nodes: “Referral to cancer genetics professional recommended.” The geneticist is the health care professional who can perform the sophisticated pedigree analysis that determines whether genetic screening is warranted. If the patient decides to undergo testing, the geneticist’s role becomes even more involved, with a mandate to “provide counseling, including psychosocial support and assessment, risk counseling, education, and discussion of genetic testing, and obtain informed consent.” This mandate is a far cry from a well-meaning but inadequately trained oncologist taking a cursory family history and ordering a blood test, the results of which might be delivered by a member of the office staff. Special attention should be given to the components of a meaningful informed consent. The American Society for Clinical Oncology Special Article on Genetic Testing for Cancer Susceptibility details 12 basic elements needed for truly informed consent for cancer susceptibility testing: information on the specific test; implications of a positive and negative result; possibility that the test will not be informative; options for risk assessment without testing; risk of passing a mutation to children; technical accuracy of testing; fees involved in testing and counseling; psychological implications of test results; risks of employer discrimination; confidentiality issues; options and limitations of medical surveillance and prevention strategies; and importance of sharing results with family members. The clinical realities of these areas are beautifully discussed in the article by Burke and Press, “Ethical Obligations and Counseling Challenges in Cancer Genetics.” The real life dilemmas posed in this article demonstrate the multidimensional decision making that must be supported as patients and families navigate this emotionally laden landscape. Also, considering the potential economic and social problems and the complexities of family dynamics, it is clear that only a dedicated professional has the expertise and skills necessary to optimally address these issues. Reading about the genetic variants and clinical implications of mutations of the RET and BRCA gene families, as outlined in the articles by Domchek et al. and Ogilvie and Kebebew, makes it manifestly clear that the geneticist must be a cancer geneticist. So, another guideline means adding another team member, and we see proof again of the power of a comprehensive set of clinical practice guidelines.

The Quickening Pace of Oncology Research

One of the hallmarks of the oncology scientific community has been a general reluctance to sensationalize advances. Although the news media tends to blare forth with the breakthrough of the week, or even du jour, investigators reporting results usually cloak them with caution and almost always point to the need for further studies. This is not to say, however, that the oncology community is shrouded in a pall of pessimism. The willingness to treat these devastating diseases and provide compassionate support and hope, grounded in realistic expectations, has earned the specialty the (sometimes begrudging) admiration of non-oncology practitioners. And for many years, one of the precepts that enabled oncologists to provide honest succor to patients was the well-grounded belief that progress was being made, if slowly, in small but well-defined increments. Thus, the breathtaking change in pace we see now in understanding the underlying mechanisms of carcinogenesis and introducing innovative approaches to therapy based on this understanding that now confronts (blesses) the oncology world evokes almost a sense of disbelief. I would guess that, for the past decade, no clinician has left a major meeting thinking, “nothing really new is happening.” Multiple myeloma, highlighted in this issue, may well serve as the cover disease for this remarkable change of pace. When first published, the NCCN Multiple Myeloma Clinical Practice Guidelines rested squarely on standard alkylating agents and corticosteroid treatment or well-tested regimens such as VAD that had been the mainstay of treatment for more than 30 years. Since this initial guideline was originally released, two remarkable new agents, thalidomide, reported in 1999, and bortezomib, reported in 2003, have been added to the list of efficacious agents for the management of advanced disease. Patients with refractory or relapsing myeloma now have solid options for achieving meaningful responses, with increases in time to progression and perhaps even survival. Ongoing studies are now incorporating these agents into new combinations, and these studies will, hopefully, lead to even more beneficial responses. The area of high-dose therapy with bone marrow support has shown the greatest changes. As detailed in the review by Bensinger, researchers appear to have solid evidence for the role of high-dose, autologous-supported chemotherapy, either up front or at the time of relapse, in improving overall survival. Of possibly greater import is the profusion of studies of allogeneic-oriented therapies that may lead to even more durable control of the disease. The path is not an easy one; transplant-related toxicity and mortality is still a reality. However, experiments with non-myeloablative regimens and controlled graftversus-myeloma interactions make cautious optimism a reasonable outlook. And as repeatedly pointed out in JNCCN articles, the goal must always be defined in terms of patient benefit. Lee’s review of the role of quality of life studies being interjected into all phases of myeloma testing speaks to the tremendous emphasis on assessing new therapies from a quality as well as quantity perspective. This becomes especially essential for treatments that carry significant side-effects. For instance, meaningful assessment of the role of interferon is not 269