How Long Is Long Enough

Mrs. Smith, an otherwise healthy 58-year-old woman, is in your office to review the results of a computed tomography–guided needle biopsy of a suspicious lung nodule three years after she completed adjuvant chemotherapy for stage II breast cancer. You empathetically explain to her that the results confirm a diagnosis of metastatic breast cancer (MBC) which, like the primary tumor, lacks hormone and HER2 receptor overexpression. Mrs. Smith coughs a cough that has only developed after her computed tomography scan revealed numerous bilateral pulmonary nodules. You explain the role for cytotoxic chemotherapy in attempting to achieve a remission, improving cancer-related symptoms, and you hope, prolonging survival. You explain the laundry list of possible adverse effects from your planned chemotherapy regimen. Mrs. Smith then asks, “Doctor, how long will I need to be on this chemotherapy?” Depending on who her medical oncologist is and, to some extent, on geography, Mrs. Smith may get different recommendations. For example, one oncologist might say, “We will treat you for 4 to 6 months and then stop and observe. We can always treat you again as the need arises.” Another might say, “The duration of your chemotherapy cannot be determined in advance; it will depend on how well your cancer responds to treatment and how well you tolerate it.” Can both approaches be correct, or in fact, is there only one right answer? In their systematic review and meta-analysis examining the duration of first-line chemotherapy for MBC, Gennari et al inch us a bit closer to the “longer (duration) is better” stance on this issue, albeit with some significant caveats. Their meta-analysis was conducted on a group of randomized trials with admittedly heterogeneous designs. The number of studies (n 11) and patients (n 2,269) is modest; this ishardlyameta-analysisofthemagnitudethatwehavetheluxuryofinthe adjuvant setting. By comparison, contemporary individual randomized phaseIII trialscomparingtwofirst-linechemotherapyregimensforMBC typically enroll 500 to 700 or more patients. Unlike the Oxford overview, thismeta-analysis isconductedonpublisheddata,notrawdata.It is also divorced from clinical practice, given that oncologists may choose, in the absence of progression, to continue a drug or regimen at much lower doses and with quite acceptable toxicity compared with those permitted by dose reduction rules that apply to clinical trials. Despite these considerations, Gennari et al report improved overall survival (OS) of marginal statistical significance (hazard ratio, 0.91; 95% CI, 0.84 to 0.99; P .046) with assignment to longer first-line chemotherapy duration. By contrast, the improvement in progression-free survival is more robust (hazard ratio, 0.66; 95% CI, 0.60 to 0.72; P .001). This is expected, given the quite plausible notion that postprogression therapy can impact OS; that is, that what comes next matters. The recent observations that the combination of lapatinib plus trastuzumab and eribulin prolong survival in settings well beyond first-line therapy support this. An older finding that the relative lack of taxane use as secondor subsequent-line therapy wasassociatedwithshortersurvivalamongpatientsrandomlyassignedto nontaxane first-line chemotherapy should sober us regarding the limitation of OS as a meaningful end point in trials that simply examine chapter one of the often multichapter story of MBC. Collectively, these trials seem totellus that,whenlessof thestoryremainstoberead,prolongingasingle chapter is more likely to make the story longer. Perhaps secondand third-line chemotherapy for MBC resembles first-line therapy for non– small-cell lung cancer (NSCLC) in this respect. To be sure, many oncologists experienced in the management of this disease recognize that the heterogeneity in the biology and clinical behavior of MBC argue for more individualized treatment strategies than anyonetrialormeta-analysiscanaddress. Indeed,oneshoedoesnotfitall feet. The therapeutic index of first-line chemotherapy—the balance betweenefficacyandtoxicity—isdynamic,notstatic.Earlyonduringchemotherapy, typically in the first few cycles, patients usually experience the most obvious reduction in tumor volume and cancer-related symptoms, whereas cumulative treatment-related toxicities (eg, neuropathy, fatigue, hand-foot syndrome, cardiomyopathy) may emerge later on, lowering the therapeutic index and arguing for dose reduction, delay, or a break fromtherapyortreatmentholiday.Althoughthismeta-analysis arguesin favor of the “longer is better” approach, this is the point in the clinic when the art of medicine intersects with the science of medicine. Patients like Mrs. Smith may hear many aphorisms applied in response to the duration of chemotherapy question—such as “If it is not broken, do not fix it,” or “The natural history of breast cancer is to progress and ultimately cause death. If we are altering that natural history without unacceptable toxicity, we should keep at it” (ie, treat to progression) or “The treatment should not be worse than the disease” (ie, stop and observe whether toxicities are excessive). I admit that I employ each of these mantras in selected situations. The current metaanalysis, with the limitations noted, does indeed argue in favor of more sustained duration of first-line chemotherapy. So assuming these aphorisms are reasonable, how can one satisfy them in clinical practice? For the patient with HER2-overexpressing MBC, it is fairly common practice to administer first-line chemotherapy with trastuzumab, on the basis of the demonstrated survival advantage of this approach. It is also quite common to stop the cytotoxic chemotherapy component (commonly, but not exclusively, a taxane) at the point of maximal response and/or limiting toxicity, when the therapeutic index narrows and to simply continue trastuzumab. There are fewer more JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 16 JUNE 1 2011