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Originally published as JCO Early Release 10.1200/JCO.2004.08.176 on April 26 2004 © 2004 American Society of Clinical Oncology. Are Chemotherapy Response Rates Related to Treatment-Induced Survival Prolongations in Patients With Advanced Cancer?From the Department of Oncology, Mayo Clinic, Rochester, MN. Address reprint requests to Tait Shanafelt, MD, 200 First St SW, Rochester, MN 55905; e-mail: shanafelt.tait{at}mayo.edu
PURPOSE: Patients with incurable cancer are faced with difficult decisions regarding whether to take chemotherapy in an attempt to preserve the quality and/or prolong the quantity of their lives. The average prolongation in survival with chemotherapy compared with best supportive care has not been well described. METHODS: We performed a literature search using PUBMED combined with expert inquiry to identify trials comparing cytotoxic chemotherapy with best supportive care. Twenty-five randomized, controlled clinical trials comparing cytotoxic chemotherapy with best supportive care were identified. Sixteen trials (64%) were in patients with non–small-cell lung cancer (NSCLC). Data were extracted and analyzed. RESULTS: Sufficient data for statistical modeling were available for NSCLC trials. The mean sample size of the NSCLC trials was 175 patients. Response rates in the treatment arms for NSCLC ranged from 7% to 42%. A relationship between response rate and survival was observed for NSCLC. The estimated relationship for NSCLC suggested that each 3.3% increase in response rate correlated, on average, with a 1-week increase in median survival, and each 2% increase in response rate correlated, on average, with a 1% increase in 1-year survival. The mean increase in 1-year survival for trials of agents with at least a 20% response rate in NSCLC was 16%. Formulas are provided to help estimate how a given response rate may effect median and 1-year survival relative to best supportive care alone for NSCLC. CONCLUSION: We found a relationship between response rate and both median and 1-year survival in NSCLC. This information may help oncologists estimate how an NSCLC chemotherapy regimen with a given response rate can, on average, impact survival relative to supportive care alone.
Patients with incurable cancer are faced with difficult decisions regarding whether to take cytotoxic chemotherapy in an attempt to preserve the quality and prolong the quantity of their lives. Because palliation of symptoms can often be accomplished with aggressive supportive care with less toxicity than chemotherapy, prolongation of survival is often the primary reason for a patient to take cytotoxic treatment. To make the most informed decision, a patient should understand the potential side effects of treatment, the likelihood and duration of antitumor response, whether treatment can prolong life, and, if so, how long on average this treatment will prolong life. Although clinical studies and, notably, phase II and III trials often provide oncologists with information about tumor response rates, the average prolongation in survival with treatment compared with best supportive care (BSC) has not been well described. The absence of information regarding the effect of a particular treatment on survival prolongation limits oncologists' ability to counsel patients and hinders patients from making truly informed decisions regarding treatment. Despite the fact that cancer patients may be willing to undertake aggressive treatment with only a small chance of benefit,1-3 some studies suggest that patients with incurable malignancy may be overtreated in their last months of life.4 The best method to determine the magnitude of survival prolongation for chemotherapy over BSC alone is to perform controlled trials that randomize some patients to receive chemotherapy and others to receive BSC alone. Designing and enrolling patients onto such studies is challenging, because many patients are unwilling to relegate the decision of whether or not they will receive chemotherapy to chance. In the absence of such data, some oncologists only present patients with the known data on surrogate end points such as response rate, which can be confusing or even misleading. Other oncologists present patients a subjective estimation of survival differences based on their personal experience, despite evidence that physicians' ability to estimate survival is inaccurate.5,6 Others have constructed complex prognostic models to estimate the median survival of patients with terminal illness; however, such models cannot be used to estimate the benefit of receiving additional chemotherapy relative to receiving best supportive care alone.7-10 We hypothesized that there is a relationship between tumor response rate and median prolongation of median survival in patients with incurable malignancies. If such a relationship were predictable (eg, a 50% response rate correlates with an average 6-month prolongation in survival and/or an increase in 1-year survival rates of 10% over BSC), it may allow oncologists to provide patients with a more objective estimate of how long a particular treatment with a known response rate may, on average, prolong life.
We identified randomized, controlled clinical trials using cytotoxic chemotherapy versus BSC for a variety of malignant conditions and extracted information about response rates, stable disease rates, 1-year survivals, 2-year survivals, and median survivals in those patients randomly assigned to receive chemotherapy compared with those randomly assigned to receive BSC, with or without a placebo. Trials were identified in two ways. First, a PUBMED search was performed using the key words chemotherapy, placebo, cancer, BSC, lung cancer, breast cancer, head and neck cancer, glioblastoma, gastric cancer, esophageal cancer, colon cancer, hepatic cancer, ovarian cancer, endometrial cancer, vaginal cancer, prostate cancer, melanoma, and cancer of unknown primary site. All searches were limited to English language and clinical trials. Second, experts in breast, thoracic, gastrointestinal, genitourinary, and prostate cancer were asked to identify trials of chemotherapy versus placebo or BSC in their field of expertise. Reference lists of the studies used were reviewed to identify other trials meeting the inclusion criteria that were not identified by other methods. Studies that did not report on response rate or median survival were excluded. Twenty-five trials meeting the study criteria were identified, including 16 trials of lung cancer, seven trials of gastrointestinal malignancies (three gastric, three colon/colorectal, and one hepatocellular), and one trial each for renal cell and prostate cancer. Fourteen of these trials also reported on patients with stable disease, including nine lung, four gastrointestinal malignancies (two gastric, one colon/colorectal, and one hepatocellular), and one renal cell. Three trials (all in patients with lung cancer) had two active treatment arms. For these trials, a data point for response rate and survival relative to the BSC arm was generated for each chemotherapy arm of the trial, and hence these trials each yielded two data points. Where presented, weighted averages for response rate, median survival, 1-year survival, and 2-year survival of each tumor type were calculated by weighting the data point of each trial relative to the total number of patients for all trials of that tumor type. Of the trials identified, 21 (84%) were published during or after 1990. Three trials (12%) were published in the 1980s, and one trial (4%) was published in the 1970s. The definition of BSC has evolved dramatically over this period. Although the definition of BSC varied across trials, it was the same for both arms within each trial. Other characteristics (eg, eligibility criteria, chemotherapy agents used, and so on) varied widely across trials. Prolongation of survival was measured in both absolute terms (survival of treated patients in weeks minus survival of placebo/BSC patients in weeks) as well as relative to placebo/BSC (survival of the treatment arm divided by survival of the placebo/BSC). Sufficient data were available to perform statistical analysis and modeling for trials of non–small-cell lung cancer (NSCLC). For these trials, regression techniques were used to determine whether a correlation existed between response rates and median durations of survival prolongation.
General Overview Summary statistics are listed in Table 1 for each of the NSCLC studies and in Table 2 for tumor types other than NSCLC. When all studies are considered together, the sample sizes ranged from 36 to 351 patients, with a mean sample size of 146 patients (standard deviation [SD] of 86). A total of 3,650 patients were enrolled in these 25 trials, and more than 80% (21 of 25) of the trials reviewed enrolled more than 50 patients. Response rates in the treatment arms ranged from 0% to 50%. Median survival in placebo/BSC patients ranged from 53 to 487 days. Median survival in chemotherapy-treated patients ranged from 102 to 381 days. Relative median survival for treatment arms ranged from 0.78 to 3.97 times the median survival of the placebo/BSC arm. Twenty-two trials reported 1-year survival data and 11 trials reported 2-year survival data. Tables 1 and 2 present the average response rates, median survivals, 1-year survivals, and 2-year survivals for lung cancer trials, gastric cancer trials, colorectal cancer trials, and trials of other tumor types, with each summary statistic weighted for the number of patients in each trial.
Lung Cancer Regimens Mean survival prolongation based on response rate. The majority of studies identified by our literature search were in patients with NSCLC. Sample sizes in trials of NSCLC ranged from 39 to 351 patients, with a mean sample size of 175 patients (SD of 88). More than 90% (15 of 16) of the reviewed NSCLC trials enrolled more than 50 patients. A total of 2,794 patients with NSCLC are included in the analysis. Response rates in the treatment arms for lung cancer ranged from 7% to 42%. Median survival in placebo/BSC patients with NSCLC ranged from 60 to 189 days. Median survival in chemotherapy-treated patients with NSCLC ranged from 105 to 350 days. Relative median survival for treatment arms ranged from 0.97 to 3.59 times the median survival of the placebo/BSC arm. No study of patients with lung cancer gave an absolute median survival benefit of more than 6 months for treatment over placebo/BSC.
A relationship between response rate to chemotherapy and survival in patients with NSCLC was observed, with higher response rates correlating with a longer median survival compared with placebo/BSC. A scatter plot of response rate and survival relative to placebo/BSC for NSCLC studies is presented in Figure 1. The correlation between response rate and absolute survival increase in weeks was 0.47, and the amount of variance in survival accounted for by tumor response was 24%. These results suggest that the following formula can be used to approximate how a given response rate is likely to affect median survival in patients with NSCLC:
1-year survival chance based on response rate. Fifteen trials with a total of 2,677 patients with NSCLC reported 1-year survival data. Two of these trials had two active treatment arms, bringing the total number of trials reporting 1-year survival to 17. Ten (59%) of 17 studies that reported 1-year survival data found at least a 10% increase in 1-year survival for treated patients relative to patients on placebo/BSC. Response rates for the trials reporting at least a 10% 1-year survival advantage ranged from 7% to 42%, with a mean response rate of 24% (SD of 12%). Response rates for the trials that did not report at least a 10% increase in 1-year survival ranged from 11% to 32%, with a mean response rate of 20.0% (SD of 8%).
We next evaluated how trials reporting a response rate
The correlation between response rate and 1-year survival rate increase was 0.45, and the amount of variance in survival accounted for by tumor response was 30%. These results suggest that the following formula can be used to approximate how a given response rate is likely to affect 1-year survival in patients with NSCLC:
2-year survival chance based on response rate. Eight trials with a total of 1,687 patients with NSCLC reported 2-year survival data. One of these trials had two active treatment arms, bringing the total number of trials reporting 2-year survival to nine. Two (22%) of nine studies that reported 2-year survival data found at least a 10% increase in 2-year survival for treated patients relative to patients on placebo/BSC. Response rates for the two trials reporting at least a 10% 2-year survival advantage were 13% and 16%, with a mean response rate of 14.5% (SD of 2.1%). Counterintuitively, response rates for trials that did not report at least a 10% increase in 2-year survival were higher, ranging from 8% to 42%, with a mean response rate of 25% (SD of 13%). Evaluation of 20% threshold as criteria for meaningful response. If we take a cutoff of a 20% tumor response rate as a successful regimen, the relative survival benefit for trials achieving this benchmark is 1.8 (odds ratio) or an average of an additional 2.8 months of life for patients receiving the treatment. For agents that failed to achieve a 20% response rate, the relative survival benefit was only 1.3 (odds ratio) or an additional 1.3 months of life for patients receiving treatment. Other models. We explored other statistical models and found similar results. Modeling the square root of survival as a function of response rate resulted in a model with approximately the same explanatory power as the original linear model (R2 of 0.26 v 0.24 for the original model). The exponential model had a significant fit but was not as good as the original linear model (R2 of 0.23). Polynomial models (quadratic and so on) did not fit the data well. Regardless of the model we applied, the relationship between response rate and survival was present.
Non–Lung Cancer Studies
The data from this review support our prestudy hypothesis and suggest that there is a relationship between response rate and survival for NSCLC. Although the strength of this relationship seems relatively modest, this information may help physicians approximate how an observed response rate from a phase II or III trial may, on average, impact survival probabilities for their NSCLC patients over supportive care alone. Amid the vagaries of the above statistics, several simple principles may be clinically relevant. Oncologists have classically considered regimens with response rates of greater than 20% as useful in treating malignancy. Our results support this benchmark. Seventy percent (seven of 10) of NSCLC trials and 80% (12 of 15) of all trials that reported a response rate of at least 20% found a 1-year survival advantage greater than 10%. In contrast, only 43% of NSCLC and 33% of all trials with regimens with a response rate less than 20% achieved this benchmark. The mean increase in 1-year survival over placebo/BSC for NSCLC trials with at least a 20% response rate was approximately 16%, suggesting that, on average, one additional patient will be alive 1 year later for every six patients treated. These are numbers most patients can understand and are more clinically relevant to treatment decisions than the likelihood of whether a tumor will shrink. The above analysis also provides some insight into the incremental benefit of response on median survival for NSCLC. Roughly, each 3.3% increase in response rate translates into 1 additional week of survival. Using the formulas generated by our analysis [(Increase in Survival in Weeks = (Response rate + 9.6)/3.3; Increase in 1-Year Survival = (Response Rate+2.5)/2)], a regimen with a 25% response rate may, on average, be expected to increase survival approximately 10 weeks and 1-year survival by approximately 14%. Again, although these are very crude estimates and must be interpreted with caution, they may provide oncologists and patients with a better understanding of how a treatment with a given response rate may impact survival (Table 3). In the absence of definitive data, this may allow patients to make a better informed decision about treatment.
Certainly, caution must be taken when interpreting and applying these data. First, the above analysis was based on a limited number of trials with adequate data for analysis only in NSCLC. The applicability of these data to patients with other types of cancer is unknown. Second, this study only considered trials of cytotoxic chemotherapy, and the relationship found between response rate and survival cannot be extrapolated to trials of hormonal or biologic therapies. Third, response rates observed in phase II studies are often higher than those observed in phase III trials. To illustrate this phenomenon, Table 4 presents response rates in the phase III trials used in our analysis compared with the response rates reported in corresponding phase II trials of the same regimens. On average, using the middle value of the range presented in Table 4 to calculate the difference between phase II and phase III response rates, the response rates in the phase II trials were 11% higher than they were in the randomized phase III trials. Therefore, it could be argued that the use of response rates from phase II trials may need to be discounted before applying the formulas proposed in this article.
Finally, the analysis is likely limited by publication bias. Recent work suggests that up to one of four large, phase III, randomized controlled trials presented at the American Society of Clinical Oncology Annual Meeting are not published within 5 years of presentation and that studies with nonsignificant results are significantly less likely to be published than those with positive results.64 Given that trials with negative result are less likely to be published and hence are not included in our model, our results may imply a stronger relationship between response rate and survival than actually exists. Similarly, publication bias could also influence the degree of benefit per unit of response generated by our analysis. Our analysis cannot, and is not intended to, be used to determine the most effective chemotherapeutic treatment for an individual patient. Only randomized clinical trials can demonstrate the superiority of one chemotherapy regimen over another. Oncologists must continue to select the best regimen for an individual patient based on their comorbid disease, performance status, toxicity from prior treatments, and both renal and hepatic function. Once a given regimen with a known response rate is selected, our analysis may serve as an aid to help oncologists translate how a given response rate may (on average) impact survival relative to supportive care alone. Although the estimates drawn from our analysis are imperfect, they provide evidence to guide oncologist's approximations, which, at present, are almost purely anecdotal and subjective. Hopefully, this information can allow physicians and patients to make better informed decisions. It is important to note that the relationship between response rate and survival found in our analysis was modest. Multiple potential explanations exist why a stronger relationship between response rate and survival was not found. First, stable disease may be important, and the response rate may not completely capture all the potential benefit from treatment. To evaluate this possibility, the above analysis was repeated with trials that reported on patients with stable disease to assess its effect on survival. When patients who experienced either a response or stable disease were analyzed, the relationship with survival was less pronounced (data not presented) and thus do not seem to support this theory. A second possible explanation is that toxicity from treatment may hasten death in some patients and offset the benefits of therapy. The available data do not evaluate this hypothesis directly. An increasing number of studies have reported potential palliative benefits of chemotherapy.11,28,65-69 The goal of treatment in this scenario is relief of symptoms rather than prolongation of survival. In such circumstances, the question for the patient and oncologist is whether or not chemotherapy offers a palliative advantage over BSC. The above analysis was not designed to answer this question, and our findings cannot be applied to this situation. Counseling patients with incurable malignancy about the risks and benefits of additional treatment is one of the most challenging tasks in the practice of oncology.1,2 Despite the limitations, the simple principles presented here may help oncologists more objectively translate outcomes from phase II and III trials and help them answer their patient's question, "Will this treatment prolong my life, and, if so, by how much?"
The authors indicated no potential conflicts of interest.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31–June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20% affected 1-year survival. Seven (70%) of 10 trials in NSCLC reporting a response rate of 
