Responses, Survival & Placebo: Defining an Effective Cancer Therapy

January 1, 2018

There are over 2,000 cancer therapies in clinical trials.¹ Some are better than others, but how is that determined? How are the results of these trials weighed and scored? How is one treatment deemed to be superior to another? In this article we examine how oncologists assess their therapies so that patients can make more informed treatment decisions with their doctor.

Cancer therapies are described as “active” when “evaluable” patients “respond.” Understanding what these terms mean and how they relate to survival is important.

Active – A treatment or drug that is described as “active” means that in animal models, cell cultures or patients the treatment kills cancer cells, shrinks tumors, or decreases biochemical tumor markers such as CEA or PSA scores. But, temporarily shrinking a tumor may not be the same as extending survival.

Response – Similar to the term “active,” a response means that patients had their cancers shrink or disappear. The overwhelming majority of clinical cancer trials use response as an endpoint. Typically, there are four measures of response. The definitions can vary, but generally they are:

Complete Response – all signs of the cancer and disease related symptoms disappear (this may include improvements in tumor markers).
Partial Response – 50% or more decrease in all measurable lesions (i.e. tumors) and no new lesions.
Progressive Disease – an increase of 25% or more in the current lesions, reappearance of a lesion that had previously disappeared, or the appearance of a new lesion.
Stable Disease – does not meet criteria for complete response, partial response or progressive disease.

There are two major limitations to using “response” as an outcome measure. First, response is really not a surrogate for survival. A complete response does not equate with survival. For example, in this study involving children with medulloblastoma (a type of brain cancer) six children “responded” to the chemotherapy and all six children died. “Six of six evaluable patients responded to chemotherapy… All six patients have subsequently died…” ²

The second limitation is that measuring a response is inherently subjective. For example, in one study an “institutional review” documented a 33% response rate. However, when the same patients were seen by the “central review” the response rate dropped to 18%. “Of 79 patients with evaluable post-operative residual tumor on CT or MRI scans 26 (33%) were determined on institutional evaluation to have had an objective response. However, central review of scans documented responses on only 14 (18%)…”³

Evaluable – How the math is performed is critical to how results are measured. Some studies exclude from their results the patients that died before the treatment protocol was completed. This can obviously inflate the response and survival rates. For example, “Twenty-two consecutive patients with recurrent malignant brain tumors after radiation therapy and systemic combination chemotherapy with BCNU and vincristine, four of whom were not evaluable due to early death, were treated with etoposide…” ⁴

Survival – Given the fact that response rates and survival rates are not equivalent, survival becomes a more meaningful outcome measure for patients. The advantage to survival rates is that it is a more objective measure. However, survival rates are not perfect. They are probabilities based on different sets of assumptions and follow-up times. (Usually they are Kaplan-Meier survival curves based on median figures).

Treatment versus Placebo – Most studies compare one treatment with another, not a treatment versus no treatment. Placebo controlled studies are infrequently performed because many clinicians consider it unethical to administer a cancer patient a “sugar pill.” This is a valid point, but occasionally a few placebo controlled studies are performed (usually not in the U.S.). Interestingly, a significant percentage of these studies find that the placebo is as effective as or more effective than the treatment. For example, in a study of high-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma, the three month survival rate was higher for the patients who received placebo.⁵ In another study comparing 5-fluorouracil (5-FU) plus leucovorin to placebo for metastatic colorectal carcinoma, the authors concluded that the drugs did not improve survival.⁶ In a study that compared two combination regimens versus minimal chemotherapy in non-small-cell lung cancer, the authors concluded that “treatment was not a significant factor for survival.”⁷ And in a survival analysis of Tuscan residents in Italy diagnosed with malignant pleural mesothelioma the researchers concluded that “there was no significant difference in survival between treated versus untreated patients.”⁸

Obviously, these few studies do not mean that all cancer therapies are ineffective, but they do remind us to ask our doctors questions such as:

For the treatment you are recommending is its efficacy (effectiveness) based on improved response rates or survival rates?
What was the median survival rate?
Were the results based on all patients who were enrolled or only a subset of the patients considered evaluable?
Has there ever been a placebo-controlled study that demonstrated that treatment is superior in extending survival for my type of cancer?

Answers to questions like these can only assist a cancer patient to make more informed treatment decisions with their doctor because the better the information, the better the decision.

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¹According to the National Cancer Institute Clinical Trials Search Results, there are 2,286 clinical trials if one searches for all types of cancer and all types of trials on October 13, 2005.
²Lefkowitz IB, et al., Results of treatment of children with recurrent medulloblastoma/ primitive neuroectodermal tumors with lomustine, cisplatin, and vincristine. Cancer 1990 Feb 1; 65(3): 412-7.
³Finlay JL, et al., Pre-irradiation chemotherapy in children with high-grade astrocytoma: tumor response to two cycles of the “8-drugs-in-1-day” regimen. A Childrens Cancer Group study, CCG-945. J Neurooncol 1994; 21(3):255-65.
⁴Tirelli U, et al., Etoposide (VP-16-213) in malignant brain tumors: a phase II study. J Clin Oncol 1984 May; 2(5): 432-7.
⁵Chow PK, et al., High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology. 2002 Nov;36(5):1221-6.
⁶Madden M, et al., Double-blind randomised trial comparing 5-fluorouracil plus leucovorin to placebo for metastatic colorectal carcinoma. Colorectal Dis. 2005 Sep;7(5):507-12. This study reported, “The median survival time in the chemotherapy group was 8.7 months (95% confidence interval (CI) 6.9-11.0 months) compared to 6.7 months in the placebo group (95% CI 5.3-7.9 months). Chemotherapy did not affect performance status but slowed the rise of CEA and caused appreciable toxicity. CONCLUSIONS: In this double-blind trial, chemotherapy with 5-fluorouracil plus leucovorin did not improve survival, did not impair performance, but caused appreciable toxicity.
⁷Luedke DW, et al., Randomized comparison of two combination regimens versus minimal chemotherapy in nonsmall-cell lung cancer: a Southeastern Cancer Study Group Trial. J Clin Oncol. 1990 May;8(5):886-91.
⁸Gorini G, et al., Survival of malignant pleural mesothelioma cases in the Tuscan Mesothelioma Register, 1988-2000: a population-based study. Eur J Cancer Prev. 2005 Jun;14(3):195-9.

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