¹ Percentage of patients whose tumors shrank by at least 30% in volume
² Length of time before half of patients had tumor progression (tumors grew at least 20% in volume or new tumors appeared)
³ Percentage of patients whose tumors did not progress over the specified time period
⁴ Whether the clinical trial included only patients with progressive disease (growing or new tumors)
* Abstract (not article)

In reviewing the history of Phase II clinical trials in ACC, it is important to take note of some key factors:

• Progression Requirements – Did the clinical trial require ACC patients to have documented progression prior to starting therapy? ACC patients with metastases may have long periods of stable disease, making it difficult to determine whether stable disease in a study was the natural course of the disease or the result of the drug. Clinical trials that require progression prior to entry give a better indication of the drug’s effectiveness. Whether disease progression was an inclusion criterion for each study is indicated in the second column from the right in the table above.
• Clinical Benefit Greater than 6 Months – Did the patient have an objective response (tumor shrinkage of at least 30%) or stable disease, either of which lasted longer than 6 months? Sometimes patients have rapid tumor shrinkage that qualifies as an objective response, but then there is a rapid reversal and progression. Or a slow-growing ACC tumor, unaffected by the drug, may take 3 months to reach 20% growth; the patient will be classified as having stable disease despite the drug’s lack of efficacy. By using a longer horizon, this metric attempts to measure meaningful patient benefit. “Progression Free Duration”, the third column from the right in the table above, indicates what portion of treated patients did not have disease progression over various time periods.
• Patient Selection – The types of patients included in a trial may impact the efficacy and toxicity of a treatment. For example, ACC patients with NOTCH-activated tumors may have more aggressive disease, leading to lower response rates and/or progression free survival than other ACC patients. Similarly, patients with later-stage disease may respond less impressively than those with earlier-stage disease, and this may reflect geographic differences in when patients enroll in clinical trials.

Patients should keep in mind that objective responses and stable disease are measures of tumor volume, not overall survival. It is reasonable to assume that smaller tumors mean a longer lifespan, but it is not always the case. Once a treatment stops being effective, tumors may grow back more quickly.

Patients must weigh the potential side effects of any treatment against the possibility of extended survival and reduced pain from tumor shrinkage. More fragile patients may be able to tolerate only drugs with moderate side effects (Vorinostat), while more robust patients may be willing to tolerate drugs with significant side effects (Everolimus, Sorafenib, Regorafenib and Sunitinib). Progressing ACC patients should discuss these issues with their physicians.

Patients enrolling in clinical trials perform an incredibly honorable service for the entire patient community. Without them, it would not be possible to determine systematically whether a particular treatment is effective or safe. Even clinical trials that show that a drug is ineffective are valuable as future patients are spared the unnecessary side effects and may try more promising drugs. Some physicians prescribe approved cancer drugs “off-label” (i.e., approved for tumor types different from the treated tumor) to their patients who cannot travel to or do not qualify for a clinical trial. Unfortunately, those results are not tabulated and shared with others as is the case with clinical trials. Without a doubt, current ACC patients owe a debt of gratitude to those who have helped guide our current understanding of how ACC responds to systemic therapies.