Table 2.
Endpoints for early phase (I, II) clinical trials in radiation oncology*
| Endpoint | Example | Advantages | Disadvantages |
|---|---|---|---|
| Toxicity | |||
| Toxicity acute | Mucositis (head and neck cancer); diarrhea (prostate cancer) | Requires short follow-up. Often used to determine MTD. | Reversible and may not correlate with chronic toxicity, which may be more clinically important endpoint. |
| Toxicity late | Bowel stricture (abdominal radiation), cognitive decline (brain tumors), fibrosis | Frequently irreversible, clinically important. | Many subjects die prior to developing late toxicity, often considered too late an event to be used to determine MTD. |
| Mechanism | |||
| Target and pathway engagement (surrogate tissue) | Skin biopsy (gefitinib), peripheral blood mononuclear cells (vorinostat), hair (PI3K) | Fairly easily obtainable. May provide biological insight into normal tissue. | May not reflect target inhibition in tumor (43). |
| Target and pathway engagement (tumor tissue) | Immunohistochemistry for pathway activation | May provide biological insight into tumor tissue. | Post treatment biopsy and/or resection rarely possible (rectal cancer an exemption). |
| Clinical efficacy | |||
| Overall survival | — | Potentially assesses safety and efficacy. | Long follow-up may be required. |
| Local-regional control | Lung cancer | Requires smaller sample size. Overcomes crossover problem. | Difficult to define in certain areas (eg, brain). May not correlate with overall survival. Analysis and interpretation may be complicated by competing events (eg, distant failures). Most tumors shrink after RT; therefore difficult to assess added benefit of drug. Introduction of bias, based upon evaluation frequency. |
| Biological activity | |||
| Pathological response | Rectal cancer | Hard endpoint. Translational research can be incorporated. | Post-treatment biopsy and/or resection not possible for most cancers. |
| Progression-free survival | — | An earlier endpoint than overall survival. | Requires validation for each cancer site. Introduction of bias, based upon evaluation frequency. |
| Systemic biomarkers of clinical efficacy | PSA, β-HCG | Allows for rapid assessment of treatment efficacy | Requires formal validation. Sample timing and preparation critical. |
| Novel biological imaging | Post-treatment PET scan | Noninvasive. Rapidly emerging technology. | Problematic to standardize between institutions. Not fully reproducible |
| Miscellaneous | |||
| Systemic biomarkers of clinical toxicity | TGF-β1, IL-6 | Lack clinical meaning | Requires formal validation. Sample timing and preparation critical. |
| Circulating tumor cells | — | Fairly easily obtainable | A developing technology. Reflects disease within and outside of RT field. |
| Quality of life measure and neurocognitive testing | — | Reflect patient experienced symptoms. | Requires validation. Compliance poor in sicker patients. |
* Some information extracted from LoRusso et al. (102). HCG = human chorionic gonadotropin;. IL-6 = interleukin 6; MTD = maximum tolerated dose; PET = positron emission tomography; PI3K = phosphoinositide 3 kinase inhibitor, PSA = prostate-specific antigen; RT = radiation therapy; TGF-β1 = transforming growth factor beta 1.