A computer-implemented method of determining a radiation treatment plan for delivering radiation to a patient using an external-beam radiation treatment system, the method comprising: receiving, via a user interface of a computer system, a first clinical goal and a second clinical goal, wherein the first clinical goal includes a first acceptable threshold value and a first desired threshold value for a first quality index relating to a first statistical quantity of a dose distribution, and the second clinical goal includes a second acceptable threshold value and a second desired threshold value for a second quality index relating to a second statistical quantity of the dose distribution; receiving, by the computer system, a first clinically significant change and a first clinically insignificant change for the first quality index specified by a user, and a second clinically significant change and a second clinically insignificant change for the second quality index specified by the user; obtaining, by the computer system, a cost function including a first term, a second term, and a third term, wherein the first term is proportional to a value of the first quality index in excess of the first acceptable threshold value and proportional to a value of the second quality index in excess of the second acceptable threshold value, the second term relates to the first clinically insignificant change for the first quality index and to the second clinically significant change for the second quality index, and the third term relates to the first clinically significant change for the first quality index and to the second clinically insignificant change for the second quality index; and performing, by the computer system, optimization using the cost function to obtain an optimal radiation treatment plan having an optimal value for the cost function; wherein the first clinically insignificant change is a difference between the first acceptable threshold value and the first desired threshold value, and the second clinically insignificant change is a difference between the second acceptable threshold value and the second desired threshold value, and wherein the first clinically significant change is greater than the first clinically insignificant change, and the second clinically significant change is greater than the second clinically insignificant change. receiving, via a user interface of a computer system, a first clinical goal and a second clinical goal, wherein the first clinical goal includes a first acceptable threshold value and a first desired threshold value for a first quality index relating to a first statistical quantity of a dose distribution, and the second clinical goal includes a second acceptable threshold value and a second desired threshold value for a second quality index relating to a second statistical quantity of the dose distribution; receiving, by the computer system, a first clinically significant change and a first clinically insignificant change for the first quality index specified by a user, and a second clinically significant change and a second clinically insignificant change for the second quality index specified by the user; obtaining, by the computer system, a cost function including a first term, a second term, and a third term, wherein the first term is proportional to a value of the first quality index in excess of the first acceptable threshold value and proportional to a value of the second quality index in excess of the second acceptable threshold value, the second term relates to the first clinically insignificant change for the first quality index and to the second clinically significant change for the second quality index, and the third term relates to the first clinically significant change for the first quality index and to the second clinically insignificant change for the second quality index; and performing, by the computer system, optimization using the cost function to obtain an optimal radiation treatment plan having an optimal value for the cost function; wherein the first clinically insignificant change is a difference between the first acceptable threshold value and the first desired threshold value, and the second clinically insignificant change is a difference between the second acceptable threshold value and the second desired threshold value, and wherein the first clinically significant change is greater than the first clinically insignificant change, and the second clinically significant change is greater than the second clinically insignificant change.