In terms of moderate and severe adverse effects, as expected with these combinations of radiation and chemotherapy, one can expect to see leukopenia, thrombocytopenia and other hematologic toxicities, but if you can look through this, you will see that in the patient’s with the complex regimen here, consisting of the three drugs, incidence of leukopenia was clearly higher, also thrombocytopenia as opposed to patient’s who got the weekly cisplatin together with radiation therapy.

In will conclude here by pointing out that we seem to have been able with combining chemotherapy and radiation therapy to demonstrate that there is somewhat of a survival benefit when both treatments are given simultaneously, that means not one before or after the other. In truth, however, the magnitude of the benefit remains somewhat in doubt because in some of the studies that the gynecological college group has done, the radiation therapy time is not considered to be optimal because of it being more than eight weeks, and in some cases the total dose which was given would be considered at the present time to be less than what we want to give in some of these larger tumors. So which drugs or which regimens do we want to use remains to be determined, although a the present time, weekly cisplatin seems to have a therapeutic ratio that is advantageous compared to the other ones.

I want to summarize some important facts to keep in mind. Obviously, when one delivers radiation therapy, the radiation field needs to encompass the tumor at least, portals need to be designed with the best information available to encompass the tumor. The dose needs to be appropriate for the amount of cancer one wants to eradicate. High energy equipment needs to be used which is not a problem in this day and age in most instances, the combination of external beam therapy needs to be used together with brachy therapy and then the length of treatment needs to be sufficiently short so that no in adverse effects can be seen as a result of that. This is a typical radiation portal when measured on the patient would be 15 x 15 cm. For smaller tumors, one can put the upper limit of this radiation field here at L5-S1, for larger tumors, L4-5 and even higher up for extended radiation fields. This can be extended upwards to T12, L1 to include paraortic nodes. Similar attention has to be paid to the design of the lateral ports.

It’s important, and that has been realized in recent years, to keep all this radiation treatment within a certain amount of time because when the treatment time is longer than what it should be, for instance in this lower curve where treatment exceeds nine weeks, one can see a decrease in survival as a result of prolonged treatment time. So who are the patient’s who fail with cervical carcinoma, what are the patterns of failure. I basically already explained to a certain extent. In patient’s who have disease that is not bulky and confined to the cervix, a lot of the relapses have a component of distant metastatic disease, 85% of them. So if we want to expect further improvements in the treatment of those patient’s, that will have to wait until we can define effective systemic therapy because systemic disease is the problem. In patient’s with bulky pelvic disease, we see that pelvic failures are an important component of the failure rate. So by improving pelvic control of the disease, one may be able to improve survival. The reality is, at the same time, still 60% of the relapses in patient’s with advanced cervical cancers are going to include distant component, so when I say that better pelvic control may improve survival, at the same time, this statement indicates that the expected rate of improvement or magnitude of improvement is going to be modest.

The gynecologic oncology group looked at a fairly large group of patient’s with carcinoma of the cervix that was stage IIB, III, stage IVA, these patient’s were surgically staged and shown to have negative paraortic nodes. By the way, surgical staging of carcinoma of the cervix is clearly more accurate than clinical staging but has no place in common clinical practice. It has not been shown to lead to improved outcomes, and therefore, is not recommended outside clinical trial such as this. Patient’s were randomized between the following regimens; regimen one, radiation to the pelvis and brachy therapy and concurrent cisplatin given weekly; regimen two, radiation and brachy therapy with cisplatin 5FU and hydroxyurea and regimen three, radiation therapy and hydroxyurea which is given orally. These are the outcomes in terms of progression free survival, progression free survival in the patient’s who are treated with cisplatin together with radiation or with cisplatin and 5FU and hydroxyurea was significantly better than progression free survival in patient’s who got radiation therapy and hydroxyurea only. The same is true for survival where patient’s who got the cisplatin based regimen which are the two overlapping top curves here did significantly better overall as opposed to the patient’s who were treated with radiation therapy and hydroxyurea