Firm recommendations on the management of fallopian tube carcinomas are difficult because of the lack of extensive clinical studies. Using the best evidence available, there are four basic groups of patients.

Intramucosal Lesions Only

For patients with intramucosal lesions only, cure is excellent with surgical resection. Patients should undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed closely with no further therapy.

Mucosal Wall Invasion

For patients with mucosal wall invasion, the recurrence rate approximates 50 percent. These patients are candidates for adjuvant therapy, but there are no data to support the use of such treatment. If adjuvant therapy is to be used, choices similar to those for high-risk ovarian carcinoma seem reasonable. If radiation therapy is to be used, it would seem appropriate to treat the entire abdominal cavity. A preferable approach would be the use of platinum-based chemotherapy on the assumption that this disease responds similarly to celomic epithelial carcinoma.

Penetration of the Serosa

For patients with penetration of the serosa but no gross spread, recurrence rate exceeds 75 percent. An even stronger case for the use of adjuvant therapy can be made. The choices are similar to those noted above.

For patients with obvious spread of disease to locoregional and distant sites, platinum-based chemotherapy is a reasonable choice. The overall strategy should be similar to that used for patients with advanced or recurrent celomic epithelial carcinoma of the ovary.

The fallopian tube is the least common site of origin in the female genital tract for cancer. The most common histologic type of cancer, accounting for 90 percent of all malignancies of the tube, is papillary serous adenocarcinoma, but even this type is rare, with only 300 cases reported annually in the United States. The pattern of spread is similar to that seen with celomic epithelial lesions of the ovary, with dissemination throughout the peritoneal cavity perhaps the most important route of spread; hence, it is often difficult to distinguish between ovarian and fallopian tube primary tumors. Criteria have been set for lesions designated to be of fallopian tube origin: the main tumor arises from the endosalpinx and is in the tube, the histologic pattern shows a papillary pattern, a transition zone between benign and malignant epithelium must be demonstrable if the wall is involved, and the ovaries and endometrium must be either normal or less involved than the tube.

As a reflection of the propensity of tubal cancer to spread by intraperitoneal dissemination, 5-year survival rates correlate well with the degree to which the primary lesion penetrates the wall of the tube: 91 percent for intramucosal lesions, 53 percent for those with mucosal wall invasion, and 25 percent or less for lesions that penetrate the tubal serosa. The actual staging system employed, however, is a modification of the FIGO staging system for ovarian cancer.

In contradistinction to ovarian cancer, fallopian tube cancers tend to present at an earlier stage of development, with roughly 33 percent as stage I, 33 percent as stage II, and 33 percent as more advanced disease. The mainstay of therapy for patients with limited disease is surgical resection. Whether postoperative radiation therapy is of value as an adjuvant treatment in patients whose tumors have been completely resected is unclear in the absence of a randomized trial. If radiation therapy does have a role, it would seem to be in patients who have no gross disease.

Studies of chemotherapy in fallopian tube carcinoma are anecdotal. Agents noted to produce responses are the same noted to be active in celomic epithelial carcinoma of the ovary. It would seem reasonable to base the choice of systemic therapy in advanced or recurrent disease on extrapolation from data in ovarian carcinoma.

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

There was indeed a significant advantage to the chemotherapy and radiation therapy arm in that progression free survival was significantly longer and overall survival 88% versus 77% were significantly better in the patient’s treated with concurrent radiation and chemotherapy.

I want to go on and talk a little bit about a difficult treatment category where the exact treatment remains to be determined. This graph shows you how with increasing tumor size, whether or not lymph nodes are present that are positive, like in the upper curve or negative, one can see that the recurrence rate constantly goes up either with positive pelvic lymph nodes, negative pelvic lymph nodes and function of the size of the tumor. This is in patient’s who had radical hysterectomy and pelvic lymphadenectomy for treatment. The same is true for patient’s with stage IB carcinoma of the cervix who have been treated with radiation therapy. Here, you can see the pelvic failure rate, the distant failure rate, the disease free survival and the overall survival and function of tumor size, and with increasing tumor size, you will see an increase in pelvic failure rates and increase in the distant failure rate, the decrease and disease free survival as well as the overall survival. So, tumor size adversely affects prognosis and outcome.

If you keep in mind what a typical dose distribution is of an intracavitary implant that is used for the treatment of carcinoma of the cervix, it has this pear shaped distribution, the white here represents the tumor, this would be a barrel-shaped lesion of the cervix, a bulky lesion of the cervix, you can see here that a substantial amount of the tumor will actually be outside this radiation field which may contribute to local failure. Not surprisingly a variety of treatment approaches have been suggested for this suboptimal treatment situation of bulky or barrel-shaped tumors of the cervix, surgery, radiation therapy, radiation followed by an extra fascial or simple hysterectomy, radical hysterectomy and radiation therapy, adjuvant chemotherapy then followed by surgery or chemotherapy followed by radiation, radiation and chemotherapy at the same time, hypofractionation, that means the different varieties of radiation therapy. None of those have really consistently been shown to be breakthroughs or advantages in treatment, and again, the gynecologic oncology group reported recently on their experience and their treatment of patient’s with bulky, defined as more than 4 cm carcinoma of the cervix. Again, 368 patient’s were entered in a study and they were randomized as follows: Regimen one was radiation therapy to the pelvis and brachy therapy in the conventional way, and at the same time, cisplatin 40 mg per meter square weekly for six courses. The patient’s then went on to have an extra fascial hysterectomy which was at the time of the inception of this study still believed to be a potentially helpful maneuver. Regimen two, radiation therapy to the pelvis, brachy therapy and extra fascial hysterectomy.

This study shows a clear survival advantage. This is overall survival in the patient’s in the upper curve here, who got radiation therapy with concomitant chemotherapy at the same time, this is approximately a 30 to 45% improvement in survival here as opposed to patient’s who got radiation therapy with extra fascial hysterectomy, no concurrent chemotherapy. In the more advanced stages of cervical carcinoma, the treatment of choice is clearly radiation therapy and radiation therapy when we talk about it as a reminder, consists of internal beam radiation therapy and brachy therapy.

Let’s move on to the larger carcinomas of the cervix, stage IB and stage IIA. Here we have basically two treatment options; the treatment of choice in cervical cancer as a disease as a whole as you know, is radiation therapy. In these particular stages, there may be a choice in selective cases between radical hysterectomy and bilateral pelvic lymphadenectomy, this can be done vaginally or abdominally, and radiation therapy with external radiation of the whole pelvis and brachy therapy. The bottom line is simple, they are comparable local control and survival rates with both modalities. So how does one choose? Well it’s basically based, and I try to sympathize it here on a number of points such as institutional preference, physician preference and training, tumor characteristics and here, the size of the tumor appears to be an important determinant, what is the growth pattern, is it an exophytically growing tumor, is it an endophytic growing tumor which involves the endocervical canal predominantly, what is the general condition and the age of the patient, is the patient a surgical candidate, what is our concern about possibly preserving ovarian function which is also of concern in young women which is often proposed to be better with surgery than with radiation therapy. And then basically we know that there are different patterns of adverse effects with radiation therapy or radical hysterectomy. With hysterectomy, the side effects tend to be either immediate, or to occur in the short term, and surgically related. Fistula rates are lower, between 1 and 2%, urinary tract fistulas are more common with radical surgery as opposed to with radiation therapy where the intestinal fistulas tend to be more common. ‘

With radiation therapy, adverse effects can occur within six months, from six months to a year or after a year, in which case they are called late adverse effects which are of concern in young patients and include intestinal dysfunction which can be protracted fistulas. In patient’s who undergo a radical hysterectomy, we have learned there are a number of factors that can be found that will affect prognosis, and they are, the presence of positive pelvic lymph nodes, positive margins, parametrial extension of the tumor, deep stromal invasion, large tumor volume, lymphovascular space invasion is less consistently shown to be an adverse prognostic factor. This is just a compilation of a number of studies where patient’s who had a radical hysterectomy were treated with adjuvant radiation through the whole pelvis because of the presence of one of these poor prognostic factors, and you can see there is a range here of patient’s between 9% all the way up to 38%, 35% of patient’s who had a radical hysterectomy and then went on to have pelvic radiation therapy.

The problem here is that you can see there is also a significant rate of complications, and I should point out that those are severe complications, those are not just minor complications occurring anywhere from 3 to 30% in those patient’s. The message I want to share with you here is that if at all possible, we would prefer to stay out of this kind of situation where patient’s are subjected to two radical treatment modalities; one is surgery, another radiation therapy, which means that I would be an advocate of trying to do either one but not both, so selection of the patient’s will be important. It has traditionally not been shown beyond any doubt that adding radiation therapy after radical hysterectomy when lymph nodes were involved really added to survival. Last year, a study was reported where 243 patient’s were accrued, they had radical hysterectomy and pelvic lymphadenectomy for stage IAII, IB and IIA carcinoma of the cervix, they have negative paraortic nodes and they were randomized between two treatment regimens; regimen one was radiation to the pelvis with concurrent cisplatin and IV 5FU given every three weeks for intended course of four cycles, and regiment two was radiation therapy to the pelvis alone.