Browse Author: David B.

At that same meeting at ASCO

At that same meeting at ASCO the fly in the ointment was presented. That was GOG protocol 132. This study was done while we were waiting for the data on GOG 111 to mature. This randomized patients with large volume advanced disease to either cisplatin, Taxol or a combination of Taxol plus cisplatin, with the Taxol given as a 24 hour infusion. Again, each regimen was given every three weeks for a total of six cycles.

While we thought we knew what the results of this study would be before we started, and what we found out was that there is no significant different difference in overall survival. The Taxol single agent arm gave a lower response rate and a shorter progression-free survival, but overall survival was exactly the same. You might ask yourself, “Why did this study differ from OV10 and GOG111?” Well the circumstances were quite different. When GOG111 and OV10 were done Taxol was not available for salvage therapy in those countries. In the U.S. for 111 and in Canada and Europe for OV10. So patients who were assigned a Cytoxan/cisplatin did not get salvage Taxol. On the other hand, when this study was done, Taxol was commercially available and in fact what happened was that at the end of six cycles of therapy if patients had any residual disease left, they immediately got salvage therapy.

Patients assigned to the cisplatin arm got Taxol and patients assigned to the Taxol arm got cisplatin.

Patients assigned to the combination arm got a whole hodgepodge of different things, most of which probably did absolutely nothing or even harmed the patient.

So as a result, half the patients got some form of salvage therapy and we believe the crossover to the opposite drug accounts for the blunting of the survival differences that you see in the study. Also this was not merely salvage therapy. This was immediate use of the other drug without waiting for disease progression to take place. So in effect what we were really studying here was sequential cisplatin for six cycles followed by Taxol for 6-12 cycles or Taxol for six cycles followed by cisplatin for six cycles, or concurrent therapy. We proved something here that I think is going to turn out to be very useful for us. We’ve proved that you can give drugs concurrently or sequentially and achieve the same results. That sort of approach is going to be applied in trying to introduce additional active new agents to up front therapy, that is, sequential doublets will probably be used in that experimental approach.

Now the most recent study to be completed was ICON-3, the International Collaborators on Ovarian Neoplasms study number 3. This study was conducted in the United Kingdom and Italy. About 70% of the patients came from the United Kingdom, about 30% from Italy. Patients here were randomized to the experimental arm of Taxol/carboplatin, Taxol given as a three hour infusion followed by carboplatin. Or to one of two control arms. Each institution had to select which control arm the institution would use; either carboplatin alone or a three drug combination of Cytoxan, Adriamycin and cisplatin.

All stages of the disease were allowed onto this study. So this study includes stage I, stage II, stage III and stage IV patients. One-third of the patients in the study on the control arm also received salvage Taxol. So there will be some blunting of any survival differences as you would expect, because of the salvage therapy. Seventy percent of the control patients received single agent carboplatin as a control, 30% received a three drug combination. Now I should tell you that there was an ICON study, ICON-2, that showed no difference between the three drug combination and carboplatin so it’s reasonable to lump the control arms. Now if you attended ASCO and attended the GYN session you know that the ICON investigators presented the following data; in terms of progression-free survival, no difference between the two arms.

In terms of overall survival, no difference between the two arms. What they did not present was presented by Dr. McGuire in his discussion and was obtained from one of the ICON collaborators and that is a more detailed breakdown of the data. And this is a very important subset analysis; 622 of the patients had stage I disease. Only 83 events had occurred in that subset. Too few events to allow any meaningful conclusions to be drawn. But 1,452 of the patients had either stage III or stage IV disease and among those 1,452 there had been 544 events, enough events to allow valid conclusions to be drawn. In this subset, which is the same subset studied in OV10 and a similar subset to GOG111, hazard ratio was 0.82 and that is statistically significant at a P value of 0.03. So in the same population of patients studies in OV10 and GOG111 you see the same result, a benefit from concurrent Taxol, platinum administration. If you put all four of these trials on the same slide you will note that three of the four, GOG111, OV10 and ICON-3, show a clear value for the Taxol/platinum combination. One, GOG132, shows no difference but is accounted for the immediate rather than the salvage use of the opposite drug. The weight of evidence in these four studies speaks to the standard of care as being a combination of Taxol and platinum. And if you are asked that on the Boards, that’s what your answer is.

Prophylactic oophorectomy

With regard to prophylactic oophorectomy; there have been publications in the literature, most notably from Buffalo, suggesting that prophylactic oophorectomy in women with positive family histories was indicated. But if you look at their own data published in 1993 in Cancer, what you find is that after prophylactic oophorectomy – and they had a total of 324 women who underwent prophylactic oophorectomy because of positive family histories – their incidence of primary peritoneal neoplasia at a median follow-up of six years was already 1.8% which exceeds the risk in the general population for ovarian carcinoma, and begins to approach the risk in patients with positive family histories. So it would appear that what we are doing here is removing only a small portion of the tissue at risk. Most of the tissue at risk, that is the coelomic epithelium that lines the peritoneal cavity is left in place. The risk of other problems after oophorectomy will increase. So as of right now the only group for which prophylactic oophorectomy is recommended for serious consideration is in those who have hereditary syndromes. And the recommendation was to consider that beginning at age 35 and later. And that came from the Ovarian Cancer Consensus Conference held in August 1994 at the National Cancer Institute. But that was based, as the conference report said, on no data, merely speculation that this would work. So as of right now there is really no truly scientifically defined role for prophylactic oophorectomy. There is a consensus role for those with hereditary syndromes.

Screening for ovarian carcinoma; if you read luminary medical journals like Cosmopolitan and Redbook you will find that screening is something you really ought to be doing for your ovarian cancer patient. What those journals recommend is a combination of pelvic examination by the physician once a year, serial CA125’s annually, and annual transvaginal sonography. But the actual figures on the use of these show that, first of all, pelvic examination has no impact. We know that from numerous studies. When you combine transvaginal sonography and CA125 done in a serial fashion, the positive predictive value for finding ovarian carcinoma is 26.8%, which is really quite good. But, most of those cases are going to be stage III at diagnosis. The positive predictive value for stage I and stage II disease is 9.8% and by most standards a value of greater than 10% is required before you can label an approach as a valid screening test. Not only that, but the studies that have been done to date show that for every one laparotomy that you do for ovarian carcinoma, you are going to do somewhere between 14 and 39 for benign causes that did not require exploration. So there really is a downside for screening for ovarian carcinoma. So at least for right now screening is not recommended, there is no scientific basis for using the combination of transvaginal sonography and CA125 to screen for ovarian carcinoma. There is an ongoing randomized trial that we hope will at least in part answer this question.

Pathologically, coelomic epithelial carcinomas of the ovary fit into four broad categories; serous, endometrioid, mucinous and clear cell. You will note that the two most common types are serous and endometrioid and that’s fortunate, because the two poor-risk types are mucinous and clear cell carcinomas. These two tumors have a much poorer prognosis than the serous and the endometrial types. If you look just at patients with stage III and stage IV disease what you find is less than 10% of the patients have either mucinous or clear cell carcinomas. Almost 90% will have either serous or endometrioid tumors. We don’t know what to do differently for the mucinous and clear cell tumors, currently, to hopefully impact greater on their outcome. So right now that histology has very little impact on how you are going to manage the patient clinically, except to know that the patient is at much greater risk for death due to disease if they have a mucinous or clear cell carcinoma. The only part of histology that really makes a difference in our approach to the tumors is if the pathologist identifies a particular ovarian cancer as being a borderline ovarian carcinoma. That is, it appears to be a well-differentiated tumor with no underlying stromal invasion. These tumors have an excellent prognosis, even if you simply observe them, do nothing to treat them other than an attempt at surgical resection. And even those with intraabdominal spread, that is stage III disease, have an 80% survival at five years. In a large study done by the GOG, no stage I ovarian borderline tumor has occurred as yet at ten years of follow-up. So the treatment for borderline tumors is resection if possible, and then no further treatment until the tumor declares itself as a more aggressive tumor. At that point you would introduce systemic therapy.

Clinical staging

CLINICAL AND PATHOLOGIC (SURGICAL) STAGING
A standardized system for the clinical and pathologic staging of pancreatic cancer does not currently exist in the United States. The system modified from the American Joint Committee on Cancer and the TNM Committee of the International Union Against Cancer appears in Table 32.4-4 (Table Not Available) . However, this staging system is rarely used because it is difficult to apply, the stages do not directly correlate with treatment or prognosis, and lymph node status cannot be determined without surgical treatment. Pathologic staging can be applied only to patients who undergo pancreatectomy; in all other patients, only clinical staging, based on radiographic examinations, can be done. Treatment and prognosis are based on whether the tumor is potentially resectable, locally advanced, or metastatic, definitions that do not directly correlate with TNM status. For example, both potentially resectable and locally advanced tumors may be stage T3. Further, because lymph node metastases are often small (2 to 4 mm) and not accurately assessed by preoperative imaging, many patients who undergo complete negative-margin pancreaticoduodenectomy are found to have positive regional lymph nodes on permanent-section pathologic analysis of the resected specimen. Such patients would then be classified as having stage III disease. However, a patient with unresectable, locally advanced disease is usually classified as having stage II (T3, N0) disease because operative (pathologic) staging is not performed.

Tumors of the pancreas are unlike other solid tumors of the gastrointestinal tract in that accurate diagnosis, clinical staging, and pathologic evaluation of resected specimens require extensive interaction and cooperation between physicians of different specialties. Accurate clinical staging requires high-quality computed tomography (CT) to accurately define the relationship of the tumor to the celiac axis and superior mesenteric vessels. The development of objective radiographic criteria for preoperative tumor staging allows physicians to develop detailed treatment plans for their patients, avoid unnecessary laparotomy in patients with locally advanced or metastatic disease, and improve resectability rates.
Similar standardized criteria are needed for the pathologic analysis of pancreaticoduodenectomy specimens to allow accurate interpretation of survival statistics.

 Retrospective pathologic analysis of archival material does not allow accurate assessment of margins of resection or number of lymph nodes retrieved. However, these are the most accurate predictors of outcome. In the recent study by Yeo and colleagues, resection margin, lymph node status, and tumor size and DNA content were the tumor characteristics that most strongly predicted survival by multivariate analysis. To determine which patient subsets may benefit from the most aggressive treatment strategies, accurate pathologic staging and histologic assessment of response are mandatory.

Adjuvant Chemotherapy

Early studies showed a lower risk of relapse when fewer than six nodes were involved and no node was 2 cm; and higher when 6 nodes or more were involved, any node was larger than 2 cm, or extranodal extension was present.
Surveillance is a treatment choice for compliant patients with fewer than six involved nodes and none larger than 2 cm. Surveillance requires close monitoring, and chemotherapy is reserved for patients who relapse. Patient compliance, psychologic factors, age, or other issues may make adjuvant chemotherapy the preferred choice in rare patients. Three or four cycles of cisplatin-based therapy will be required at relapse according to disease status at that time.

Adjuvant chemotherapy remains a strong consideration in patients when six nodes or more are involved, any node is larger than 2 cm, or there is extranodal extension. In the late 1970s, treatment programs based on cisplatin, vinblastine, and bleomycin were given as adjuvant therapy following RPLND, and nearly 100% of patients survived relapse free. Considerable treatment-related morbidity was associated with these regimens, prompting efforts to reduce toxicity. Two cycles of cisplatin-based chemotherapy are nearly always effective in preventing relapse. A randomized trial showed that observation with standard treatment at relapse and two cycles of adjuvant chemotherapy had equivalent survival. Etoposide has replaced vinblastine in adjuvant regimens. A recent study suggests that etoposide plus cisplatin alone is adequate, and that bleomycin is unnecessary as part of adjuvant therapy.

Disorders information

Neuroanatomy

Antegrade ejaculation requires coordination of three separate events: (1) closure of the bladder neck, (2) seminal emission, and (3) ejaculation. The sympathetic fibers that mediate seminal emission emanate primarily from the T12 to L3 thoracolumbar spinal cord. In the midretroperitoneum, after leaving the sympathetic trunk, the fibers converge toward midline and form the hypogastric plexus near the aortic bifurcation. From the hypogastric plexus, sympathetic fibers travel via pelvic nerves to innervate the vas deferens, seminal vesicles, prostate, and bladder neck. Ejaculation is mediated by combined autonomic and somatic innervation originating at the sacral and lumbar spinal cord levels. Sympathetic stimulation tightens the bladder neck, while pudendal somatic innervation from S2 to S4 causes relaxation of the external urethral sphincter and rhythmic contraction of bulbourethral and perineal muscles. Preservation of ejaculatory capacity requires preservation of paravertebral sympathetic ganglia and their fibers that converge at the superior hypogastric plexus around the aortic bifurcation. Sympathetic chains and postganglionic sympathetic fibers can be prospectively identified, meticulously dissected, and preserved.

Nerve-sparing RPLND may be of two types: nerve dissecting or nerve avoiding. With nerve dissection, about 90% of patients will be left with normal ejaculatory status postoperatively. Despite pathologic stage II disease in patients selected for this procedure, recurrences in the retroperitoneum are rare. In addition, spontaneous recovery of ejaculation has been reported following a modified RPLND. Modified, nerve-avoiding RPLND templates were designed to avoid the contralateral sympathetic fibers responsible for ejaculation and were developed for use in clinical stage I or IIA disease. These template dissections do not attempt to identify specific nerve fibers. Instead, their design minimizes trauma to the hypogastric plexus by limiting the contralateral dissection to the level above the takeoff of inferior mesenteric artery. This method avoids transsection of the contralateral nerves and results in preservation of ejaculation rates ranging from 51% to 88%. These rates are higher for a right-sided, nerve-avoiding template dissection compared to modified, left-sided dissection. Preservation of ejaculation appears to be more successful when nerves are prospectively identified and spared, compared to modified template dissection, although duration of operation is usually longer for the former. Regardless of technique, retrograde ejaculation is a potential risk with any RPLND; therefore, preoperative sperm banking is recommended. alpha-Adrenergic drugs such as ephedrine, pseudoephedrine, and imipramine occasionally promote antegrade ejaculation in patients who are anejaculatory following RPLND. The low number of reported such cases suggests substantial case selection, and many patients will probably not respond to alpha-adrenergic stimulation. Transrectal electroejaculation provides an option for patients who fail sympathomimetic agents.

Cancer treatment information

Nonseminomatous Germ Cell Tumors

NONSEMINOMATOUS GERM CELL TUMORS

Nonseminomatous histology comprises about 50% of all GCTs, and most frequently presents in the third decade of life. Most tumors are mixed, consisting of two or more cell types. Seminoma may be a component, but the definition of a pure seminoma excludes the presence of any nonseminomatous cell type. The presence of any nonseminomatous cell type (other than syncytiotrophoblasts) imparts the prognosis and management principles of a nonseminomatous tumor.

Embryonal Carcinoma
Embryonal carcinoma is the most undifferentiated somatic cell type. Individual cells are epithelioid in appearance and may be arranged in glandular or tubular nests and cords or as solid sheets of cells. Tumor necrosis and hemorrhage are frequently observed.

Choriocarcinoma

By definition, choriocarcinoma consists of both cytotrophoblasts and syncytiotrophoblasts. If cytotrophoblasts are not present, then the diagnosis of choriocarcinoma cannot be made. Pure choriocarcinoma is an extremely rare presentation usually associated with widespread hematogenous metastases and high levels of hCG. Hemorrhage into the primary tumor is frequent and is an occasional severe complication when it spontaneously occurs at a metastatic site. Elements of choriocarcinoma are frequently found in mixed tumors but appear to have no prognostic importance. Syncytiotrophoblastic giant cells can be seen as a component of any GCT (including pure seminoma). They impart no prognostic value by themselves.

Yolk Sac Tumor

Yolk sac tumor (endodermal sinus tumor) is often confused with a glandular form of embryonal carcinoma. This tumor mimics the yolk sac of the embryo and produces alpha-fetoprotein (AFP). The cells may have a papillary, glandular, microcystic, or solid appearance; and may be associated with Schiller-Duval bodies, which are perivascular arrangements of epithelial cells with an intervening extracellular space. Rarely, embryoid bodies resembling the early embryo can be seen. Yolk sac histology is rarely present as the only histologic subtype except in the mediastinum where pure yolk sac tumors account for a substantial minority of primary tumors. Pure yolk sac histology is the most common histology found in childhood GCT.

Teratoma
A teratoma is composed of somatic cell types derived from two or more germ layers (ectoderm, mesoderm, or endoderm). Mature teratoma consists of adult-type differentiated elements such as cartilage, glandular epithelium, nerve tissue, or other differentiated cell types. Immature teratoma generally refers to a tumor with partial somatic differentiation, similar to that seen in a fetus. Teratoma with malignant transformation refers to a form of teratoma in which one of its components, either immature or mature, develops aggressive growth and histologically resembles another malignancy. These usually take the form of sarcomas (most frequently embryonal rhabdomyosarcoma); and, less frequently, carcinomas (e.g., enteric-type adenocarcinoma), neuroectodermal tumors, or combinations of these. Acute nonlymphocytic leukemias have arisen in the context of mediastinal GCT, but not from other primary sites. Acute lymphocytic leukemia has been described. Although a mature teratoma may be histologically benign, it is derived from a totipotential, malignant precursor cell (embryonal carcinoma or yolk sac tumor). Therefore, a primary testicular tumor in a postpubertal male that displays only teratoma must be considered to be a fully malignant GCT, and management should proceed as if malignant components are present.

Histology

HISTOLOGY
CARCINOMA IN SITU

Carcinoma in situ (CIS) (intratubular germ cell neoplasia) precedes invasive testicular GCT in virtually all cases of typical and anaplastic seminoma and all nonseminomatous histologies in the adult. CIS is frequently present in retroperitoneal presentations and is rarely, if ever, present in mediastinal presentations. It has not been described in spermatocytic seminoma and rarely in tumors arising in prepubertal patients. Cytologically, CIS preceding seminoma and nonseminoma is identical. The median time for progression of CIS to invasive disease is 5 years. In the general population, the incidence of CIS is very low, while in men with impaired fertility, the incidence is about 0.5%. The incidence of CIS is 2% to 5% in both cryptorchid testes and the contralateral testis in patients with a documented prior testicular GCT.
SEMINOMA

Seminoma accounts for approximately 50% of all GCT and most frequently appears in the fourth decade of life. The typical or classic form consists of sheets of large cells with abundant cytoplasm and round, hyperchromatic nuclei with prominent nucleoli. A lymphocytic infiltrate or granulomatous reaction with giant cells, or both, is frequently present. Trophoblastic giant cells capable of producing human chorionic gonadotropin (hCG) are present in 15% to 20% of tumors. The presence of syncytiotrophoblastic giant cells in an otherwise pure seminoma does not influence prognosis or treatment. Anaplastic seminoma is an older term used when three or more mitotic figures are seen per high-powered field, and it has no clinical or prognostic importance. Stage for stage, anaplastic seminoma is similar in response and prognosis to classic seminoma.

An atypical form of seminoma has been described with unusual immunohistochemical features. While the cells cytologically resemble classic seminoma, lymphocytic infiltrate and granulomatous reaction are absent, necrosis is more common, and the nuclear: cytoplasmic ratio is higher. These tumors must be distinguished morphologically from solid variants of embryonal carcinoma and yolk sac tumor. Atypical seminoma frequently shows cytoplasmic expression of low-molecular-weight keratin or the type 1 precursor to the blood group antigens, while typical seminoma stains negative. Electron microscopic studies have shown that the individual tumor cells acquire cytoplasmic cytokeratin intermediate filaments, suggesting epithelial differentiation. There has been no specific association of atypical seminoma with an adverse prognosis, and its management is currently the same as any other seminoma.

Spermatocytic seminoma is a rare histologic variant seen almost exclusively in men above the age of 45. The relationship of spermatocytic seminoma to other GCTs is not clear, because it is not associated with CIS or bilaterally, does not express placental alkaline phosphatase (PLAP) (see later), and has not been shown to have the same genetic abnormalities as other GCTs. Metastatic potential is minimal.