NWTS 2 Stage I No patients bene \201t from radiotherapy regardless of age. 6 months of VCR and AMD is as good as 15 months. Stages II, III, and IV Addition of doxo to VCR and AMD improves survival. Other \201ndings Stages II and III have the same survival. Local spillage and invasion of the renal vein do not affect outcome. NWTS 3 Stage I 10 weeks therapy with VCR/AMD is as effective as 6 months. Stage II Intensive VCR/AMD is as effective as three drugs. Addition of radiotherapy does not affect survival. Stage III Intensive VCR/AMD is as effective as three drugs. 10 Gy \202ank irradiation is as effecti ve as 20 Gy. Other \201ndings Addition of cyclophosphamide to VCR/AMD/doxo does not improve survival. Key: VCR = vincristine; AMD = actinomycin D; doxo = doxorubicin OHO-22(389-416) 11/18/02 8:33 AM Page 397 WILM \200\231S tumor 397 Table 22.3 Outcome for patients in NWTS III Stage 2-year relapse-free survival (%) 2-year overall survival (%) Treatment I 92 97 10 weeks vincristine + actinomycin D II/III 87 91 15 months vincristine + actinomycin D + doxorubicin III 78 86 10 Gy + vincristine + actinomycin D +/- doxorubicin IV + UH 72 81 UH = Unfavorable histology Table 22.4 Outcome for patients in UKW1 Stage 3-yr event- free survival (%) 3-yr overall survival (%) 6-yr event- free survival (%) 6-yr overall survival (%) I 90 96 89 96 II 85 94 85 93 III 82 83 82 83 IV 58 65 50 65 Study Group (UKCCSG). An essential part of all therapy protocols is the \200\230stage \200 \231 of the tumor. The NWTS staging system is: (cid:2) Stage I (cid:2) Stage II Tumor within renal capsule and fully resected. Tumor outside renal capsule but fully resect ed; biopsy; ruptured; con \201ned to the \202ank. Tumor outside capsule and incompletely resected; lymph-node involvement at the hilum or paraortic chain. (cid:2) Stage III (cid:2) Stage IV Haematogenous metastases e.g. to lungs, liver, bone, or brain. Bilateral renal tumors. (cid:2) Stage V OHO-22(389-416) 11/18/02 8:33 AM Page 398 GENITOURINARY CANCERS 398 Cancer of the bladder and ureter Etiology The occupational risk of developing bladder cancer for workers in the dye industry was established more than 90 years ago. The association was supported when 2-napthylamine was shown to cause bladder cancer in animals and related carcinogens were associated with i ncreased risk for those working in the aniline dye and the rubber industries. Now, the rang e of known human bladder carcinogens identi \201es risks associated not only within these industries mentioned but also for those working in: (cid:2) Gas works (cid:2) Rodent care ( cid:2) Laboratory work (cid:2) Sewage work (cid:2) Textile printing (cid:2) Manufacture of \201relighters. Squamous cancers of the bladder are associated with chronic bladder infec tion by Schistosoma haematobium. Cigarette smoking is known to increase, 2 \200\2236-fold, the risk of devel- oping bladder cancer. Epidemiology The incidence increases with age with rates of 90 per 105 population in Americ an men aged 60 \200\22369 years and 26 per 105 for women of the same age. These incidences almost double in the age range 70 \200\22379 years. Pathology The majority of urothelial tumors presenting in the UK are transi- tional cell ca rcinomas. Pure squamous carcinomas and adenocarcino- mas represent 5% of tumors, though met aplasia can occur in a primary transitional tumor. There is a link between adenocarcinoma o f the bladder and presentation of the tumor in the bladder dome, often associated with pers isting urachal remnant. This type of tumor also occurs in the context of a congenital malfo rmation exstrophy. Primary squamous cancers are the commonest subtype with bladder schistos omiasis. Transitional carcinomas have a number of characteristic chromo- somal abnormalities includi ng, in particular, loss of chromosome 9. Other common abnormalities include a mutation of t he p53 gene that appears more often in advanced cancers and has been associated with an inc reased risk of treatment failure. OHO-22(389-416) 11/18/02 8:33 AM Page 399 CANCER OF THE BLADDER AND URETER 399 Transitional cancers are characterized by de \201nition of both grade and local T stage. T here is a strong association between well- differentiated tumors and early stage. Most rece nt reports are based on the UICC TNM staging classi \201cation (1987): (cid:2) T1 tumors a re con \201ned to the urothelium. (cid:2) T2 tumors invade super \201cial muscle. (cid:2) T3 tumors extend to deep muscle and through the bladder wall. (cid:2) T4 tumors extend int o adjacent organs. Even when the tumor is localized the T stage is highly relevant to progn osis, with \201ve-year survival rates of 75% for T1 tumors, 40 \200\22350% for T2 tumors, 20 \200\22330% for T3 tumors, and 10% or less for T4 tumors. Recently, this classi \201ca tion has been revised in UICC TNM staging (1997). Typical metastatic sites include: (cid:2) Pelvic and para-aortic lymph nodes (cid:2) Lung \201elds (cid:2) Liver (cid:2) Bo ne Bone metastasis is recognized increasingly as more patients have systemic control of dis ease with combination chemotherapy. Presentation The commonest presentation is with macroscopic haematuria, though some patient s also have frequency of micturition, dysuria, or symptoms of metastases. Haematuria should be con \201rmed by urine analysis and investigated by analysis of the cy tology of voided urine and by cystoscopy. An IVU can demonstrate the possibility of disease involving the ureter and the diagnosis is established by resection of the primary tumor at cysto- scopy. During the same procedure, bimanual examination is per- formed and this, tog ether with the biopsy \201ndings with associated evidence of depth of tumor invasion, ena ble the T stage of the tumor to be established. Nodal and metastatic staging is achieved wi th a CT scan of the thorax and abdomen. MRI is an excellent alternative for investigating t he local extension of disease and the pos- sibility of pelvic lymphadenopathy. The staging demonstrated following radical cystectomy may in many cases be different from t hat established from pure clinical investigation; this is important for comparison of diffe rent treatment series. Treatment options (cid:2) Super \201cial tumors (Ta, T1) \200\224resection \200\224super \201cial recurrence is common (60%) \200\224poorly diff erentiated, worse prognosis OHO-22(389-416) 11/18/02 8:33 AM Page 400 GENITOURINARY CANCERS 400 (cid:2) Frequent recurrences/high-risk tumors \200\224intravesical chemotherapy: mitomycin C; doxorubicin \200\224intravesical immunoth erapy: BCG monitored by cystoscopy reduces recurrences; no long-term effect on survival (cid:2) Muscle-invasive, local tumor \200\224radical radiotherapy \200\224radical cystectomy \200\224occasionally radiotherap y followed by salvage cystectomy (cid:2) Metastatic disease \200\224palliative chemotherapy \200\224usually relapse again after 2 years Surgical principles The usual procedure is cystoprostatectomy in male patients or anteri- o r bladder exenteration in female patients, with dissection of local lymph nodes. Bladder re section is associated with urinary diversion \200\224 most commonly, a non-re \202uxing il eal conduit and urinary bag. Complications include loss of sexual potency in the male and l oss of the vagina in the female. It is important for patients to have advice from a special ized stoma therapist before surgery. In specialist centers, excellent results can be achieved in selected patients treated by ra dical cystectomy with continent diversion based on urinary tract reconstruction by ileocyst ostoplasty. This can pro- duce urinary continence and, in experienced centers, the surgical complication rates are less than 10% and operative mortality less than 2%. Radical radiotherapy based on CT scan has led to increased pre- cision and more accurate do simetry. Usually, the entire bladder is treated to encompass the risk of subclinical diseas e at other sites in the urothelium. The technique uses either three or four \201elds and the common fractionation regimens include treatment to a dose of 64 Gy in 32 fractions over 6 weeks or 55 Gy in 20 fractions over 4 weeks. Most patients suffer some side-effects duri ng radiotherapy, such as increased frequency of micturition, dysuria, and, occasionally, st ran- gury requiring analgesics. There may also be proctitis associated with diarrhea. Chron ic side-effects of this type are uncommon. 1 2 Chemotherapy Combination chemotherapy has an established role in the palliation of patients with incurable bladder cancer. M-VAC comprises: (cid:2) Methotrexate (cid:2) Vinblastine ( cid:2) Adriamycin (cid:2) Cisplatin OHO-22(389-416) 11/18/02 8:33 AM Page 401 CANCER OF THE BLADDER AND URETER 401 CMV comprises: (cid:2) Cisplatin (cid:2) Methotrexate (cid:2) Vinblastine These regimens ca n be toxic, especially for an elderly patient with poor general health and impaired renal f unction associated with the primary tumor, and achieve a response with palliation of sympto ms in approximately 50 \200\22360% of patients. However, complete responses are uncommon (a pproximately 20%) and prolonged complete response is rare (less than 10% of patients). Chemotherapy is being investigated as an adjuvant therapy in local- ized disease either pri or to, or following, de \201nitive local treatment with surgery or radiotherapy. As yet, t he role of chemotherapy in this context is controversial since trials have failed to show c linically signi \201cant impact on survival. Future treatments New drugs under investigation for the management of bladder cancer includ e the taxanes, gemcitabine and ifosphamide. There is continued investigation of the role of these agents as a complement to de \201nitive local therapies for patients with local mus cle-invasive cancers. Controversies in management Super \201cial, poorly differentiated cancers Conventionally, these are managed by transur ethral resection. However, the relatively poor prognosis of these tumors has led to investi gation of adjuvant treatments with cytotoxic chemotherapy intravesically, BCG, or external- beam radiotherapy to the bladder. Results of these studies are awaited. Localized muscle invasive cancer Internationally, the commonest pattern of management is ra dical cys- tectomy. Prospective trials comparing cystectomy with radical radio- therapy hav e not show a signi \201cant survival difference and the use of radiotherapy in order to se ek tumor control with organ conservation is preferred by some clinicians and patients. Impr oved tumor char- acterization and other methods of establishing appropriate local treat- me nt should enable better selection of patients for organ conservation with a low risk of loc al tumor recurrence. Adjuvant chemotherapy in local disease Trials reported so far have failed to demonstrate a clinically signi \201cant bene \201t to early adjuvant chemotherapy and more intensive re gimens are currently being explored. Promising results have been reported recently with che mo-irradiation. OHO-22(389-416) 11/18/02 8:33 AM Page 402 GENITOURINARY CANCERS 402 Prostate cancer Introduction Cancer of the prostate gland is one of the most controversial malig- nancies. Its pathogenesis is clearly androgen-dependent, and men who are castrated or are hypopituit ary before 40 years rarely develop this tumor. Age is the most important risk factor and it is estimated that 70% of men over 80 years have histological evidence of cancer in the pro state; 5% of cases are due to inheritance of a susceptibility gene such as BRCA1. Other cli nical observations such as the increased inci- dence in African \200\223Americans are unexp lained. During the last 20 years the incidence and the number of deaths from prostate cancer in the US and Europe has inexorably risen. Since the development of assays to measure serum prost ate-speci \201c antigen (PSA) to diagnose prostatic disease, the condition has been increa s- ingly diagnosed at an earlier stage. In 1974, in the UK, more than 50% of patients prese nted with metastatic disease. Twenty years later, more than 50% of patients are diagnosed a s a result of PSA testing without any symptoms of prostatic disease. The use of PSA has proved to be an ambiguous advance. In the US, in 1995, with widespread u se of PSA testing in asymptomatic men, nearly 400 000 patients were diagnosed suffering fro m prostate cancer; in the same year approximately 38 000 patients died of prostate cancer. In Europe, 85 000 patients were diagnosed and around 20 000 died of prostate cancer. These \201gures suggest that too many cases were diagnosed in the US and treated without clear evi- dence that they would have died of the disease, or that European patients were diagnos ed too late for curative treatment with a conse- quent higher death rate. In either case th e net result is that more patients are presenting with early stage disease and suitable tre atment strategies are required to cure those that can be cured and palliate optimally those that cannot. Assessment of disease (cid:2) PSA measurement \200\224routine screening not recommended in UK \200\224measure in all patients with out \202ow symptoms \200\224PSA > 4 ng/ml: clinical suspicion, requires transrectal ultrasoun d and needle biopsy \200\224PSA > 50 ng/ml: often distant metastases (cid:2) Pathological grading: Gleasons \200\231 score predicts behavior Isotope bone scan, CT, MRI in selected patients (cid:2) OHO-22(389-416) 11/18/02 8:33 AM Page 403 PROSTATE CANCER 403 Table 22.5 TNM staging of prostate cancer T0 No evidence of tumor T1a Tumor, incidental \201nding at TURP (<5% chippings) T1b Tumor, incidental \201nding at TURP (>5% chippings) T1c Impalpable tumor identi \201ed by raised PSA T2a Tumor involves half of a lobe or less T2b Tumor involves more than a half of a lobe but not both lobes T2c Tumor involves both lobes T3a Unilateral extracapsular extension T3b Bilateral extracapsular extension Tumor involves seminal vesicles T4 Tumor invades bladder neck, rectum, pelvic side-wall Treatment of localized prostate cancer A localized prostate cancer of 1 cm diameter will me tastasize within 8 years in over half the patients, regardless of their age. Furthermore, p atients who present with metastatic disease with >10 metastases in the skeleton and symptom s from metastases will, in spite of optimal palliative therapy, die within three years. Bet ween these ends of the spectrum, patients \200\231 therapy should be tailored to the indivi dual needs of the patient and his cancer. Organ-con \201ned disease (cid:2) Age less than 70 years (cid:2) Co-morbidity not signi \201cant (cid:2) Consider ra dical local therapy \200\224prostatectomy \200\224radiotherapy (cid:2) No trials (cid:2) Staging lymph node dissection, may be done laparoscopically (cid: 2) Surgery may be better long-term for local control but effect on survival is uncertain (cid:2) High dose of conformal radiotherapy or brachytherapy may be as good (cid:2) Complications \200\224radical prostatectomy: 50% impotence; 8 \200\22315% long-term incontinence \200\224radical radiotherapy: 40% impotence; rectal stricture/bladder irritation but no incontinence (cid:2) Patients over 70 years \200\224 \200\230wait and see \200\231 policy OHO-22(389-416) 11/18/02 8:33 AM Page 404 GENITOURINARY CANCERS 404 Locally extensive disease (cid:2) Localized T3, T4 disease not cured by radical surgery or radio- therapy (cid:2) Good results with neo-adjuvant anti-androgen therapy \200\224if fol- lowed by radiotherapy, better results than radiotherapy alone Node-positive disease (cid:2) USA \200\224radical prostatectomy followed by surgical castration (cid:2) Europe \200\224hormone therapy and radiotherapy \200\224early hormone therapy prolongs survival in Mo cases The treatment of metastatic disease Once the tumor has spread beyond the local lymph nodes and par- ticularly if bony metastases are present, the chances of the patient dying of pros tatic is 75%, regardless of age. Nonetheless, useful pallia- tion of the disease can be rea dily achieved by hormonal therapy. A number of treatments may be used to exert much the same bio- logical effect, namely the c essation of androgen-driven growth of the cancer. The following will produce symptomatic re sponse in about 70% of men with bone metastases, with a median response duration of 12 \200 \22318 months: (cid:2) Surgical castration (cid:2) Oestrogens (no longer used because of ca rdiovascular toxicity) (cid:2) Steroidal anti-androgens such as cyproterone acetate (best a voided for long-term use because of occasional hepatotoxicity) (cid:2) Non-steroidal anti-androgen s ( \202utamide, bicalutamide) (cid:2) Medical castration with LHRH agonists More than 20% of patients will continue to respond for up to \201ve years. The price for this is the t oxicity of long-term castration, including: (cid:2) Loss of libido and potency (cid:2) Hot \202ushes (cid:2) Alteration of body form (cid:2) Loss of energy Inability to concentrate (cid:2) (cid:2) Osteoporosis Although initial reports on the combination of medical castration and anti-androgen therapy (Maximal Androgen Blockade or MAB) sug- gested a bene \201t over mon otherapy, recent meta-analysis has shown that monotherapy and combined treatment are equiva lent in ef \201cacy. At least 30% of patients who relapse following androgen antagonist pr imary therapy will respond to subsequent medical or surgical OHO-22(389-416) 11/18/02 8:33 AM Page 405 PROSTATE CANCER 405 castration. In addition, some patients respond to withdrawal of anti- androgens. However, t he responses to second-and third-line endo- crine therapy are incomplete and short-lived, a nd ultimately patients return with hormone refractory metastatic disease. The results of ch emotherapy in this disease are poor, although responses to anthra- cyclines and the related mitoxantrone have been reported. Radiation therapy offers useful palliation of advanced disease both in bone and soft tissue . In addition, radioactive strontium given by IV injection (150 MBq) has proved effective i n relieving bone pain and delaying the progression of symptomatic bone disease. OHO-22(389-416) 11/18/02 8:33 AM Page 406 GENITOURINARY CANCERS 406 Screening for prostate cancer Introduction Prostate cancer is the second most common cause of cancer death in the UK and causes over 9500 deaths each year. The incidence of prostate cancer appears to be rising. I t is dif \201cult to know whether this re \202ects a real increase, an increase in case \201nding, or the fact that men are living longer and failing to die from other causes. In tuitively, it would seem obvious that early detection of pro- state cancer would lead to ea rlier treatment and an increased cure rate. In the US, where treatment has been historically more aggressive than in the UK, death rate s from prostate cancer have gone down (despite increasing incidence). Surgical pundits attr ibute this to earlier surgery. This is not entirely supported by data. Screening can be de \201ned as a performance of tests in apparently well men, to detect th ose with unrecognized prostate cancer. The ultimate aim of screening is to reduce morbidity and mortality from a disease by its detection and treatment before symptoms appear. Procedure Screening for prostate cancer involves the examination of asymptomatic men, \201rstly by digital rectal examination (DRE) and a blood test of prostatic-speci \201c an tigen (PSA). Those men with a suspicious DRE or raised PSA are then investigated by ultraso und transrectally (TRUS) and/or biopsy, either randomly of the prostate or of suspicious ar eas. Those who have the disease can then be staged and offered treatment, such as radical prosta tectomy or radical radiotherapy, or monitored until they develop symptoms. National screening Screening for prostate cancer has operated in Germany since 1978 and rec tal examination is included in insurance annual check-ups in Belgium. In France, work-site PSA screening has been launched by Occupational Health Services for men aged 50 \200\22365. However, no con- sensus exists on the validity of such screening. The US National Cancer I nstitute stated there is insuf \201cient evidence to establish that a decrease in mortalit y from prostate cancer occurs with screening by DRE, TRUS, or serum markers; yet the Americ an Urological Association and the American Cancer Society have published guide- lines advoc ating annual DRE and PSA testing for men over the age of OHO-22(389-416) 11/18/02 8:33 AM Page 407 SCREENING FOR PROSTATE CANCER 407 50. Although formal screening is not taking place widely, there is cer- tainly marked case \201nding in many parts of the world. There have been a number of small screening studies, but many rely on volunteers willing to respond to invitations for screening and this introduces selection bias. The cancers that are con \201ned to the prostate can be slow-growing and may be biological ly insigni \201cant as far as the patient is concerned, and yet 70% of tumors detected thr ough screening are organ- con \201ned and could potentially be eradicated by radical prost atectomy. This eradication is measured by undetectable PSA levels for up to 10 years after surgery. Slowly growing or latent tumors may be more likely to be detected by screening but might ha ve a longer pre-clinical course. The rate of detection of these tumors would increase if th e screening was applied over a number of years. Other factors that must be addressed before the introduction of screening include the morbi dity of screening \200\224the unnecessary anxi- ety it induces, especially for a high propo rtion of men found to have a falsely positive initial result. Finally, and probably most im portantly, there is lack of true evidence regarding the effective treatment for early prost ate cancer. There is a debate as to the desirability of including DRE at the initial screen. Although i ts use will increase the number of cancers detected, there is some evidence that DRE may mi ss life-threatening tumors. Although in two GP studies in the UK, DRE and PSA were accept- able to members of the general male population, in larger pilot studies in Belgium and the Netherlands acceptance rates were as low as 35 \200\22340% when both tests were used. Accep tance rates in UK males of screening for other diseases by blood tests are of a higher orde r, up to 60%. The combination of serum PSA and DRE screening results in a higher overall cancer detection rate than each used in isolation \200\224 4 \200\2236%. This means, however, that 20% of t he screened population will require biopsy. If PSA is used alone, three patients must under go biopsy to \201nd one case of prostate cancer. In PSA-based screening, over 97% of canc ers detected on initial evaluation are clinically local- ized to the prostate. The case for screening would therefore appear to be strong, except for one major \202aw: there have been no randomized controlled trials with suf \201cient power to detect any imp rovements in mortality from medical intervention. Two trials evaluating randomized treatmen t of prostate cancer after detection \200\224the PIVOT study in the US and a smaller Scanda navian study \200\224will soon report. In those patients who have organ-con \201ned prostate cancer, about 90% are free of PSA re lapse at \201ve years after radical prostatectomy, as are about 70% of men with only foca l capsular penetration. Prior to OHO-22(389-416) 11/18/02 8:33 AM Page 408 GENITOURINARY CANCERS 408 PSA testing, many patients were found to have positive lymph nodes, but the trend now is to operate on patients with lower PSAs and to focus on those who can theoretically be cured. The absence of data to support prostatic screening does not mean such a bene \201t may not exist. OHO-22(389-416) 11/18/02 8:33 AM Page 409 SCREENING FOR PROSTATE CANCER 409 OHO-22(389-416) 11/18/02 8:33 AM Page 410 GENITOURINARY CANCERS 410 Testicular cancer Introduction The majority of testicular cancers are germ cell tumors. Germ cell tumors are relatively rare, being the fourteenth most common can- cer in men overall. It is, however, the commonest cancer in young men (20 \200\22340 years) and its incidence has doubled over the last 30 years. The reason for this increase in incidence is not clear. The age group wh ich the disease affects and the fact that the majority of patients are cur- able, even when the disease has metastasized, makes this a particularly important disease for oncologists. It is one of the few curable solid tumors once it has metastasized and there is an overall survival of about 90%. Pathology Germ cell tumors arise from the germinal epithelium and both semi- nomas and tera tomas are thought to arise from pre-existing carcino- mas in situ. In the UK, the British c lassi \201cation is still the most commonly used. The natural history of seminoma and teratoma differs and these differences largely dictate the variation in management between the two. The majority of seminomas (75%) present with S tage I disease \200\224 that is with no evidence of metastases. Spread tends to be predicta ble, to the para-aortic lymph nodes in the \201rst instance and, subsequently, to the sup ra-diaphragmatic lymph nodes and thereafter to other metastatic sites. Table 22.6 Pathological classi \201cation of testicular cancers British WHO Seminoma Spermatocytic seminona Seminoma Spermatocytic serinoma Teratoma Non-seminomatous germ cell tumor Mature teratoma Teratoma differentiated (TD) Malignant teratoma intermediate (MTI) Embryonal carcinoma with teratoma (teratocarcinoma) Malignant teratoma undifferentiated (MTU) Yolk sac tumor, embryonal carcinoma Malignant teratoma trophoblastic (MTT) Yolk sac tumor; choriocarcinoma OHO-22(389-416) 11/18/02 8:33 AM Page 411 TESTICULAR CANCER 411 Only about half of testicular teratomas present as Stage I disease and spread tends to be l ess predictable, with blood-borne metastases occurring earlier than with seminoma. In addit ion to this, teratomas produce markers in the form of the human chorioric gondotrophin (HCG ) and/or alpha feta protein (AFP) in 75% of cases. Seminomas on the other hand have no reli able tumor marker to monitor disease, although the HCG may be raised in about 25% of cases. The lactate dehydrogenase (LDH) may be raised in both tumors and is useful for de \201nin g a prognostic group, but is not a reliable marker for monitoring response to treatment or subsequent relapse. Presentation (cid:2) Lump in/on testis (cid:2) Metastases \200\224back pain (para-aortic nodes) \200\224chest symptoms (lung secondaries) (cid:2) Differential diagnosis \200\224epididymo-orchiditis Initial management of testicular germ cell tumors This includes: (cid:2) Ultrasound of both testicles (cid:2) Chest X-ray (cid:2) Blood levels of the testicular tumor markers (AFP, H CG, LDH) Where the patient has obvious and widespread metastases, immediate referral for ch emotherapy may be necessary, but in general the initial management will be inguinal orchide ctomy. A biopsy of the contra- lateral testis should be considered where there is a high ri sk of carcino- ma in situ. Such patients include those with a history of maldescent, a smal l testis (less than 12 ml), and patients less than 30 years. Further staging investigations will usually be performed post-operatively. Staging investigations and prognostic grouping Staging investigations will include, in all patients, a CT scan of the tho- rax, abdomen, and pelvis. In patients with a high HCG (grea ter than 10 000 international units per liter) or bulky mediastinal disease, a brain scan i s advisable. Post-operative tumor markers should be serially checked, if raised, to assess whether or not they are falling according to a satisfactory half life (4 \200\2236 days for AFP, 24 hours for HCG). Other investi- gations such as a bone scan may be necessary if spe ci \201cally indicated. Until recently the Royal Marsden Hospital (RMH) staging has been used for both teratomas an d seminomas. The IGCCC prognostic grouping is now more applicable, particularly for teratom as. Sperm storage Sperm count and storage should be considered at an early stage where patients are likely to require further therapy. It should be remembered OHO-22(389-416) 11/18/02 8:33 AM Page 412 GENITOURINARY CANCERS 412 Table 22.7 RMH staging 1 No evidence of disease outside the testis 1M As above but with persistently raised tumor markers 11 Infradiaphragmatic nodal involvement 11A Maximum diameter <2 cm 11B Maximum diameter 2 \200\2235 cm 11C Maximum diameter 5 \200\22310 cm 11D(*) Maximum diameter >10 cm III Supra-and infradiaphragmatic node involvement Abdominal nodes a, b, c, as above Mediastinal nodes M+ Neck nodes N+ IV Extralymphatic metastases Abdominal nodes a, b, c, as above Mediastinal or neck nodes as for Stage III Lungs: \200\224L1<3 metastases \200\224L2 multiple metastases <2 cm in diameter \200\224L3 multiple metastases >2 cm in diameter Liver involvement H+ Other sites speci \201ed The Stage IID category was formulated at the 1989 Seminoma Consensus Conference that up to 50% of patients with testicular germ cell tumor may be subfertile at presentatio n. Management The management of seminoma and teratoma depends on the stage of disease and invo lves all three major modalities for the treatment of cancer \200\224surgery, radiotherapy, and chemotherapy. Management of carcinoma in situ Carcinoma in situ will progress to invasive cancer, either seminoma or teratoma, with 50% producing invasive tumors \201ve years from diag- nosis. O nce this diagnosis is made, treatment should be offered, although this may not need to be g iven immediately. Carcinoma in situ can be eradicated by low-dose radiotherapy to the testi s (20 cGy in 10 fractions given over two weeks). The advantage of this treatment is that, i n the majority of cases, it will not affect Leydig cell function, and long-term hormone the rapy with its attendant problems should not be necessary. OHO-22(389-416) 11/18/02 8:33 AM Page 413 TESTICULAR CANCER 413 Table 22.8 IGCCCC prognostic grouping Teratoma (NSGCT) Seminoma Good prognosis with all of: Testis/retroperitoneal primary Any primary site No non-pulmonary visceral metastases No non-pulmonary visceral metastases AFP <1000 ng/ml Normal AFP HCG <5000 iu/ml Any HCG LDH 1.5 upper limit of normal Any LDH 56% of teratomas: 5-year survival 92% 90% of seminomas: 5- year survival 86% Intermediate progress with any of: Testis/retroperitoneal primary Any primary site No non-pulmonary visceral metastases Non-pulmonary visceral metastases AFP >1000 and <10 000 ng/ml Normal AFP HCG >5000 and <50 000 iu/ml Any HCG LDH >1.5 normal <10 normal Any LDH 28% of teratomas: 5-year survival 80% 10% of seminomas: 5-year survival 73% Poor prognosis with any of: Mediastinal primary No patients in this group Non-pulmonary visceral metastases AFP >10 000 ng/ml HCG >50 000 iu/ml LDH >10 normal 16% of teratomas: 5-year survival 48% Management of Stage I seminoma (cid:2) 20% seminomas recur after orchidectomy (cid:2) 90% of relapse is in para-aortic nod es (cid:2) Radiotherapy to para-aortic/pelvic nodes reduces relapse to 4% (cid:2) Current trials for chemotherapy in Stage 1 seminoma (cid:2) Radiotherapy to para-ao rtic nodes in all stages (T10 \200\223S1) (cid:2) Risk factors for pelvic node involvement \200\224previous inguino-scrotal surgery \200\224maldescent If risk factor is present giv e pelvic node radiotherapy (cid:2) OHO-22(389-416) 11/18/02 8:33 AM Page 414 GENITOURINARY CANCERS 414 IVU to identify kidney position \200\224limit radiation to kidney \200\224horseshoe kidne y is contraindication to radiotherapy (cid:2) (cid:2) Standard dose of radiotherapy is 30 Gy in 15 fractions over 3 weeks (cid:2) Side-ef fects of radiotherapy \200\224nausea \200\224tiredness Stage 2a and 2b seminoma (cid:2) Radiotherapy \200\22430 Gy in 15 fractions over 3 weeks Stage 2c, 3, and 4 seminoma (cid:2) Chemotherapy (cid:2) Toxic in older patient (cid:2) Bleomycin pneumonitis common Stage 1 teratoma (cid:2) Relapse rate after orchidectomy alone \200\22425% (cid:2) Vascular or lymphatic inv asion relapse rate \200\22450% If vascular or lymphatic invasion \200\2242 courses of BEP reduce relapse rate to 1% (cid:2) (cid:2) No vascular or lymphatic invasion \200\224surveillance (90% cure rate) (cid:2) Surv eillance is \200\230active \200\231 \200\224monthly clinic visits for \201rst year \200\2243 CT scans \201rst year \200 \22480% who relapse do so in \201rst year Stage 2, 3, and 4 teratoma (cid:2) Standard treatment for metastases \200\224Bleomycin \200\224Etoposide \200\224Cis platin (cid:2) Cure rates \200\224good prognostic group (90%) \200\224intermittent group (75%) \200\224poor prognosis (50%) (cid:2) Role of high-dose chemotherapy, marrow or stem cell transplanta- tion \200\224not clear (cid:2) Chemotherapy side-effects common \200\224nephropathy \200\224neuropathy \200\224ototoxiciy \200\224myelosupression \200 \224Bleomycin pneumonitis (fatal in 10%) (cid:2) Results better in specialized centers (cid:2) Monitor response \200\224scans, tumor markers OHO-22(389-416) 11/18/02 8:33 AM Page 415 TESTICULAR CANCER 415 Post-chemotherapy surgery or residual masses Where residual masses are present after chemot herapy for metastatic testicular teratoma, surgery should be performed to resect these. The majority of these will be in the retroperitoneum, and extensive and dif \201cult surgery is often necessary for a complete resection. The resid- ual masses may contain differentiat ed teratoma, \201brosis, or indeed viable tumor, and further chemotherapy may be indicate d. Surgery should usually only be undertaken when markers have normalized. Residual pulmonary masses should also be resected where possible. The problem of surgical t echnique and anesthetic risk, particularly as most patients will have been exposed to Bleom ycin, again demand that patients are seen and operated on in a center experienced in this s urgery. Following primary management of metastatic disease, fairly intens- ive follow-up is necessa ry as in those patients who relapse, salvage therapy can be effective in about 25% of cases . Non-germ cell testicular tumors. These represent a very small proportion of testicular tumo rs. Stromal tumors such as those arising from Leydig cells are generally thought to be beni gn, but metastases have been reported in approxi- mately 10% of cases. Unfortunately, patho logical examination of the primary tumor does not give a good indication of the propensity to metastasize, making management dif \201cult. It is reasonable to perform normal staging investigations and monitor such patients for about two years. Testicular lymphomas are the commonest testicular cancer in elderly men and should be treated along the same principles as lymphomas arising at other sites. Psychological issues There is undoubtedly a signi \201cant psychological morbidity associa ted with diagnosis and subsequent management of men with germ cell tumors. The loss of a te sticle alone in many patients is considered mutilating, and a testicular prosthesis should be inserted when possi- ble. The optimal support for these patients is not clear, but psych olog- ical help should be available. OHO-22(389-416) 11/18/02 8:33 AM Page 416 GENITOURINARY CANCERS 416 Further reading Atzpodien, J. et al. (1990) Home therapy with recombinant interleukin-2 and interferon (cid :2)- 2b in advanced human malignancies. Lancet 353, 1509 \200\22312. Cookson, M.S., Herr, H.W., Zhang, Z.F., et al. (1997) The treated natural history of high risk super \201cial bladder cancer: 15 year outcome. J Urol 158, 62 \200 \2237. MRC Renal Cancer Collaborators. (1999) Interferon-(cid:2) and survival in metastatic renal carcinoma: early results of a randomized controlled trial. Lancet 353, 14 \200\22317. Raghavan, D., Shipley, W.U., Garnick, M.B., Russell, P.J., and Richie, J.P. (1990) Biology and management of bladder cancer. N Eng J Med 322, 1129 \200\22338. Scottish Intercollegiate Guidelines Network (2000). Management of adult testicular germ cell tumors: a national clinical guideline. OHO-23(417-442) 11/18/02 8:34 AM Page 417 Chapter 23 Gynecological cancer Ovarian cancer 418 Cancer of the uterine corpus 422 Cancer of the cervix 426 Vaginal and vu lval cancer 432 Trophoblastic tumors 436 OHO-23(417-442) 11/18/02 8:34 AM Page 418 gynecological CANCER 418 Ovarian cancer Introduction Ovarian cancer is the \201fth commonest cancer in women with nearly 6000 cas es diagnosed and over 4000 women dying of the disease each year. The majority of cases occu r over the age of 55 years with the peak in the 65 \200\22375 age group. Treatment consists of surgery, followed for most patients by chemotherapy which, for over 20 years, has consi sted of platinum-based regimens. Etiology The risk of ovarian cancer appears to relate to the number of ovula- tory cycles i n a woman \200\231s lifetime and multiple pregnancies. Use of the oral contraceptive pill s eems to offer protection, infertility raises the risk. Less than 5% are clearly hereditary \200\224associated with BRCA1 or BRCA2 or Lynch II families. Pathology More than 80% of ovarian malignancies are epithelial, the rest com- prise germ ce ll and stromal tumors. Epithelial cancers are classi \201ed by their cell type (serous, mu cinous, endometrioid, Brenner, mixed) and by their grade. CA125 80% of women with advanced ovarian cancer have elevated serum CA125 and this marker i s valuable in monitoring response to therapy and in the detection of early relapse. However , it is not speci \201c for ovarian cancer and is elevated in association with other perit oneal pathologies. Presentation and staging The vast majority of women present with disease that has spread be yond the ovary to involve the peritoneum and other abdomino- pelvic organs. The most common symptoms are of abdominal dis- comfort and swelling; vaginal bleeding and gastrointestinal and urinary symptoms also occur. The two main prognostic factors in ovarian cancer are stage and the amount of residual dise ase after surgery. Five-year survival rates according to stage are as follows: 75% (cid:2) Stage I 45% (cid:2) Stage II 20% (cid:2) Stage III OHO-23(417-442) 11/18/02 8:34 AM Page 419 OVARIAN CANCER 419 Table 23.1 Staging of ovarian cancer Stage Description Ia Tumor con \201ned to one ovary Ib Tumor con \201ned to both ovaries Ic Tumor Stage I but with capsule ruptured or malignant ascites II Tumor with pelvic extension III Tumor with peritoneal implants outwith the pelvis or involved small bowel; retroperitoneal or inguinal nodes IV Distant metastases