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Purpose: The optimal dose and range of radiation therapy for central nervous system nongerminomatous germ cell tumors (NGGCTs) have not been uniformly established. Therefore, this study aimed to investigate the effect of individualized radiation therapy, based on the response to induction chemotherapy combined with surgery, on the prognosis of patients with NGGCTs., Methods and Materials: Based on the imaging examination and tumor markers after induction chemotherapy and pathologic results of second-look surgery, patients with NGGCT received different radiation therapy strategies, including 30.6 Gy whole ventricular irradiation + tumor-bed boost to 54 Gy, 30.6 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, 36 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, and 36 Gy craniospinal irradiation + 54 Gy tumor-bed boost with 45 Gy to metastatic spinal lesions., Results: A total of 51 patients were enrolled between January 2015 and March 2021, with a median age of 10.3 years. The 3-year event-free survival and overall survival (OS) of the entire cohort were 70.2% ± 6.9% and 77.5% ± 6.0%, respectively. The 3-year OS of patients achieving partial response after induction chemotherapy was higher than that of patients with stable disease (P = .03) or progressive disease (P = .002). The 3-year event-free survival and OS of the 18 patients receiving 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed boost were 88.9% ± 7.4% and 94.4% ± 5.4%, respectively., Conclusions: The results suggest that an individualized radiation therapy strategy based on response to induction chemotherapy and surgery is a feasible and promising means of achieving reduction in dose and extent of radiation in patients while still providing good response., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Chemotherapy (CHT) or radiation therapy (RT) are first-line treatments for clinical stage II (CS-II) testicular seminoma. Historically, clinical stage I (CS-I) seminoma was also treated with CHT or RT, but in the past 2 decades practice has shifted toward active surveillance for CS-I with RT or CHT reserved for patients with progression to CS-II. Limited data exist on contemporary RT techniques and patient stratification (ie, de novo [CS-II at orchiectomy] vs relapsed [CS-II diagnosed during surveillance after orchiectomy for CS-I]). We investigated outcomes in CS-II patients treated with RT in the modern era across 2 institutions., Methods and Materials: A retrospective review identified 73 patients treated with RT for CS-II A or B seminoma between 2001 and 2022. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method and univariate analyses were performed with log-rank or Cox proportional hazard regression. Recurrence was defined as biopsy-proven metastatic seminoma after RT completion. Second malignancies were defined as a biopsy-proven malignancy originating in the prior RT field., Results: Thirty-eight (52%) patients presented with de novo CS-II and 35 (48%) patients had relapsed CS-II. Median follow-up was 4.8 years (IQR: 2.3-8.1). Five-year RFS was 82% overall (92% in relapsed patients and 73% in de novo patients). Relapsed CS-II disease had lower recurrence rates after RT compared with de novo CS-II disease. All recurrences occurred outside the prior RT field and were salvaged. Disease-specific survival was 100%. Two second malignancies occurred (prostate, colorectal cancer at 67 months and 119 months post-RT, respectively)., Conclusions: In patients with CS-II seminoma treated with modern RT, there were no in-field recurrences. Presentation with de novo CS-II is associated with out-of-field recurrence. Subject to further larger-scale validation, our results suggest that compared with CS-II at time of relapse, de novo CS-II may portend more aggressive or micrometastatic disease beyond the retroperitoneum, raising the possibility of benefit from CHT after radiation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy., Methods and Materials: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse., Results: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression., Conclusions: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

We examined adjuvant irradiation of the scrotum in primary testicular lymphoma (PTL) by means of a literature review in MEDLINE, a telephone survey among Dutch institutes, and an in silico planning comparative study on scrotal irradiation in PTL. We did not find any uniform adjuvant irradiation technique assuring a safe planning target volume (PTV) coverage in published reports, and the definition of the clinical target volume is unclear. Histopathologic studies of PTL show a high invasion rate of the tunica albuginea, the epididymis, and the spermatic cord. In retrospective studies, a prescribed dose of at least 30 Gy involving the scrotum is associated with best survival. The majority of Dutch institutes irradiate the whole scrotum without using a planning computed tomography scan, with a single electron beam and a total dose of 30 Gy. The in silico planning comparative study showed that all evaluated approaches met a D(95%) scrotal dose of at least 85% of the prescription dose, without exceeding the dose limits of critical organs. Photon irradiation with 2 oblique beams using wedges resulted in the best PTV coverage, with a mean value of 95% of the prescribed dose, with lowest maximum dose. Adjuvant photon or electron irradiation of the whole scrotum including the contralateral testicle with a minimum dose of 30 Gy is recommended in PTL. Computed tomography-based radiation therapy treatment planning with proper patient positioning and position verification guarantees optimal dose coverage., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Postorchiectomy adjuvant radiotherapy (RT) for Stage I seminoma can be associated with long-term toxicity, and management strategies with a lower treatment burden achieve the same excellent cure rate. Because studies suggest that radiation oncologists in the United States continue to recommend RT for these patients, we sought to identify factors associated with management recommendations., Methods and Materials: We conducted a one-time internet-based survey among 491 randomly selected American radiation oncologists self-described as specializing in genitourinary oncology., Results: Response rate was 53% (n = 261). Forty-nine percent of respondents worked in university-affiliated practices. Sixty-two percent of respondents always/usually recommended adjuvant RT for patients with Stage I seminoma, whereas 21% always/usually recommended surveillance and 3% always/usually recommended chemotherapy. One third (33%) expressed concerns that patients who experienced relapse during surveillance could not be salvaged. Although 88% of physicians were aware of an increased risk of second malignant neoplasms (SMN) after adjuvant RT, 85% underestimated its magnitude. Compared with physicians not typically recommending RT, physicians who always/usually recommended RT were more likely to believe that patients might not be salvaged at relapse during surveillance (p = 0.008) and were less aware of the association between RT and SMN (p = 0.04)., Conclusions: Respondents who always/usually recommend postorchiectomy RT for patients with Stage I seminoma are more likely to underestimate late RT morbidity and to believe that surveillance is associated with increased mortality. Given the equivalent efficacy and reduced morbidity of surveillance compared with RT, our findings underscore the need for ongoing physician education to increase appropriate clinical implementation of surveillance strategies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Virtually all patients with Stage I testicular seminoma are cured regardless of postorchiectomy management. For patients treated with adjuvant radiotherapy, late toxicity is a major concern. However, toxicity may be limited by radiotherapy techniques that minimize radiation exposure of healthy normal tissues. This article is an evidence-based review that provides radiotherapy treatment planning recommendations for testicular seminoma. The minority of Stage I patients who choose adjuvant treatment over surveillance may be considered for (1) para-aortic irradiation to 20 Gy in 10 fractions, or (2) carboplatin chemotherapy consisting of area under the curve, AUC = 7 × 1-2 cycles. Two-dimensional radiotherapy based on bony anatomy is a simple and effective treatment for Stage IIA or IIB testicular seminoma. Centers with expertise in vascular and nodal anatomy may consider use of anteroposterior-posteroanterior fields based on three-dimensional conformal radiotherapy instead. For modified dog-leg fields delivering 20 Gy in 10 fractions, clinical studies support placement of the inferior border at the top of the acetabulum. Clinical and nodal mapping studies support placement of the superior border of all radiotherapy fields at the top of the T12 vertebral body. For Stage IIA and IIB patients, an anteroposterior-posteroanterior boost is then delivered to the adenopathy with a 2-cm margin to the block edge. The boost dose consists of 10 Gy in 5 fractions for Stage IIA and 16 Gy in 8 fractions for Stage IIB. Alternatively, bleomycin, etoposide, and cisplatin chemotherapy for 3 cycles or etoposide and cisplatin chemotherapy for 4 cycles may be delivered to Stage IIA or IIB patients (e.g., if they have a horseshoe kidney, inflammatory bowel disease, or a history of radiotherapy)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Photon radiotherapy has been the standard adjuvant treatment for stage I seminoma. Single-dose carboplatin therapy and observation have emerged as alternative options due to concerns for acute toxicities and secondary malignancies from radiation. In this institutional review board-approved study, we compared photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities., Methods and Material: Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ-specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors., Results: Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p < 0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.22-5.01), large bowel (0.81; 95% CI, 0.39-1.01), and bladder (0.03; 95% CI, 0.01-0.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, -0.01-0.06)., Conclusions: For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients with a life expectancy of 40 years from the time of radiation treatment with protons instead of photons. Proton radiation therapy also allowed significant sparing of most critical structures examined and warrants further study for patients with seminoma, to decrease radiation-induced toxicity., (Published by Elsevier Inc.)

Purpose: Men with cryptorchism can have aberrant abdominopelvic lymph node (LN) drainage or a different natural history if they develop Stage I seminoma. If so, the nodal echelons for metastases will not be reliable, and adjuvant radiotherapy (RT) would not be an ideal strategy., Methods and Materials: Two prospectively maintained oncology databases were reviewed for men with a history of testicular seminoma and cryptorchidism. The primary endpoint was the 5-year relapse-free rate., Results: A total of 23 men were identified, most (n = 13) had had a tumor in a scrotal location after orchiopexy. After orchiectomy, 5 men were managed with surveillance, and 18 underwent RT to a median dose of 25 Gy (range, 20-30 Gy). All the radiation fields included the para-aortic LNs, and 13 included the ipsilateral pelvic LNs. After a median follow-up of 64 months (range, 2-148), 2 patients developed a relapse. One did so 4 months into a surveillance program in the para-aortic and ipsilateral pelvic LNs, sites that would have been treated had he undergone RT. The other patient developed a relapse in the contralateral testis 46 months after having undergone RT. It is likely that the latter patient had a metachronous primary rather than a relapse; hence, the 5-year relapse-free rate was 80% for surveillance and 100% for RT. Both patients underwent successful salvage treatment, and all patients were disease free and alive at the last follow-up visit., Conclusion: A history of cryptorchism does not appear to confer a greater risk of relapse for men with Stage I seminoma managed with radiotherapy. RT, surveillance, and adjuvant carboplatin chemotherapy are treatment options for these patients.

Purpose: To evaluate the roles of radiation dose, chemotherapy, and other factors in the etiology of stomach cancer in long-term survivors of testicular cancer or Hodgkin lymphoma., Methods and Materials: We conducted a cohort study in 5,142 survivors of testicular cancer or Hodgkin lymphoma treated in the Netherlands between 1965 and 1995. In a nested case-control study, detailed information on treatment, smoking, gastrointestinal diseases, and family history was collected for 42 patients with stomach cancer and 126 matched controls. For each subject, the mean radiation dose to the stomach was estimated. Relative risks (RRs) of stomach cancer and the radiation-related excess relative risk (ERR) per gray were calculated by conditional logistic regression analysis., Results: The risk of stomach cancer was 3.4-fold increased compared with the general population. The risk increased with increasing mean stomach dose (p for trend, <0.001), at an ERR of 0.84 per Gy (95% confidence interval [CI], 0.12-15.6). Mean stomach doses of more than 20 Gy were associated with a RR of 9.9 (95% CI, 3.2-31.2) compared with doses below 11 Gy. The risk was 1.8-fold (95% CI, 0.8-4.4) increased after chemotherapy and 5.4-fold (95% CI, 1.2-23.9) increased after high doses of procarbazine (>or=13,000 mg) vs. <10,000 mg. The RR of smoking more than 10 cigarettes per day vs. no smoking was 1.6 (95% CI, 0.6-4.2)., Conclusions: Stomach cancer risk is strongly radiation dose dependent. The role of chemotherapy, particularly of procarbazine and related agents, needs further study, because of the relatively small numbers of chemotherapy-treated subjects.

Purpose: To study the effect of 16 Gy radiotherapy (RT) vs. 20 Gy RT on Leydig cell function in men treated with radiotherapy against carcinoma in situ (CIS) of the testis., Methods and Materials: Fifty-one men who were treated between 1985 and 2005 were included. Fourteen men had been treated with 20 Gy and 37 with 16 Gy RT. Measurements of sex hormone-binding globulin and basic and stimulated testosterone, as well as luteinizing hormone levels were performed., Results: The follow-up periods for the patients treated without additional chemotherapy were for the 20 Gy and 16 Gy group mean/median/min-max: 9.0/10.0/1.0-20.3 years and 4.0/3.1/0.4-14.1 years, respectively. During the follow-up period, men treated with 16 Gy RT had stable testosterone levels (-1.1%/year, p = 0.4), whereas men treated with 20 Gy had an annual decrease of 2.4% (p = 0.008). For the latter group, the testosterone decrease was most pronounced in the first 5 years, leveling off during the following 5 years. Additionally, more men treated with 20 Gy needed androgen substitution treatment. Our study showed an increased luteinizing hormone level for the men treated with 16 Gy, although this was not significant (p = 0.5). We anticipated a similar increase in the patients treated with 20 Gy but instead observed a decrease (-3.1%, p = 0.01)., Conclusion: RT at 16 and 20 Gy seem to affect Leydig cell function differently, with 16 Gy RT better preserving testosterone levels and thus being preferred from an endocrinological point of view.

Purpose: To estimate and compare the secondary cancer risk (SCR) due to para-aortic (PA), dogleg field (DLF), or extensive field (EF) radiotherapy (RT) at different dose levels for Stage I testicular seminoma., Methods and Materials: The organ equivalent dose concept with a linear, plateau, and linear-exponential dose-response model was applied to the dose distributions to estimate the SCR. The dose distributions were calculated in a voxel-based anthropomorphic phantom. Three different three-dimensional plans were computed: PA, DLF, and EF. The plans were calculated with 6-MV photons and two opposed fields, using 20 Gy in 10 fractions., Results: The estimated cumulative SCR for a 75-year-old patient treated with PA-RT at age 35 was 23.3% (linear model), 20.9% (plateau model), and 20.8% (linear-exponential model) compared with 19.8% for the general population. Dependent on the model, PA-RT compared with DLF-RT reduced the SCR by 48-63% or 64-69% when normalized to EF-RT. For PA-RT, the linear dose-response model predicted a decrease of 45% in the SCR, using 20 Gy instead of 30 Gy; the linear-exponential dose-response model predicted no change in SCR., Conclusion: Our model suggested that the SCR after PA-RT for Stage I testicular seminoma is reduced by approximately one-half to two-thirds compared with DLF-RT, independent of the dose-response model. The SCR is expected to be equal or lower with 20 Gy than with 30 Gy. In the absence of mature patient data, the organ equivalent dose concept offers the best potential method of estimating the SCR when discussing treatment options with patients.

Purpose: The aim of this study was to review retrospectively the results of low-dose radiotherapy for Stage I seminoma using four different fractionation schedules and target volume definitions., Methods and Materials: A total of 191 patients underwent irradiation for histologically proven Stage I seminoma after undergoing an inguinal orchiectomy. Fractionation schedules were used one after another as follows: Total dose 30 Gy (dose/fraction 1.5 Gy, 16 patients), total dose 25.5 Gy (dose/fraction 1.5 Gy, 62 patients), total dose 20 Gy (dose/fraction 2 Gy, 69 patients), total dose 26 Gy (dose/fraction 2 Gy, 29 patients). The remaining 12 patients were excluded from this study. In the same period the target volume was gradually reduced. In 1983 the paraaortic, pelvic and inguinal regions were irradiated; later the target volume was reduced to the paraaortic region exclusively., Results: Overall survival and event-free survival were identical in all groups ranging from 95% to 100% /5 years. Three patients experienced a lymph node metastasis during follow-up, 3 patients a distant metastasis to the lung and the bones. Mild acute side effects were noted in 8% to 15% of the patients, and very mild long-term side effects in 1% to 5% of patients. Multivariate analysis showed no prognostic significance of total dose, dose per fraction, or target volume. In univariate analysis, a higher frequency of acute side effects to the skin and the bowel was related to a higher total dose, and an elevated frequency of nausea was related to a higher daily dose per fraction., Conclusion: Using lower doses and limiting the target volume to the paraaortic region exclusively did not result in a worse prognosis in our patient series.

Purpose: Radiation-induced chromosome aberrations are routinely used in biologic dosimetry to monitor radiation exposure. Translocations are considered stable aberrations with time after exposure. This study was performed to determine the temporal persistence of radiation-induced translocations during a 36-month period in therapeutically irradiated testicular seminoma patients who underwent partial body exposure (>10% of bone marrow)., Methods and Materials: Chromosome analyses were carried out in peripheral lymphocytes of 11 patients with testicular seminoma (n = 9), germinoma (n = 1), or follicular non-Hodgkin's lymphoma (n = 1). All patients received radiotherapy with photons from a linear accelerator; in 1 case, additional electron beams were used. Doses ranged from 26 Gy (seminoma) to 45 Gy (non-Hodgkin's lymphoma). None of the patients received chemotherapy. From each patient, blood samples were taken during the 36 months after irradiation at defined points. Chromosomal aberrations were scored after fluorescence in situ hybridization painting of chromosomes 1, 4, and 12 in combination with a pancentromeric probe., Results: For 9 patients (7 with testicular seminoma, 1 with germinoma, and 1 with non-Hodgkin's lymphoma), a significant temporal decline of translocations, with a mean decline rate of 4.4% +/- 0.4% monthly, could be detected. Two testicular seminoma patients showed no temporal decline of aberration frequencies., Conclusion: Most partial body irradiated patients (9 of 11) showed a significant temporal decline of translocation frequencies during a 36-month period. Thus, reciprocal translocations after partial body irradiation cannot be regarded as stable over time. The temporal decline of aberration frequencies has to be taken into account for retrospective dose estimations.

Purpose: Adjuvant postoperative para-aortic lymph nodal irradiation is an acceptable alternative to para-aortic and ipsilateral pelvic irradiation postorchiectomy for patients with Stage I seminoma of the testis. In this article, we report the long-term results of our prospective evaluation of para-aortic irradiation only for such patients., Methods and Materials: Between March 1991 and September 2000, 71 patients with Stage I seminoma were treated with adjuvant irradiation to the para-aortic region only after radical inguinal orchiectomy. Radiotherapy was delivered using parallel-opposed fields extending from T11 to L5. A total dose of 25 Gy in 15 fractions was prescribed to midpoint. Follow-up was performed every 3 months for the first year, every 4 months for the second and third years, every 6 months for the fourth and fifth years, and annually thereafter. Chest X-ray, tumor markers, and computed tomography scan of the pelvis were performed routinely as part of the follow-up investigation., Results: At a median follow-up of 75 months, 68 of 71 patients are alive and free of relapse. Only 1 patient (1.4%) experienced failure in the ipsilateral inguinal nodal region. Two patients (2.8%) died of unrelated causes. The actuarial 10-year relapse free survival is 98.5% and the actuarial 10-year overall survival is 92%. No late toxicity has been encountered., Conclusion: Patients with Stage I seminoma of the testis may be safely treated with para-aortic radiotherapy only. Risk of pelvic failure is very low and treatment toxicity minimal.

Purpose: To determine the outcome in men with Stage I seminoma treated with low-dose para-aortic radiation., Materials and Methods: Between January 1988 and December 2000, 431 men with Stage I seminoma were treated with para-aortic radiation to a midplane dose of 20 Gy in 8 fractions over 10 days., Results: At a median follow-up of 62 months, 15 patients (3.5%) had relapsed, with a median time to relapse of 13 months (range: 9 to 39 months). Nine patients had pelvic nodal relapse; in addition, 1 patient had para-aortic involvement, and 2 had distant disease. Four had metastatic disease only (mediastinum 2, lung 2). One patient had scrotal recurrence, and 1 was treated for progressive rise in human chorionic gonadotrophin without identifiable disease. Initial treatment at relapse was chemotherapy (12), radiation (2), and surgery (1). One patient died from progressive disease. Thirteen men (3%) have developed second malignancies, including 7 contralateral testicular tumors, 5 solid malignancies, and 1 leukemia. The overall 5-year survival was 98%, and the estimated recurrence-free survival at 5 years was 96.3%. On log-rank univariate analysis, lymphovascular invasion, involvement of the tunica, and a preoperative human chorionic gonadotrophin level of greater than 5 were found to be of prognostic significance for recurrence., Conclusions: These data support short-duration, limited-field radiation as an optimal safe and effective protocol in the management of Stage I seminoma patients.

Purpose: Prophylactic left supraclavicular fossa irradiation has been suggested to reduce relapse rates in patients treated for Stage IIA/B testicular seminoma. To address this issue, we reviewed patterns of failure and treatment outcome in patients treated with radiation therapy at our institution., Methods and Materials: Between 1981 and 1999, 79 men with Stage II seminoma (IIA, 49; IIB, 30) were treated with radiation therapy (RT) to the para-aortic and ipsilateral (+/- contralateral) pelvic lymph nodes (dose: 25-35 Gy)., Results: With a median follow-up of 8.5 years, the 5-year relapse-free rate was 91% (standard error: 3%), and 2 patients have died of seminoma, giving a 5-year cause-specific survival of 97%. A total of 7 patients have relapsed with 2 isolated to the left supraclavicular fossa. Five of 7 patients have been successfully salvaged., Conclusions: Prophylactic left supraclavicular fossa irradiation might have prevented relapse in 2 of 79 patients in Stage IIA/B seminoma. However, 97% of patients would have received unnecessary left neck RT, so we continue to recommend, as standard treatment, infradiaphragmatic RT only.

Purpose: External beam radiation therapy (EBRT) of most intrapelvic and testicular tumors has been generally performed with large fields encompassing both the primary disease and lymphatic drainage. This study was carried out to map the pelvic and periaortic lymphatics by means of iliopelvic lymphoscintigraphy (IPL) in preparation for radiotherapy planning., Methods and Materials: Between January 2000 and October 2001, 70 patients scheduled for EBRT (61 operated on, 52 females, 18 males, mean age 61, range, 24-80), affected with uterine (43), rectal (11), testicular (8), anal (4), penile (2), and vulvar (2) cancers were enrolled in the study. IPL was performed by injection of 99mtechnetium-nanocolloids in the bipedal (70 cases) or bipedal plus perianal (20 cases) sites. The sensitivity of IPL in mapping the lymphatic anatomy was evaluated first. Then three radiation oncologists scored the modifications induced by IPL on the planning target volume (PTV) which had been previously delineated only on the basis of bony landmarks. The original fields were classified "inadequate" if they failed to match the new PTV by more than 1 cm., Results: IPL sensitivity in showing the inguinal, external iliac, common, and periaortic lymphatics was 100%, 90%, 80%, and 70% in anterior-posterior (A-P) projections, and 100%, 80%, 70%, and 60% in lateral projections respectively. For the presacral and hypogastric ones the sensitivity was 40%. When compared with bony landmarks, IPL changed the delineation of PTV in 24 of 70 A-P P-A fields (34%) and 22 of 58 (38%) lateral fields. Furthermore, 8/12 (67%) lymphadenectomies resulted in being incomplete. No IPL-related toxicity was observed., Conclusion: IPL is a safe, inexpensive (cost: 100 Euros), and effective method to map the lymphatic chains. In the A-P scintigrams these structures were detected in 85% (70-100%) of the patients referred for total pelvis irradiation, and this figure could be higher in subjects not operated on. IPL can also give a reliable evaluation of the lymphadenectomies in order to schedule the proper treatments after surgery. Finally, IPL may change the conventional PTV for pelvic irradiation in about 36% (34-38%) of the cases; therefore, the fields should be tailored more around the lymphatic landmarks than the bony landmarks.

Purpose: Orchiectomy followed by infradiaphragmatic irradiation is the standard treatment for Stage I-II testicular seminoma in The Netherlands. Because body image and sexual functioning can be affected by treatment, a retrospective study was carried out to assess treatment outcome, body image, and changes in sexuality after orchiectomy and radiotherapy., Methods and Materials: The medical charts of 166 patients with Stage I-II testicular seminoma were reviewed. A questionnaire on body image and current sexual functioning regarding the frequency and quality of erections, sexual activity, significance of sex, and changes in sexuality was sent to 157 patients (at a mean of 51 months after treatment)., Results: Seventy-eight percent (n = 123, mean age 42 years) completed the questionnaire. During irradiation, almost half of patients experienced nausea and 19% nausea and vomiting. Only 3 patients had disease relapse. After treatment, about 20% reported less interest and pleasure in sex and less sexual activity. Interest in sex, erectile difficulties, and satisfaction with sexual life did not differ from age-matched healthy controls. At the time of the survey, 17% of patients had erectile difficulties, a figure that was significantly higher than before treatment, but which correlated also with age. Twenty percent expressed concerns about fertility, and 52% found their body had changed after treatment. Cancer treatment had negatively influenced sexual life in 32% of the patients., Conclusions: Orchiectomy with radiotherapy is an effective and well-tolerated treatment for Stage I-II testicular seminoma. Treatment-induced changes in body image and concerns about fertility were detected, but the sexual problems encountered did not seem to differ from those of healthy controls, although baseline data are lacking.

Purpose: In Stage I seminoma, treatment with radiation therapy (RT) after radical inguinal orchiectomy reduces the likelihood of relapse by 15%, but does not improve survival, thus making quality of life an important outcome measure. The purpose of this study was to use utilities to assess the quality of life benefits associated with adjuvant RT in this setting., Materials and Methods: One hundred healthy men were interviewed using a utility assessment tool. Utilities for five health states were measured using the standard gamble technique: (A) adjuvant RT with 5% recurrence risk; (B) recurrence after RT, salvaged with chemotherapy; (C) orchiectomy alone with 20% recurrence risk; (D) recurrence after orchiectomy alone, salvaged with RT; and (E) recurrence after orchiectomy alone, salvaged with chemotherapy., Results: The median age was 25. Utilities were highest for nonrecurrent health states, and lowest for recurrence salvaged with chemotherapy. All differences in utilities between health states were significant, except between states A and C and B and E. Variability in utilities was not explained by the sociodemographic factors examined., Conclusions: Our results suggest that healthy males do not value the 15% reduction in recurrence risk achievable with adjuvant RT. However, they do predict that an actual recurrence, especially one requiring salvage chemotherapy, will lead to significant decline in quality of life. We intend to use these utilities to further evaluate the cost-effectiveness of RT in this setting.

Purpose: To assess the outcome and patterns of failure in patients with testicular lymphoma treated by chemotherapy (CT) and/or radiation therapy (RT)., Methods and Materials: Data from a series of 36 adult patients with Ann Arbor Stage I (n = 21), II (n = 9), III (n = 3), or IV (n = 3) primary testicular lymphoma, consecutively treated between 1980 and 1999, were collected in a retrospective multicenter study by the Rare Cancer Network. Median age was 64 years (range: 21-91 years). Full staging workup (chest X-ray, testicular ultrasound, abdominal ultrasound, and/or thoracoabdominal computer tomography, bone marrow assessment, full blood count, lactate dehydrogenase, and cerebrospinal fluid evaluation) was completed in 18 (50%) patients. All but one patient underwent orchidectomy, and spermatic cord infiltration was found in 9 patients. Most patients (n = 29) had CT, consisting in most cases of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with (n = 17) or without intrathecal CT. External RT was delivered to scrotum alone (n = 12) or testicular, iliac, and para-aortic regions (n = 8). The median RT dose was 31 Gy (range: 20-44 Gy) in a median of 17 fractions (10-24), using a median of 1.8 Gy (range: 1.5-2.5 Gy) per fraction. The median follow-up period was 42 months (range: 6-138 months)., Results: After a median period of 11 months (range: 1-76 months), 14 patients presented lymphoma progression, mostly in the central nervous system (CNS) (n = 8). Among the 17 patients who received intrathecal CT, 4 had a CNS relapse (p = NS). No testicular, iliac, or para-aortic relapse was observed in patients receiving RT to these regions. The 5-year overall, lymphoma-specific, and disease-free survival was 47%, 66%, and 43%, respectively. In univariate analyses, statistically significant factors favorably influencing the outcome were early-stage and combined modality treatment. Neither RT technique nor total dose influenced the outcome. Multivariate analysis revealed that the most favorable independent factors predicting the outcome were younger age, early-stage disease, and combined modality treatment., Conclusions: In this multicenter retrospective study, CNS was found to be the principal site of relapse, and no extra-CNS lymphoma progression was observed in the irradiated volumes. More effective CNS prophylaxis, including combined modalities, should be prospectively explored in this uncommon site of extranodal lymphoma.

Purpose: To compare the outcome of patients with Stage II seminoma treated with prophylactic mediastinal irradiation, without any supradiaphragmatic irradiation, and with prophylactic left supraclavicular irradiation (PLSCI)., Methods and Materials: Between 1960 and 1999, 73 men with Stage II seminoma received postorchiectomy radiotherapy. Before 1984, 36 received prophylactic mediastinal irradiation (Series I); between 1984 and 1992, 17 received no supradiaphragmatic irradiation (Series II); and after 1992, 20 received PLSCI (Series III). The outcomes in these series were compared., Results: The abdominal tumor sizes were as follows: Series I, 2 and 5 and 2 and 5 and 2 and 5 and

Purpose: Testicular intraepithelial neoplasia (TIN) is a consistent precursor of most invasive germ cell tumors, currently treated by radiotherapy with 20 Gy, which destroys TIN but preserves Leydig cells. Nevertheless, analysis has shown dose-dependent dysfunction even with low therapeutic doses of 20 Gy in some cases. Therefore, we tested a dose reduction regimen by delivering smaller fractional doses to enhance the tolerance of Leydig cells., Methods and Materials: Between 1993 and 1999, 9 patients were treated for TIN in a prospective multicenter trial. A total dose of 13 Gy was administered in 10 fractions of 1.3 Gy. Hormonal levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were assayed serially., Results: During a median follow-up time of 36 months, no patient showed evidence of local disease. A first postradiation biopsy was obtained 3-12 months after radiotherapy; 5 patients underwent a second biopsy 2-3 years after treatment. All biopsies showed a Sertoli cell-only pattern. Follicle-stimulating hormone levels continued to increase 1 year after radiotherapy, signaling eradicated spermiogenesis. Luteinizing hormone and testosterone remained within the normal range 2 years after radiotherapy., Conclusions: In the treatment of TIN, there seems to be a dose reduction potential to 13 Gy by lowering single fractional doses, which enhances the therapeutic ratio in favor of the Leydig cells.

Purpose: The evaluation of radiation-induced chromosomal translocations in peripheral lymphocytes using fluorescent in situ hybridization is a promising method for retrospective dosimetry after a radiation accident. We evaluated the genomic frequency of chromosomal translocations in patients with testicular seminoma who received adjuvant radiotherapy to the retroperitoneal lymph nodes, to evaluate the time-effect relationship of radiation-induced stable aberrations after partial body irradiation., Methods: In 13 patients, peripheral lymphocytes could be evaluated before radiotherapy and at several time points after radiotherapy. In 17 additional patients, lymphocyte samples were obtained after radiotherapy. Thirteen healthy men served as age-matched controls for the aberration frequency before radiotherapy. Fluorescent in situ hybridization was performed using whole chromosome probes against chromosomes No. 4, No. 6, and No. 7., Results: Nearly all patients displayed an increased spontaneous rate of genomic translocations (F(G)) before radiotherapy compared to age-matched, healthy men. The difference was significant in the paired ranks test (p < 0.0001). After adjuvant radiotherapy, the F(G) increased 2- to 8-fold in individual patients. Within 20 months after radiotherapy, the F(G) returned to pretherapeutic levels., Conclusions: The frequency of genomic translocations after partial body irradiation is time dependent. A persistence of chromosomal aberrations, which is to be expected after total body irradiation, could not be observed. It is likely that the dose and the volume of the irradiated bone marrow are playing a role in the persistence of stable chromosomal aberrations. Patients with testicular seminoma displayed an increased frequency of spontaneous genomic translocations before the initiation of radiotherapy. This chromosomal instability might be related to the known increased rate of secondary cancers in this patient group.

Purpose: A retrospective review of patients with Stage I and II seminoma treated at a regional cancer center was performed to assess the long term efficacy and toxicity associated with post operative radiotherapy., Methods and Materials: Between 1950 and 1995, 212 patients seen at the London Regional Cancer Centre received adjuvant radiotherapy following orchiectomy for Stage I (169) and II (43) seminoma. Median follow-up for the group was 7.5 years., Results: Progression free, cause specific, and overall survival were 95%, 98%, and 95% at 5 years, and 94%, 98%, and 94% at 10 years respectively. An increased risk of failure was noted among patients with bulky Stage II disease. No other prognostic factors for relapse were identified. Late toxicity was uncommon with only 12/212 (6%) developing any late GI toxicity potentially attributable to radiotherapy. The incidence of second malignancies (excluding second testicular tumors) was 6/212 (actuarial:1%, 1%, 6% at 5,10,15 years respectively). There was a trend toward increased acute complications for patients treated with larger volumes of radiation. No prognostic factors associated with increased risk of late toxicity or second malignancy were identified, likely a consequence of the small number of these events., Conclusion: Survival and toxicity were comparable to that reported in the literature. Post-operative radiotherapy remains a safe and efficacious adjuvant treatment for Stage I and early Stage II seminoma.

Purpose: Results of treatment of patients with Stage I seminoma with orchiectomy and radiotherapy are excellent. Even without adjuvant radiotherapy, the relapse rate is only 15-20%; most of the patients fail in the retroperitoneum, with rare failures observed in the pelvis (0.5-2%). In 1991, we began a prospective study evaluating para-aortic lymph node radiation as the only adjuvant treatment for such patients. This paper reports our preliminary results., Materials & Methods: Between March 1991 and January 1996, 35 patients with histologically proven Stage I seminoma were entered in the study. Median age was 37.9 years (range: 27-65 years). A radical inguinal orchiectomy was performed in all patients. Staging workup consisted of a chest X-ray; B-HCG, alpha-fetoprotein, and CT scan of the abdomen and pelvis in all patients. Lymphangiogram was done in 23 (66%) of 35 patients for further evaluation of the retroperitoneal lymph nodes. Radiotherapy consisted of treatment to the para-aortic region only. Parallel opposed fields extending from the top of T11 to the bottom of L5 were used. The median field size was 8.7 x 21.8 cm (range: 7-11 x 18-26 cm). The median total dose, prescribed at midpoint, was 25 Gy given in 15 daily fractions of 1.66 Gy. Follow-up was performed every 3 months for the first year, every 4-5 months for the second and third years, and every 6 months thereafter. Chest X-ray, tumor markers, and CT scan of the pelvis were performed routinely as part of the follow-up investigation., Results: At a median follow-up of 39.7 months (range: 16-74 months), 34 (97.1%) of 35 patients are alive with no evidence of disease for an overall actuarial survival rate of 97.1% at 5 years and a cause-specific actuarial survival rate of 100%. Treatment morbidity was limited to Grade I-II acute side effects in 18 (51.4%) of 35 patients. No late side effects were seen., Conclusion: From our preliminary results, adjuvant radiation treatment limited to the para-aortic lymph node region, without ipsilateral pelvic irradiation, appears to be adequate treatment for Stage I seminoma. Such an approach in our patients resulted in minimal toxicity and excellent disease-free survival.

Purpose: A prospective multicenter study was carried out to estimate the treatment outcome of radiotherapy in Stage II seminoma after the application of modern staging and radiotherapy techniques. The lower margin of the iliac field was positioned on the upper rim of the acetabulum to reduce the amount of scattered irradiation to the remaining testicle., Methods and Materials: The study was carried out in 25 centers in Germany. Patients with pure seminoma, negative AFP-values, and retroperitoneal lymph node metastases of less than 5 cm in diameter were entered into the study. All patients received a ventrodorsal opposed field irradiation of the para-aortic and the ipsilateral iliac lymph nodes. The fields extended from the top of the 11th thoracic vertebra to the top of the acetabulum. Patients in Stage IIA (lymph nodes <2 cm ) received 30 Gy, and patients with Stage IIB (lymph nodes between 2 and 5 cm) 36 Gy total dose., Results: 39 patients in Stage IIA and 19 patients in Stage IIB were evaluated. After a median observation time of 37 months all patients are alive and disease free. Recurrence free survival in stage IIA was 100%. Two patients in Stage IIB experienced a recurrence 10 and 17 months after the end of radiotherapy. The actuarial recurrence free survival estimate in Stage IIB was 94.1% for 1 year and 87.4% for 2 years. One recurrence in Stage IIB occurred in the mediastinum, one in the mediastinum, and one the lung. Both patients could be salvaged by chemotherapy. There were no pelvic recurrences. The treatment was well tolerated, with nausea being the most common side effect (56.9% Grade 1, 15.5% Grade 2, and 8.6% Grade 3). Diarrhea occurred in 15.5% (Grade 1), 15.5% (Grade 2), and 5.2% (Grade 3) of the patients., Conclusions: The outcome of para-aortic and ipsilateral iliac irradiation in Stage IIA/B testicular seminoma is excellent with the currently available staging methods and treatment facilities. The treatment is well tolerated. The lower margin of the iliacal field can be placed at the acetabulum.

Purpose: To analyze the clinical characteristics, prognosis, and treatment outcome of pelvic cryptorchid seminoma (PCS), and to determine whether whole abdominal-pelvic irradiation for Stage I disease is necessary., Methods and Materials: From 1958 to 1991, 60 patients with PCS were treated at the Cancer Hospital of Chinese Academy of Medical Sciences, Beijing. They presented with a lower abdominal mass and showed a predominance for the right side. A high proportion of patients with PCS [26 of 60 (43%)] had metastatic disease, compared to 20% of those with scrotal seminoma, and there was a tendency toward a higher frequency of pelvic nodal metastases. There were 34 Stage I, 6 Stage IIA, 11 Stage IIB, 5 Stage III, and 4 Stage IV patients. Of these 60 patients, 56 underwent laparotomy with or without cryptorchiectomy (37 radical orchiectomy, 7 partial orchiectomy, and 12 biopsy of the primary or cervical node), and 4 cervical node biopsy only. All patients were further treated with radiotherapy, chemotherapy, or a combination of both. Patients with Stage I and II disease received radiotherapy, whereas patients with Stage III and IV were treated with chemotherapy., Results: The overall and disease-free survivals at 5 and 10 years were 92% and 87%, and 88% and 84%, respectively. The 5- and 10-year survivals were 100% for Stage I, 94% and 87% for Stage II, and 56% and 42% for Stage III/IV, respectively (p < 0.05). Volume of irradiation, i.e., whole abdominal-pelvic radiotherapy (10 patients), versus hockey-stick encompassing paraaortic, ipsilateral iliac nodes and the primary tumor or tumor bed (17) did not influence outcome in Stage I patients. Five patients relapsed within 2-12 years after treatment, and four of these patients were successfully salvaged. Four patients developed a second malignant tumor and died., Conclusion: Stage I and II PCS can be adequately controlled by radiotherapy regardless of the surgical procedure. Whole abdominal-pelvic irradiation for Stage I and IIA disease is not required, and fields can be limited to the paraaortic, ipsilateral iliac nodes and primary tumor or tumor bed. We recommend platinum-based chemotherapy for Stage IIB-IV PCS.

Purpose: The results of Southwest Oncology Group Study 8711 (Group 2B) are presented. The objective was to evaluate the natural history of sperm concentration and selected hormonal parameters in patients with testicular cancer treated with orchiectomy and radiotherapy., Methods and Materials: Of a total of 207 patients enrolled on SWOG 8711, 53 pure seminoma patients were identified who were treated with orchiectomy and radiotherapy only. Sperm concentration, follicle-stimulating hormone (FSH) levels, and sexual satisfaction scores were the main parameters followed., Results: A fraction of the patients were infertile prior to receiving radiotherapy. Our analysis indicates that incidental radiation dose to the remaining testicle affects time to recovery of fertility, and at an aggregate level, changes in FSH mirror changes in sperm concentration over time. This phenomenon is the same as that described in patients free from testicular cancer. These men evaluated their sexual activity as good after orchidectomy., Conclusion: Our data support the use of clamshell-type testicular shields as a means of providing maximum protection to the remaining testicle.

Purpose: To establish a predictive model for the estimation of the gonadal dose during adjuvant para-aortic (PA) or dog leg (DL: PA plus ipsilateral iliac) field radiotherapy in patients with testicular seminoma., Methods and Materials: The surface gonadal dose was measured in patients with seminoma Stage I receiving PA or DL radiotherapy. Sperm cell analysis was performed before and 1 year after irradiation. PA and DL radiotherapy were simulated in the Alderson phantom while we measured the dose to the surface and middle of an artificial testicle, varying its position within realistic anatomical constraints. The symphysis-to-testicle distance (STD), field length, and thickness of the patient were experimental variables. The developed mathematical model was validated in subsequent patients., Results: The mean gonadal dose in patients was 0.09 and 0.32 Gy after PA and DL irradiation, respectively (p < 0.001). DL radiotherapy, but not PA irradiation led to significant reduction of the sperm count 1 year after irradiation. The gonadal dose-reducing effect of PA irradiation was confirmed in the Alderson phantom. A significant correlation was found between the STD and the gonadal dose during DL irradiation. A mathematical model was established for calculation of the gonadal dose and confirmed by measurements in patients., Conclusions: During radiotherapy of seminoma, the gonadal dose decreases with increasing STD. It is possible to predict the individual gonadal dose based on delivered midplane dose and STD.

Purpose: To assess the accuracy of field alignment in a homogeneous group of patients undergoing radiotherapy of the abdomen (adjuvant treatment of the paraaortic region in Stage I testicular seminoma). To evaluate the predictive value of the first verification on field placement errors during subsequent treatment delivery., Methods and Materials: In 45 patients, linear and rotational discrepancies were measured between simulation and first check and between 10 consecutive verification films., Results: For the total group of patients, the distribution of all deviations showed mean values between 2.3 mm and -2.7 mm with standard deviations of 3.9 mm to 4.7 mm for linear discrepancies, and -0.5 degree to 0.3 degree with standard deviations of 1.2 degrees to 2.1 degrees for rotational discrepancies, respectively. For all patients, deviations for the transition from simulator to the treatment machine were similar to deviations during subsequent treatment delivery, with 95% of all absolute deviations < 10.0 mm and 4 degrees, respectively. When performing correlation analysis between deviations at first check and during treatment delivery, a correlation for lateral displacements and a borderline correlation for caudal displacements could be found. There was no correlation for cranial and rotational displacements., Conclusions: Although a trend of deviations for subsequent treatment delivery may be shown at first check, our analysis indicates that the first verification cannot reliably predict inaccuracies during treatment delivery. Random fluctuations of field displacements of up to 1.0 cm prevail. They must be considered when prescribing the safety margins of the planned target volume and determining cutoff points for corrective actions in abdominal radiation therapy.

Purpose: To review the survival, cure rate, and pattern of relapse or progression of patients with histologically confirmed Stage I testicular seminoma who underwent orchiectomy and radiation therapy to paraaortic lymphatics only. The pelvic ipsilateral lymph nodes were not irradiated., Methods and Materials: Between 1978 and 1992, 150 patients with Stages I or II testicular seminoma received treatment at the Department of Radiation Oncology of the University of Wuerzburg. The distribution by stage was Stage I, 117 patients of which 93 were pT1 N0 M0 and 24 were pT2 N0 M0. Four patients were staged as Stage II (pT3 N0 M0), and in 29 patients the T Stage was not specified. Eighty-six patients from the 117 Stage I (pT1-pT2, N0 M0 according to the TNM classification) seminoma received postorchiectomy irradiation, and are analyzed for outcome in this article. The distribution of the Stage I patients by pT Stage was 71 pT1 and 15 pT2 patients. All these 86 patients had their paraaortic nodes (the biological target volume extending from top of L1 to the bottom of L5) irradiated with four field technique. Tumor dose was specified at normalization point along the central axis. The median tumor dose was 30 Gy given in 1.8-2.0 Gy fractions. Elective irradiation to the ipsilateral hemipelvis (iliac nodes) was totally abandoned., Results: The 10-year disease-free survival and overall survival were 95.3 and 100%. No recurrence in the irradiated field was noted. Four patients (4.7%) experienced relapse of disease outside the treated volume. The most common site of solitary failure was the ipsilateral hemipelvis (one iliacal and one inguinal). One patient developed metastatic disease to the lung. One patient developed a mediastinal recurrence with superior vena cava syndrome and was successfully salvaged by mediastinal irradiation and chemotherapy., Conclusions: Recommendation for the future management of Stage I seminoma include: reduced biological target volume to the paraaortal lymph nodes (from lumbar vertebra L1 to L5). Complete elimination of irradiation to the pelvic nodes is warranted. Radiation dose should not exceed 30 Gy.

Purpose: Early-stage testicular seminoma is among the most radiosensitive tumors, with an overall cure rate of over 90%. Among those cured of the disease by orchiectomy and postoperative irradiation, there is a risk of having a second malignancy. We conducted a study to determine the relative risk of the occurrence of secondary malignancy., Methods and Materials: From 1964 through 1988, 128 patients with histologically confirmed early-stage seminoma of the testis underwent orchiectomy and postoperative irradiation at the Radiation Oncology Center, Mallinckrodt Institute of Radiology, and affiliate hospitals. The follow-up periods ranged from 5 to 29 years, with a median of 11.7 years. The expected rate of developing a second cancer was computed by the standardized incidence ratio using the Connecticut Tumor Registry Database. The rate is based on the number of person-years at risk, taking into account age, gender, and race., Results: Nine second nontesticular malignancies were found; the time of appearance in years is indicated in brackets: two squamous cell carcinomas of the lung [3, 11], one adenocarcinoma of the rectum [15], one chronic lymphocytic leukemia [2], one adenocarcinoma of the pancreas [14], one diffuse histiocytic lymphoma of the adrenal gland [7], one sarcoma of the pelvis [5], and two transitional cell carcinomas of the renal pelvis and ureter [14, 17]. One patient who developed a contralateral testicular tumor was excluded from risk assessment. The actuarial risk of second nontesticular cancer is 3%, 5%, and 20%, respectively, at 5, 10, and 15 years of follow-up. When compared with the general population, the overall risk of second nontesticular cancer in the study group did not reach the 0.05 significance level, with an observed/expected (O/E) ratio of 2.09 (95% confidence interval, 0.39-3.35). When analyzed by the latency period after radiation treatment, during the period of 11 to 15 years, the risk was higher (O/E ratio of 4.45, 95% confidence interval, 1.22-11.63) than expected. The median duration for developing a second cancer was 11 years for tumors arising from tissues outside the irradiated field and 14 years for those within or near the irradiated area., Conclusions: The overall observed incidence of second nontesticular malignancy among patients with early-stage testicular seminoma treated with adjuvant radiation therapy was not significantly increased in comparison with the expected incidence. Clinical implications are discussed.

Purpose: A retrospective analysis of 74 patients with pure seminoma, treated at the University of Florida between 1964 and 1989, was undertaken., Methods and Materials: All patients received megavoltage irradiation, with chemotherapy reserved for salvage. At 10 years, the probability of relapse-free survival was 91% for Stage I, 93% for Stage IIA, 83% for Stage IIB, and 75% for Stage III patients., Results: There were seven recurrences, none of which occurred in irradiated areas. Only two of seven patients (29%) with recurrence were salvaged., Conclusion: A literature review revealed an increasing rate of mediastinal or supraclavicular recurrence, correlating with the size of the subdiaphragmatic disease, in Stage II patients who did not receive elective mediastinal irradiation. Recommendations are made regarding the role of elective mediastinal irradiation for Stage II disease. We conclude that patients with Stage I or II seminoma can have high cure rates when treated with radiotherapy alone. Patients with Stage III seminoma should be treated initially with cisplatin-based chemotherapy.

Purpose: This study was undertaken to investigate whether the hypertension observed in a subgroup of patients with progressive radiation-induced nephropathy has a renovascular component., Methods and Materials: Fifteen patients with prospectively documented renal injury after high-dose radiation treatment for various abdominal malignancies were studied, 8 of them having hypertension. 99mTc-DTPA renography and plasma renin activity measurements were performed before and after an oral dose of 50 mg captopril. In patients with a positive captopril renography, a selective angiography was performed to exclude preexisting central renal artery stenosis and to assess the type and extent of the vascular changes., Results: The captopril 99mTc-DTPA renography demonstrated a longer time until maximal renal activity (Tmax) compared with the baseline study in five out of eight hypertensive patients. This increase in Tmax was observed in both high-dose (40 Gy/5.5 weeks) and in low-dose (12-13 Gy/3 weeks) irradiated kidneys. No increase in Tmax was observed in the normotensive patients. In the five hypertensive cases with an increased Tmax, selective angiography demonstrated severe stenotic and tortuous changes in the small intrarenal branches of the high-dose irradiated kidneys without stenosis of the main renal artery. Captopril induced an increase in peripheral plasma renin activity in the hypertensive group, but not in the normotensive patients., Conclusion: These data suggest a radiation-induced hypertension, mediated by the renin-angiotensin system due to damage in predominantly small renal arteries. It was possible to demonstrate hypertensive changes with a captopril 99mTc-DTPA renography, even after presumed subthreshold radiation doses for clinical radiation nephropathy.

Purpose: To review the survival, cure rate, treatment morbidity, and late sequelae of histologically confirmed seminoma patients who underwent orchiectomy and radiation therapy at the Radiation Oncology Center, Mallinckrodt Institute of Radiology, from 1964 to 1988., Methods and Materials: There were 128 patients, with a median patient age of 37 years (range, 17-79 years). Follow-up ranged from 1-24 years, with a median of 6.7 years. There were 95 patients with Stage I and 33 with Stage IIA disease. All patients were treated with orchiectomy followed by iliac and paraaortic irradiation (median tumor dose: 2500 cGy for Stage I and 3400 cGy for Stage IIA patients). Twenty-five of 33 patients with Stage IIA disease received prophylactic mediastinal and left supraclavicular irradiation (median dose, 2700 cGy)., Results: For patients with Stage I disease, 5-year disease-free survival, overall survival, and survival corrected for intercurrent disease were 97%, 100%, and 100%, respectively. For patients with Stage IIA disease, the 5-year disease-free survival, overall survival, and survival corrected for intercurrent disease were 93%, 89%, and 97%, respectively. Four patients (3%) had recurrences; all were outside the radiation treatment field. Three of four were successfully salvaged with chemotherapy and rendered disease-free; the other patient refused treatment. There were no mediastinal recurrences whether prophylactic mediastinal irradiation was administered or not. Bowel obstruction and necrosis developed in one patient who received 3363 cGy midplane dose to the pelvic and paraaortic areas as well as additional intraperitoneal colloidal 198Au (150 mCi) for a ruptured seminoma from an undescended testis., Conclusion: In summary, radical orchiectomy and irradiation of the iliac and paraaortic lymphatics is the treatment of choice for patients with Stage I and IIA testicular seminoma.

Purpose: From 1956 to 1986, we have retrospectively studied 184 patients with a Stage I testis seminoma treated by orchidectomy and radiotherapy at the Institut Gustave Roussy., Methods and Materials: The 184 patients received adjuvant radiotherapy to the para-aortic and ipsilateral iliac nodes. Of the 184 patients, 133 received additional mediastinal and supraclavicular irradiation, 47 received supraclavicular without mediastinum irradiation, 98 patients received additional radiotherapy given to inguino-scrotal area. The mean dose of irradiation is 21 Gy which is the lowest dose published. The actuarial survival rate is, respectively, 96%, 93%, 83% and 77% at 5, 10, 15, and 20 years., Results: Four patients relapsed, and four died of progressive disease. Four patients presented cardiovascular disease, all of them had mediastinal irradiation, two were heavy smokers. Seventeen second malignancies were observed, six tumors in the contralateral testis. The actuarial risk of developing a second malignancy is 10% at 10 years, 21% at 20 years. The cure rate and relapse rate in our patients is the same as that obtained by higher dosage of irradiation., Conclusion: We conclude that low dose of prophylactic irradiation in lumbo aortic and ipsilateral iliac lymph nodes is active and safe in the treatment of Stage I testis seminoma.

Purpose: To clarify the controversy about the management and prognosis of human chorionic gonadotropin-producing seminoma, the records of 132 patients with abnormal human chorionic gonadotropin values treated with radiotherapy were analyzed., Methods and Materials: The records of 1169 patients with pure seminoma treated in 10 institutions were screened for serum or urinary human chorionic gonadotropin. One hundred and thirty two patients with elevated human chorionic gonadotropin were found: 96 Stage I, 20 IIA, 7 IIB, 8 III and 1 IV. Median age was 34 y., mean follow-up was 5.0 years [range 1-12 y]. All received infradiaphragmatic radiotherapy (median dose 30 Gy), 25 (2 Stage I, 11 IIA, 5 IIB and 7 III) supradiaphragmatic radiotherapy (median dose: 28.5 Gy) and 10 had also initial chemotherapy (3 Stage IIB 6 III and 1 IV). Patients were allocated to three groups according to human chorionic gonadotropin values: (a) moderate elevation: up to 10 times (104 pts), (b) high elevation: 10 to 100 times (20 pts), (c) very high elevation: over 100 times the upper limit of normal value (8 pts)., Results: The proportion of Stage I, II and III was 76%, 19%, 5% in the ME group versus 50%, 35%, 15% in the high elevation group (p < 0.05). In the very high elevation group there were 7 Stage I and 1 Stage IV. Of 132 patients, six died (three dead of disease, two suicides, one acquired immunodeficiency syndrome). The 5 years overall survival probability was 94%. There were seven recurrences (initial stage: 1 Stage I, 2 IIB, 3 III and 1 IV). Of these, there were one in-field recurrence, 3 out of field and 3 in both sites. In 5 of 7, the human chorionic gonadotrophin level was again elevated at recurrence. The 5 years recurrence-free-survival probability was 94% (98% for Stage I, 100% for Stage IIA and 65% for Stage IIB and III [p < 0.001 between I and IIB + III, p < 0.05 between IIA and IIB + III]). Four of the 7 recurrences were salvaged by chimiotherapy +/- radiotherapy. In the high elevation and very high elevation groups, the 5 years recurrence-free-survival was 88%, vs. 96% for the moderate elevation group (p = 0.10)., Conclusion: Based on this series of patients, human chorionic gonadotropin production is not an unfavorable prognostic factor in pure seminoma. Even in the subgroups with high or very high human chorionic gonadotropin levels (who had a higher proportion of advanced stages), the prognosis remained excellent. In Stage I and IIA seminoma with abnormal human chorionic gonadotropin levels, recurrence rate after post-operative radiotherapy alone is extremely low.

Purpose: To determine what proportion of patients with Stage I testicular seminoma will be cured with orchidectomy alone., Methods and Materials: From August 1984 to December 1991 148 patients with Stage I testicular seminoma were entered on a prospective study of surveillance following orchidectomy. The eligibility criteria included a normal chest X ray, lymphogram, computed tomography (CT) of the abdomen and pelvis, and normal post-orchidectomy tumor markers (AFP and BHCG). Patients were followed with a clinical assessment (markers, chest X ray and CT abdomen and pelvis) at 4 to 6 monthly intervals., Results: With a median follow-up of 47 months (range 7-87 months), the actuarial relapse-free rate was 81% at 5 years. Twenty-three patients have relapsed with a median time to relapse of 15 months (range 2-61 months). Four patients (17%) relapsed at 4 or more years from diagnosis. Twenty-one of the 23 relapses occurred in the paraaortic lymph nodes, one patient relapsed in the mediastinum and ipsilateral inguinal nodes and one patient had an isolated ipsilateral inguinal node relapse. Nineteen patients were treated for relapse with external beam radiation therapy of which three developed a second relapse and were salvaged with chemotherapy. Four patients were treated for first relapse with chemotherapy and one developed a second relapse and died of disease. Age at diagnosis was the only prognostic factor for relapse, with patients age < or = 34 having an actuarial relapse-free rate at 5 years of 70% in contrast to a 91% relapse-free rate in those > 34 years of age., Conclusions: We recommend that surveillance in Stage I testicular seminoma should only be performed in a study setting until further data regarding the risk of late relapse and the efficacy of salvage chemotherapy is available.

Purpose: A patient series was analyzed retrospectively as an example of whole organ kidney irradiation with an inhomogenous dose distribution to test the validity of biophysical models predicting normal tissue tolerance to radiotherapy., Methods and Material: From 1969 to 1984, 142 patients with seminoma were irradiated to the paraaortic region using predominantly rotational techniques which led to variable but partly substantial exposure of the kidneys. Median follow up was 8.2 (2.1-21) years and actuarial 10-year survival (Kaplan-Meier estimate) 82.8%. For all patients 3-dimensional dose distributions were reconstructed and normal tissue complication probabilities for the kidneys were generated from the individual dose volume histograms. To this respect different published biophysical algorithms had been introduced in a 3-dimensional-treatment planning system., Results: In seven patients clinical manifest renal impairment was observed (interval 10-84 months). An excellent agreement between predicted and observed effects was seen for two volume-oriented models, whereas complications were overestimated by an algorithm based on critical element assumptions., Conclusions: Should these observations be confirmed and extended to different types of organs corresponding algorithms could easily be integrated into 3-dimensional-treatment planning programs and be used for comparing and judging different plans on a more biologically oriented basis.

Purpose: In 1984 the following changes were made in the management of testicular seminoma at The University of Texas M.D. Anderson Cancer Center: (1) abdominopelvic computerized tomography replaced the bipedal lymph-angiogram for evaluating retroperitoneal nodes; (2) elective mediastinal radiation was totally abandoned; (3) patients with abdominal adenopathy < 10 cm were classified as having Stage IIA disease. This report evaluates the impact of these management policy changes on disease outcome., Methods and Materials: Between 1960 and 1991, 350 patients with Stages I or II testicular seminoma received post-orchiectomy radiation. The 241 patients treated prior to 1984 constitute our old series, and the 109 patients treated since then are our new series. The outcomes in the new series were compared to those in the old series., Results: The distribution of patients by stage was Stage I, 282 (old series, 190; new series, 92); Stage IIA, 55 (old series, 39; new series, 16); Stage IIB, 13 (old series, 12; new series, 1). The freedom-from-relapse at 5 years correlated with stage: Stage I, 97%; Stage IIA, 87%; Stage IIB, 69%. Elevated post-orchiectomy chorionic gonadotropin levels or involvement of the spermatic cord were adverse for disease relapse in Stage I but not Stage II disease. Patients with Stage I disease fared extremely well in both series (freedom-from-relapse 97%); the outcome for patients with Stage IIA was significantly worse in the new series (5-year freedom-from-relapse 73% vs. 92%) because of a 20% actuarial incidence of apparently solitary left supraclavicular nodal relapse. Although elective mediastinal radiation in the old series prevented this failure pattern, such treatment appeared to significantly decrease the survival of patients older than 40 years., Conclusions: (1) Abdominopelvic computerized tomography scanning is adequate for the evaluation of abdominal lymph nodes in patients with seminoma; (2) Post-orchiectomy radiation to the para-aortic and ipsilateral hemipelvic regions remains the treatment of choice for patients with Stage I disease; (3) Patients with Stage IIA disease experience a 20% relapse rate especially in the left supraclavicular fossa and we recommend elective radiation to this site delivered concomitantly with para-aortic irradiation.

Purpose: To evaluate functional post-radiotherapy arterial change in a select patient population., Methods and Materials: Thirty-five seminoma patients were identified in the Radiation Oncology departmental records at Indiana University Medical Center. In this group the ipsilateral pelvis is treated with the contralateral pelvis available for evaluation as a matched control. Additionally, this group is generally young and unlikely to have pre-existing vascular disease, and shows excellent radiocurability with historically standard radiotherapy. Nineteen patients volunteered for a noninvasive vascular evaluation which included: Doppler ultrasound, segmental leg pressures, pulse volume recordings, and post-exercise testing. Average age at treatment was 36 (range 14-68) with an average follow-up of 8.8 years (range 1-20) with five patients now over 15 years post-treatment. The majority of the patients received 2500-2600 cGy., Results: Three of 19 patients had abnormal vascular evaluations. Of these, two had bilateral abnormalities not felt to be solely associated with irradiation. The remaining patient showed both resting and post-exercise ipsilateral vascular abnormalities. Irradiation was the only identifiable etiologic agent for this patient's vascular abnormality., Conclusion: Subclinical vascular change attributable to low dose radiotherapy was identified in one of 19 patients (5%). Considering the radiocurability of seminoma patients this incidence is acceptable. In light of this slight, yet documented, arterial abnormality occurring with low dose radiotherapy, we recommend additional study of high dose radiotherapy patients to determine the incidence and morbidity of radiation-induced arteriopathy in this group.

Acute/subacute side effects were evaluated in 39 testicular cancer patients before infra-diaphragmatic radiotherapy, twice during therapy and 3, 6, and 12 months after treatment discontinuation. The evaluation was primarily based on questionnaires filled in by the patients. At the end of radiotherapy nausea was reported by all responding patients, and 29 patients complained of diarrhea. Two-thirds of the patients reported abdominal pain and/or meteorism, and one-half complained of retching and/or vomiting. During therapy the median weight was significantly reduced by three kilos and the median value of the performance status decreased by 20%. The hematological and biochemical toxicity was low. At the 3-month evaluation more patients complained of nausea, abdominal pain, and meteorism than before irradiation. Compared to the pretreatment situation the patients evaluated their physical condition to be reduced during treatment and at the first follow-up visit. One year posttreatment the patients had regained their physical fitness. All patients in income-producing activity were on sick leave during the period of radiotherapy and for 5 weeks (median) thereafter. In conclusion, infra-diaphragmatic radiotherapy leads to significant but reversible acute/subacute side effects lasting for a median of 9 weeks. It is hoped that better symptomatic therapy and modifications of the radiotherapy technique will reduce the side effects.

We reviewed the clinical characteristics, treatment methods, and outcome of 26 patients presenting with seminoma arising in an undescended testis. The tumor-bearing testis was located in the iliac fossa in 17 patients and in the inguinal canal in nine. The most common presenting symptoms were pain or an enlarging mass. At diagnosis, the tumors tended to be relatively advanced, and 16 of 26 patients (62%) had nodal metastases. In addition to the paraaortic nodes, metastases were frequent to the ipsilateral iliac and inguinal nodes even in the absence of prior inguinal-scrotal surgery. Four patients had documented pelvic peritoneal tumor seeding. All patients received treatment in addition to resection of the primary tumor. Fifteen patients received radiotherapy only, 10 received chemotherapy only, and one received both modalities. At a median follow-up of 9.6 years, only one patient had relapsed. He was initially treated with radiation and after relapse was successfully salvaged with chemotherapy. The 5 and 10-year disease-free rate was 96%, and the 5 and 10-year survival rates were 92% and 79%, respectively. Appropriate treatment of seminoma arising in an undescended testis results in an excellent outcome equivalent to that observed for the more usual scrotal seminomas.

Purpose: The followup of 387 patients in a USA national survey of seminoma treated with radiation in 1973 and 1974 has been extended beyond 15 years to assess the long-term benefits and problems resulting from treatment., Results: Survival at 15 years is 83% for Stage I, 68% for Stage II; freedom from recurrence at 15 years is 93% for Stage I, 96% for Stage II; NED survival at 15 years is 80% for Stage I, 68% for Stage II; cause specific freedom from cancer death is 98% for Stage I and 97% for Stage II at 15 years. Second malignancy rates were 8% at 15 years, and observed in 14 patients versus 4.2 expected (p < .001). Deaths due to these second cancers were also increased with seven observed versus two expected (p < .01). Non-cancer intercurrent disease death occurred in 23 patients versus 7.5 expected (p < .01). The most frequent cause was cardiac death which appeared in 10 patients versus 4.4 expected (p < .05) and 8 of the 10 patients received mediastinal radiation. Two additional patients died of pulmonary fibrosis after mediastinal radiation. Mediastinal radiation correlated with all intercurrent disease and cardio-pulmonary deaths (p < .05), but not with second malignancies. With the exception of one, all patients experiencing cardiac death after mediastinal irradiation were 40 years or older at the time of treatment, with a range of 32-58 years and a mean interval to death of 9.8 years., Conclusions: Recommendations for the future management of seminoma include: reducing the irradiated volume in the treatment of Stage I patients, completely eliminating mediastinal radiation in the treatment of patients with Stage IIA seminoma and treating patients with Stage IIB seminoma with chemotherapy. Radiation dose should not exceed 30 Gy for Stage I or 35 Gy for Stage IIA.