Mediastinal Nonseminomatous Germ Cell Tumors: The Role of Combined Modality Therapy

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Mediastinal Nonseminomatous Germ Cell Tumors: The Role of Combined Modality Therapy Nicholas J. Vogelzang, M.D., Derek Raghavan, M.B., B.S., Robert W. Anderson, M.D., Juan Rosai, M.D., Seymour H.

1 Mediastinal Nonseminomatous Germ Cell Tumors: The Role of Combined Modality Therapy Nicholas J. Vogelzang, M.D., Derek Raghavan, M.B., B.S., Robert W. Anderson, M.D., Juan Rosai, M.D., Seymour H. Levitt, M.D., and B. J. Kennedy, M.D. ABSTRACT Twelve male patients with mediastinal nonseminomatous germ cell s were treated with chemotherapy (with or without operation and radiation therapy) between 1963 and Eight patients, treated with only chemotherapy and radiotherapy, died with a median survival from diagnosis of 6 months (range, 3 to 12 months). The 4 survivors remain alive at 12, 15, 34, and 56 months from diagnosis; all are without evidence of disease. All surviving patients were treated with surgical resection of disease either before or after chemotherapy. A major problem in the management of mediastinal nonseminomatous germ cell s is the persistence of local disease, which may be overcome by vigorous cytoreductive intervention. Multicenter collaboration will be required to define the optimal combined-modality approach. The occurrence of germ cell s in primary extragonadal sites is an uncommon, but welldocumented phenomenon [l-51. Pure seminomas (germinomas), which occur in such sites as the mediastinum, retroperitoneum, and pineal region, can be treated effectively with radiotherapy [3, 5-91 and are associated with a relatively good prognosis. Conversely, nonseminomatous germ cell s occurring in the mediastinum and other extragonadal sites have responded poorly in the past to operation, radiotherapy, or conventional single- and multiple-agent chemotherapy. Of 20 patients with nonseminomatous mediastinal s treated at Memorial Sloan- Kettering Cancer Center between 1949 and From the Departments of Medicine (Section of Medical Oncology), Therapeutic Radiology, Laboratory Medicine and Pathology, and Surgery, University of Minnesota Medical School and the Masonic Cancer Center, Minneapolis, MN. Accepted for publication July 2, Address reprint requests to Dr. Vogelzang, Box 286 Mayo Memorial Building, 420 Delaware St, Minneapolis, MN , only 1 patient remains alive. The median survival of the other 19 patients was 7 months [2]. The experience at Walter Reed Hospital was similar with only 2 long-term survivors among 18 patients [lo]. Other series have reported only modestly better results [ll, 121. The introduction of cisplatin to the treatment of metastatic testicular germ cell neoplasms has resulted in improved median survivals; of the initial 28 patients treated with this regimen at the University of Minnesota, 24 remain alive and free from disease with a minimum follow-up of two years. In this report, we review a series of patients with mediastinal nonseminomatous germ cell s to evaluate the influence of cisplatin-based chemotherapy and cytoreductive operation on survival. Material and Methods Between January, 1963, and July, 1980, 12 male patients ranging from 14 to 33 years old (mean age, 24 years) were treated for nonseminomatous germ cell s that appeared to arise in the anterior mediastinum without clinical involvement of the testes. Eleven patients had an antecedent duration of symptoms of 4 months or less (mean, 1.8 months), and 1 patient was seen with a 12-month history. All patients underwent a thorough physical examination (including the gonads) at the initial visit and on subsequent visits. Clinical examination of the testicles was repeatedly negative in all patients, but surgical examination was not performed. Staging procedures were performed as previously reported [13]. The management of patients with extragonadal seminomas at this center has been discussed elsewhere [3], and these data are not duplicated here. Histological sections were classified by a method previously reported [14], and a tissue diagnosis was achieved in all patients. Serum markers (a-fetoprotein and human by The Society of Thoracic Surgeons

334 The Annals of Thoracic Surgery Vol 33 No 4 April 1982 chorionic gonadotropin [HCG]) have been assayed routinely since 1977 using a double antibody radioimmunoassay [15].

2 334 The Annals of Thoracic Surgery Vol 33 No 4 April 1982 chorionic gonadotropin [HCG]) have been assayed routinely since 1977 using a double antibody radioimmunoassay [15]. Prior to the introduction of chemotherapy with a combination of cisplatin, vinblastine, and bleomycin (PVB), patients were treated either with vinblastine, 0.2 mg per kilogram of body weight intravenously on days 1 and 2, plus bleomycin 30 U as an intravenous infusion for 5 days, or with a variety of other drugs as first- and second-line therapy (Table). Six patients were treated with PVB combination chemotherapy every three weeks according to the following schedule: vinblastine, 0.15 mg per kilogram intravenously on days 1 and 2; bleomycin, 30 U intravenously on days 2,9, and 16; and cisplatin, 20 mg per square meter of body surface area intravenously on days 1 through 5. A seventh patient was treated with the VAB-6 (vinblastine, actinomycin D, bleomycin, cisplatin, cyclophosphamide) regimen [16] every three weeks. Nine patients received radiation therapy. Four of them (Patients 1, 4, 5, and 11) received 4,500 to 6,000 rads in 200-rad fractions to the mediastinum (k supraclavicular fossae) over four to six weeks. One patient (Patient 3) was treated with 3,600 rads to the lumbar vertebrae for an isolated metastasis that occurred 4 months after surgical excision of a mediastinal teratocarcinoma and seminoma. The other 4 patients (Patients 2, 7, 8, and 10) received less than 3,000 rads to the primary lesion. response was defined as the regression of all disease with normal levels of a- fetoprotein and HCG when measured. A partial response was defined as a greater than 50% reduction in the size of all measurable lesions. Patients who had only a slight response, no response, or progression of disease were classified as having no response. Survival was calculated from the day of initial diagnosis. Results of the patients was seen initially with distant metastases, although evidence of local extension was seen in 10 patients. Three patients were seen with superior vena cava syndrome. There was, therefore, a low index of suspicion that any of the symptoms represented a regressed primary of the testis [17]. The presenting symptoms of the patients were as follows: chest pain, 8 patients; fever, 4; flulike syndrome, 3; dyspnea, 4; gynecomastia, 1; abnormality on routine chest roentgenogram, 1; and nonspecific, such as malaise or weight loss, 8. Histological examination of the s showed the whole gamut of nonseminomatous germ cell patterns, pure or in combination. Four patients had teratocarcinoma or malignant teratoma of the mediastinum, and 3 had pure yolk-sac. The other 5 patients had mixed nonseminomatous germ cell s, 3 of which contained elements of yolk sac. The marker a-fetoprotein was elevated in 8 of 8 patients and HCG was elevated in 5 of 10 patients in whom it was measured. Because of the small number of patients and the poor survival, no meaningful statement can be made to relate initial levels of markers or histology to prognosis. Details of the clinical courses of the 5 patients treated without cisplatin-based chemotherapy are summarized in the Table (Patients 1 through 5). Two patients achieved a complete clinical remission with the initial radiotherapy. Two patients (Patients 3 and 5) achieved complete remissions with the initial operation, and 1 patient showed no response to initial chemotherapy. All patients in this group died within a year of diagnosis, except for the patient alive at 50 months who was treated with a debulking operation, followed immediately by radiotherapy and adjuvant chemotherapy with vinblastine, bleomycin, and cyclophosphamide (Patient 4). Postmortem examination on 2 patients demonstrated extensive local disease in both, with liver and brain metastases in 1. The other 2 patients had clinical evidence of liver, lung, and bone marrow metastases before death. The clinical courses of the 7 patients treated with cisplatin-containing combination chemotherapy are summarized in the Table also (Patients 6 through 12). No patient achieved a complete response to chemotherapy alone. Two patients achieved partial remission, 2 had no

3 335 Vogelzang et al: Mediastinal Nonseminomatous Germ Cell Tumors Summary of Clinical Data on 12 Male Patients with Mediastinal Nonseminomatous Germ Cell Tumors Duration Survival of Initial from Patient Age Symptoms a- Initial Diagnosis No. (yr) (mo) Fetoprotein HCG Histology Therapy Response (mo) Not done Not done Not done Not done Teratocarcinoma Teratocarcinoma Not done 100 Tera tocarcinoma/ Mithramycina ; chlorambucil,b methotrexate,p actinomy cind Cyclophosphamide, methotrexate,e V Opera tion seminoma V,B, methotrexate,e 12 cyclophosphamide, actinomycind Mi thram ycin Not done Not done <3 Teratocarcinoma/ seminoma Yolk sac Operation Adjuvant radiotherapy; adjuvant V,B, cyclop hosphamide Adjuvant V,B, actinomycind 56 + A,P ,000 <3 Yolk sac ,200 <3 Embryonal carcinoma/ yolk sac Teratocarcinoma , , ,800 < ,460 <3 Malignant tera toma Embryonal carcinoma/ yolk sac Yolk sac / choriocarcinoma Yolk sac P V B V,B, cyclophosphamide, actinomycind ; Decadron; VAB-6 Operation Operation VAB Operation, adjuvant P,B,A,VP amithramycin = 50 CLgikg intravenously three times a week to toxicity. Thlorambucil = 10 mg orally a day to toxicity. Methotrexate = 5 to 10 mg orally per day to toxicity. Actinomycin D = 0.5 mg intravenoudy 5 consecutive days each month. Urinary HCG values. Markers normalized. HCG = human chorionic gonadotropin; V = vinblastine; B = bhmycin; A = Adriamycin (doxorubicin hydrochloride) (60 mp/m* heavenously for three to four weeks); P = cisplatin; Decadron = dexamethasone; VAB-6 = vinblastine, actinomycin D, bleomycin, cisplatin, cyclophosphamide; VP = VP-16 (100 mpim intravenously on days 1, 3, and 5 for four weeks)

336 The Annals of Thoracic Surgery Vol 33 No 4 April 1982 objective decrease in the size of the mediastinal mass but both the a-fetoprotein and HCG were normalized, and 3 showed no response.

The effectiveness of cisplatin-based chemotherapy was demonstrated when one of the "partial" responders (Patient 6) died suddenly 2 weeks after the fourth course of PVB chemotherapy.

4 336 The Annals of Thoracic Surgery Vol 33 No 4 April 1982 objective decrease in the size of the mediastinal mass but both the a-fetoprotein and HCG were normalized, and 3 showed no response. Four of these 7 patients died within 12 months of diagnosis. All 4 patients died with evidence of persistent local disease, and 2 had widespread metastases involving the liver, brain, and bone marrow. The effectiveness of cisplatin-based chemotherapy was demonstrated when one of the "partial" responders (Patient 6) died suddenly 2 weeks after the fourth course of PVB chemotherapy. Postmortem examination revealed a necrotic rectal ulcer and evidence of generalized clostridial sepsis, but no evidence of viable tissue was found. There was extensive necrotic tissue in the mediastinum, which correlated with the persistent mediastinal shadow on roentgenograms (hence the clinical classification as a "partial" responder). The necessity for cytoreductive operative intervention was illustrated in all 3 survivors (Patients 8, 9, and 12) treated during the era of cisplatin-based combination chemotherapy. Case Reports PATIENT 8. A 20-year-old man was seen with a 1-month history of fever, hemoptysis, and dyspnea. A chest radiograph demonstrated a large anterior mediastinal mass, and a paramediastinotomy revealed a teratocarcinoma. Postoperatively, superior vena cava syndrome occurred. The patient was treated with dexamethasone and radiation therapy (1,475 rads in seven treatments). The superior vena cava syndrome improved, and the VAB-6 regimen was begun. The a-fetoprotein and HCG normalized, but the mediastinal mass remained after three courses of chemotherapy. The mediastinum was then explored, and a firm 15 x 10 x 10 cm mass adherent to the pericardium and mediastinal structures was removed. Pathological evaluation revealed extensive necrosis, immature cartilage, benign-appearing cysts, and areas of viable malignant cells. The patient was given two more courses of cisplatin-based chemotherapy and remains in complete remission 30 months from diagnosis. PATIENT 9. A 34-year-old man was seen with gynecomastia and chest pain. A biopsy was done of a large anterior mediastinal teratocar- A B Fig 1. (A) Chest radiograph demonstrating a large anterior mediastinal mass, unchanged after four courses of vinblastine, bleomycin, and cisplatin. (B) Postoperative chest radiograph demonstrates results of cytoreductive operation. cinoma, and the was deemed unresectable on clinical grounds. After four courses of PVB chemotherapy, the a-fetoprotein and HCG had normalized and the mass exhibited areas of cystic change on computerized tomographic scan. The chest radiograph demonstrated no change in the mediastinal mass (Fig 1A). At sternotomy the mass was easily shelled out of

5 337 Vogelzang et al: Mediastinal Nonseminomatous Germ Cell Tumors Fig 2. Malignant teratoma after four courses of chemotherapy. Areas of mucinous epithelium (E) and cartilage (C) are within a mixed benign and malignant stroma (S). (HDE; x140.) the anterior mediastinum (Fig 1B). Macroscopically the consisted of multiple cysts, cartilagelike material, and dense fibrosis. Microscopically, there was a predominance of benign teratomatous tissue interspersed with islands of malignant (Fig 2). The patient was given two further courses of PVB and is free from disease. PATIENT 12. A 21-year-old man was treated with PVB chemotherapy for a pure mediastinal yolk-sac. Despite adequate drug dose, the a-fetoprotein continued to rise. After four courses of PVB, surgical exploration of the mediastinum demonstrated a bulky necrotic, which could be excised. Postoperatively the a-fetoprotein remained elevated. The patient was treated with two courses of "salvage" chemotherapy utilizing high-dose cisplatin, bleomycin infusion, doxorubicin hydrochlo- ride (Adriamycin), and VP [18]. The a- fetoprotein normalized with the appropriate half-life, and a period of complete remission occurred. A new peripheral pulmonary nodule and an elevated a-fetoprotein were noted 10 months after diagnosis. Two courses of "salvage'' chemotherapy were administered with a normalization of the a-fetoprotein. The pulmonary nodule was then excised, and a mature teratoma was found. The patient is free from disease 20 months after diagnosis. Comments Nonseminomatous germ cell s found first at extragonadal sites have been difficult to diagnose [19] and have carried a poor prognosis, with the exception of well-differentiated teratomas in adults and children and some sacrococcygeal teratomas in newborn infants [l, 2, 5, 10, 111. Most published data have documented the experience with these patients prior to the introduction of cisplatin-containing combination therapy, and there has been speculation as to whether the application of

6 338 The Annals of Thoracic Surgery Vol 33 No 4 April 1982 cisplatin-based therapy would alter the prognosis of these patients. Our patient population illustrates several previously documented features: young men with a relatively short history of disease, locally advanced disease at the initial visit, and rapidly progressive disease despite therapy. Our experience prior to the introduction of PVB mimics that reported from other centers [2, 10, 111, with only 1 surviving patient. The introduction of PVB combination chemotherapy has dramatically improved the prognosis of patients with metastatic testicular germ cell s [20]. However, our results with PVB as initial chemotherapy for mediastinal germ cell s are disappointing compared with our results with testicular germ cell s [211. Only 1 patient (Patient 6) achieved a complete remission (which was documented postmortem following sudden death two weeks after the fourth course of chemotherapy). Three other patients (Patients 8, 9, and 11) had evidence of an antineoplastic effect from the initial chemotherapy, while 3 patients did not respond to PVB. Similar results with a series of 11 patients were reported in 1980 by the Southwest Oncology Group [221, although there are isolated case reports of the successful use of PVB [231. In a series from Memorial Sloan- Kettering Cancer Center using platinum-based chemotherapy, 15 of 19 patients with mediastinal germ cell s died with a median and mean survival of approximately one year [24]. Einhorn [25] reported the results in 12 patients treated with platinum-based regimens: 4 complete remissions, 7 partial remissions, and 1 no response. Six patients remain alive with a median follow-up of 8 months (range, 2 to 24 months). Cytoreductive operation as the primary modality of therapy has been ineffective, as shown by the poor survival data previously reported [2, 101. In this series of 12 patients, initial resection of the was completed in only 2 patients, although most patients were not subjected to vigorous surgical attempts. An additional 3 patients underwent complete resection after cisplatin-based chemotherapy. Three of these 5 surgically treated patients sur- vive without evidence of disease. All 3 patients were also treated with combination chemotherapy, with or without radiotherapy. It thus appears that cytoreductive operative intervention may be a part of the combined modality management of the nonseminomatous germ cell s. Tentative guidelines for the management of these s should include a debulking procedure as initial therapy if technically feasible, followed immediately by cisplatin-based chemotherapy for four to six courses of therapy. Levels of HCG and a-fetoprotein should be measured each week, since these markers correlate well with the course of the disease [26]. If the markers do not normalize, radiotherapy could be added or, alternatively, VP based chemotherapy could be tried [18]. If a debulking operation is not initially technically feasible, cisplatin-based combination chemotherapy should be begun immediately and determinations of HCG and a-fetoprotein made at weekly intervals. If the serum markers normalize, four courses of PVB or VAB-6 should be given, followed by a cytoreductive intervention. Further chemotherapy or radiotherapy could then be added, depending on the histological findings. If markers do not become normal, consideration should be given to a debulking operation followed by further chemotherapy or radiotherapy. This combined modality approach has been successfully applied to patients with testicular germ cell neoplasms and bulky abdominal disease [16, 20, 211. Because of the rarity of these s, multicenter collaboration will be required to find the optimal combined modality approach. Supported in part by Grant CA from the National Cancer Institute of the United States Public Health Service, American Cancer Society Clinical Fellowship (CF-4308A), the Minnesota Medical Foundation, and the Masonic Hospital Fund, Inc. References 1. Johnson DE, Laneri JP, Mountain CF, et al: Extragonadal germ cell s. Surgery 73:85, Martini N, Golbey RB, Hajdu SI, et al: Primary

339 Vogelzang et al: Mediastinal Nonseminomatous Germ Cell Tumors mediastinal germ cell s. Cancer 33:763, 1974 3.

7 339 Vogelzang et al: Mediastinal Nonseminomatous Germ Cell Tumors mediastinal germ cell s. Cancer 33:763, Medini E, Levitt SH, Jones TK, et al: The management of extratesticular seminoma without gonadal involvement. Cancer , Raghavan D, Barrett A: Mediastinal seminomas. Cancer 46:1187, Raghavan D: Extragonadal germ cell s. In Peckham MJ (ed): The Management of Testicular Tumours. London, Edward Arnold (in press) 6. Abell MR, Fayos JV, Lampe I: Retroperitoneal germinomas (seminomas) without evidence of testicular involvement. Cancer 18:273, Rubin P, Kramer S: Ectopic pinealoma: a radiocurable neuroendocrinologic entity. Radiology 85:512, Maier JG, Dejong D: Pineal body s. Am J Roentgenol 99:826, Bagshaw MA, McLauchlin WT, Earle JD: Definitive radiotherapy of primary mediastinal seminoma. Am J Roentgenol 105:86, Cox JD: Primary malignant germinal s of the mediastinum. Cancer 36:1162, Samuels ML, Lanzotti VJ, Holoye PY, et al: Combination chemotherapy in germinal cell s. Cancer Treat Rev 3:185, Walden PAM, Woods RL, Fox B, et al: Primary mediastinal trophoblastic teratomas. Thorax 32752, Fraley EE, Lange PH, Williams RD, et al: Staging of early nonseminomatous germ-cell testicular cancer. Cancer 45:1762, Nochomovitz LE, Rosai J: Current concepts on the histogenesis, pathology and immunochemistry of germ cell s of the testis. Pathol Annu 13:327, Lange PH, McIntire KR, Waldmann TA, et al: Serum alpha-fetoprotein and human chorionic gonadotropin in the diagnosis and management of non-seminomatous germ-cell testicular cancer. N Engl J Med 295:1237, Vugrin D, Dukeman M, Whitmore W, et al: Progress in chemotherapy of germ cell s (GCT) (abstract). Proc Am Assoc Cancer Res and ASCO 21:426, Prym P: Spontanheilung eins borsartigen, wahrscheinlich chorionepitheliomatossen Grewachses in Hoden. Virchows Arch , Vogelzang NJ, Kennedy BJ: "Salvage" chemotherapy for refractory germ cell s (abstract). Proc Am Assoc Cancer Res and ASCO 22: Richardson RL, Schoumacher RA, Fer MF, et al: The unrecognized extragonadal germ cell cancer syndrome. Ann Intern Med 94:181, Einhom LH, Donohue J: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 87:293, Bosl GJ, Lange PH, Fraley EE, et al: Vinblastine, bleomycin and cis-diamminedichloroplatinum in the treatment of advanced testicular carcinoma. Am J Med 68:492, Feun L, Samson MK, Stephens RL: Vinblastine (VBL), bleomycin (Bleo), cis-diamminedichloroplatinum (DDP) in disseminated extragonadal germ cell s. Cancer 45:2543, Van Hoesel QGCM, Pinedo HM: remission of mediastinal germ-cell s with cis-dichlorodiammineplatinum (11) combination chemotherapy. Cancer Treat Rep 64:319, Reynolds TF, Yagoda A, Vugrin D, et al: Chemotherapy of mediastinal germ cell s. Semin Oncol 6:113, Einhom LH: Extragonadal germ cell s. In Einhorn LH (ed): Testicular Tumors: Management and Treatment. New York, Masson USA, 1980, pp Burt ME, Javadpour N: Germ-cell s in patients with apparently normal testes. Cancer 47:1911, 1981

Results The results are presented in terms of the primary method of treatment, and are analyzed in terms of

Results The results are presented in terms of the primary method of treatment, and are analyzed in terms of A Multidisciplinary Approach to Primary Nonseminomatous Germ Cell Tumo~s of the Mediastinurn P. H. Kay, F.R.C.S., F. C. Wells, F.R.C.S., and P. Goldstraw, F.R.C.S. ABSTRACT The introduction of cis-platinum-based