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Ann Thorac Surg 2000;69:337-343
© 2000 The Society of Thoracic Surgeons
a Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Address reprint requests to Dr Walsh, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Box 109, 1515 Holcombe Blvd, Houston, TX 77030
Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.
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Abstract |
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Methods. From 1993 to 1998, 20 patients were referred for the management of PNSGM. All were male, with a median age of 30.5 years (range 18 to 48). Eighteen of 20 (90%) presented with symptoms. Most tumors were large, with a median diameter of 10 cm (range 3 to 20 cm). Thirteen patients (65%) had metastatic disease at the time of presentation. Eleven patients had received no prior treatment (initial group) and 9 were referred for salvage therapy after progression of their tumors, following treatment at other facilities (salvage group). All had elevated serum tumor markers (ßhCG and 
-fetoprotein). Preoperative chemotherapy included alternating cycles of combinations of 3 or more drugs, including cisplatin, bleomycin, etoposide, vincristine, methotrexate, actinomycin, cyclophosphamide, and doxorubicin. An average of 10 cycles of chemotherapy was given to each patient in the initial group, and six to those in the salvage group. Five patients (25%) developed transient renal insufficiency, and 35% developed pulmonary infiltrates related to bleomycin. There were 3 chemotherapy related deaths.
Results. After chemotherapy, 11 patients underwent operation, with 10 complete resections of the residual mediastinal tumors. There were no perioperative deaths. The 2-year survival in the initial group is 72%, and 42% for the salvage group.
Conclusions. An aggressive, multidisciplinary approach of alternating cycles of chemotherapy, followed by complete surgical resection of all remaining disease in patients whose markers normalize, can be associated with prolonged survival in patients with PNSGM.
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Introduction |
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Extragonadal germ cell tumors can occur in the midline of the body from the pineal gland, through to the mediastinum, retroperitoneum, and sacrum. Several theories exist as to their development, including the abnormal migration of germ cells along the urogenital ridge during embryogenesis [5, 6]. They are not felt to represent metastasis from occult testicular primaries [7, 8].
The mediastinum represents the most common site of extragonadal primaries (50% to 70%). Germ cell tumors of the mediastinum, which include benign teratomas, nevertheless are rare and represent only 1% to 6% of the total number of mediastinal tumors. Primary malignant germ cell tumors of the mediastinum are categorized histologically as seminomas or nonseminomatous germ cell tumors. Seminomas are very responsive to both chemotherapy and radiation therapy, and are cured even in a mediastinal location greater than 80% of the time. Nonseminomatous germ cell tumors, represent the least common but most aggressive malignant mediastinal germ cell tumor and represent the patient population which is the focus of this paper.
A review of the literature over the past 15 years often describes a variety of treatment modalities at different centers with small numbers of patients collected over sometimes decades [9–14]. Long-term disease-free survival varies from 13% to 58% [15, 16]. Even large academic centers, with an expertise in managing these tumors, rarely are able to collect a large series of patients in a relatively short time frame to permit a more uniform multidisciplinary approach to these patients. While some centers have attempted to improve response rates in this poor risk patient group, by increasing the individual doses of chemotherapy with autologous stem cell or bone marrow transplantation rescue, we have attempted to enhance the dose intensity by maintaining standard drug dosages, but reducing the chemotherapy intervals [17]. We report a single institutional experience with primary mediastinal nonseminomatous germ cell tumors referred to us over the past 5 years treated with a standardized alternating chemotherapy regimen followed by surgical resection when possible.
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Material and methods |
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Symptoms were present at the time of presentation in 18 of 20 patients (90%) (Table 1). Two patients presented with asymptomatic neck masses. The median duration of symptoms prior to diagnosis was 25 days (range, 8 to 240 days). All of the tumors were located in the anterior-superior mediastinum. The average largest dimension was 10 cm (range, 4 to 20 cm).
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Before chemotherapy, patients had to have adequate bone marrow function, with platelet counts greater than 100,000, and absolute granulocyte counts of greater than 1500. They required normal hepatic function and a predicted creatinine clearance of greater than 40 cc/min. Baseline gallium scans and spirometry were performed before bleomycin administration, and spirometry examination preceded each course of bleomycin. If the baseline spirometry had deteriorated by more than 10%, a repeat gallium scan was performed.
Histologies and tumor markers
The histologies are as follows: endodermal sinus tumor (n = 9), choriocarcinoma (n = 4), embryonal (n = 3), and mixed histology (n = 4). One or both tumor markers of -fetoprotein (-FP) or the beta subunit of human choriogonadotropin (ßhCG) were elevated in all patients at the time of their diagnosis, with 9 patients having an isolated -FP elevation (range, 5.9 to 50,000), 3 had elevated ßhCG only (range, 21.5 to 87,252), and 8 with both markers elevated (ßhCG range, 3.1 to 100,000, and -FP range, 19.6 to 40,000).
Initial group
Demographics
The median age of this group was 28 years (range 18 to 38). The histologies were endodermal sinus tumors (n = 4), embryonal carcinomas (n = 2), choriocarcinoma (n = 2), and mixed histologies in 3. Five out of the 11 in the initial group presented to MDACC with metastatic disease (lung n = 2, mediastinal lymph nodes n = 2, and liver n = 1).
Chemotherapy regimens with anticipated course intervals
Combination chemotherapy consisted of an alternating sequence of courses of BOP (bleomycin 30 units, vincristine 2 mg, and cisplatin 100 mg/m2), followed in 7 days by CISCA (cisplatin 100 mg/m2, cyclophosphamide 400 mg/m2/day for 48 hours, and adriamycin 35 mg/m2/day for 48 hours), followed in 14 days by POMB (cisplatin 100 mg/m2, vincristine 2 mg, methotrexate 300 g/m2 with leucovorin rescue, bleomycin 30 units), and followed in 10 days by ACE (actinomycin D 0.5 mg per day for 3 days, cyclophosphamide 500 mg/m2, etoposide 100 mg/m2 for days 1 and 5). The cycle is repeated in 2 weeks. The day after completion of each course of chemotherapy, G-CSF is administered at 5 µg/kg/day for a minimum of 5 days, until the absolute granulocyte count is greater than 1,000. The next course of chemotherapy requires a recovery of platelets to at least 50,000 and resolution of grade 3/4 nonhematologic toxicities. Through the routine use of growth factors, we are able to start a subsequent course of chemotherapy at a much lower platelet level than routinely practiced in the general oncology community.
Salvage group
Nine patients were referred for salvage therapy (endodermal sinus tumors [n = 5], choriocarcinoma [n = 2] mixed [n = 1], and embryonal carcinoma [n = 1]). The median age of this group was older than the initial group: 37 years (range, 23 to 48). One patient had undergone an attempted surgical resection with incomplete margins, followed by radiation therapy, further chemotherapy, and a peripheral stem cell transplantation. One patient had received chemotherapy and an incomplete surgical resection. The 7 others had received chemotherapy alone. These patients had received a variety of treatment regimens (total of 54 courses of chemotherapy [range, 2 to 13]) for an average of 6 courses per patient referred. A combination of bleomycin, etoposide, and cisplatin (BEP) was the most common regimen administered in 28 of 54 outside courses. Etoposide (VP16), ifosfamide, and cisplatin (VIP) had been given for 8 courses; cisplatin, velban, and ifosfamide in 5; taxol and ifosfamide in 2; carboplatin and VP16 in 3; daily VP16 in 2; and taxol and carboplatin in 3 courses. Eight of these 9 patients, at the time of presentation to MDACC, also had radiographic evidence of metastatic disease. Solitary sites of metastasis were identified in 4 patients, 2 sites of metastatic disease in 2 patients, and 3 separate sites of spread in 2 others. These sites included the pulmonary parenchyma (n = 8), brain (n = 3), liver (n = 1), mediastinal nodes (n = 1), and bone (n = 1).
Chemotherapy
The alternating regimen described above was utilized for the salvage patients as well. Three patients, in addition to the above regimen, had treatment with courses of VIP, taxol and cisplatin, taxol alone, and VP16 alone, and cisplatin, velban and ifosfamide. A total of 9 courses of chemotherapy, in addition to our standard regimen, were administered.
Operation
Patients in both groups were considered for surgical resection, if after chemotherapy their markers normalized and there remained a residual mediastinal mass. Surgical resection included all gross disease with en bloc resection of all involved structures which could be sacrificed. Patients in whom the final pathologic examination of the resected mediastinal mass demonstrated complete necrosis and/or mature teratoma did not receive additional chemotherapy, and were followed every 3 months with radiographs and serum tumor markers for the first year, every 4 months for the second year, every 6 months for the third year, and then yearly thereafter. Patients who were found to have viable tumors had further postoperative chemotherapy.
Statistics
Survival data was calculated from the date chemotherapy was started, until their last known follow-up day, or date of death. For those patients referred to our institution for salvage therapy, the day that chemotherapy was first administered at the outside hospital (or date of diagnosis, if chemotherapy date was not known) was used to calculate survival time. The date that chemotherapy was reinstituted at MDACC was also recorded. Survival differences between groups were evaluated by the log-rank test.
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Results |
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Three patients had normalization of their markers. One patient had a complete response of the mediastinal tumor, and did not undergo thoracic operation, but required resection of a residual brain metastasis. One patient had removal of the residual mediastinal tumor and a solitary brain metastasis, and in the third patient, only resection of the mediastinal tumor was required. Radiographic responses to therapy did not necessarily correlate with histologic response, as large residual masses could be 100% necrotic on final pathological sectioning. One patient had a persistent elevation and rise of his tumor marker, despite salvage therapy (-FP from 165-924), and was referred for attempted salvage operation. He is the only patient of the entire group who underwent operation without complete normalization of the markers. Although all gross disease was resected, he had a massive recurrence of his tumor within a few months after operation, and died 13 months after the start of chemotherapy.
Operation
A total of 11 patients were considered surgical candidates for resection of their residual mediastinal tumors after chemotherapy: 8 in the initial group, and 3 in the salvage group. Eight of these procedures were performed through a midline sternotomy, and the remaining 3 by posterolateral thoracotomy. A severe desmoplastic mediastinal reaction was encountered in all cases. Partial pericardial resection was required in all cases, to completely excise the tumor. This also facilitated the dissection of the great vessels, although sharp dissection along the adventitia of the ascending and arch of the aorta was usually required. Dissections along the superior vena cava and innominate vein were often difficult. These tumors often totally replaced the thymus, which was routinely removed. Complete resection of all gross tumors was possible in 10 patients. En bloc resections were performed, and included lung in 9 (formal lobectomies in 2, and wedge resections in 7), innominate vein in 3, superior vena cava in 2, a unilateral phrenic nerve in 3, and left recurrent nerves in 2 patients. Cardiopulmonary bypass was not required in any case. The median surgical time was 3.2 hours, with a range of 2.3 to 11.6 hours. The median blood loss was 600 mL (range 200 to 5000). Median days on ventilator was 0, with a mean of 0.55 days (range, 0 to 2). Median surgical intensive care unit stay was 1 day (range, 0 to 3), and median hospital stay was 6 days (range, 4 to 19). There were no surgical mortalities. Morbidities occurred in 2 patients, including a postoperative coagulopathy requiring transfusions in 1 patient, and a left lower lobe pneumonia in 1 patient. The remaining patients had uneventful postoperative courses. It was interesting to note that nearly all of these patients in the postoperative period would manifest a persistent sinus tachycardia between 120 to 140, despite adequate fluid resuscitation and urine output, acceptable hemoglobin levels, and adequate pain control. It would take several days for this tachycardiac response to improve, although many would be discharged with heart rates above 100.
Pathology of resected specimens
Of the 11 completely resected tumors, three demonstrated 100% necrosis of the tumor, one demonstrated necrosis and mature teratoma, three with mature teratomas only, two with over 99% necrosis with one microscopic focus of viable tumor (one suspected as a angiosarcoma, a second with a microscopic focus of endodermal sinus tumor), and two with viable tumors. Of the 2 patients with gross viable tumor, 1 patient recurred within months after operation (described above with persistent elevation of -FP at the time of operation), was not well enough to receive chemotherapy, and subsequently died. The second patient developed acute leukemia before restarting chemotherapy and died. Hematologic malignancies are well-recognized to occur with germ cell tumors [18]. One patient with a microscopic focus of tumor, suggestive of angiosarcoma, received two courses of adriamycin and ifosfamide as a sarcoma regimen, and has done well at follow-up 3 years after resection of his large primary tumor and a contralateral metastasis (Fig 3) [19, 20]. The final patient, who had over 99.9% of the tumor necrotic with only one microscopic focus of disease identified, has been followed closely radiographically and with tumor markers, and has not received further chemotherapy. The patient who could not be completely resected has received six more courses of chemotherapy, with a complete response both radiographically and by tumor markers, although he has developed severe pulmonary bleomycin toxicity and requires home oxygen.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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We have focused on increasing the dose-intensity of chemotherapy by decreasing the interval between each course of chemotherapy, and alternating drugs from course to course. Growth factors are used throughout, and further courses are started when platelet counts have only partially recovered to 50,000, while most centers would delay therapy until the platelet count is above 100,000. We believe that survival in this poor prognostic group will be improved with an upfront, more aggressive, initial treatment regimen, despite the toxicities associated with this program, rather than utilizing more standard germ cell protocols (BEP) that have worked well for germ cell tumors of testicular origin, but have higher treatment failures in PNSGTM. Our results demonstrate a 2-year survival of 72% in patients referred to our center initially, but less success (42% 2-year survival) in trying to salvage those who failed standard regimens elsewhere.
The acute toxicities of this regimen are substantial, and require clinical expertise for their management. These include platelet and packed red blood cell transfusions, management of routine infections and neutropenic fevers, and severe mucosal toxicity resulting in stomatitis and diarrhea. Electrolyte imbalances are characterized by hypomagnesemia that has been managed with oral and/or intravenous magnesium replacement. Renal insufficiency requiring inpatient and/or outpatient intravenous fluids occurs frequently. Renal failure requiring dialysis may also occur. All patients suffer ototoxicity (high frequency hearing loss and tinnitus) and peripheral neuropathy. Ototoxicity or peripheral neuropathy limiting the patient’s ability to return to a normal function has not occurred. We are presently utilizing ethyol to minimize these neuropathic complications.
Operations for the remaining mediastinal tumors is important for several reasons. Further chemotherapy in the adjuvant setting may also be considered in select patients, where viable tumor is identified. If mature teratoma or complete necrosis is identified, then follow-up is all that is required. Mature teratomas must be removed, as they can grow and cause severe, life-threatening mechanical complications within the chest, and dedifferentiation into a carcinoma is possible. Operations for patients whose markers have not normalized with therapy is usually futile.
These operations are usually technically challenging, with a dense fibrous reaction around the great vessels, and adherence or invasion of surrounding structures. The degree of difficulty is often directly related to the number of courses of chemotherapy required to normalize the tumor markers. While reduction of the size of the mass is gratifying, and often corresponds to the reduction in tumor markers, there may be total necrosis of the tumor with little change in the overall volume of the tumor. Patients who present with severe exercise and pulmonary limitations, may be significantly helped by removing the mass and allowing the often compressed lung to reexpand. Unilateral phrenic nerve resection may be necessary. Volume overload and high-inspired oxygen concentrations are avoided intraoperatively and postoperatively, as respiratory failure can occur in these patients who have received bleomycin. While these operations can be extremely tedious, the postoperative courses, in these otherwise healthy young men, is usually uneventful. The severe neuropathies that they suffer during the induction chemotherapy can impede their ability to ambulate postoperatively.
In summary, a multimodality aggressive treatment of primary nonseminomatous germ cell tumors, treated by alternating cycles of a dose-intensified chemotherapeutic program, and followed by complete surgical excision of remaining mediastinal masses, was associated with a 2-year survival of 72% in patients initially referred to our institution. While this is one of the highest 2-year survival rates described in the literature, these results should be regarded as preliminary, as it is unclear at this point whether or not the survival benefits will remain durable. The frequency of acute toxicity during our chemotherapeutic regimen is universal and severe, however. For this reason, we recommend that all patients be treated in a center with significant experience in dealing with the complications that result from these agents.
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