Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan

BACKGROUND: Surgery remains the mainstay of treatment for thymic epithelial tumors, and radiation and chemotherapy also have been applied widely as adjuvant and palliative procedures. METHODS: We compiled records of 1,320 patients with thymic epithelial tumors who were treated from 1990 to 1994 in 115 institutes certified as special institutes for general thoracic surgery by The Japanese Association for Chest Surgery. RESULTS: Patients with stage I thymoma were treated with only surgery, and patients with stage II and III thymoma and thymic carcinoid underwent surgery and additional radiotherapy. Patients with stage IV thymoma and thymic carcinoma were treated with radiation or chemotherapy. The Masaoka clinical stage is an excellent predictor of the prognosis of thymoma and thymic carcinoma, but not thymic carcinoid. In stage III and IV thymoma, the 5-year survival rates of total resection, subtotal resection, and inoperable groups were 93%, 64%, and 36%, respectively. On the other hand, in thymic carcinoma, the 5-year survival rates of total resection, subtotal resection, and inoperable groups were 67%, 30%, and 24%, respectively. Prophylactic mediastinal radiotherapy could not prevent local recurrences effectively in patients with totally resected stage II and III thymoma. Adjuvant therapy including radiation or chemotherapy did not improve the prognosis in patients with totally resected III and VI thymoma and thymic carcinoma. CONCLUSIONS: Total resection is the most important factor in the treatment of thymic epithelial tumors. There is value in debulking surgery in invasive thymoma, but not in thymic carcinoma. We doubt that adjuvant therapy is valuable for patients with totally resected invasive thymoma and thymic carcinoma.     

Thymic carcinoma. Clinical institutional experience with 15 patients.

OBJECTIVE: We retrospectively evaluated 15 patients with thymic carcinoma treated with various modalities and investigated overall management of this disease. METHODS: From 1983 to 2003, we treated 15 patients with thymic carcinoma (12 squamous cell carcinomas, 2 undifferentiated carcinomas and one adenocarcinoma). According to Masaoka's staging system, they consisted of 2 at stage II, 5 at stage III, 4 at stage IVa and 4 at stage IVb. RESULTS: Ten patients were histologically diagnosed preoperatively, and 5 patients underwent an exploratory procedure under the diagnosis of thymoma or benign teratoma. Complete resection was performed in 9 patients (2 stage II, 5 stage III and 2 stage IVa), which included 4 patients who received induction therapy, 4 who received postoperative radiation therapy, and 1 who received postoperative chemotherapy. Six patients with unresectable tumors were treated by irradiation (40-60 Gy) with or without chemotherapy. The median survival was 13 months for patients without resection, and 57 months for patients with a complete resection. Total 3-year and 5-year survival rates were 51.9 and 39.0%, respectively. CONCLUSIONS: We concluded that a complete resection is mainstay of therapy when possible, but chemoradiation therapy being potential benefit in the management of thymic carcinoma. However, considering the high prevalence of advanced stage patients, to establish the effective regimen of induction therapy in the additional multicenter trials should be mandatory.     

Induction therapy for thymic malignancies

Thymic malignancies are rare tumors of the chest that express a broad range of biological behaviors. Surgery remains the mainstay of therapy, and complete surgical resection is the primary predictor of long-term survival. Although there is a paucity of clinical trials assessing the role of induction/adjuvant chemotherapy and/or radiation therapy in the treatment of thymic malignancies, existing data suggest that induction therapy should be offered for the treatment of advanced-stage disease, and postoperative radiation for specific stages.     

Therapy for thymic epithelial tumors

Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes. The rarity of this tumor has somewhat obscured the optimal treatment for this disease. The World Health Organization classification system, which published in 1999, appears to be an advance in our understanding of thymoma. The Masaoka classification is now the most widely accepted and is an excellent predictor of the prognosis of thymoma. Now the International Thymic Malignancy Interest Group is currently engaged in the development of a validated formal TNM classification system for thymic malignancies. The optimal treatment of thymoma is performed according to its clinical stage. Surgery remains the mainstay of treatment for thymic epithelial tumors. Minimally invasive surgery including thoracoscopic surgery and robotic surgery for stage I and II thymomas is increasing now. The value of postoperative radiotherapy in completely resected stage II or III tumors is questionable. As thymomas have a moderate response rate to chemotherapy or radiotherapy, multimodality therapy involving surgery, chemotherapy and radiotherapy appears to increase the rate of complete resection and survival in the advanced (stage III and IV) thymomas.     

Thymoma and thymic carcinoma

Thymic tumors comprise a heterogeneous group of neoplasms with a wide spectrum of clinical presentations. The evolution of the disease is often unpredictable, ranging from an indolent attitude to the possibility of intra- and extrathoracic spread. From the histological point of view, thymoma and thymic carcinoma are the most frequent subtypes and arise only from thymic epithelial cells. Other histological types are even more rare and are usually considered separately. A number of prognostic factors have been validated as predictors of outcome: staging, World Health Organization histological classification, diameter of the tumor, associated paraneoplastic syndromes, completeness of resection, and early onset of recurrence. Complete surgical resection is the key factor for cure and should be considered the gold standard at any stage. Especially for more aggressive lesions, surgery should be considered with a multimodality approach, involving induction and adjuvant therapy according to the stage. Multimodality therapy protocols have been designed based on the integration of clinical staging and histology. Neoadjuvant therapy is now administered before surgical resection in patients with tumors considered inoperable as it improves resectability and survival and reduces the risk of recurrence. Adjuvant treatment has been extensively reported after both complete or partial resection. New targeted therapies are in the developmental stage, and in the future they will be part of the standard protocols. Integrated treatment modalities require strict cooperation between medical and radiation oncologists, thoracic surgeons, and pathologists.     

Chemotherapy for thymic tumors: induction, consolidation, palliation

Although thymoma and thymic carcinoma are rare malignancies, they constitute a large proportion of tumors of the anterior mediastinum. Surgery forms the mainstay of therapy; however, thymic malignancies are sensitive to chemotherapy and radiation therapy also. Systemic chemotherapy is primarily used for treatment of metastatic or recurrent disease. Chemotherapy is also used as a component of multimodality treatment in the neoadjuvant setting with the aim of increasing the chances of achieving a complete surgical resection. In this article we outline various clinical trials that have been performed to evaluate the role of chemotherapy in the treatment of thymic malignancies.     

Esthesioneuroblastoma: the impact of treatment modality

BACKGROUND: We evaluated the impact of treatment modality on esthesioneuroblastoma. METHODS: Between 1976 and 1996, 25 patients with esthesioneuroblastoma were treated at Mallinckrodt Institute of Radiology. There were 11 male and 14 female patients; their ages ranged from 16 to 73 years (median, 57 years). The tumors were Kadish stage A in 3, Stage B in 13, C in 8, and modified D in 1 (cervical nodal metastasis). Seventeen patients were treated with surgery and radiation therapy, six were treated with irradiation alone, and two were treated with surgery only. Eight patients received neoadjuvant chemotherapy. Median follow-up was 8 years (range, 2-24 years). RESULTS: The 5-year actuarial overall survival, disease-free survival, and local tumor control rates were 66.3%, 56.3%, and 73.0%, respectively. Kadish stage was not a significant prognosticator for local control or disease-free survival. Five-year local control rates were 87.4% for the combination of surgery and radiation therapy and 51.2% for irradiation alone. Two patients with Kadish stage A and B disease underwent surgical resection alone; both failed locally. In contrast, 33.3% of patients (three of nine) with Kadish stage A or B disease who received adjuvant radiation therapy had a local recurrence develop. With adjuvant radiation therapy, the surgical margin status did not influence local tumor control. Among the eight patients who received neoadjuvant chemotherapy, six patients showed no response, one had partial response, and one showed a complete response. CONCLUSIONS: Surgical resection plus adjuvant radiation therapy yielded the best treatment outcome. More effective chemotherapy agents with a reproducible effectiveness are needed for patients with locally advanced esthesioneuroblastoma.     

Results of aggressive treatment of gastric sarcoma

Background: Leiomyosarcoma and leiomyoblastoma are subtypes of gastric smooth muscle tumors. These rare tumors are usually treated with surgical resection. However, there is controversy regarding the optimal surgical management for these malignancies and little information is available on the efficacy of radiation and chemotherapy in the adjuvant or palliative setting. Methods: The records of 32 patients with gastric leiomyosarcoma or leiomy-oblastoma were reviewed. Survival data were obtained and patient outcome was analyzed with respect to the type of treatment given. Four different staging systems were compared for their ability to predict survival. Results: Thirty patients with leiomyosarcoma and two patients with leiomy-oblastoma were followed after surgery. All 32 patients were explored, and 21 curative and 11 palliative procedures were performed. Adjacent organs were included in 38% of resections. Only three patients did not undergo gastric resection. Local recurrence developed in eight patients after curative resection for a local control rate of 62%. Eight other patients developed metastatic disease for an overall recurrence rate of 76% after curative resection. Median survival of patients undergoing curative resection was 40 months compared with 8 months for those having a palliative procedure. The estimated 5-year survival was 34% and 10%, respectively (p=0.05). Twenty-five patients with advanced disease received systemic, hepatic arterial, or intraperitoneal chemotherapy. Eighty percent of patients received a regimen including doxorubicin. Four partial and one complete response were noted. Seven patients received postoperative radiation therapy. Fourteen patients underwent debulking surgery of recurrent or persistent disease in conjunction with chemotherapy. Chemotherapy, radiation therapy, and debulking surgery did not result in statistically significant prolongation of survival. Seven patients remain alive, two with liver metastases. Four different staging systems for gastric sarcomas were compared, but none of them were found to be clearly superior in predicting survival. Conclusions: Curative gastric resection was achieved in 66% of patients and resulted in a significant prolongation of survival as compared with patients who had a palliative procedure. Wedge resection of tumor or partial gastric resection appears to be an acceptable surgical approach to these tumors as long as negative margins can be obtained. Chemotherapy, radiation therapy and debulking surgery did not result in significant prolongation of survival in the face of advanced disease. None of the staging systems for gastric sarcoma currently in use is completely satisfactory. Tumor grade and extent of disease seem to be the most important factors when determining prognosis or considering adjuvant therapy.The results of this study were presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Pineal tumors.

Tissue diagnosis is necessary for optimal treatment of pineal region tumors in children. Preoperative staging should include craniospinal MR imaging with and without gadolinium DTPA enhancement, CSF sampling for cytology, and measurement of biologic tumor markers in serum and CSF. Surgical approach is determined by results of preoperative MR imaging and the extent of resection by the results of staging and intraoperative frozen-section histopathologic evaluation. There is no longer a role for the radiation test dose (2000 cGy) in the management of these tumors. Postoperative treatment is based on histopathology and extent of disease. Benign tumors are treated with surgery only, and nondisseminating focal tumors with surgery and focal radiation therapy. Non-germinoma malignant germ cell tumors are best treated with neoadjuvant chemotherapy followed by radiation therapy given focally for focal disease; craniospinal radiation therapy is reserved for patients with evidence of disseminated disease at the completion of induction chemotherapy.     

Multimodality preoperative treatment for advanced cancer of the head and neck

Neoadjuvant induction chemotherapy with cisplatin, methotrexate, and bleomycin appears to improve the results of treatment of advanced stage IV head and neck cancer, compared with results in historical control subjects. Patients treated with induction chemotherapy and radiation therapy had a 29 percent overall survival rate at 3 years, which represents approximately a twofold improvement in the survival rate. Patients who were treated with chemotherapy and radiation therapy followed by surgery had more than a threefold increase in the survival rate (49 percent at 3 years), compared with historical data from our institution and elsewhere for such patients [9-11]. Distant metastases developed in 25 percent of the patients, and it thus appears that long-term, effective consolidation and maintenance chemotherapy [12,13] need to be developed for patients who receive combination therapy before surgery for head and neck cancer.     

Long-term outcome after multimodality treatment for stage III thymic tumors

BACKGROUND: Surgery remains the cornerstone of therapy for thymic tumors, but the optimal treatment for advanced, infiltrative lesions is still controversial. The introduction of multimodality protocols has substantially modified survival and recurrence rate. We reviewed our 13-year prospective experience with multimodality treatment of stage III thymoma and thymic carcinoma. METHODS: Since 1989 we have prospectively used a multimodality approach in 45 stage III thymic tumors. Sixteen patients (35%) had myasthenia gravis. Twenty-three patients (51%) had pure or predominantly cortical thymoma (group 1), 11 (24.5%) had well-differentiated thymic carcinoma (group 2), and 11 (24.5%) had thymic carcinoma (group 3). Tumors that were not considered radically resectable at preoperative workup underwent biopsy and induction chemotherapy (15 patients, 33%) followed by surgical resection; all patients were referred for adjuvant chemoradiotherapy. RESULTS: No operative mortality was recorded; 1 treatment-related death during adjuvant chemotherapy was observed in group 1. Complete resection was feasible in 91% of patients in groups 1 and 2 and 82% in group 3. The overall 10-year survival was 78%. Ten-year survival for groups 1 and 2 was 90% and 85%, respectively; 8-year survival for group 3 was 56%. During follow-up, tumor recurrence was noted in 3 patients (13%) from group 1, 3 (27%) from group 2, and 3 (27%) from group 3. CONCLUSIONS: Multimodality treatment with induction chemotherapy (when required) and adjuvant chemoradiotherapy offers encouraging results for stage III thymic tumors; the outcome is more favorable for cortical thymoma and well-differentiated thymic carcinoma.     

Changing concepts in the treatment of advanced seminomatous tumors

The treatment of patients with advanced seminomatous tumors represents a challenge for the medical and urological oncologists. In contrast to the reported excellent results of radiotherapy in the treatment of patients with clinical stages I and II disease the survival rate for those with advanced seminomatous disease is only around 40 per cent. Six consecutive patients with metastatic seminomas were treated with systemic chemotherapy and all achieved a complete response. The combination of vincristine, cis-platinum, bleomycin and prednisone was used in 4 patients and an excellent tolerance was observed even in patients with previous radiation therapy. Two other patients who had had radiation therapy to the mediastinum were treated with VP-16 and cis-platinum and again a complete response was observed. However, a significant potentiation of myelosuppressive effect of VP-16 was observed in the previously radiated patients. In view of the observed sensitivity of seminomatous tumors it appears that all patients who present initially with metastatic or bulky retroperitoneal disease should be treated with multiple drug chemotherapy and cytoreductive surgery similar to the treatment modalities used for nonseminomatous germ cell tumors. Radiation therapy for patients with this stage of the disease seems to be not only ineffective but also may compromise the benefits of aggressive chemotherapy.     

Current Advances and Changes in Treatment Strategy May Improve Survival and Quality of Life in Patients With Potentially Curable Gastric Cancer

Background: The treatment strategy for gastric cancer is determined by the stage of disease. Advances in diagnostic techniques such as endoscopic ultrasound (EUS) and in staging have increased the accuracy of pretreatment staging. Correct staging is a prerequisite for the optimal treatment of gastric cancer patients. Long-term expected survival and quality of life (QOL) are the major criteria determining the therapeutic strategy.Results: Surgical resection offers excellent survival rates for early gastric cancer (EGC) patients. D1 resection is sufficient for mucosal cancers (T1m) and for most submucosal cancers (T1sm); however, for the rest (about 5%) of these patients with N2 disease a D2 resection is required for complete tumor resection (R0). Considering QOL, endoscopic mucosal resection (EMR) or laparoscopic wedge resection is the best frontline therapy for several mucosal cancers. Prediction and selection of node-negative patients with the help of certain macroscopic and histologic criteria can eliminate the possibility for residual disease in perigastric lymph nodes. However, long-term survival data are needed before these new techniques become more generally accepted. In contrast, an aggressive approach is necessary for the treatment of advanced gastric cancer. Total gastrectomy, with the exception of distal tumors that can be treated by subtotal gastrectomy, is the procedure of choice. Splenectomy is indicated for proximal advanced tumors. Distal pancreatectomy should be avoided, however, because its adverse effect has been documented in all randomized trials. Although the survival benefit of extended (D2) lymphadenectomy is unproven in randomized trials, D2 resection increases the R0 resection rate and may improve survival in some selected nodepositive patients. D2 resection has little effect on preventing peritoneal tumor spread and liver metastasis, and the traditional late administration of chemotherapeutic drugs has been proven ineffective. Current data suggest a possible beneficial effect of combined treatment for patients with local advanced gastric cancer (LAGC). Ongoing phase III randomized trials will prove whether patients with LAGC treated by neoadjuvant chemotherapy plus D2 resection versus surgery alone or surgery plus intraoperative intraperitoneal chemotherapy derive any benefit from these combined treatment modalities.Conclusion: Evaluation of all information concerning tumor stage, location, histologic type, expected survival, and QOL after resection is of paramount importance for the surgeon planning the extent of surgery. The therapeutic approach should be stratified according to the stage of disease.     

Controversies and Challenging Therapeutic Modalities in Gastric Cancer

Gastric cancer is still the fourth common neoplasm worldwide. Gastric ulcers, adenomatous polyps, and intestinal metaplasia have been associated with an increased relative risk. Tissue diagnosis and anatomic localization of the primary tumor are best obtained by upper gastrointestinal endoscopy. Despite new screening techniques peritoneal tumor spread and occult liver and lymph node metastases are only detected intra-operatively. Therapy is becoming more and more complex comprising surgical resection, investigational neoadjuvant, adjuvant or palliative chemotherapy, or supportive care. Complete surgical eradication of a tumor with resection of adjacent lymph nodes represents the best chance for long-term survival. The choice of operation depends upon the location of the tumor, the clinical stage, and the histologic type. Chemotherapy can provide symptom palliation, improve quality of life, and prolong survival in patients with advanced gastric cancer. Preoperative radiation therapy may allow for tumor downstaging and reduced probability of residual microscopic disease at surgery.     

Should aggressive surgery ever be part of the management of small cell lung cancer?

CMT with surgery and chemotherapy is feasible, the toxicity is manageable, and postoperative morbidity and mortality rates are acceptable. Patient selection is important, and the results of the LCSG trial indicate that surgical resection will not benefit most patients who have limited SCLC. The chances of long-term survival and cure are strongly correlated with pathologic TNM stage. Consideration of surgery for patients who have SCLC should be limited to those with stage I disease and perhaps some patients with stage II tumors. Therefore, before surgery is undertaken, patients should undergo extensive radiologic staging with CT, MRI, and perhaps even positron emission tomographic scanning and mediastinoscopy, even if the radiologic assessment of the mediastinum is negative. Surgery may be considered for patients with T1-T2 NO SCLC tumors, and whether it is offered as the initial treatment or after induction chemotherapy remains controversial [40,43]. If SCLC is identified unexpectedly at the time of thoracotomy, complete resection and mediastinal lymph node resection should be undertaken, if possible. Chemotherapy is recommended postoperatively for all patients, even those with pathologic stage I tumors. Surgery likely has very little role to play for most patients with stage II disease and virtually no role for patients with stage III tumors. Even though chemotherapy can result in dramatic shrinkage of bulky mediastinal tumors, the addition of surgical resection does not contribute significantly to long-term survival for most patients, as shown conclusively by the LCSG trial. The final group of patients who may benefit from surgical resection are those with combined small cell and non-small cell tumors. If a mixed-histology cancer is identified at diagnosis, the initial treatment should be chemotherapy to control the small cell component of the disease, and surgery should be considered for the non-small cell component. For patients who demonstrate an unexpectedly poor response to chemotherapy, and for patients who experience localized late relapse after treatment for pure small cell tumors, a repeat biopsy should be performed. Surgery may be considered if residual NSCLC is confirmed.     

Multidisciplinary Management of Locally Advanced Breast Cancer

▪ Abstract: The treatment of locally advanced breast cancer is aimed at achieving long-term local control with local surgery and/or radiation therapy and at improving disease-free and overall survival through the application of systemic cytotoxic chemotherapy and hormonal therapy. Studies of local therapy alone with surgery or radiotherapy have demonstrated high rates of local recurrence and low rates of long-term survival. The application of anthracycline-based neoadjuvant chemotherapy has resulted in rates of response ranging from 72% to 97%, clinical complete responses of 12–52%, and pathologic complete responses of 4–33%. Multidisciplinary treatment with neoadjuvant therapy, followed by local surgery and/or radiation therapy, followed by additional chemotherapy, has resulted in rates of local control that exceed 80%, and 5-year survival rates exceeding 50% are not unusual. The use of anthracycline-based neoadjuvant chemotherapy in the treatment of locally advanced breast cancer is thus now firmly established. Research in the treatment of locally advanced breast cancer is needed to further define the optimal method of local therapy and the role of new agents such as the taxanes. ▪     

Stage IVA thymoma: patterns of spread and surgical management

Stage IVA disease can be de novo disease or more commonly represent recurrent disease. The pleura is the most common site of relapse after thymoma resection. Local pleural disease is usually simply resected. This is usually combined with either induction or adjuvant chemotherapy. The ultimate extended surgery for advanced thymic tumors is an extrapleural pneumonectomy done for extensive pleural disease. This rarely performed operation is done for both stage IVA disease found at initial presentation and for recurrent disease as a salvage procedure. Again, these advanced patients with pleural spread are probably best managed by induction chemotherapy followed by resection.     

Long-term follow-up after curative surgery for early gastric lymphoma.

OBJECTIVE: This study was designed to examine the long-term survival of a homogenous group of patients with stage IE or IIE-1 gastric lymphoma after complete surgical resection. SUMMARY BACKGROUND DATA: The management of gastric lymphoma remains controversial. Enthusiasm for multimodality approaches for gastric lymphoma has lead to the current trend of using chemotherapy as primary treatment, thus avoiding gastric resection. Surgery, however, may result in improved long-term survival rates. METHODS: The records of all patients with the diagnosis of gastric lymphoma from 1980 to 1991 were reviewed retrospectively. Of 106 patients examined, 34 underwent curative resection and regional lymphadenectomy for pathologically staged IE or IIE-1 (pN1) gastric lymphoma. Fifteen patients underwent surgery alone, whereas 19 also received postoperative adjuvant therapy. RESULTS: The median follow-up time was 74 months. The 10-year actuarial disease-free survival was 91% for stage IE disease (n = 23) and 82% for stage IIE-1 disease (n = 11). There were no operative deaths and a 26% morbidity rate. No difference in survival was found for those treated with adjuvant therapy. CONCLUSIONS: The results compare favorably to those reported with the use of primary chemotherapy and radiation therapy and suggest that surgery remains the best frontline therapy for early gastric lymphoma.     

Preoperative and adjuvant chemotherapy in locally advanced non-small cell lung cancer

The continued favorable results with surgery in early stage lung cancer have led many investigators to use radiation and chemotherapy to reduce the size of unresectable tumors either before or after definitive surgery. Although earlier results with both radiation and chemotherapy have been poor, the newer cisplatin-containing combination chemotherapy regimens have yielded decreased local recurrence rates when used postoperatively following a complete resection and have produced increased complete resection rates when given preoperatively to patients with locally advanced and unresectable non-small cell lung cancer at diagnosis.     

Role of chemotherapy in malignant thymoma

Thymomas and thymic carcinomas, which are rare epithelial tumors arising from the thymus gland, are the most common tumors of the anterior mediastinum. Surgery is the principal treatment and is curative in early stage disease. Radiation therapy, either alone or in combination with chemotherapy, may be an option both in not completely and completely resected disease. Chemotherapy is offered to patients with locally advanced or metastatic thymoma and induces excellent responses race and prolonged survival.