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Locally Advanced Lung Cancer
Locally Advanced Lung Cancer* Case Presentation Anthony Abner, MD This clinical presentation demonstrates the clinical options available for treatment of a locally advanced nonsmall cell lung cancer. (CHEST 1995; 107:291S-293S)
The optimum treatment for patients with locally advanced (nonmetastatic) lung cancer remains undefined. Both preoperative chemotherapy and radiation therapy have been used in an attempt to render such patients resectable. These patients are at high risk for both local recurrence and distant metastases if treated with surgery alone. The following case presentation describes the treatment of a patient with such disease. CASE REPORT
The patient was a 62-year-old white man who presented with a cough and shortness of breath. He had a lo ng history of tobacco abuse. A chest x-ray film revealed a ri ght upper lobe mass, and a chest CT (Fig 1) showed a mass adjacent to the superior vena cava. The patient underwent a metastatic workup consisting of a bone scan and aCT head scan, both of which showed no evidence of distant metastatic spread. Pu lmonary function studies revealed an FEV 1 of 1.99 Land FVC of 2. 72 L. He was therefore considered to be a surgical candidate. The patient underwent staging mediastinoscopy, which showed no e vidence of mediastinal disease, with biopsies of the primary lesion positive for non-small cell lung cancer (NSCLC). We considered the following treatment options: (l) chemotherapy; (2) palliative radiation therapy; (3 ) radical radiation therapy; (4) combined-modality therapy (chemotherapy plus radiation ); (5) primary surg ica l resection. The patient underwent a thoracotomy with attempted resection. The tumor was found to encircle the superior vena cava, and the attempt to resect it was terminated. Potential treatment strategies at this tim e in clu ded the following: (1) no further treatment; (2) radical (high-dose) radiation therapy; (3) preoperative radiation therapy with attempted excision; (4) preoperative chemotherapy and radiation therapy with attempted excision. We recommended that the patient consider an aggress ive approach-combination chemotherapy and radiation therapywith the goa l of making the tumor resectable. He initially agreed lo this proposal but later decided against chemotherapy. The patient therefore received preoperative radiation therapy to a p la nned dose of 40 Gy in 20 fractions to the tumor and mediastinum using parallel-opposed anteroposterior:posteroanterior (AP:PA) fields. A repeat CT scan 4 weeks after completion of radiation therapy showed marked reduction in the tumor, as seen in Figure 2. Pulmonary function stud ies were repeated and showed his FEV 1 had increased to 2. 73 L, with a FVC of 3. 76 L. A nuclear scan revealed 68 % of perfusion was to the left lun g and *From the Joint Center for Radiation Therapy, Harvard Medical School, Boston.
f iGURE l. Initial CT of chest at the level of the carina, showing large mass invading mediastinum with probable postobstructive changes of distal lung.
F1cunE 2. Follow-up CT obtained after 40 Gy external beam radiation therapy, also at the level of the carina, showing substantial regression of mass with resolution of postobstr uctive changes. 32% to the right lung. Potential treatment strategies at this time included the following: (1) no further treatment; (2) continue radiation to a radical dose of 60 to 68 Gy; (3 ) repeat attempt at surgical resection; (4) repeat recommendation for chemotherapy. The pat ient und erwent a repeat thoracotomy 6 weeks after radiation therapy with a successful right pneumonectomy. The tumor was adherent to the superior vena cava but cou ld be separated by blunt dissection. The final pathologic report revealed NSCLC. He was extubated on the first postoperative day and was able to walk within 24 h. Possible treatment options at this time included the fo ll owing: (1) no further therapy; (2) continue radiation due to high risk of local relapse; (3) repeat suggestion for chemotherapy due to high risk of systemic relapse. On the fifth postoperative day, the patient died of a pulmonary embolus. CHEST I 107 I 6 I JUNE, 1995 I Supplement
2915
DISCUSSIO]'.;
Locally advanced, potentially resectable NSCLC represents a heterogeneous group of tumors characterized by invasion of the chest wall, mediastinal pleura, diaphragm, or parietal pericardium (American Joint Committee on Cancer stage T3); or heart, mediastinum, great vessels, esophagus, vertebral body, or carina (American Joint Committee on Cancer stage T4). The current case illustrates the clinical decision-making process that led to a successful resection but ultimate death of the patient. After determining that a patient with NSCLC has no evidence of metastatic disease, the treatment team must decide whether to proceed with a potentially curative approach. Since survival with radiation therapy alone is poor, 1·2 it seems reasonable to proceed with an aggressive strategy in an otherwise healthy patient. In the current case, the initial evaluation was not diagnostic of local invasion, and the patient was thought to have primarily resectable disease. Staging mediastinoscopy found no evidence of metastatic disease, and the surgeons discovered at thoracotomy that the tumor was locally adherent to the superior vena cava. Thus, the next issue to be resolved is whether the disease is categorically unresectable or if the patient might be considered for resection if reduction of tumor bulk is achieved. Both chemotherapy and radiation therapy have been used for this purpose. The potential synergism of concurrent chemoradiation8 -5 led the treating physicians to recommend this approach in the current case. The patient, however, declined this course of treatment due to his concern about the perceived side effects of chemotherapy, but he agreed to undergo radiation therapy alone. The optimum dose of preoperative radiation therapy is unknown. Doses too high may cause severe fibrosis and impair wound healing after resection, whereas inadequate dosing may not result in sufficient regression to allow surgery. We chose to use standard fractionation (2 Gylday) to a moderate total dose of 40 Gy. The radiation treatments were well tolerated, with the expected side effects of dysphagia and skin irritation. Next, it must be determined when to repeat the CT scan to decide whether to proceed with surgery or continue with full-course radiation therapy. The decision is influenced by the possibility of continuing tumor regression after the course of treatment is completed; however, it has been shown6 that the risk of intrathoracic relapse is decreased when radiation therapy is given without a break in treatment. It therefore appears reasonable to perform the CT scan around the final week of radiation therapy. If the results show adequate tumor regression, radiation therapy may be stopped; if there is minimal shrink2925
age, plans may be made to continue external radiation without a prolonged interruption. Assuming adequate disease regression has been achieved, the next decision concerns the timing of the operation. Once again, the trade-off involves allowing maximum disease regression while avoiding the potential complication of radiation fibrosis. We prefer to perform the operation between 4 and 8 weeks following completion of radiation therapy. However, it must be acknowledged that this will create an undesirable break in treatment, should postoperative radiation therapy be required. The type of surgery (lobectomy vs pneumonectomy) will depend on the pulmonary function of the patient and the extent of tumor invasion. Fowler et aF described a higher complication rate following pneumonectomy in patients treated with preoperative chemotherapy and radiation. Finally, the issue of further adjuvant therapy must be addressed. While the patient may have had good local control from the treatment described above, he or she would still be at substantial risk for distant metastases. The role of systemic therapy in this situation remains undefined. Recent studies8 suggest a significant reduction in distant metastases with adjuvant CAP (cyclophosphamide I doxorubicin I cisplatin) chemotherapy in early stage disease. Whether a similar advantage will be shown in advanced disease is unknown. We have recently implemented a phase II protocol to explore these issues at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. Patients with T3NO or T3Nl disease without distant metastases are being given high-dose PFM (cisplatinl 5-fluorouracil/methotrexate) chemotherapy with concurrent radiation therapy. The preoperative radiation dose is 36 Gy given in 20 fractions 4 days per week, thus allowing two cycles of chemotherapy to be administered together with the radiation. Postoperative radiation is given based on the tumor margin status. We hope that as we gain experience with this chemotherapy regimen, this study may be expanded to the cooperative group setting. REFERENCES
1 Dosoretz DE, Katin MJ, Blitzer PH, et al. Radiation therapy in the management of medically inoperable carcinoma of the Iung: results and implications for future treatment strategies. In t J Radiat Oncol Bioi Phys 1992; 24:3-9 2 Kaskowitz L, Graham MV, Emami B, et al. Radiation therapy alone for stage 1 non-small-cell lung cancer. Int J Radiat Oncol Bioi Phys 1993; 27:517-23 3 Schaake-Koning C, van den Bogaert W, DalesioO, et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall-cell lung cancer. N Eng! J Med 1992; 326:524-30 4 Faber LP, Kittle CF, Warren WH, et al. Preoperative chemotherapy and irradiation for stage III non-small-cell lung cancer. Ann Thorac Surg 1989; 47:669-77 Multimodality Therapy of Chest Malignancies: Update '94
5 Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Nat! Cancer Inst 1991; 83:417-23 6 Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation.
Int J Radiat Oncol Bioi Phys 1986; 12:539-47 7 Fowler WC, Langer CJ, Curran W Jr, et a!. Postoperative complications after combined neoadjuvant treatment of lung cancer. Ann Thorac Surg 1993; 55:986-89 8 Niiranen A, Niitamo-Korhonen S, Kouri M, et al. Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study. J Clin Oncol1992; 10:1927-32
CHEST /107/6/ JUNE, 1995/ Supplement
293S
The optimum treatment for patients with locally advanced (nonmetastatic) lung cancer remains undefined. Both preoperative chemotherapy and radiation therapy have been used in an attempt to render such patients resectable. These patients are at high risk for both local recurrence and distant metastases if treated with surgery alone. The following case presentation describes the treatment of a patient with such disease. CASE REPORT
The patient was a 62-year-old white man who presented with a cough and shortness of breath. He had a lo ng history of tobacco abuse. A chest x-ray film revealed a ri ght upper lobe mass, and a chest CT (Fig 1) showed a mass adjacent to the superior vena cava. The patient underwent a metastatic workup consisting of a bone scan and aCT head scan, both of which showed no evidence of distant metastatic spread. Pu lmonary function studies revealed an FEV 1 of 1.99 Land FVC of 2. 72 L. He was therefore considered to be a surgical candidate. The patient underwent staging mediastinoscopy, which showed no e vidence of mediastinal disease, with biopsies of the primary lesion positive for non-small cell lung cancer (NSCLC). We considered the following treatment options: (l) chemotherapy; (2) palliative radiation therapy; (3 ) radical radiation therapy; (4) combined-modality therapy (chemotherapy plus radiation ); (5) primary surg ica l resection. The patient underwent a thoracotomy with attempted resection. The tumor was found to encircle the superior vena cava, and the attempt to resect it was terminated. Potential treatment strategies at this tim e in clu ded the following: (1) no further treatment; (2) radical (high-dose) radiation therapy; (3) preoperative radiation therapy with attempted excision; (4) preoperative chemotherapy and radiation therapy with attempted excision. We recommended that the patient consider an aggress ive approach-combination chemotherapy and radiation therapywith the goa l of making the tumor resectable. He initially agreed lo this proposal but later decided against chemotherapy. The patient therefore received preoperative radiation therapy to a p la nned dose of 40 Gy in 20 fractions to the tumor and mediastinum using parallel-opposed anteroposterior:posteroanterior (AP:PA) fields. A repeat CT scan 4 weeks after completion of radiation therapy showed marked reduction in the tumor, as seen in Figure 2. Pulmonary function stud ies were repeated and showed his FEV 1 had increased to 2. 73 L, with a FVC of 3. 76 L. A nuclear scan revealed 68 % of perfusion was to the left lun g and *From the Joint Center for Radiation Therapy, Harvard Medical School, Boston.
f iGURE l. Initial CT of chest at the level of the carina, showing large mass invading mediastinum with probable postobstructive changes of distal lung.
F1cunE 2. Follow-up CT obtained after 40 Gy external beam radiation therapy, also at the level of the carina, showing substantial regression of mass with resolution of postobstr uctive changes. 32% to the right lung. Potential treatment strategies at this time included the following: (1) no further treatment; (2) continue radiation to a radical dose of 60 to 68 Gy; (3 ) repeat attempt at surgical resection; (4) repeat recommendation for chemotherapy. The pat ient und erwent a repeat thoracotomy 6 weeks after radiation therapy with a successful right pneumonectomy. The tumor was adherent to the superior vena cava but cou ld be separated by blunt dissection. The final pathologic report revealed NSCLC. He was extubated on the first postoperative day and was able to walk within 24 h. Possible treatment options at this time included the fo ll owing: (1) no further therapy; (2) continue radiation due to high risk of local relapse; (3) repeat suggestion for chemotherapy due to high risk of systemic relapse. On the fifth postoperative day, the patient died of a pulmonary embolus. CHEST I 107 I 6 I JUNE, 1995 I Supplement
2915
DISCUSSIO]'.;
Locally advanced, potentially resectable NSCLC represents a heterogeneous group of tumors characterized by invasion of the chest wall, mediastinal pleura, diaphragm, or parietal pericardium (American Joint Committee on Cancer stage T3); or heart, mediastinum, great vessels, esophagus, vertebral body, or carina (American Joint Committee on Cancer stage T4). The current case illustrates the clinical decision-making process that led to a successful resection but ultimate death of the patient. After determining that a patient with NSCLC has no evidence of metastatic disease, the treatment team must decide whether to proceed with a potentially curative approach. Since survival with radiation therapy alone is poor, 1·2 it seems reasonable to proceed with an aggressive strategy in an otherwise healthy patient. In the current case, the initial evaluation was not diagnostic of local invasion, and the patient was thought to have primarily resectable disease. Staging mediastinoscopy found no evidence of metastatic disease, and the surgeons discovered at thoracotomy that the tumor was locally adherent to the superior vena cava. Thus, the next issue to be resolved is whether the disease is categorically unresectable or if the patient might be considered for resection if reduction of tumor bulk is achieved. Both chemotherapy and radiation therapy have been used for this purpose. The potential synergism of concurrent chemoradiation8 -5 led the treating physicians to recommend this approach in the current case. The patient, however, declined this course of treatment due to his concern about the perceived side effects of chemotherapy, but he agreed to undergo radiation therapy alone. The optimum dose of preoperative radiation therapy is unknown. Doses too high may cause severe fibrosis and impair wound healing after resection, whereas inadequate dosing may not result in sufficient regression to allow surgery. We chose to use standard fractionation (2 Gylday) to a moderate total dose of 40 Gy. The radiation treatments were well tolerated, with the expected side effects of dysphagia and skin irritation. Next, it must be determined when to repeat the CT scan to decide whether to proceed with surgery or continue with full-course radiation therapy. The decision is influenced by the possibility of continuing tumor regression after the course of treatment is completed; however, it has been shown6 that the risk of intrathoracic relapse is decreased when radiation therapy is given without a break in treatment. It therefore appears reasonable to perform the CT scan around the final week of radiation therapy. If the results show adequate tumor regression, radiation therapy may be stopped; if there is minimal shrink2925
age, plans may be made to continue external radiation without a prolonged interruption. Assuming adequate disease regression has been achieved, the next decision concerns the timing of the operation. Once again, the trade-off involves allowing maximum disease regression while avoiding the potential complication of radiation fibrosis. We prefer to perform the operation between 4 and 8 weeks following completion of radiation therapy. However, it must be acknowledged that this will create an undesirable break in treatment, should postoperative radiation therapy be required. The type of surgery (lobectomy vs pneumonectomy) will depend on the pulmonary function of the patient and the extent of tumor invasion. Fowler et aF described a higher complication rate following pneumonectomy in patients treated with preoperative chemotherapy and radiation. Finally, the issue of further adjuvant therapy must be addressed. While the patient may have had good local control from the treatment described above, he or she would still be at substantial risk for distant metastases. The role of systemic therapy in this situation remains undefined. Recent studies8 suggest a significant reduction in distant metastases with adjuvant CAP (cyclophosphamide I doxorubicin I cisplatin) chemotherapy in early stage disease. Whether a similar advantage will be shown in advanced disease is unknown. We have recently implemented a phase II protocol to explore these issues at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. Patients with T3NO or T3Nl disease without distant metastases are being given high-dose PFM (cisplatinl 5-fluorouracil/methotrexate) chemotherapy with concurrent radiation therapy. The preoperative radiation dose is 36 Gy given in 20 fractions 4 days per week, thus allowing two cycles of chemotherapy to be administered together with the radiation. Postoperative radiation is given based on the tumor margin status. We hope that as we gain experience with this chemotherapy regimen, this study may be expanded to the cooperative group setting. REFERENCES
1 Dosoretz DE, Katin MJ, Blitzer PH, et al. Radiation therapy in the management of medically inoperable carcinoma of the Iung: results and implications for future treatment strategies. In t J Radiat Oncol Bioi Phys 1992; 24:3-9 2 Kaskowitz L, Graham MV, Emami B, et al. Radiation therapy alone for stage 1 non-small-cell lung cancer. Int J Radiat Oncol Bioi Phys 1993; 27:517-23 3 Schaake-Koning C, van den Bogaert W, DalesioO, et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall-cell lung cancer. N Eng! J Med 1992; 326:524-30 4 Faber LP, Kittle CF, Warren WH, et al. Preoperative chemotherapy and irradiation for stage III non-small-cell lung cancer. Ann Thorac Surg 1989; 47:669-77 Multimodality Therapy of Chest Malignancies: Update '94
5 Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Nat! Cancer Inst 1991; 83:417-23 6 Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation.
Int J Radiat Oncol Bioi Phys 1986; 12:539-47 7 Fowler WC, Langer CJ, Curran W Jr, et a!. Postoperative complications after combined neoadjuvant treatment of lung cancer. Ann Thorac Surg 1993; 55:986-89 8 Niiranen A, Niitamo-Korhonen S, Kouri M, et al. Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study. J Clin Oncol1992; 10:1927-32
CHEST /107/6/ JUNE, 1995/ Supplement
293S