Neoadjuvant therapy of stage III non-small cell lung cancer]

Locally advanced stage III disease constitutes 30 to 40% of the entire group of non-small cell lung cancer. Surgery is the only curable modality in this stage disease, but resection rate is less than 40%. Even in completely resected patients 5-year survival is only 30%. Several reports have evaluated postoperative chemotherapy and radiotherapy. Prospective randomized studies, however, have failed to demonstrate a survival advantage from adjuvant therapy. Neoadjuvant therapy is under investigation in attempt to improve survival of stage III patients. Preliminary data show that neoadjuvant therapy could increase resection rate and improve survival with moderate toxicities. However, there are many problems in study design such as the use of single-arm studies with short duration of follow-up, lack of accurate staging of selected patients and no precise definitions of resectability for stage III disease. Therefore, there is an urgent need for well designed randomized trial to confirm whether neoadjuvant therapy offers a survival advantage on locally advanced stage III disease.     

Resection of stage III non-small cell lung cancer following induction therapy

Approximately 25%–30% of all patients with non-small cell lung cancer (NSCLC) present with stage III tumors. Except for specific subsets, these tumors are not usually amenable to complete surgical resection and are associated with a 5-year survival of 10% or less. Because patients with stage III NSCLC die of distant metastases, recent efforts to improve the prognosis of these tumors have focused on neoadjuvant therapy using chemotherapy or chemoradiotherapy as induction treatment and subsequent surgical resection for local control. Many trials have now shown the feasibility of neoadjuvant therapy and suggest that overall survival is approximately double that seen after surgical resection or radiation alone. Future clinical trials will define whether surgical resection after induction therapy provides better local control and survival than chemotherapy and high-dose radiation alone.

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Resumen Aproximadamente 25–30% de la totalidad de los pacientes con cáncer pulmonar de células no pequeñas se presentan con tumores en estado III. A excepción de algunos subgrupos específicos, tales tumores usualmente no son susceptibles de resección quirúrgica completa y se asocian con una tasa de sobrevida de 5 años de 10% o menos. Debido a que los pacientes en estado III mueren por metástasis distantes, los esfuerzos recientes encaminados a mejorar el pronóstico se han concentrado en la terapia neoadyuvante utilizando quimioterapia o quimioradioterapia como tratamiento de inducción y resección quirúrgica subsiguiente para el control local de la enfermedad. Muchos ensayos clínicos han demostrado la factibilidad de la terapia neoadyuvante y sugieren que la tasa global de sobrevida es aproximadamente el doble de la que se ve en pacientes sometidos a resección quirúrgica o a irradiación solamente. Los futuros ensayos clínicos deben definir si la resección quirúrgica luego de la terapia de inducción resulta en mejor control local y mejor sobrevida que con la quimioterapia o la irradiación solamente.

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Résumé Environ 25–30% de tous les patients ayant un cancer autre qu'à petites cellules du poumon (non-small cell lung cancer ou «NSCLC») se présentent au stade III de leur maladie. Exceptés des sous-groupes spécifiques, ces tumeurs ne sont généralement pas traitables par la résection chirurgical complète et leur survie à 5 ans est de 10% ou moins. Parce que les patients des stades III des NSCLC meurent habituellement des métastases à distance, des efforts récents pour améliorer le pronostic se sont centrés sur la chimiothérapie néoadjuvante, c'est-à-dire par la chimiothérapie ou la chimioradiothérapie en induction suivie de résection locale. Beaucoup d'essais ont démontré la faisabilité de la thérapie néoadjuvante, et suggèrent que la survie globale est environ la double de celle après résection chirurgicale ou radiothérapie seule. Des essais cliniques futurs sont seuls capables de démontrer si la résection après l'induction thérapeutique par la chimiothérapie adjuvante peut contrôler la maladie et améliorer le pronostic par rapport à la chimiothérapie et la radiothérapie seules.

     

The biological operability of stage III non-small cell lung cancer

Stage III non-small cell lung cancer represents a broad spectrum of anatomical and histological subsets of patients with differing biological characteristics and prognostic expectations. Our experience with 161 consecutive patients undergoing complete resection for Stage III non-small cell lung cancer at the M. D. Anderson Hospital and Tumor Institute from 1965 through 1980 includes 69 patients with T3 N0 or N1 disease and 92 patients with an N2 classification. The cumulative 5-year survival overall was 30%: 35.6% for the T3 N0 or N1 group and 26% for the N2 patients. Seventy-three patients had squamous cell carcinoma and 76, adenocarcinoma. Small numbers of patients had other miscellaneous classifications (N = 12). In the T3 N0 or N1 subset, 43% of the patients with squamous cell carcinoma (N = 37) and 23% of those with adenocarcinoma (N = 25) survived 5 years. In the N2 subset, 39% of the patients with squamous cell carcinoma (N = 36) and 14% of the group with adenocarcinoma (N = 52) achieved long-term survival. Failure of treatment was clinically documented in 61 patients. The first observed recurrence or metastasis was at a distant site in the majority of these patients. Operative intervention for patients with Stage III M0 non-small cell lung cancer is effective and reflects the impact and limitations of resection on disease progression. Adjuvant irradiation was not shown to improve the outcome over the results of operation alone. Effective systemic therapy will be required to produce substantial changes in end results.     

Preoperative chemotherapy and irradiation for stage III non-small cell lung cancer

Surgical therapy for stage III non-small cell lung cancer (NSCLC) has not resulted in substantial long-term survival. Neoadjuvant treatment programs that could down-stage the tumor and achieve increased long-term survival would be of obvious benefit. We have used preoperative simultaneous chemotherapy and irradiation in 85 patients with clinical stage III non-small cell lung cancer considered candidates for surgical resection. One group of 56 patients was treated with cisplatin, 5-fluorouracil, and simultaneous irradiation for five days every other week for a total of four cycles. After treatment, 39 patients underwent resection, and the operative mortality was 2 (5%) of 39. A second trial was undertaken in which etoposide (VP-16) was added because of its synergism with cisplatin. In this group, 29 patients were considered to have potentially resectable disease, and 23 underwent thoracotomy with 1 operative death (4%). Of the total of 62 patients having thoracotomy, 60 underwent resection (97%). Complications were major, and there were four bronchopleural fistulas. For the 85 patients eligible for surgical intervention in these two groups of patients, the Kaplan-Meier median survival estimate is 40% at 3 years. The median survival of the 62 patients having thoracotomy is 36.6 months. Combination preoperative chemotherapy and irradiation is feasible with acceptable toxicity and operative mortality in patients with clinical stage III non-small cell lung cancer. Prospective randomized studies are suggested for further evaluation of this treatment program.     

Stereotactic body radiation therapy for stage I non-small cell lung cancer

Image-guided SBRT with the delivery of a BED greater than 100 Gy is feasible and safe in the treatment of peripherally located inoperable stage I NSCLC. The 3- to 5-year local control and overall survival rates for SBRT seem to be much better than the rates for conventional radiotherapy, and the toxicity rate is minimal. Particularly for stage Ia (T1N0M0) disease, survival rates with SBRT were comparable with rates seen with surgical resection. SBRT is becoming the standard treatment for inoperable stage I NSCLC. Its role in operable stage I NSCLC. however. is not clear. To balance improved targeting accuracy with minimized treatment-related toxicity. a reliable immobilization device and consideration of image-guided tumor motion are crucial. The optimal dose regimen remains unclear, but a BED greater than 100 Gy seems warranted.     

Role of postoperative radiation therapy in stage IIIa non-small cell lung cancer

One hundred forty-six patients with pathological stage IIIa non-small cell lung cancer were retrospectively analyzed to determine whether postoperative radiation therapy improves survival and reduces locoregional recurrences. The survival rate of the overall group at 1, 3, and 5 years was 56%, 24%, and 17%, respectively. Regarding the type of resection and histology, we did not observe statistically significant differences. Patients with N0 and N1 disease were grouped and compared with the N2 group, and survival at 3 and 5 years was 41% and 27%, respectively, for the T3 N0-1 group and 17% and 15%, respectively, for the T3 N2 group (p less than 0.001 and p = 0.05, respectively). Eighty-six patients received postoperative irradiation (45 to 50 Gy) and 60 did not. We have not observed any improvement in survival with postoperative radiation therapy, except in those patients with N2 disease. Median survival time was 6 months for patients without irradiation and 15 months for those with irradiation (p = 0.071). According to locoregional recurrences, a slight benefit with postoperative radiation therapy was observed.     

Neoadjuvant therapy in non-small cell lung cancer. Prognostic impact of "mediastinal downstaging"]

In the course of a prospective multicenter study, 40 (26 squamous cell and 14 adenocarcinomas) patients with stage IIIA and IIIB non-small cell lung cancer (NSCLC) were submitted to surgery after neoadjuvant radiochemotherapy. Pretherapeutic clinical lymph node status was compared to the lymph node involvement established in the resection specimens. Therapy-induced tumor regression was classified according to a three-step tumor regression grading system. In 29 patients (72.5%) a downward shift in lymph node involvement could be established,whereas in 27.5% ( n=11) pretherapeutic lymph node status was maintained. Of 26 patients with post-therapeutic N0 or N1 status, 21 revealed less than 10% vital tumor tissue in the resection specimens (regression grades IIb or III). Patients with post-therapeutic N0 or N1 lymph node status were found to have a survival benefit compared to patients with N2 lymph node involvement, though this difference was not statistically significant (p=0.27). On the other hand, tumor regression showed a significant correlation to the overall survival period (p=0.02). Thus, therapy-induced tumor regression grading seems to be a more precise method to predict the outcome of the disease.     

Targeted therapy for non-small cell lung cancer

The overall survival for the treatment of lung cancer patients is less than 15%, despite advances in chemotherapy, radiation therapy, and surgery, due to the inability to control metastatic disease. Over the past three decades, the genetics of lung cancer has been progressively delineated. Small molecule drugs or monoclonal antibodies have been developed that target and inactivate specific cancer-related proteins, such as growth factor receptors or their kinases. This article will review the therapeutic implications of molecular changes associated with non-small cell lung cancer and the status of targeted therapies in its treatment.     

Heavy-ion therapy for non-small cell lung cancer

Since carbon beam therapy for non-small cell lung cancer (NSCLC) was initiated in October 1996, seven trials have been conducted; three have already closed and the remaining four are ongoing. The local control rate, cause-specific survival rate, and overall survival rate of 141 patients with clinical stage I NSCLC were 82%, 58%, and 42%, respectively. Radiation pneumonia was rare (2.1%) and not serious. In the phase II clinical study, the local control rate achieved in 50 patients was 100%, with no radiation pneumonia, resulting in a 60% overall survival rate. Carbon beam therapy could be an alternative to surgery, especially for lung cancer patients of advanced age and/or with complications. For locally advanced lung cancer treated with carbon beam therapy, excellent local control comparable to that in stage INSCLC has been demonstrated and offers hopeful prospects for the treatment of lung cancer.     

Assessment of induction therapy and resection in stage IIIb non-small cell lung cancer]

Twelve patients with stage IIIb non-small cell lung cancer underwent induction therapy and resection from January 1990 to July 1998. They were divided into two groups; group A (n = 5) received two (to four) preresectional cisplatin and videsine chemotherapy, group B (n = 7) received chemoradiotherapy (radiation with concurrent low-dose-daily cisplatin). All patients in both groups had clinically down-stage and had no major side effects preventing surgery. 3 patients underwent radical pneumonectomy and 9 patients had radical lobectomy with no operative mortality. In 9 patients the disease was pathologically downstaged. Overall five-year survival was 27%, while in group A it was 50%. In group B 2-year survival was 18% and the longest survivor had pulmonary recurrence four years after surgery. Our data show better prognosis in group A than in group B. This results suggest that chemotherapy may be superior pre-resectional therapy to chemoradiotherapy.     

Value of accelerated multimodality therapy in stage IIIA and IIIB non-small cell lung cancer

OBJECTIVES: This study was undertaken to assess accelerated multimodality therapy in patients with IIIA and IIIB non-small cell lung cancer in terms of toxicity, feasibility, response, survival, and recurrence (value) and to identify predictors of pathologic response and improved survival. METHODS: Between October 1994 and September 2000, a total of 105 patients with stage pIIIA (n = 78) or pIIIB (n = 27) non-small cell lung cancer were enrolled in a study of accelerated multimodality therapy, consisting of hyperfractionated radiotherapy with concurrent chemotherapy (paclitaxel and cisplatin) followed by resection and postoperative chemoradiation. Multivariable correlates of pathologic response and survival were assessed. RESULTS: Toxic effects related to induction therapy necessitated hospitalization in 40% of patients (n = 42); treatment-related mortality was 9% (n = 9). With respect to feasibility, 100% of patients completed induction therapy, 93% (n = 98) of cancers were operable, 79% (n = 83) of cancers were curatively resectable, and 77% (n = 81) of patients completed all therapy. Sterilization of mediastinal nodes was similar (P =.6) for pN2 (35%) and pN3 (30%) disease. Median, 2-year, and 5-year survivals were 27 months, 53%, and 32%, respectively. Locoregional recurrence, distant recurrence, and both were seen in 6% (n = 6), 45% (n = 47), and 3% (n = 3) of patients, respectively. Pathologic response was not predictable. Nodal status predicted incrementally decreasing survival for patients with cancers downstaged to ypN0 or ypN1 (n = 35) versus ypN2 (n = 44) versus ypN3 (n = 20; P <.001). In addition, advancing age, squamous histologic type, and higher pT predicted poorer survival. CONCLUSIONS: Accelerated multimodality therapy is equally valuable in IIIA and IIIB non-small cell lung cancers. Despite unpredictable response to induction therapy, younger patients and those with nonsquamous histologic type, sterilization of mediastinal lymph nodes, and lower pT benefit most. A ypN2 stage reduces but does not preclude long-term survival.     

Neoadjuvant chemotherapy in stage III breast cancer

Neoadjuvant chemotherapy in advanced breast cancer can potentially downstage disease prior to definitive surgery. In this study, a doxorubicin-based neoadjuvant regimen was administered to stage III breast cancer patients to assess 1) primary tumor response, 2) tumor involvement of resection margins, and 3) predictive value in cancer outcome. Eighty-two patients with stage IIIA and IIIB breast cancer diagnosed between 1990 and 2003 were studied. All patients received similar chemotherapy regimens, consisting of doxorubicin, cisplatin, and 5-fluorouracil, plus surgery and radiation therapy. End points measured include primary tumor response [complete response (CR) = 100%, partial response (PR) > 50%, or no response (NR) < or = 50%], resection margins for tumor, disease-free, and overall survival. Kaplan-Meier and log-rank tests were performed. Of the 82 patients studied, 34 received neoadjuvant therapy, 48 received conventional postoperative treatment. Seventy-two per cent of the stage IIIB and 22 per cent of the stage IIIA patients received neoadjuvant therapy. In the neoadjuvant group, 29 (85%) patients demonstrated tumor response, 9 (26%) of which were CR. Tumor-free resection margins were achieved in 94 per cent of the neoadjuvant group. Survival analysis demonstrated no benefit comparing neoadjuvant versus postoperative adjuvant therapy but hints at improved disease-free survival in neoadjuvant CR patients (log-rank test, P = 0.07). Eighty-five per cent of patients with stage III breast cancer treated with neoadjuvant chemotherapy experienced clinical response, with 26 per cent CR, and 97 per cent tumor-free resection margins. CR may portend a better cancer outcome.     

Current surgical therapy for stage IIIA (N2) non-small cell lung cancer

Local therapy alone (surgery or radiation) leads to poor overall survival in patients with stage III non-small cell lung cancer because most of these patients die of distant metastases. During the past 20 years, studies have focused on developing effective chemotherapy regimens that can be combined with local therapies (surgery and/or radiation). The role of surgery has been evaluated, and the selection criteria for resection have been defined.     

Heavy ion therapy for non-small cell lung cancer

Carbon beam radiation has well-balanced dual actions on cancer: efficient dose localization and potent biological anticancer effect due to high RBE (Relative Biological Effectiveness). Two phase I/II clinical studies on the carbon beam radiation treatment of inoperable stage I non-small cell lung cancer (NSCLC) were carried out in our institution from October 1996 to February 1999. The dose-limiting toxicity was found to be radiation pneumonia. In the first protocol, 47 patients received 18 fractions of increasing doses from 59.4 GyE by 10% over 6 weeks. The maximum tolerated dose was found to be 95.4 GyE, while the complete tumor control dose was 85.6 GyE. In the second protocol, 34 patients received 9 fractions of in creasing doses from 68.4 GyE by 5% over 3 weeks. The maximum tolerated dose was 79.2 GyE, and the complete tumor control dose was > 68.9 GyE. The 4-year survival rate estimated by the Kaplan-Meier method was 56% for patients receiving the first protocol. Because a higher local control rate was achieved in the second protocol, the 5-year survival rate is estimated to be higher and similar to that achieved after surgery. Another phase II clinical study in patients with stage INSCLC is ongoing. Heavy-particle radiotherapy is a new modality for the treatment of lung cancer which holds promise for the 21st century.     

Assessment of surgery for stage IV non-small cell lung cancer

We assessed the survival of surgery for stage IV non-small cell lung cancer. Forty-two patients were operated on lung cancer for stage IV from 1986 to 2005. Overall median survival time (MST) was 12.3 months and 5-year survival rate was 9.8%. There was significant difference in survival between pulmonary metastasis (pm2) and other sites metastasis (p<0.05). In pm2 patients there was significant difference between ipsilateral metastasis and contralateral metastasis (MST 21.9 months, 2-year survival rate 48.6%, 5-year survival rate 21.6% and MST 12.3 months, 2-year survival rate 0%) [p<0.05], and between complete resection and incomplete resection (MST 36 months, 2-year survival rate 64.8%, 5-year survival rate 28.8% and MST 12.3 months, 2-year survival rate 0%) [p<0.01]. In patients with brain metastasis, surgery of brain metastasis was better prognosis than radiation therapy (MST 12.5 months, 3-year survival rate 33.3% and MST 8.3 months, 2-year survival rate 0%) [NS].     

Preoperative induction therapy in non-small cell lung cancer

The clinical significance of preoperative induction therapy for non-small cell lung cancer (NSCLC) is reviewed. As the survival rate in locally advanced NSCLC patients remains poor, preoperative therapy has been attempted in order to improve survival. Whereas some prospective phase II and phase III studies have demonstrated that preoperative cisplatin-based chemotherapy with or without concurrent radiation may improve the prognosis, the efficacy has not been established. Recently, some new chemotherapeutic agents such as paclitaxel and gemcitabine have been introduced, and it has been suggested that preoperative therapy using these new drugs may be more effective. To establish effective preoperative therapy regimens, more sophisticated, prospective, randomized studies in sufficient numbers of homogenous populations such as mediastinoscopy-proven stage IIIA, T1-2N2 patients should be conducted.