The treatment of limited small cell lung cancer: a report of the progress made and future prospects.

The improvements in the treatment of small cell lung cancer over the last 30 years have been realised by understanding that it is a systemic disease, but that areas of bulk and sanctuary require a complementary therapy. Despite successful strategies using combinations and thoracic radiotherapy, there remains uncertainty about what the best regimens are, their timing and their intensity. However, earlier concurrent therapy and rather brief intense chemotherapy and radiotherapy seem to produce the best results in moderately fit patients of all ages. How to select the fit patients and what to do about the less fit ones remains controversial and have economic consequences for governments and payers. Despite a meta-analysis demonstrating the success of prophylactic cranial irradiation (PCI), doubts linger about its safety, despite nothing more than anecdotal evidence from a previous era. The role of surgery continues to be explored, more in Europe than North America or Asia. Strategies for treatment of minimum residual disease seem a focus. New drugs, molecular targeted therapy, immunotherapy and other molecular therapies offer promise and theory, but there is little evidence about their place in the treatment protocols of today.

Ten-year follow-up of Southwest Oncology Group 8269: a phase II trial of concomitant cisplatin-etoposide and daily thoracic radiotherapy in limited small-cell lung cancer.

PURPOSE: To report the long-term follow-up of Southwest Oncology Group-8269, a phase II North American cooperative group trial of concurrent cisplatin, etoposide, vincristine (PEV), and thoracic radiotherapy (TRT) for limited small-cell lung cancer (L-SCLC). METHODS: 114 eligible patients from 47 institutions enrolled between April, 1985 and March 1986. Patients had documented L-SCLC. Induction chemotherapy consisted of three cycles of PEV. TRT was administered at 1.8 Gy/fraction in 25 daily fractions to a total dose of 45 Gy, to begin concomitantly. Consolidative chemotherapy included two cycles of vincristine, methotrexate, etoposide, doxorubicin and cyclophosphamide. Prophylactic cranial irradiation (PCI) was concurrent with the 3rd cycle of chemotherapy. The PCI dose was 30 Gy in 15 fractions of 2 Gy/fraction. RESULTS: As of May 2000, 5 of 114 remain alive and progression-free with a minimum follow-up interval of 13.2 years, as of May 2000. The median follow-up interval is 14.2 years. Thirty eight patients died of causes other than SCLC and five patients are still alive and progression-free. Of the remaining 71 patients dying of SCLC, local failure (LF) occurred in 24% (17 patients), distant metastasis (DM) occurred in 35% (25 patients), simultaneous LF and DM occurred in 25% (18 patients), and was indeterminate in 16% (11 patients). Thus, LF was a component of failure in 49%. Twenty patients had the CNS as the initial site of failure. Eleven patients (10%) developed fatal second primary cancers, including two with acute myelogenous leukemia, two with squamous cell lung cancer, one each with breast, pancreas, prostate, renal cell, and myelodysplasia. One patient developed both a melanoma and non-Hodgkin's lymphoma. CONCLUSION: There are long-term survivors with concomitant TRT and PEV. LF and DM are common. Pattern of failure suggests needs to improve local and systemic control.

Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.

PURPOSE: High-dose radiation may improve outcomes in non-small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated. MATERIALS AND METHODS: A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes >or= 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine. RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions. CONCLUSION: Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.

Limited small-cell lung cancer: a potentially curable disease.

Patients with limited-stage small-cell carcinoma of the lung are treated with combined-modality therapy with the intent to cure. Standard therapy consists of platinum-based combination chemotherapy, thoracic irradiation, and for responders, prophylactic cranial irradiation. Despite this aggressive approach, too few patients achieve 5-year survival. In the past several years, new chemotherapeutic agents, including the taxanes and the topoisomerase I inhibitors, have demonstrated substantial activity against small-cell carcinoma. These agents are now being incorporated into clinical trials for patients with limited-stage disease. The best combination of these agents with platinum-based regimens is yet to be determined, and data supporting increased survival are awaited. Other studies are exploring thoracic radiation issues. Questions remain regarding optimal timing, dose, volume, and fractionation schemes. The most effective combination of thoracic irradiation and the newer chemotherapy agents also remains to be determined. The current approach to limited-stage small-cell carcinoma is reviewed, ongoing trials are described, and future directions are explored.

Similar outcome of elderly patients in intergroup trial 0096: Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma.

BACKGROUND: Elderly patients comprise a significant portion of patients with limited stage small cell lung carcinoma. However, the prognostic importance of age has been controversial, and concern for toxicity often hinders enthusiasm for offering full dose therapy. METHODS: In this retrospective analysis of Intergroup Trial 0096, the authors compared the outcome of patients 70 years or older to those younger than 70 years. Patients received cisplatin 60 mg/m(2), Day 1 and etoposide 120 mg/m(2), Days 1-3 for 4 cycles and either once or twice daily concurrent thoracic radiotherapy to 45 grays. RESULTS: Of 381 patients, 50 (13%) were age 70 years or older. The elderly group did not differ significantly from those younger than 70 years with respect to gender distribution, performance status, or weight loss. Severe hematologic toxicity (Grade 4-5: 61% vs. 84%; P < 0.01) and fatal toxicity (1% vs. 10%; P = 0.01) occurred more often among older patients. There were no differences in the frequency of nonhematologic toxicities. Response rate (88% vs. 80%; P = 0.11), event free survival rate (5 year, 19% vs. 16%; P = 0.18), time to local failure, and duration of response did not differ between groups. Overall survival rates (5 year, 22% vs. 16%; P = 0.05) favored those younger than 70 years. Much of the difference in overall survival rates between age groups occurred within the first 6 months on study. CONCLUSIONS: Elderly patients had similar response and survival rates compared with those younger than 70 years. However, toxicity, particularly hematologic, was greater among the elderly. Selected older patients, such as those with a good performance status, should be considered for optimum treatment approaches.

Counterpoint: better radiation treatment of non-small cell lung cancer using new techniques without elective nodal irradiation.

The treatment of non-small cell lung cancer has continued to evolve with the advent of improved staging technologies, chemotherapeutic agents, and methods of radiation delivery. Treatment of clinically uninvolved, regional lymph nodes historically has been delivered in the attempt to cover unseen disease, reduce regional failure, and improve survival. None of these suppositions has been tested nor are they supported by data. With enhanced staging using modalities like positron emission tomography and esophageal ultrasonography, treatment portals can be designed to encompass known disease with greater accuracy and confidence. Data for early-stage non-small cell lung cancer is now increasing and strongly suggest that eliminating elective nodal irradiation does not result in a high incidence of nodal relapse and does not compromise survival. Three-dimensional conformal radiotherapy incorporates better targeting and beam directions to effect smaller treatment volumes that include only clinically evident disease. It provides treatment techniques that maximize tumor dose and minimize normal tissue toxicity. Using smaller fields that do not incorporate elective nodal regions may allow higher doses, and these may help improve local control and survival in a disease where current results are unacceptable.

Surgery versus radiation therapy for patients with aggressive fibromatosis or desmoid tumors: A comparative review of 22 articles.

BACKGROUND: Desmoid tumors (aggressive fibromatoses) are benign neoplasms with high rates of recurrence after surgery. Radiotherapy is sometimes reported to prevent recurrences, but not in all studies. In order to evaluate the effect of radiation, comparative analysis was performed. METHODS: The authors conducted a MEDLINE search and collected all articles in the English language on the treatment of "desmoid tumor" or "aggressive fibromatosis" from the years 1983-1998. They categorized treatment into three groups: surgery alone (S), surgery with radiotherapy (S + RT), or radiotherapy alone (RT). The S and S + RT groups were each subdivided according to whether margins were free (-), positive (+), or unknown. Each subgroup was divided into cases with primary, recurrent, or unknown tumor. RESULTS: The local control rates after treatment for cases in the S group with (-) margins, (+) margins, and overall were 72%, 41%, and 61%, respectively. For the S + RT group the local control results were 94%, 75%, and 75%, respectively, significantly different when compared with the results for the S group. For the RT group, the local control was 78%, significantly superior to that of the S group (61%). Cases with primary and recurrent tumors had significantly superior local control rates with S + RT or RT versus S. Radiotherapy complications noted were fibrosis, paresthesias, edema, and fracture. CONCLUSIONS: RT or S + RT results in significantly better local control than S. Even after dividing the groups into cases with free and positive margins and cases with primary and recurrent tumors, the best local control is achieved with RT or S + RT.

Radiotherapy in prostate cancer: improvements in an effective treatment and future prospects of further gains.

Radiation therapy has useful applications in the management of all stages of prostate cancer. Modern advances have improved the efficacy of radiotherapy, and have lowered the toxicity. Radiotherapy offers patients with early stage, clinically localized disease a non-invasive curative option that has low toxicity. Patients with metastatic prostate cancer can be palliated with judicious use of radiotherapy.

Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients.

Tumor control probability (TCP) model calculations may be used in a relative manner to evaluate and optimize three-dimensional (3-D) treatment plans. Using a mathematical model which makes a number of simplistic assumptions, TCPs can be estimated from a 3-D dose distribution of the tumor given the dose required for a 50% probability of tumor control (D50) and the normalized slope (gamma) of the sigmoid-shaped dose-response curve at D50. The purpose of this work was to derive D50 and gamma from our clinical experience using 3-D treatment planning to treat non-small cell lung cancer (NSCLC) patients. Our results suggest that for NSCLC patients, the dose to achieve significant probability of tumor control may be large (on the order of 84 Gy) for longer (> 30 months) local progression-free survival.

Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.

BACKGROUND: For small-cell lung cancer confined to one hemithorax (limited small-cell lung cancer), thoracic radiotherapy improves survival, but the best ways of integrating chemotherapy and thoracic radiotherapy remain unsettled. Twice-daily accelerated thoracic radiotherapy has potential advantages over once-daily radiotherapy. METHODS: We studied 417 patients with limited small-cell lung cancer. All the patients received four 21-day cycles of cisplatin plus etoposide. We randomly assigned these patients to receive a total of 45 Gy of concurrent thoracic radiotherapy, given either twice daily over a three-week period or once daily over a period of five weeks. RESULTS: Twice-daily treatment beginning with the first cycle of chemotherapy significantly improved survival as compared with concurrent once-daily radiotherapy (P=0.04 by the log-rank test). After a median follow-up of almost 8 years, the median survival was 19 months for the once-daily group and 23 months for the twice-daily group. The survival rates for patients receiving once-daily radiotherapy were 41 percent at two years and 16 percent at five years. For patients receiving twice-daily radiotherapy, the survival rates were 47 percent at two years and 26 percent at five years. Grade 3 esophagitis was significantly more frequent with twice-daily thoracic radiotherapy, occurring in 27 percent of patients, as compared with 11 percent in the once-daily group (P<0.001). CONCLUSIONS: Four cycles of cisplatin plus etoposide and a course of radiotherapy (45 Gy, given either once or twice daily) beginning with cycle 1 of the chemotherapy resulted in overall two- and five-year survival rates of 44 percent and 23 percent, a considerable improvement in survival rates over previous results in patients with limited small-cell lung cancer.

Gemcitabine and radiation therapy for non-small cell lung cancer.

Patients with stage III non-small cell lung cancer (NSCLC) frequently progress either within the irradiated field or systemically, due to uncontrolled microscopic dissemination present before the time of initial diagnosis. The use of combined modality therapy has led to improved survival rates in recent years. In particular, the use of cisplatin and vinblastine as induction chemotherapy is supported by two large randomized clinical trials. Nevertheless, the large majority of patients still die of progressive disease, thus providing a rationale for the integration of new active agents into the overall treatment plan of these patients. Gemcitabine has demonstrated significant single-agent activity in NSCLC. In addition, preclinical and early clinical data indicate that it is a powerful radiation enhancer. Clinical trials investigating this drug with concurrent radiation therapy in NSCLC are reviewed.

Integrating thoracic radiotherapy in the treatment of limited small-cell lung cancer.

Although the need to combine thoracic radiotherapy with systemic chemotherapy in the curative treatment of limited small-cell lung cancer is now widely acknowledged, there is substantial disagreement on how best to do this. This paper reviews radiotherapeutic factors but also highlights the important interactions that occur with some classes of chemotherapeutics. Studies examining variables like dose and volume are clearly in order. Concurrent therapy given early has been adopted throughout most of the world, except Europe. The reasons for this are explored. Multiple studies are now showing excellent results with fewer total cycles of chemotherapy. Integration of newer drugs is another challenge for clinical investigators at the close of this century.

Fraction size and dose parameters related to the incidence of pericardial effusions.

PURPOSE: The influence of treatment parameters, such as (a) fraction size and (b) average and maximum dose (as derived from three-dimensional (3D) distributions), on the incidence of pericarditis was analyzed. To understand and predict the dose and volume effect on the pericardium, a normal tissue-complication probability model was tested with these complication data. METHODS AND MATERIALS: Patients (n = 57) entered in 3 consecutive University of Michigan protocols of combined modality for treatment of localized esophageal carcinoma, and having 3D treatment planning for radiation therapy were the subject of this study. Univariate and multivariate analyses were performed to determine the significance of the effect of fraction size and dose parameters on the development of any grade of pericarditis. Dose distributions were corrected for the biological effect of fraction size using the linear-quadratic method. Normal tissue complication probability (NTCP) was calculated with the Lyman model. RESULTS: Nonmalignant pericardial effusions occurred in 5 of the 57 patients; all effusions were in patients who received treatment with 3.5 Gy daily fractions. On multivariate analysis, no dose factor except fraction size predicted pericarditis, until the dose distributions were corrected for the effect of fraction size ("bio"-dose). Then, both "bio-average" and "bio-maximum" dose were significant predictive factors (p = 0.014). NTCPs for the patients with pericarditis range from 62% to 99% for the calculations with the "bio"-dose distributions vs. 0.5% to 27% for the uncorrected distributions. DISCUSSION: A normal tissue complication probability (NTCP) model predicts a trend towards a high incidence of radiation pericarditis for patients who have high complication probabilities. It is important to correct the dose distribution for the effects of fractionation, particularly when the fraction size deviates greatly from standard (2.0 Gy) fractionation.

Concurrent chemoradiotherapy for limited small-cell lung cancer.

It is now established that the treatment of choice for limited small-cell lung cancer (SCLC) in the United States, Canada, and Japan is thoracic radiotherapy (TRT) combined with etoposide (VePesid), either alone or in conjunction with other agents, especially a platinum agent. The specific factors related to the use of TRT in the treatment of limited SCLC are: (1) dose (total and daily), (2) volume to be irradiated, (3) fractionation, (4) timing of radiation relative to chemotherapy (concurrent, at the same time; alternating, using both within weeks; or sequential, all of one followed by all of the other without any overlap), (5) whether radiation should be given earlier or later in the treatment course, and (6) whether to use a split course (rest intervals during a course of radiotherapy) or a continuous course of radiation. This paper discusses each of these factors.

Volume and dose parameters for survival of non-small cell lung cancer patients.

BACKGROUND AND PURPOSE: To determine the effect of tumor volume and dose factors derived from 3-D treatment planning dose distributions on survival outcome for non-small cell lung cancer patients. MATERIALS AND METHODS: Seventy-six consecutive patients diagnosed with medically inoperable or locally advanced, unresectable non-small cell lung cancer planned with 3-D treatment planning between 1986 and 1992 were the subject of this retrospective study. Patient characteristics and dosimetric parameters were analyzed for influence on overall survival and local progression-free survival (LPFS) using univariate and multivariate analysis. RESULTS: Nodal stage and stage were the most significant factors for overall survival and LPFS duration on both univariate and multivariate analysis. We found a wide range of primary tumor volume sizes for each stage. Patients with tumor volumes <200 cm3 had longer survival (P = 0.047). In an analysis stratifying patients into four groups by tumor volume (<200 cm3 versus >200 cm3) and nodes (negative versus positive), patients in the group with no nodal disease and <200 cm3 tumor volumes survived longer than patients in any other group (P = 0.046). No dose factors were statistically significant for longer survival. Longer LPFS was seen for (a) isocenter dose >70 Gy (P = 0.055) for the overall group of patients, (b) within a subgroup with no nodal disease and >73 Gy (P = 0.054), and (c) within a subgroup with no nodal disease and tumor volume <200 cm3 receiving >73 Gy (P = 0.086). CONCLUSIONS: Several findings from the volume and dosimetric analysis in this study are noteworthy. Stage was found to be a poor predictor of primary tumor volume size. Also, tumor volume size (<200 cm3) in conjunction with nodal status (negative nodes) had an impact on survival though there was a mix of stage (I, IIIa, IIIb) in this group of patients. Finally, dose appears to influence local control (LPFS) for the overall group of patients and when tumor volumes are <200 cm3. Our data indicate that outcome following radiation may be better predicted by a staging system that takes into account tumor volume and nodal spread rather than a system that is largely based on anatomic location of disease. Dose prescription for lung cancer treatment might better be written based on tumor volume size.

Dose escalation for non-small cell lung cancer using conformal radiation therapy.

PURPOSE: Improved local control of non-small cell lung cancer (NSCLC) may be possible with an increased dose of radiation. Three-dimensional radiation treatment planning (3D RTP) was used to design a radiation therapy (RT) dose escalation trial, where the dose was determined by (a) the effective volume of normal lung irradiated, and (b) the estimated risk of a complication. Preliminary results of this trial were reviewed. METHODS AND MATERIALS: A graph of the iso-normal tissue complication probability (NTCP) levels associated with a dose and effective volume (V(eff)) was derived, using normal tissue parameters derived from the literature. This led to a dose escalation schema, where patients were sorted into 1 of 5 treatment bins, determined by the V(eff) of the best possible treatment plan. The starting doses ranged from 63 to 84 Gy. Each treatment bin was then escalated separately, as in Phase I dose escalation fashion, with Grade > or = 3 radiation pneumonitis defined as dose limiting. To allow for dose escalation, we required patient follow-up to be > or = 6 months for at least three patients. 3D treatment planning was used to irradiate only the radiographically abnormal areas, with 2.1 Gy (corrected for lung inhomogeneity)/day. Clinically uninvolved lymph nodes were not treated prophylactically. RESULTS: A total of 48 NSCLC patients have been treated (Stage I/II: 18 patients; Stage III: 28 patients; mediastinal recurrence postsurgery: 2 patients). No radiation pneumonitis has been observed in the 30 patients currently evaluable beyond the 6-month time point. All treatment bins have been escalated at least once. Current doses in the five treatment bins are 69.3, 69.3, 75.6, 84, and 92.4 Gy. None of the 15 evaluable patients in any bin with > or = 30% NTCP experienced clinical radiation pneumonitis, implying that the actual risk is < 20% (beta error rate 5%). Despite the observation of the clinically negative lymph nodes at high risk, there has been no failure in the untreated mediastinum as the sole site of first failure. Three of 10 patients receiving > or = 84 Gy have had biopsy proven residual or locally recurrent disease. CONCLUSION: Successful dose escalation in a volume-dependent organ can be performed using this technique. By incorporating the effective volume of irradiated tissue, some patients have been treated to a total dose of radiation over 50% higher than traditional doses. The literature-derived parameters appear to overestimate pneumonitis risk with higher volumes. There has been no obvious negative effect due to exclusion of elective lymph node radiation. When completed, this trial will have determined the maximum tolerable dose of RT as a single agent for NSCLC and the appropriate dose for Phase II investigation.