Radiotherapy in Non-small Cell Lung Cancer

decreases were not statistically significant. However, radiotherapy did produce a striking and significant reduction in recurrences to the ipsilateral lung and mediastinum. Moreover, overall recurrence rates were reduced by radiotherapy in patients with N2 disease (p <0.05), although even this subgroup had no evidence of improved survival. The conslusion is that radiotherapy can reduce local recurrences after resection, but that it does not increase survival rates. A prospectively randomized trial of radiation therapy, using state-of-the-art equipment and treatment planning techniques, in patients with resected N2 disease, is a critical need. However, the benefits of such modern radiotherapeutic techniques may be masked in this poor prognosis group because of the frequency of distant failure outside of the port. New staging technologies to accurately ascertain which patients have regionally advanced disease only might allow such a study to truly answer the question. ADJUVANT CHEMOTHERAPY TO SURGERY IN NSCLC

Until now, there was no good evidence suggesting the benefit of adjuvant chemotherapy after surgical resection for NSCLC. Resected stage II and III patients have served as the major focus for these adjuvant trials, but the published results have been generally disappointing. It is only recently that a reproducible response rate in the range of 30-40% has been obtained with chemotherapy in inoperable NSCLC. Adjuvant chemotherapy after surgical resection has been carried out by the Lung Cancer Group in stages II and III adenocarcinoma and large cell undifferentiated carcinoma. Patients were randomized after surgery and careful intraoperative staging to receive chemotherapy with CAP (48 patients), an immunotherapy with BCG and levamisole (46 patients). There was a significant prolongation in the disease-free survival among the patients who received adjuvant chemotherapy. ADJUVANT IMMUNOTHERAPY TO SURGERY

Most studies using immunotherapy in NSCLC have failed to demonstrate any efficacy at the approach. BCG was the most employed immunostimulant after resection of the lung. All the studies failed to demonstrate a significant increase in survival rates in patients with operable bronchogenic carcinoma when BCG immunotherapy was given. In all of these studies, the number of patients with N2 disease are very small. Other immunostimulating agents or drugs were studied and, once again, all these studies showed that no immunotherapy resulted in any significant improvement in survival. Occasional responses have been claimed with adoptive immunotherapy using interleukin-2 and LAK cells in NSCLC; this approach, in spite of being a very demanding procedure, deserves further studies.

Radiotherapy in Non-small Cell Lung Cancer ·An Overview Maurice Thbiana, M.D.*

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RT IN PoTENTIALLY OPERABLE NSCLC

irst, in NSCL, as in all other cancers, postoperative RT can have an impact on survival only in patients without occult metastases at the time of initial treatment and in whom residual tumor has been left by the surgeon. This subset of patients ought to be limited, because ifthe tumor is small, the surgeon will be able to resect it completely; if it is large and has spread along the lymphatic pathways, resection is difficult and there is a high likelihood of distant dissemination. The natural history of breast cancer is fairly well quantitated, and it was estimated that for breast cancer the subset of patients who can benefit from postoperative radiotherapy is not larger than approximately 20% of patients. This subset is probably smaller in patients with NSLC because postmortem examinations in patients who died shortly after an apparently satisfactory surgical resection of NSLC suggest that residual tumor is present in about one third and that occult metastases are already present in at least half of these. Therefore, the maximum gain in survival which can be expected is about 15%. To demonstrate such a small increase in survival, a controlled clinical trial should include at least 650 patients. However, even this relatively large number is too small, because to identify the subset of patients in whom survival is increased, a proper stratification is mandatory at least by stage (TNM) and histology. Therefore, 1,200 patients is a good compromise both for the statisticians who wish to include a large number of patients to increase the reliability of the data and the clinicians whose intent is to shorten the duration of the trial. These considerations emphasize the fact that controlled trials which include only a few hundred patients cannot lead to significant results and can even be misleading. Trials with a small number of patients can contribute to the advancement of knowledge only if designed to be included in a metaanalysis; otherwise, they merely initiate discussions or controversies but fail to provide valid answers. Ampil et al compared in a retrospective study the survival of 36 patients irradiated soon after surgery and 22 patients irradiated later for recurrent neoplasms. Contrary to expectations, there was no apparent advantage with early postoperative RT. However, it is difficult to draw any conclusion from this nonrandomized study performed on a small number of patients. In fact, the preliminary data of a randomized trial carried out by Alberti et al clearly conflict with these conclusions. They compared in a 3-arm trial immediate RT, CT + RT, and delayed RT. So far, the survival is higher in patients receiving immediate treatment (borderline significance). One of the problems with RT studies is that the dose or the fractionation is often not optimal. Proper evaluation of the effectiveness of postoperative RT requires not only a large number of patients but also an adequate irradiation technique. The dose should be as high as 60 Gy and the *lnstitut Gustave Roussy, Villejuif, France. CHEST I 96 I 1 I JULY, 1989 I SUpplement

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number of fractions per week equal to or larger than 4. These requirements are taken into account in the ongoing French study 04 CB 86, but its results will be available only in a few years.

Combination of Postoperative RT with Chemotherapy A few data reported during this meeting deserve to be mentioned, although they may appear premature since there is no unambiguous demonstration of a survival advantage produced by postoperative Rf or CT. Minet et al carried out a retrospective study on 595 patients. In patients with complete resection and without lymph node involvement (No), no benefit was obtained, and the mean survival was even shorter in patients treated with RT +cr. Conversely. in the subgroup of N1 + N2 patients with complete tumor resection, the data suggest that the administration ofRf + CT might prolong survival, but the number of patients is small (58 patients) and the difference not significant. Finally. when the resection was only partial, the mean survival was found significantly larger in patients treated by RT +CT. A few trials compared RT alone vs RT +CT. Ayoub et al reported a higher relapse rate in N + patients treated by Rr, but the number of patients (40 in each arm) is too small to allow any definite conclusion. Chastang et al randomized 268 patients between immediate Rf (60 Gy) or sequential administration of RT and CT (CO PAC). The lack of difference between the 2 arms led to an early arrest of the study. Several papers or posters addressed another important question, the effectiveness of preoperative Rf (20-40 Gy), with or without adjuvant CT in patients with marginally resectable tumor, fe, on tumors which are of relatively limited size but for which total resection is unlikely. Unfortunately. no clear conclusion emerged from these studies. This may be due to the small number of patients (generally much smaller than 100) included in each of these studies. Some data, eg, those of Rush et al, suggest that neoadjuvant therapy can alter the pattern of relapse and slightly improve local control. However, again, only properly designed trials will be able to provide answers to the 2 main questions: (1) Does preoperative RT (or RT + CT) increase complete tumor resectability? (2) What is the impact on survival of these preoperative treatments? UNRESECTABLE TUMOR

It is generally agreed that RT is the standard treatment for these patients. However, there are 2 possible strategies. First, RT is intended to be palliative. Ifso, the dose should be limited to 30 Gy. Second, RT is to be delivered with a curative intent; the dose should then be as high as 65-70 Gy. Some data indicate that a higher survival might be produced in patients treated with high doses. However, long-term survival is so low whichever regimen is adopted that evaluation is difficult. High doses improve local control but due to the presence of occult metastases in most patients with large tumors, the greater efficacy of locoregional treatment only has a small impact on long-term survival. Moreover, besides the duration of survival, the quality of life during and after treatment should be taken into account. Unfortunately. there is no appropriate end point for meas88S

uring quality of life as yet. This is a topic which requires further study. Many avenues for research are currently being explored. The first is to select among patients with inoperable cancer those subsets of patients who are likely to benefit from high doses. Hayakawa et al analyzed the prognostic factors which can help to predict the outcome following radiotherapy. The result suggests that high doses {60-70 Gy) are justified in patients with epidermoid cancer, when the size of the field is below 100 em•. Schuster-Uitterhoeve et al from their study on 215 patients concluded that local cure or long-term palliation is obtained in only one third of patients; a high dose should be given to patients with stage 1 tumors, peripheral tumors, or tumors located in the upper lobe. S. McDonald et al advocate for selected patients the use of a high dose associated with CT scan for tumor volume definition, simulator and computer-assisted dosimetry. Several papers discussed treatment techniques. There are data in favor of a dose-effect relationship with an optimal dose somewhere between 65 and 74 Gy. The relation between histology and the optimal dose is an important question which deserves further study. However, the most significant progress in this regard and perhaps one of the most important results reported during this meeting is that of the RTOG study presented by Cox et al on fractionation. This study was performed on 1,300 randomized patients. Its results clearly show that hyperfractionation (two sessions of 1,2 Gy per day) is significantly superior to conventional daily fractionation. The late effects are decreased; thus, the total dose can be increased, resulting in an improvement in tumor control and survival. This is a very important result, because it shows that more effective local treatment can improve survival. Saunders and Dische reported preliminary data of a pilot study on hyperfractionated accelerated radiotherapy (36 sessions given during a period of 12 days). The results are better than those of conventional fractionation, and the probability of survival at 1 and 2 years appears higher. A randomized trial is being planned to confirm these results. Hypofractionation was investigated in 2 studies. Bleehen et al compared 8,5 Gy X 2 with 3 Gy x 10 and found no difference. They concluded that hypofractionation might be useful for irradiation with a palliative intent. Slawson et al carried out a prospective, randomized trial comparing 5 Gy once a week with standard fractionation {2 Gy x 5 per week). They concluded that hypofractionation merits further study in conjunction with chemotherapy or radiosensitizers and is a safe, convenient treatment in inoperable nonmetastatic lung cancer. Several randomized or nonrandomized trials have assessed the additional benefit resulting from the combination of RT +CT. However, no valid conclusion has been reached because the data are conflicting. The number of patients included in each of these studies was relatively small (<100), and the RT technique was not always optimal. The lack of clear benefit is probably also related to the insufficient effectiveness of the current CT regimens. These uncertainties underline the need for a well-designed, controlled clinical trial including a large number of patients and with RT delivered up to full dose {>65 Gy). The experience gained from the studies carried out in small cell lung tumors 5th World Conference on Lung Cancer

clearly shows that low doses are not sufficiently effective even when combined with CT. A promising field for research is combination with radiosensitizers. Several groups are exploring the radiosensitizing effect of small doses of CIS-Pt. Schaake-Koning reported the results of an EORTC study in which 100 patients were randomized between RT alone, RT and 300 mg/m2 CDDP once a week, RT and 6 mg/m2 daily. The incidences of local recurrence were, respectively, 56%, 47%, and 32%. Early and late toxicity were acceptable. Soresi et al randomized 103 patients between RT alone (50 Gy) and RT with CDDP (15 mg/m2 weekly), with local recurrence rates, respectively, 43% and 24%. These two promising results have led to further studies on larger numbers of patients. Trovo et al and Lapukino et al in nonrandomized pilot studies have observed encouraging results. Currently randomized trials are and merit to be carefully watched, but conclusions have not yet been reached. INNOVATIVE RADIOTHERAPY

A few studies can be grouped under this heading. Three groups have reported studies on Lonidamine, an antispermatogenic agent. Magno et al presented data that suggest a favorable effect of Lonidamine, whereas Gallo-Curcio et al did not find any difference in the mean survival time. Maroun et al confirmed that the combination ofLonidamine and RT is well tolerated. Kato described a new modality of RT under increased tumor oxygen tension with angiotensin 2. A nonrandomized pilot study on a small number of patients suggests a more rapid regression of the tumors. This observation needs confirmation. The use of a radiosensitizer (misonidazole) was investigated by Abbrat et al; the preliminary results show promising response but neurotoxicity is high. This

Adf"uvant Therapy for Non-small Ce I Lung Cancer WK. Evans, M.D. •

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rogress in our efforts to increase the lung cancer cure rate has been frustratingly slow despite considerable effort in many countries worldwide. Nonetheless, there have been several promising developments in the adjuvant therapy of lung cancer which provide leads for future advances against this disease. The problem of lung cancer is formidable both because of the numbers of individuals affected and their poor overall survival despite current best therapy. It is estimated that annually there are about 1 million new cases of lung cancer worldwide. Surgery is still the only modality which offers any substantial possibility of cure for patients with non-small *From the Ontario Cancer Treatment and Research Foundation, Ottawa Regional Cancer Centre, Ottawa, Canada. Reprint requests: Dr. Evans, 190 Melrose Avenue, Ottawa, Ontario, Canada KlY 4K7

approach should be reinvestigated with less toxic radiosensitizers. Photodynamic therapy with a hematoporphyrin derivative was investigated by Furuse et al and Kato et al for cancers within the reach of a flexible bronchofiberscope. The results suggest that this type of treatment might be able to control small (less than 2 em in diameter) unresectable lesions. Further, Komato et al showed that such treatment can be indicated in cases of superficial invasion on bronchial mucosa, thus reducing the extent of resection. The validity of this approach should be tested with rigor in controlled studies. Three retrospective studies reported the results of lowdose rate intracavitary brachytherapy alone or in combination with laser for endobronchial tumors. This treatment is well tolerated and may have a palliative value; however, as stated by Huber et al, this must be proved in a randomized study. A large number of avenues for research have been explored. However, most of the promising data need confirmation. This underlines the urgent need for large, welldesigned controlled clinical trials. Only such studies will be able to objectively evaluate the role of RT in the treatment of this cancer, which unfortunately remains so difficult to control. Trials with an insufficient number of patients only add to the current controversies; only well-stratified studies will be able to identify the small subsets of patients for whom RT can improve local control and long-term survival. The increase in survival of patients with unresectable NSCLC which has been reported by Cox and the RTOG during this meeting show that better radiotherapy techniques can result in a higher percentage oflocal control and cure. This is a very promising observation which gives some hope.

cell lung cancer. Unfortunately, only about half of all patients present with localized disease, and only about one third overall are candidates for an attempt at curative resection. It is well recognized that the results of surgical resection correlate with pathologic stage as defined by tumor size and nodal status. The TNM definitions and stage groupings have recently undergone refinement. The new international staging system has a number of important changes from the previous AJC staging system. Stage 1 now includes only T1 and T2 NO disease. Tl Nl has been placed in stage 2. Stage 3 disease has now been divided into stages 3A, and 3B, and a new stage 4 has been created. The careful use of this staging system to define groups for study and to report results of therapeutic interventions will be critical for the evaluation of adjuvant therapies in the future. A review of the results of surgery according to tumor stage and histopathology helps to identify groups of patients in need of adjuvant therapy. FouJ'oyear postoperative survival data from the American Lung Cancer Study Group experience are helpful in this regard. 1 The LCSG has the largest series of modern surgically staged cases available and CHEST I 96 I 1 I JULY, 1989 I Supplement

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