Combined chemotherapy and radiation in NSCLC

Combined chemotherapy and radiation in NSCLC

Abstracts formed vs. best supportive care? What is the optimalized sequence of therapeutic modalities in SCLC? What kind of cure rate can be achieved ...

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Abstracts formed vs. best supportive care? What is the optimalized sequence of therapeutic modalities in SCLC? What kind of cure rate can be achieved by radical therapy? What risks are acceptable for these patients? (c) What is the rationale followup algorhytm? What rehabilitation procedures have to be introduced? These are questions, the answer to which seems to be partly controversial. The lecture tries to respond on the basis of evidence based medicine (1). 1. ASCO Special Article: Clinical Practice Guidelines for the Treatment of Unresecable Non-Small-Cell Lung Cancer. J.Clin. Oncol. 15, 2996-3018, 1997. Combined chemotherapy and radiation in NSCLC Jacek Jassem, Department of Oncology and Radiotherapy, Medical University of Gdan«sk, Poland Radiation therapy has traditionally been considered the mainstay of treatment in inoperable stage III NSCLC. Despite the continued refinement of radiotherapy techniques, local tumour control has remained poor. Moreover, radiotherapy does not prevent uncontrolled systemic disease, the major cause of death in locally advanced tumour. In a search for improving the outcome several approaches have been tested, including escalation of total radiation dose, altered fractionations and combining chemotherapy with radiation. The addition of chemotherapy to radiation may potentially increase the cure rate not only by improved locoregional tumour control but also by elimination of micrometastases outside the radiotherapy field. Two most frequently tested combined modality strategies include chemotherapy preceding radiation (induction chemotherapy) and application of both modalities concurrently. Induction chemotherapy allows for drug delivery in full doses and in principle aims at reduction of micrometastatic disease, whereas the principal rationale for concurrent chemoradiation is improving locoregional control by making tumour cells more vulnerable to radiotherapy. The results of phase III trials comparing radiation alone to radiation combined with chemotherapy have been equivocal. Early studies were negative but the introduction of cisplatin-based regimens resulted in modest but significant survival benefit. Both, multidrug induction chemotherapy1-3 and low-dose chemotherapy applied concurrently with radiotherapy4,5 have been found to result in prolonged survival. Most recently, several new agents including taxanes, vinorelbine, gemcitabine and camptotecine derivatives have appeared promising in NSCLC but their role in combined modality regimens warrants further clinical research. The interpretation of many combined modality studies in locally advanced NSCLC is difficult due to small patient samples and methodological flaws. Nevertheless, one can conclude that chemotherapy may have a role as an adjunct to radiation in this tumour. The gain from combined modality approach should, however, be weighted against increased early and late toxicity. Further studies built upon recent positive results should focus on identifying the means of optimal interactions between the two modalities. This research should define the most effective types and doses of anticancer agents as well as the optimal features of radiotherapy. REFERENCES: 1. Le Chevalier T, et al.: Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable nonsmall cell lung carcinoma. Lung Cancer 1994; 10, S239. 2. Sause W, et al.: RTOG 88-08, ECOG 4588, preliminary results of a phase III trial in regionally advanced, unresectable non-small cell lung cancer. J Natl Cancer Inst 1995; 87, 198. 3. Dillman RO, et al.: Improved survival in stage III non-small-cell lung cancer: sevenyear follow-up of Cancer and Leukemia Group B (CALGB) 8433

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trial. J Natl Cancer Inst 1996; 88,1210. 4. Schaake-Koning C, et al.: Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 1992; 326, 524. 5. Jeremic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Natl Cancer Inst 1996; 14,1065. Chemotherapy in Stage IV NSCLC C. Manegold, Thoraxklinik, Heidelberg, Germany The results achieved by traditional chemotherapy in advanced, non-small cell lung cancer continue to be unsatisfactory and the effects are largely palliative in nature. Cisplatin-based chemotherapy is currently the standard recommended treatment. This recommendation is based upon a slightly improved survival benefit, small in extent but statistically significant, which can be attributed to this combination chemotherapy when compared with single agent therapy or Ôbest supportive careÕ. However, only a small percentage of the patients who should normally be considered for such a palliative treatment actually receive cytotoxic therapy. The reason for the low acceptance of chemotherapy may be that the current standard combinations are considered to be too toxic to be beneficial in older and polymorbide patients. It remains to be seen whether or not this skepticism toward chemotherapy containing Cisplatin can be turned around by the improved tolerability offered by the use of new drugs, such as Gemcitabine, the Taxanes, or Vinorelbine. In any case, various combinations of these new drugs are currently the subject of several large, randomized multiarmed clinical studies. Results from two-armed comparative studies have shown that a significantly higher number of objective responses can be achieved when Cisplatin is combined with the new drugs as compared to the traditional combinations. However, an improvement in the survival parameters has not yet been demonstrated. Combination Chemotherapy Results

RR MS 1-y-S MTTP

Cisplatin/ Vinorelbine

Cisplatin / Etoposide

26 % 8 mo 36 % 4 mo

14 % 8 mo 35 % 4 mo

Carboplatin / Cisplatin / Cisplatin / Paclitaxel Gemcitabine Mitomycin / Ifosfamide 22 % 38 % 26 % 8 mo 9 mo 10 mo 35 % 33 % 34 % 4 mo 5 mo 5 mo

At the same time, considering the current low acceptance for combination chemotherapy, the concept of single-agent therapy also appears to be an attractive alternative, especially when the ultimate goal of palliation can be similarly achieved by a less toxic chemotherapy with increased practicability, i.e. the possibility of outpatient administration. The previously mentioned new drugs would seem to be the ideal candidates for single-agent therapy, since they are well tolerated and have been shown to have a comparatively high tumor-activity rate both in first-line as well as second-line therapy. For this reason these drugs are currently being clinically tested as single agent therapy in phase II and in randomized phase III studies, to evaluate their effectiveness in first and second-line therapy and for Ôsequential administrationÕ. The preliminary data published appear to be promising, since they indicate that single agent therapy compared to best supportive care can prolong survival and improve quality of life.