Chemotherapy in Stage IV 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 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.

S6 Single agent-first line-Therapy vs Best Supportive Care alone days 1, 8 q3w Vinorelbine 30 mg/m2 i.v. days 1, 8, 15 q4w Gemcitabine 1000 mg/m2 i.v. 2 (3h) day 1 q3w Paclitaxel 200 mg/m i.v. day 1 q3w Docetaxel 100 mg/m2 i.v.

Abstracts

(Gridelli) (Anderson) (Thatcher) (Roszkowski)

References: Rowinsky E.K., Ettinger D.S.: Drug development and new drugs for lung cancer. In: H.I. Pass, J.B. Mitchell, D.H. Johnson, A.T. Turrisi (eds.): Lung Cancer Ñ principles and practices, Lippincott-Raven, Philadelphia, New York, 793-810, 1996. Bonomi P.: Non-small cell lung cancer chemotherapy. In: H.I. Pass, J.B. Mitchell, D.H. Johnson, A.T. Turrisi (eds.): Lung Cancer Ñ principles and practices, Lippincott-Raven, Philadelphia, New York, 811-823, 1996. Albain K.S., Crowley J.J., LeBlanc M., Livingston R.B.: Survival determinants in extensive-stage non-small cell lung cancer: The Southwest Oncology Group Experience. J Clin Oncol 9, 9, 1618-1626, 1991. Somerfield MR (for ASCO): Clinical practice guide lines for the treatment of unresectable non-small cell lung cancer. J Clin Oncol 15, 8, 2996-3018, 1997 The role of surgery for lung cancer at the end of the 2nd millenium Giovanni Motta, MD, FECTS, Department of General and Thoracic Surgery, University of Genoa, School of Medicine, Genova (Italy) The present clinical setting in Lung Cancer Diagnosis and Therapy has already been for a long time steadily fluctuating around the established rates of survival, according to the Stage of Disease. In this setting, the surgical approach represents the best option for cure, provided that the disease is limited. Unfortunately, this favourable condition is still represented by low numbers and, therefore, the positive results obtained after surgery, are still not representative enough to positively rebut the criticism that they have been accrued from selected cohorts of patients. As a consequence, the unmodified low ratio of 15-20% as maximum level of the cumulative cure for Lung Cancer, is reminding us that, in spite of the general improvement achieved in the knowledge of the disease and the advances in the related diagnostic and therapeutic plans, the ultimate cure of this malignancy still remains an unsolved problem. Anticipating the diagnosis of Lung Cancer and improving the efficiency of combined treatment protocols are, from a prospective point of view, the two most important steps forwards, which we are expecting to reach in the near future. Along the years, the Staging Rationale, while giving a large body of advanced knowledge, has also helped us to realise that a uniform standard in the Staging methodologies is basically requested if one wants to obtain really comparable clinical data and, with it, real prognostic anticipations and sound guidelines for the best treatment strategies as well. Nonetheless, despite the diagnostic advances presently available, this programme has not been realised yet. Indeed, it is enough to think that the approach to the mediastinal N2 is still different, being basically conceived as a lymph nodes sampling by the West, while it is pursued as a systematic mediastinal dissection by the Japanese. As a consequence, the correct identification of N factor as well as the following Staging assignment operated by the former, are often critical. The high rate of migration from clinical to pathological Stage, as reported in the Revised Staging, with 25% rate between c and p T1N0M0-STAGE IA, 54% between c and p T2N0M0-STAGE IB and 61% between c and p T1N1M0-STAGE IIA, seems to greatly support this conclusion. Again it is not by chance if the diagnostic recognition is more lacking in Stages IA-B

and IIA where the traditional belief of a less aggressiveness of smaller sized tumors in general and the reduced risk of lymph nodes involvement in particular, has let the majority of western surgeons prefer the lighter but less accurate lymph nodes sampling procedure. Therefore, a world-wide consensus on the best surgical approach to recognise, collect and classify the mediastinal lymphatic chains is still expected. Surgery for N2 in both settings of ÒunsuspectedÓ or Òclinically assessedÓ disease as well as surgery for locally extended tumors such as the apical invasive and the other peripheral close to the chest wall, the centrally located tumors with mediastinal proximity and those involving the tracheal carina or the mediastinal organs, still represent, just because they are really frequent clinical events, a technical challenge and, meanwhile, a source of stimulating debate. Finally, the renewed attention to the Secondary Prevention of Lung Cancer through an Anticipated Recognition, let us think that a new steady opportunity is moving in support of the expectation for a more effective therapy. For the moment and only upon selected groups, an increase of the survival standards up to 45% as well as 5 yr actuarial survival rates ranging from 81% to 100%, have already been obtained, provided that an anticipated diagnosis through mass screening programmes or even with case-by-case more limited plans, have been assured. Adjuvant treatment of resected non-small cell lung cancer T Le Chevalier, F Cappuzzo, C Le Pechoux, D Grunenwald, P Girard, JP Pignon, Institut Gustave Roussy, Villejuif, France Radical surgery alone is considered the treatment of choice of early-stage non-small cell lung cancer (NSCLC) (i.e. clinical stage I-II). Nevertheless after surgical resection for stage I and II NSCLC, the 5-year survival rate without recurrence does not exceed 70% in stage I and 35% in stage II disease. That means that although a radical surgery has been performed, a consistent risk of disease relapse persists. In the last decades, several clinical trials have been conducted to evaluate if a postoperative therapy can improve the results of surgery alone. Adjuvant chemotherapy has been widely tested after surgical resection in NSCLC. The first generation of adjuvant trials (i.e. those carried out in the 60Õs and 70Õs) used long-term alkylating agents and the vast majority of patients were included in studies conducted by the Medical Research Council and the Veterans Administration (1). From the late 70Õs most trials used cisplatin (CDDP) containing chemotherapy regimens. The most well known are those conducted by the Lung Cancer Study Group (LCSG) (2-3). Chemotherapy included cyclophosphamide (CTX), doxorubicin (ADM) and CDDP (CAP regimen). A benefit was observed both in terms of overall and disease free survival in 141 patients with stage II and IIIA adenocarcinoma and large cell carcinoma. However, no benefit was observed in 283 patients with T2N0 and T1N1 NSCLC. Given the limited number of patients enrolled in these trials, it was not possible to clearly establish the role of adjuvant chemotherapy in early stage NSCLC. In view of the inconclusive results observed in most trials addressing the role of chemotherapy in NSCLC, the Medical Research Council and Institut Gustave Roussy decided to perform a large overview using updated individual data (4). More than 9000 patients from 52 randomised trials fulfilled the selection criteria. In the group comparing surgery alone to surgery followed by adjuvant chemotherapy, 14 trials were recorded with an overall accrual of 4357 patients. While in the five trials using long-term alkylating agents, adjuvant chemotherapy showed a significantly detrimental effect, in the eight trials which used a CDDP-based regimen, a 13%