In vitro radiosensitization has been observed for a number of drugs, which - when used in patients - did not show this effect within the limits of tolerance. In the late seventies cisplatin and several of its compounds were tested for radiotherapy enhancing capacities. More recently other new chemotherapeutic drugs such as gemcitabin and taxol have been claimed to show radiosensitizing effects. The exact mechanisms which play a role are not exactly defined yet for cisplatin. Inhibition of sublethal and potentially lethal damage repair, re-oxygenation of hypoxic cells, increased induction of chromosomal aberrations, binding thiols have been described. It is not certain if these are additive or supraadditive effects (1).

Cisplatin as a radiosensitizer has been applied in a number of malignant diseases eg bladder, cervical, esophagus, head and neck and lung cancer. The 3 arm EORTC randomized trial, 08844, for non-small cell lung cancer (NSCLC) which compared split course radiotherapy alone against the same radiotherapy with 30 mg/m2 cisplatin once a week and radiotherapy with 6 mg/m² cisplatin daily has yielded the following data:

1. there is a difference between the weekly and the daily combination in favor of the once a day arm.
2. the effect of cisplatin was observed on the locoregional level.
3. increased locoregional control had a positive effect on survival (2).

Jeremic et al published their favorable results about hyperfractionated radiotherapy with concurrent low-dose daily carboplatin and etoposide for stage III NSCLC as compared to the same radiotherapy: 21% vs 9% 4 year survival, P=0.021. The improvement of survival was correlated with improved local control (3).

Ball et al combined 70 mg/m² carboplatin days 1-5 and 29-33 with 60 Gy conventional and accelerated radiotherapy in unresectable NSCLC. The estimated 2 year survival is 45% for the combined accelerated radiation modality arm vs. 26% for 60 Gy conventional radiotherapy, P=0.10. The numbers of patients in each treatment arm are relatively small (4).

Against these positive facts and trends there are several negative results as e.g. published by Trovo et al, who found no difference betwee 45 Gy in 15 fractions radiotherapy and the same dose combined with daily 6 mg/m² cisplatin. A possible explanation might be the selection of patients and/or the radiotherapy dose and schedule (5).

Blanke et al reported negative results of a randomized trial which studied the effects of 70 mg/m² cisplatin added in weeks 1, 4 and 7. The study confirms the observation that cisplatin once a week or less does not raise clinical effects in terms of enhancement (6).

Differences in results between several studies might partly be related with the complicated way of defining remission and control on a locoregional level in NSCLC. If tumor progression has been diagnosed the condition of the patients and their often rapid deterioration make it impossible to assess exactly tumor stage. Head and neck cancer patients can be followed more precisely to observe locoregional tumor regression, control and progression. After promising Phase II studies randomized prospective trials will hopefully follow (7).

In the Netherlands a study by Groen and coworkers is underway randomizing radiotherapy with radiotherapy and continuous infusion of carboplatin in NSCLC after a feasibility study had been finished (8).

Schuster et al published a feasibility study based on the EORTC 08844 results. Because the split of 3-4 weeks was criticized daily 6 mg/m² cisplatin was combined with 55 Gy concomitant boost technique. As the tolerability was good the combined modality increased up to 66 Gy. This schedule will be compared with 2 cycles induction chemotherapy followed by radiotherapy. This new EORTC study will start soon (9).

In the radiobiology lab of Begg indications have been found that there is possibly a relationship between the amount of cisplatin adducts, sensitivity for cisplatin and radiotherapy and hence with survival. If such a relationship does exist, individual approach of patients will discriminate between patients who will profit from the combined treatment from those who will not. A useless overtreatment will thus be avoided (10).

In conclusion: within a decade radiotherapy enhanced by cisplatin will move from myth to reality in selected groups of patients with NSCLC; the half-way point of this road has been passed.

References
1. Begg AC. Cisplatin and radiation: interaction probabilities and therapeutic possibilities. Int J Radiat Oncol Biol Phys 1990; 19: 1183-89.
2. Schaake-Koning C, vd Bogaert W, Dalesio E et al. Effect of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. NEJM 1992; 326: 524-30.
3. Jeremic B, Shibamoto Y, Acimovic L and Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small cell lung cancer: a randomized study. J Clin Oncol 1996; 14: 1065-70.
4. Ball D, Bishop J, Smith J et al. A Phase III study of conventional and accelerated radiotherapy (RT) with and without carboplatin in unresectable non-small cell lung cancer (NSCLC). Radiother Oncol 1996; S 61: 231.
5. Trovo M, Minatel E, Franchin G et al. Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer. Int J Radiat. Oncol. Biol Phys. 1992; 24: 11-5.
6. Blanke C, Ansari R, Mantravadi R et al. Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small cell lung cancer: a Hoosier oncology group protocol. J Clin Oncol 1995; 13: 1425-29.
7. Forastiere A. Concurrent platinum and radiation for advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1995; 31: 679-680.
8. Groen HJM, vd Leest AHD, de Vries EGE et al. Continuous carboplatin infusion during 6 weeks radiotherapy in locally inoperable non-small cell lung cancer: a phase I and pharmacokinetic study. Br J Cancer 1995; 72: 992-7.
9. Schuster-Uitterhoeve L, vd Vaart PJM, Schaake-Koning C, Benraadt J. Feasibility of escalating daily doses of cisplatin in combination with accelerated radiotherapy in non-small cell lung cancer. Eur J Cancer 1996; 32A: 1314-19.
10. Vaart P vd Personal communication.

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THE COUNTLESS WAYS IN WHICH CHEMOTHERAPY AND RADIOTHERAPY HAVE BEEN COMBINED
G.V. SCAGLIOTTI and S. NOVELLO
University of Turin - Department of Clinical & Biological Sciences, Azienda Ospedaliera S. Luigi - 10043 Orbassano (Torino) - ITALY

Approximately 40% of patients with non-small cell lung cancer (NSCLC) present with disease that appears clinically confined to the chest but is nonetheless too extensive to warrant surgical resection. Over the last 30 years, most patients who presented with stage III disease received thoracic radiotherapy (TRT) alone. Until recently, 60 Gy delivered with conventional daily fractionation of 2 Gy, 5 days a week, was considered the standard treatment for these patients based on retrospective and prospective studies evaluating dose-response and local control relationships while determining acceptable toxicity limits (1). This approach achieves disease shrinkage in one-third to two-thirds of treated patients but long-term local control with this benchmark radiotherapy is poor. Recently a French study incorporating routine post-treatment biopsies revealed a local control rate of only 15% patients who received 65 Gy in 6 ½ weeks. The median time to progression is less than six months, median survival for treated patients is less than one year, the 2-year survival rate is in the range of 15-20% and the 5-year survival rate is only 5-10% (2). The curative potential of TRT in this setting is also limited by the failure to control micrometastatic disease present at the time of diagnosis (3).

These poor results in such a common disease have led toward greater intensification of local therapy through the use of altered fractionation schemes, three-dimensional conformal TRT, radiosensitizers as well as attempts to optimize chemotherapy schedules in combination with standard or altered fractionation schemes.

Recent data show 54 Gy delivered in 12 days with three fraction daily, and 69.6 Gy delivered in 1.2 Gy fractions, produced better 2- and 3-year survival rates than 60 Gy delivered via conventional fractionation (4).

Four theoretical types of interaction between radiation and chemotherapy have been formulated: a) "spatial cooperation" postulates local activity for radiation and systemic activity for chemotherapy; b) "toxicity independence" allows for administration of both treatment modalities at maximally tolerated dose not compromised by dose reductions necessitated by increased toxicity; c) "protection of normal tissues" postulates that a systemic agent would protect normal tissues (and not the tumor) from the effects of radiotherapy, resulting in an ability to deliver higher doses of radiotherapy or administer more aggressive radiation schedules; and d) a "direct interaction" between radiation and chemotherapy within the radiation field increases the local efficacy of the treatment.

On a clinical ground there are three major modalities of sequencing radiation and chemotherapy: a) sequential, in which one modality is completed prior to the start of the other; b) concurrent, where radiation and chemotherapy are given on the same days, and c) alternating, in which courses of radiation and chemotherapy are alternated so that administration of the 2 modalities is completed over the same overall time period without their concurrent administration (1).

Historically the sequential trials were begun first and allowed the demonstration of two essential points: a) the response rate of patients with stage III NSCLC to a variety of cisplatin-containing regimens given for 2 o 3 cycles before TRT was in the range of 40-60%, and b) progression within the chest during chemotherapy was quite uncommon.

Concurrent chemo-radiotherapy may be more efficacious than induction chemotherapy followed by TRT. Accelerated repopulation of tumor can occur after chemotherapy, despite apparent complete remission. Delays in starting radiotherapy after induction chemotherapy (patient non-compliance, slow recovery from chemotherapy effects, etc.) may allow tumor repopulation a headstart on radiotherapy (5). This is avoided by concurrent chemo- and radiotherapy, which take advantage of tumor cell killing and radiosensitization by chemotherapy (6). The disadvantage of concurrent chemo-radiotherapy is the increased risk of acute toxicity because chemotherapy may inhibit repair of radiotherapy sublethal damage in normal tissue, as well as in the tumor. The challenge is to balance the improved efficacy and the increased toxicity. TRT has been administered concurrently with non-cisplatin chemotherapy combinations, low-dose daily cisplatin alone, high-dose cisplatin alone, carboplatin alone and cisplatin or carboplatin-based combination chemotherapy.

The benefit of the alternating therapy recognizes that by alternating cycles of chemotherapy with accelerated fractionation of radiation, it is theoretically possible to administer both modalities at full dose in a short overall time while avoiding the acute toxicities of concurrent therapy (7).

Recently a meta-analysis of 22 randomized clinical trials comparing radiotherapy with radiotherapy and chemotherapy, including 3033 patients (11 trials used platinum-based regimens, and five used long-term alkilating agents) was performed. The hazard ratio was 0.91 when chemotherapy was used, with an estimated survival benefit at 2 years of 3% (p=0.01). For cisplatin regimens the hazard ratio was 0.87, or a benefit of 4% at 2 years while the addition of alkilating agents gave a hazard ratio of 1.02. The statistical significance of this analysis indicate that it is possible to achieve a modest increase in survival of patients with locally advanced NSCLC by combining chemotherapy with radiotherapy. However, the optimal combination of chemotherapy agents and delivery schedules and the optimal dose and schedule of irradiation have not been determined (8).

The development of rational combinations of radiation and chemotherapy for the treatment of patients with NSCLC has been greatly hampered by the lack of chemotherapeutic agents with intrinsic antitumor activity and/or tumor specific radiosensitization. However some of the newer agents, namely paclitaxel, topotecan and gemcitabine offer the prospect of useful interaction with radiation in the treatment of NSCLC and preliminary pivotal studies have yielded excellent response rates (9).

The recognition that even relatively small tumors have substantial hypoxic regions and that there are about three-fold more resistant to killing by x-rays than oxygenated cells has led to a lengthy search for ways to kill them (10). These have included the inhalation of carbogen (95% O2, 5% CO2) and clinical trials with several generation of electron-affinic nitroimidazoles. Misonidazole has been used in five randomized clinical trials but none of these studies demonstrated a benefit regarding palliation, tumor control or survival.

Another approach has been to develop agents which are selectively cytotoxic to hypoxic cells. Tirapazamine is one such agents and is currently undergoing trials (9).

References
1. Wagner H. Treatment of locally advanced and metastatic non-small cell lung cancer. Adv. Oncol. 1993 ; 9 : 22-29.
2. Green M. Chemotherapy and radiation in the nonoperative management of stage III non-small cell lung cancer : the right chemotherapy works in the right setting. In:Important Advances in Oncology, 1993. De Vita VT, Hellman S, Rosenberg SA. Eds.
3. Hazuka MB, Turrisi AT. The evolving role of radiation therapy in the treatment of locally advanced lung cancer. Semin. Oncol. 1993; 20: 173-184.
4. Sause WT, Scott C, Taylor S. RTOG 8808 ECOG 4588, preliminary analysis of a phase III trial in regionally advanced unresectable non-small cell lung cancer with a minimum of three years follow up. J. Natl. Cancer Inst. 1995 87 :198-205.
5. Byhardt R. Turning up the heat on non-small cell lung cancer: is the toxicity of concurrent cisplatin-based chemotherapy and accelerated fractionation acceptable? Int. J. Radiat. Oncol. Biol. Phys. 1995 ; 31 : 431-433.
6. Wagner H. Rational integration of radiation and chemotherapy in patients with unresectable stage IIIA or IIIB NSCLC. Chest 1993 ; 103 : S35-S42.
7. Mirimanoff RO, Rubin P, Cox JD. Concomitant and alternating radiation therapy and chemotherapy for inoperable, M0, non-small cell lung cancers : a consensus report. Lung Cancer 11 (suppl 3) : S5-S8.
8. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer : a meta-analysis using updated data on individual patients from 52 randomized clinical trial. B.M.J. 1995 ; 311 : 899-909.
9. Wagner H. Radiation therapy in the management of patients with unresectable stage IIIA and IIIB non-small cell lung cancer. Semin. Oncol. 1997 ; 24 : 423-428.
10. Saunders M. Radiotherapeutic techniques for lung cancer : accelerated hyperfractionation. Addressing hypoxic fractions. In Lung Cancer. by Pass H, Mitchell J, Johnson D, Turrisi A. Eds. Lipincott - Raven, Philadelphia, pp. 721-728.

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COMBINED MODALITY THERAPY FOR NON-SMALL CELL LUNG CANCER
W.T. SAUSE, M.D., FACR
Salt Lake City, Utah 84143, USA

Approximately 25% of patients with bronchogenic carcinoma present with Stage III disease, not amenable to the surgical resection. Traditionally these patients were candidates for primary irradiation. Radiation therapy as a local form of therapy has the advantage of anatomical coverage of the regional disease, can be delivered in a relatively non-morbid fashion and usually reduces symptoms.29 Radiation, however, is unable to sterilize large tumor volumes and does not address potentially microscopic disease.

Early and more recent studies do suggest as a dose-response relationship between the biological dose of radiation and short-term survival. RTOG 7301 suggested that 60 Gy was preferable to 40 or 50 Gy for local control and short-term survival. Five-year survival however was not affected and complications increased at 60 Gy.16 Phase II trials in Europe and the USA utilizing a variety of alternatives to standard fractionation, suggest that biologic dose escalation of irradiation may be advantageous.18, 30 These schedules are being tested in Phase III trials and I will update RTOG-8808 which evaluated one form of altered fractionation. Recent analysis of a Phase III trial in the U.K. delivering CHART (150 cGy tid x12) versus conventional radiation (6000 cGy in 6 wks) revealed a statistical benefit in survival to CHART. 32

Statistical analysis conducted in RTOG trials suggest a definite benefit to dose escalation within a subgroup of selected patients. In general, these represent patients with few systemic symptoms and good performance.15 In this subgroup of patients, benefit for survival seems to occur with more aggressive therapy.

Paralleling the evolution of aggressive schedules of irradiation has been an improved understanding of drug delivery and drug development. Several observations regarding the use of cytotoxic chemotherapy can be made in Stage IV disease. In small Phase II trials, response rates of approximately 40% 24,22 can be observed, and seemingly, those patients who respond live longer. Phase III trials do report lower response rates but in some trials a definite survival advantage was realized when compared to supportive care.23 Subsequently, meta analyses have revealed a small (6 week)25, 26, 27, 28 but definite survival advantage to chemotherapy in patients with Stage IV disease. Although the purpose of this section is not to assess chemotherapy specifically, there seems to be enough evidence to suggest that combinations containing vinca alkaloids and cisplatin are superior to other regimes.24 We are currently awaiting results of taxol containing regimes to see if an additional survival benefit will be incurred.

Phase III Trials Utilizing Combined Modality Therapy

There have been at least ten modern Phase III trials evaluating chemotherapy and irradiation in Stage III bronchogenic carcinoma.1,2,3,4,5,6,7,8,9 & 17 Two major Phase III trials utilizing sequential chemotherapy and irradiation have been negative trials. A Finish5 trial utilized split course radiation (30 Gy in 10 fractions, two week break and 25 Gy in 10 fractions) preceded by two cycles of CAP chemotherapy consisting of cytoxin, adriamycin and cisplatin followed by additional two cycles at the completion of radiation was a negative trial. The median survival was 311 versus 322 days respectively for RT and RT/CT. Subset analysis did suggest a benefit to CT/RT but this subset analysis has questionable validity.

A North Central Cancer Group3 trial was also a negative Phase III trial. Induction therapy consisted of MACC chemotherapy, methotrexate, adriamycin, cytoxan and CCNU given for two cycles followed by irradiation and then two further cycles of chemotherapy. Irradiation was delivered to 60 Gy in both arms of the study. Entry criteria was limited to patients with good performance status but weight loss was not a disqualification for study entry. The trial enrolled only 122 patients and the median survival was 317 versus 313 days for CT/RT versus RT patients.

The most recently published sequential trials have reported positive benefit to chemotherapy/radiation therapy: the RTOG trial, the CALGB trial and French Multi-National trial. Initial results of the French2 trial were negative but a 1992 analysis revealed a statistical benefit to survival. A three-year survival of 12% versus 4% was seen in the chemotherapy/radiation therapy arm versus the radiation therapy arm. In the French trial, three cycles of VCPC (vinblastine, cytoxin, cisplatin and CCNU) was followed by 65 Gy of irradiation and three cycles of chemotherapy. An interesting observation in this trial was the apparent reduction of distant metastases in the CT/RT arm but a similar local failure rate in both arms of approximately 85%.

The CALGB1 trial was initiated in 1984. Patients were randomized to RT versus CT/RT using induction Cisplatin and Vinblastine. The RT consisted of 60 Gy. Entry criteria were strictly controlled with only patients of performance status of 0 and 1, no supraclavicular adenopathy and no weight loss greater than 5% allowed entry. Unfortunately, only 180 patients were entered and only 155 patients were evaluable. The overall survival for this CT/RT arm at three years, was a 24% versus 11% for radiation therapy alone. The median survival was 11 months versus 9.7 months favoring the chemotherapy arm. This was statistically significant in favor of the CT/RT arm.

The third major Phase III trial published since the last conference was the RTOG/ECOG17 Phase III trial randomizing patients with regionally advanced non-small cell lung cancer to standard RT alone consisted of 60 Gy; hyperfractionated RT consisting of 1.2 Gy BID to 69.6 Gy; and two cycles of induction vinblastine and cisplatin followed by 60 Gy. 457 patients were placed in study resulting in approximately 150 patients per arm eligible for analysis. All patients were required to have the Karnofsky status of greater or equal to 70 and a weight loss of less than or equal to 5%. Patients with positive supraclavicular nodes were allowed study entry. Patients were clinically staged, with 44% of patients being IIIa and 50% of patients being IIIb. The median survival was as follows: RT alone 11.4 months, hyperfractionated RT 12.3 months, and the CT/RT 13.6 months. With a minimum follow-up of three years, the one and three-year survival figures were as follows: RT alone 46% and 6%; hyperfractionated RT 51% and 14%; CT/RT 57% and 12%. The one-year survival was statistically superior by the Wilcoxon method, P = 0.04 and the three-year 0.07 by the log rank method for the hyperfractionated and CT/RT arm versus RT alone. The five-year results also reveal a statistical benefit to survival.

Selected Phase II Trials

Enumerable Phase II trials utilizing combination chemotherapy and radiation therapy in non-small cell lung cancer have been reported. The American Society of Clinical Oncology annually contains nearly 100 abstracts dealing with some form of chemotherapy and irradiation in lung cancer. Since we are unable to address all studies, I would like to review the sequential RTOG trials conducted in the USA and the rationale which resulted in our current Phase III trial. When the RTOG started the large previously mentioned Phase III trial, we opened a small Phase II trial of irradiation preceded by vinblastine and cisplatin followed by concurrent cisplatin and standard irradiation to 61 Gy.31 The theory was based on the previously outlined Phase III trials of the CALGB and EORTC. In this early Phase II trial, we were able to observe a median survival of 16 months. This success encouraged us to escalate therapy intensity with concurrent vinblastine/cisplatin and RT delivered at 1.2 Gy BID to 69.6 Gy. The chemotherapy was delivered at vinblastine 5 mg per square meter weekly x 5 and cisplatin 75 mg per square meter on day 1, 29 and 50.19

Unfortunately, this trial was conducted while our large Phase III trial (88-08) was selecting good performance patients. In this trial toxicity was excessive. We experienced a 7% lethal toxicity in this mixed group of patients. In spite of an excessive lethal toxicity median survival was 13.8 months. This trial convinced us of the necessity of strict patient selection.

Our next Phase II trial compared etoposide at 50 mg twice daily for 14 days and cisplatin 50 mg IV daily on day 1 and 8 delivered with concurrent irradiation at 1.2 Gy BID to 69.6 Gy.10 The cytotoxic chemotherapy was repeated for two cycles. Because of hematological toxicity, the etoposide was reduced to 10 days rather than the initial 14 days. Entry criteria for this study were strict and required a Karnofsky performance status of greater than 60. Surprisingly, the median survival was 18.9 months and the two-year survival was 35%. This very aggressive treatment approach produced the best median survival we have yet observed with acceptable toxicity.

Because of the strikingly good results observed in these Phase II trials, we have embarked on a large Phase III trial. Our current three-arm trial randomizes patients to induction vinblastine and cisplatin was delivered as in our best arm of 88-08, followed by 60 Gy of external beam irradiation; compared to concurrent vinblastine and cisplatin and 60 Gy of irradiation delivered at 2 Gy fractions. These two arms will be compared to the oral etoposide, 50 mg BID x 10 days, cisplatin arm 50 mg BID days 1 and 8, 1.2 Gy BID to 69.6 Gy.

New Agents

In the past few years several new agents appear promising in the treatment of bronchogenic carcinoma. The four agents which will require testing in combined modality treatment include the taxanes, topoisomerase targeting agents, vinorelbine and gemcitabine.28

Several Phase I/II trials have been performed with irradiation therapy in combination with navelbine, taxol and CPT-11. Preliminary data suggests that navelbine can be given as an induction regime with cisplatin prior to irradiation. It appears as if navelbine can be used much as any vinca alkaloid with induction and concurrent RT.11, 12

Langer, et. al, have examined taxol and carboplatinum as an induction regime with concurrent RT and found good tolerance to utilizing carboplatinum at AUC of 6.25 and taxol dose of 235 mg/m2/3 hours during the irradiation.20

Hainsworth,13 et. al. have also been able to use taxol, etoposide and cisplatin as induction therapy and then concurrent CT/RT. Taxol given in their Phase II trial was at 135 mg per square meter IV for one hour infusion. The investigators report good tolerance to this regime. Graham,21 et. al, have tested topoteccan with irradiation and found excessive GI and neurologic toxicity above 0.5 mg/m2 on day 1, 5, 22 and 26 with 60 Gy.

Obviously more detailed Phase II studies need be done and Phase III trials will be required for all these new agents.

Combination chemotherapy and radiation therapy in regionally advanced non-small cell lung cancer has been shown to be effective. Undoubtedly, the natural history of the disease is altered by CT/RT in selected patients with Stage III non-small cell lung cancer. Although the magnitude of improvement is small, the results seems fairly reproducible in the most recently analyzed series. The advent of new chemotherapy agents will require a new generation of Phase III trials to find the optimum chemotherapy radiation therapy schedule. It is very likely that improved combinations, i.e., Taxol and Cisplatin will improve the median survival in these patients. The results of 8808 also raised the questions of optimal RT delivery which again will require Phase III testing. Although our success has been modest, it seems to be reproducible and has provided benefit to many patients with this disease.

References
1. Dillman RO, Seagren SL, Propert KJ, Guerro J, Eaton WL, Perry MC, Carey RW, Frei E III, Green MR. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in Stage III non-small cell lung cancer. N Engl J Med; 323:940-945, 1990.
2. Le Chevalier, Arriagada R, Quoix E, Ruffie P, Martin M, Douillard J, Tarayre M, Lacombe-Terrier MJ, Laplanche A. Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. Lung Cancer; 10:S239-S244,1994.
3. Morton RF, Jett JR, McGinnis WL, Earle JD, Therneau TM, Krook JE, Elliott TE, Mailliard JA, Drummond RG, Lauri JA, Kugler JW, Anderson RT. Thoracic radiation therapy alone compared with chemoradiotherapy for locally unresectable non-small cell carcinoma of the lung. Ann Intern Med; 115:681-686, 1991.
4. Wolf M, Hans K, Becker H, Hassler R, von Bultzingslowen F, Goerg R, Klaasen HA, Dannhauser J, Holle R, Pfab R, Havemann K. Radiotherapy alone versus chemotherapy with ifosfamide/vindesine followed by radiotherapy in unresectable locally advanced non-small cell lung cancer. Seminars in Oncology; 21:42-47, 1994.
5. Mattson K, Holsti LP, Holsti P, Jakobsson M, Kajanti M, Luppo K, Mantyla M, Nitamu-Korhanen S, Nikkannen V, Nordman E, Henri K, Platin L, Pyrhonen S, Romppanen ML, Salmi R, Tammilehto L, Taskinen PJ, Inoperable non-small cell lung cancer: Radiation with or without chemotherapy. Eur J Cancer Clin Oncol; 24:477-482,1988.
6. Schaake-Koning C, Van den Bogaert W, Dalesio O, Fister J, Hoogenhaut J, VanHoutte P, Kirkpatrick A, Koolen M, Moat B, Nijs A, Renaud A, Rodrigus P, Schuster W, Witterhave L, Sculier JP, Vahzandwijk N, Bartelisnk H. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med; 326:524-530,1992.
7. Trovo NG, Minotel E, Fravelun G, Boccieri MA, Naseemlin O, Bolzuccio G, Pizzi G, Tortelta A, Veronici A, Gobitti C, Zarelli DJ, Monfardini S. Radiotherapy versus radiotherapy enhanced by cisplatin in Stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys; 24:11-16,1992.
8. Soresi E, Clerici M, Grilli R, Borghini U, Zucoli R, Leoni M. Botturi M, Vergari C, Luporini G, Scoccia S. A randomized clinical trial comparing radiation therapy versus radiation therapy plus cis-dichlorodiammine platinum in the treatment of locally-advanced non-small cell lung cancer. Sem Oncol; 15(Suppl 7):20-25,1988.
9. Ansari R, Tokara R, Fisher W, Pennington R, Montravade R, O'Connor T, Rynardt S, Miller M, Einhorn L. A Phase III study of thoracic irradiation with and without concomitant cisplatin in locally advanced unresectable non-small cell lung cancer, a Hoosier Oncology Group study. Proc Am Soc Clin Oncol; 10:241,1991.
10. Lee JS, Farnam N, Komaki R, Fossella FV, McDonald S, Byhardt RW, Durran WJ, Dundas GS. Promising outcome of concurrent chemoradiation therapy with oral VP-16 and cisplatin for locally advanced inoperable non-small cell lung cancer. RTOG 91-06. Lung Cancer; 14:354,1995.
11. Viallet J, Rousseau P, Souhami L, Ayoub J, Del Vecchio P, Kreisman H, Guerra J, Langleben A, Kerby W, Hunt W, Hohneker J, Leyland-Jones B. A phase I/II trial of neoadjuvant chemotherapy (CT) with cisplatin and vinorelbine (navelbine) followed by accelerated thoracic irradiation (TRT) in inoperable non-small cell lung cancer (NSCLC). Lung Cancer; 14:377,1995.
12. Masters G, Drinkard L, Hoffman P, Haraf D, Krauss S, Olak J, Ferguson M, Watson S, Golomb H, Vokes EE. A phase I study of concomitant chemoradiotherapy with cisplatin (CDDP) and navelbine (NVB) for advanced malignancies of the chest. Lung Cancer; 14:378,1995
13. Hainsworth JD, Stroup SL, Spigel SC, Menchise AE, Greco FA. Treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) with paclitaxel (1-hour infusion), cisplatin, etoposide and radiation therapy. Lung Cancer; 14:383,1995
14. Sause W, Scott C, Byhardt R. Recursive partitioning analysis of 1,592 patients on four RTOG studies in non-small cell lung cancer. (Abstract) Proc Am Soc Clin Oncol; 12:336,1993.
15. Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys; 12:539,1986.
16. Sause W, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, Dar R, Cox JD. RTOG 88-08, ECOG 4588, preliminary analysis of a Phase III trial in regionally advanced unresectable non-small cell lung cancer. Jour of Natl Cancer Inst; 87#3:198-205,1995.
17. Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with >69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small cell lung carcinoma. Report of Radiation Therapy Oncology Group 83-11. J Clin Oncol; 8:1543,1990.
18. Byhardt RW, Scott CB, Ettinger DS, et al. Concurrent hyperfractionated irradiation and chemotherapy for unresectable non-small cell lung cancer: results of Radiation Therapy Oncology Group (RTOG) 90-15. Cancer; 75:2337,1995.
19. Langer C, Rosvold L, Kaplan R, Millenou M, Smith M, Kilpatric D, Movsas B, Alexander R, Eurran W, Fox Chase Cancer Center Phil PA 19111 and its network affiliates. Induction therapy with paclitaxel (Taxol) and carboplatin (CBDCA) followed by concurrent chemoradiotherapy in unresectable locally advanced non-small cell lung carcinoma (NSCLC) Preliminary report of FCCC94-001. ASCO abstract sumitted for publication 1996.
20. Graham MV, Jahanzeb M, Dresler CM, Cooper JD, Emami B, Mortimer JE. Results of a trial with topotecan dose-escalation and concurrent thoracic radiation therapy for locally advanced, inoperable non-small cell lung cancer. Abstract submitted for publication. 1995.
21. Ruckdeschel JC, Finkelstein DM, et. al. Chemotherapy for metastatic non-small cell bronchogenic carcinoma: EST:2575, generation V-a radomized comparison of four cisplatin-containing regimes. J Clin Oncol. 3:72, 1985.
22. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et.al. A randomized trial of the four most active regimens for metastatic non-small cell lung cancer. J Clin Oncol. 4:14, 1986.
23. Bonomi P, Finkelstein DM, Ruckdeschel JC, et. al. Combination chemotherapy versus single agents followed by combination chemotherapy in Stage IV non-small cell lung cancer; a study of the Eastern Cooperative Oncology Group. J Clin Oncol. 7:1602, 1989.
24. Carbone DP, Minna JD, et. al. Chemotherapy for non-small cell lung cancer. A meta-analysis suggests that benefits are small. BMJ 311:889-890, 1995
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26. Souquet PJ, Chauvin F, Boissel JP, Cellerino R, Cormier Y, Ganz PA, Kaasa S, Pater JL, Quoix E, Rapp E, Tumarello D, Williams J, Woods BL, Bernard JP. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. The Lancet, 342:19-21, 1993.
27. Wood AJJ, Ihde DC, Drug Therapy - Chemotherapy of lung cancer. New Eng Jour of Med. 327:1434-1441, 1992.
28. Sause, WT, Turrisi AT, Principles and application of preoperative and standard radiotherapy for regionally advanced non-small lung cancer. Lung Cancer Principles and Practice, 45:697-710. 1996.
29. Saunders MI, Radiotherapeutic techniques for lung cancer: accelerated hyperfractionation Lung Cancer Principles and Practice. 47:721-727, 1996.
30. Sause WT, Scott C, Taylor S, Byhardt RW, Banker FL, Thomson JW, Jones TK, Cooper JS, Lindberg RD. Phase II trial of combination chemotherapy and irradiation in non-small cell lung cancer, radiation therapy oncology group 88-04. Am J Clin Oncol (CCT) 15,#2:163-167, 1992.
31. Saunders MI, et al, J of Nat Canc, 73, 1455-1462, 1996.

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ROLE OF CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED NON SMALL-CELL LUNG CANCER (NSCLC)
T. LE CHEVALIER, C. LE PECHOUX
Institut Gustav~Roussy, 94800 Villejuif, France

Traditionally, locally advanced NSCLC have been treated with radiotherapy alone. Although thoracic radiation prolongs survival and improves symptoms, long term results are poor and less than 5 % of patients are alive at 5 years. Only 20 % of patients are in local complete remission after thoracic radiotherapy delivered al doses >55 Gy and about 50 % of these patients will relapse locally. Both local failure and the development of distant metastases are responsible for such a disappointing outcome. Although the evaluation of chemotherapy dates back to the 70s for phase II studies, it was only with the demonstration of the activity of cisplatin in the early 80s that the modern era of chemotherapy investigation in NSCLC began.

At least 12 randomized studies testing the addition of cisplatin based combination chemotherapy to thoracic radiotherapy have been performed in patients with unresectable non metastatic NSCLC. Only a few have shown a statistically significant benefit with the combined treatment compared to radiotherapy alone. In the individual data-based meta-analysis published in 1995, results from 11 trials involving a total of 1728 patients showed an absolute benefit of 4 % at 2 years and 2 % at 5 years (p= .0005). Treatment effect was consistent regardless of age, gender, histological subtype or performance status. A more recent RTOG study has confirmed this benefit. Trials using concurrent chemotherapy and radiotherapy have yielded mixed results and only one or two randomized trials testing single agent cisplatin have reported a survival benefit. Although quality and cost of extra life need to be more clearly evaluated, the combination of chemotherapy and radiotherapy should be considered standard treatment for patients with locally advanced NSCLC able to receive cisplatin-based chemotherapy. Optimization of combination chemotherapy and radiotherapy regimens, new cytotoxic drugs such as taxanes, gemcitabine, vinorelbine or new platin compounds, timing of the modalities and the use of radiosensitizing agents are areas requiring further development.

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IS THORACIC RADIOTHERAPY NECESSARY IN ALL LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER PATIENTS?
D.H. JOHNSON, M.D Professor of Medicine, Vanderbilt University Medical School and the Vanderbilt Cancer Center, Nashville, TN. 37232, U.S.A.

Less than a decade ago, thoracic radiotherapy (TRT) was widely considered to be the standard treatment for patients with locally adivanced, unresectable non-small cell lung cancer. Over the course of the past 10 years, however, combined modality therapy has supplanted TRT as the preferred means of treatment largely based on the results of several randomized trials completed within the past decade (1-5). The addition of a systemic therapy to radiation therapy makes intuitive sense in locally advanced NSCLC as individuals treated with radiotherapy alone commonly develop extrathoracic metastases and ultimately succumb to their cancer. The addition of chemotherapy to TRT lowers the incidence of distant metastases thus leading to improved survival (6).

Although combined modality treatment results in improved survival in locally advanced NSCLC, a majority of patients still die as a direct consequence of their underlying disease. Death may be due to distant metastases or local tumor progression. Indeed, conventional dose radiotherapy fails to control intrathoracic disease in more than 80% of cases (6). Given the relative ineffectiveness of TRT to control local disease, one might logically ask if TRT is necessary in the present day management of locally advanced NSCLC. Surprisingly, there are relatively few studies in the literature which have attempted to determine the utility of chemotherapy alone in locally advanced NSCLC (7, 8). One such study was conducted by the now defunct Southeastern Cancer Study Group (SECSG) (7). In the SECSG trial (LUN373), over 300 patients with locally advanced NSCLC were randomized to receive single agent vindesine alone, standard TRT (60 Gy in 6 wk) or vindesine plus standard irradiation (7). There were no differences in median or long term survival between the 3 arms indicating single agent chemotherapy was no less effective than radiotherapy (+/- chemotherapy). However, single agent vindesine has marginal activity against NSCLC so in essence, this was a trial in which immediate TRT was compared to delayed TRT. In retrospect, it is not surprising the survival rates across the three arms were virtually identical. By contrast, Kubota and colleagues found chemotherapy alone to be inferior to chemotherapy plus TRT (8). These investigators employed cisplatin-based combination chemotherapy with or without TRT. Although short term survival was similar in the two groups, long term survival was superior in patients given TRT. These data indicate optimal survival requires improved control of local tumor as well as improved control of extrathoracic disease.

Where do we go from here? Recently, several new chemotherapy agents have been identified with excellent activity against advanced NSCLC. Combined with cisplatin, some of these drugs have proved superior to drugs previously used in the treatment of NSCLC (9, 10). For example, ECOG investigators recently reported cisplatin plus paclitaxel is superior to cisplatin plus etoposide in advanced NSCLC. Other new drugs shown to be superior to cisplatin alone or cisplatin plus a vinca alkaloid or podophyllotoxin include vinorelbine and gemcitabine. In the ECOG trial (E5592), approximally 20% of patients had stage IIIB disease (10). Among this subgroup, median survival was substantially prolonged in the paclitaxeltreated population compared to those given etoposide (13.1 mo vs. 8 mo) (11) (vide infra). One-year survival was 58% in the paclitaxel treated patients compared to 39% for the etoposide treated group. It is worth noting that median survival with radiotherapy alone in locally advanced, unresectable NSCLC is typically 9-10 months and 1-year survival is commonly around 40%. Patients treated with combined modality therapy survive on average about 12-14 months and enjoy 1-year survival rates of approximately 50%-60% (12,13). Thus, even without TRT, the newer drug combination of cisplatin plus paclitaxel appears to offer a modest survival benefit in locally advanced NSCLC. The ECOG data are compared to SECSG and CALGB data in the following table:

Bibliography
1.Dillman R, Seagren S, Propert K, Guerra J, Eaton W, Perry M, Carey R, Frei E, Green M. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. New England Journal of Medicine. 1990;323:940-945.
2.LeChevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, Lacombe-Terrier M, Douillard J-Y, Laplanche A. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small cell lung cancer: First analysis of a randomized trial in 353 patients. Journal of National Cancer Institute. 1991;83:417-423.
3.Sause WT, Scott C, Taylor 5, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. Journal of the National Cancer Institute. 1995;87(3): 198-205.
4.Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer - seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 Trial. Journal of the National Cancer Institute. 1996;88(1 7): 1210-1215.
5.Johnson DH. Combined-modality therapy for unresectable, stage III non-small-cell lung cancer – caveat emptor or caveat venditor. Journal of the National Cancer Institute. 1996;88(17):1 175-1177
6.LeChevalier T, Arriagada R, Tarayre M, Lacombe-Terrier M, Laplanche A, Quoix E, Ruffie P, Martin M, Douillard J-Y. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung cancer. Journal of National Cancer Institute. 1992;84:58.
7.Johnson DH, Einhorn LH, Bartolucci A, Birch R, Omura G, Perez CA, Greco FA. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med. 1990; 113:33-38.
8.Kubota K, Furuse K, Kawahara M, Kodama N, Yamamoto M, Ogawara M, Negoro S, Masuda N, Takada M, Matsui K, et al. Role of radiotherapy in combined modality treatment of locally advanced non-small cell lung cancer. Journal of Clinical Oncology. 1994; 12(8): 1547-1552.
9.Lianes P, Chomy P, Cigolari S, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients [see comments]. Journal of Clinical Oncology. 1994; 12(2):360-7
10.Bonomi P, Kim K, Chang A, Johnson DH. Phase III trial comparing etoposide (E) cisplatin (C) versus Taxol (T) with cisplatin-G-CSF (G) versus Taxol-cisplatin in advanced non-small cell lung cancer. An Eastern Cooperative Group (ECOG) trial. Proceedings American Society Clinical Oncology. 1996; 15:382.
11.Bonomi PB, Kim K, Kugìer J, Johnson D. Comparison of survival for stage IIIB versus stage IV non-small cell lung cancer (NSCLC) patients treated with etoposide-cisplatin versus Taxol-cisplatin: an Eastern Cooperative Group (ECOG) trial. Proc Ann Meet Am Soc Clin Oncol. 1997;16:454a.
12.Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995;311(7010):899-909.
13.Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer - a meta-analysis. Annals of Internal Medicine. 1996; 125(9):723 ff.
14.Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, Houtte Pv, Kirkpatrick A, Koolen M, Maat B, Nijs A, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. New England Journal of Medicine. 1992;326:524-530.
15.Lichter AS, Ten Haken RK. Three-dimensional treatment planning and conformal radiation dose delivery. [Review]. Important Advances in Oncology. 1995:95-109.
16.Saunders Ml, Dische S, Barrett A, Parmar MKB, Harvey A, Gibson D. Randomized multicenter trials of CHART vs. conventional radiotherapy in head and neck and non-small-cell lung cancer - an interim report. Br J Cancer 1996;73(12):1455-1462.
17.Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee [see comments]. Lancet. 1997;350(9072): 161-5.
18.Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. Journal of Clinical Oncology. 1996; 14(4): 1065-70.

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COMPARATIVE STUDY OF INDUCTION CHEMOTHERAPY VERSUS RADIOTHERAPY ALONE IN STAGE III NON-SMALL CELL LUNG CANCER
Dr. K.T. BHOWMIK
Consultant in Radiotherapy to Min. of Health & F.W, Professor of Radiotherapy & Head of Department, Safdarjung Hospital, New Delhi, India.

The incidence of lung cancer is much lower in India than the corresponding rates reported worldwide by other countries. Lung cancer is the leading site of cancer according to the Delhi Cancer Registry, its incidence being 6.7 and 6.8 per 100,000 persons in males in the year 1990 and 1991 respectively, while its incidence is 1.9 and 1.6 per 100,000 persons in females over the corresponding period.

Conventional modalities for the treatment of Non-Small Cell Lung Cancer (NSCLC) are surgery, radiotherapy and chemotherapy. Surgery is the treatment of choice for Stage I, II and selected Stage III patients. However only about 20-25% of patients with Stage III NSCLC have resectable diseases. Patients with unresectable Stage III NSCLC have been traditionally managed with Radiotherapy alone, which although effective in palliation, has little impact on long term survival. NSCLC is not a very chemosensitive tumor, the most active agents being Mitomycin C, Ifosfamide, Cisplatin, Vinblastine and Vindesine. Newer agents like Paclitaxel, Docetaxel and Gemcitabine are under investigation, but have been available in India for only the last couple of years. Amongst combination chemotherapy the combination of Mitomycin C, Ifosfamide and Cisplatin has a overall response rate of 51%. Induction chemotherapy and consolidation with loco-regional radiotherapy addresses the problem of distant micro / macro metastasis and loco-regional control. Thus the rationale for induction chemotherapy is to decrease the tumor bulk and to make an immediate attack on metastatic disease. In an effort to improve upon the results of treatment in locally advanced NSCLC, a randomized trial of Induction Chemotherapy and Radiotherapy versus Radiotherapy alone was carried out at Safdarjang Hospital, New Delhi from January 1, 1992 to December 31, 1996. The study group treatment protocol consisted of induction chemotherapy comprising of Mitomycin C 6mg/m2, Ifosfamide 2gm/m2, with Mesna and Cisplatin 50mg/m2 after prior hydration (MIC). After completing 3 cycles of chemotherapy administered on a single day with 21 day intervals, patients received Radiotherapy with Cobalt –60, using 80cm SAD, to the primary disease and mediastinum to a tumor dose of 55-60Gy in 5.5- 6 weeks. The control group received Radiotherapy alone by Cobalt-60, at 80cm SAD, to the primary lesion and mediastinum to a tumor dose of 55-65Gy in 5.5-6.5 weeks. From January 1, 1995 patients who failed to respond to either induction chemotherapy and radiotherapy or radiotherapy alone were randomized to receive either Gemcitabine 1000mg/m2 on D1,D8,D15 repeated every 4 weeks for 3 cycles or oral Etoposide 50mg/m2 for 21 days and repeated every 4 weeks for 3 cycles.

506 patients with histologically proven Stage III NSCLC were randomized to receive either the study protocol of induction chemotherapy and radiotherapy or radiotherapy alone in the control group. Of the 253 patients enrolled into the study group, 228 patients were evaluable for response. After completion of 3 cycles of induction chemotherapy (MIC)5.7%(13/228) patients had complete response and 45.2%(103/228) patients had partial response, thus showing an overall response rate of 50.9%. On completion of the study protocol i.e. radiotherapy after 3 cycles of MIC, the overall response rate improved to 62.3%, with complete response in 16.2%(37/228) and partial response in 46.1%(105/228). In the control group i.e. patients who received radiotherapy alone, of the 253 patients 232 were evaluable. The overall response rate was 42.2%, with complete response in 6%(14/232) and partial response in 36.2%(84/232). The mean duration of response in the study group was 13.1 months (range 7-36 months) and 8.2 months (range 4-36 months) in the control group. The difference in overall response rates is statistically significant(p=0.005).

Patients in the study group tolerated chemotherapy well. Toxicities were moderate and manageable. There were no therapy related deaths, nor did any dose modification / reduction be required during the study. Common toxicities encountered were nausea and vomiting, which was controlled by appropriate anti-emetic therapy. Myelosuppression was frequently observed but moderate, and no life-threatening infections or hemorrhages observed.

With a follow-up of 3 years, analysis of overall survival rates observed were 20.1% in the study group and 11.2% in the control group.

80 patients who failed to respond to the study/control group treatment protocol were randomised to receive either 3 cycles of Gemcitabine or 3 cycles of oral Etoposide. Response rate to Gemcitabine was 22.5% with 7.5%(3/40) complete response and 15%(6/40) partial response, while oral Etoposide showed a response rate of 7.5%(3/40) all being partial responses with no complete response. Gemcitabine was well tolerated with only slight nausea and vomiting, while oral etoposide was also fairly well tolerated, with myelosuppression being the major toxicity observed. Both these regimen are out-patient treatment protocols, but often due to poor general condition patients were required to be hospitalised for general supportive care.

This study demonstrates the efficacy of induction chemotherapy with Mitomycin Ifosfamide and Cisplatin and Radiotherapy as a therapeutic strategy for Stage III non-resectable NSCLC, with manageable toxicities. Gemcitabine appears to be a good agent for salvage therapy and has been well tolerated.

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THORACIC CONFORMAL RADIATION THERAPY: COMBINED MODALITY TREATMENT IN CONJUNCTION WITH SEQUENTIAL AND CONCOMITANT CARBOPLATIN/PACLITAXEL IN STAGE III NON-SMALL CELL LUNG CANCER (NSCLC)
M. A. SOCINSKI, J. CLARK, J. HALLE, S. LIMENTANI, R. FRASER, W. MITCHELL, M. SCHELL, J. ROSENMAN
Multidisciplinary Thoracic Oncology Program, University of North Carolina, Chapel Hill, NC, USA

Combined modality treatment of Stage III NSCLC improves survival however the optimal treatment strategy remains undefined. Randomized trials employing a sequential strategy with induction chemotherapy followed by thoracic radiation therapy (TRT) have improved survival over TRT alone (1-3). Two of these trials (2,3) have suggested that systemic chemotherapy can reduce the rate of systemic metastases. Likewise, two trial employing low-dose concurrent chemoradiotherapy have shown improved survival over TRT alone (4,5). In both of these trials, the survival benefit was achieved by enhanced local control. Both systemic metastases and local progression remain substantial problems in Stage III NSCLC and strategies directed at improving both systemic and local control will likely contribute to improving survival.

Although the optimal chemotherapeutic regimen in NSCLC remains undefined, recent trials in advanced NSCLC have suggested that the combination of a platinum and paclitaxel is superior to non-paclitaxel containing regimens (6,7). Employing paclitaxel containing regimens in Stage III disease will likely lead to improved response rates and survival as chemotherapy is generally more active in earlier stages of disease. The use of concurrent low-dose weekly carboplatin/paclitaxel with standard TRT has been previously reported (8,9). In these Phase II trials, response rates, overall survival and toxicity profiles have been favorable.

TRT remains a crucial component of the treatment strategy. A recent trial has shown inferior survival when TRT is not included in the treatment regimen mainly due to lack of local control (10). Maximizing local control with TRT may be attempted with increased radiation dose, concurrent use of chemotherapy (or other radiosensitizing agents), improved tumor targeting in the chest, or altered fractionation schedules. Three-dimensional treatment planning may enhance local control by improved tumor targeting thereby more accurately delivering the radiation dose to the tumor mass. It may also improve the therapeutic index of TRT by limiting excessive dose to normal structures thereby reducing toxicity.

We are conducting a Phase I/II trial in which the dose of TRT is escalated utilizing conformal or three-dimensional treatment planning techniques. The treatment protocol utilizes two cycles of induction chemotherapy (carboplatin AUC=6, paclitaxel 225 mg/m2 over 3 hours) followed by concurrent chemoradiotherapy (carboplatin AUC=2, paclitaxel 45 mg/m2 over 3 hours weekly X 6) beginning on day 43. The initial dose of thoracic conformal radiation therapy (TCRT) was 60 Gy with escalation to 66 Gy, 70 Gy and 74 Gy in subsequent cohorts. Before the initiation of TCRT, all patients undergo three-dimensional treatment planning. A planning CT scan of the chest is performed with the patient in the treatment position. Lung, heart (left ventricle), skin, spinal cord, primary tumor and clinically positive lymph nodes are contoured into the treatment planning. Treatment fields are designed to deliver the first 50 Gy to the prechemotherapy primary tumor volume and mediastinum with a 1.0-2.0 cm margin. Between 45 and 50 Gy, the patients undergo another diagnostic CT scan of the chest to allow a second three-dimensional treatment plan. The boost volume includes the original tumor volume; however, no more than 25% of the lung volume receives more than 50 Gy as determined by dose-volume histograms. All radiographically positive lymph nodes present after 50 Gy are included in the mediastinal volume with a 1 cm margin. The spinal cord is excluded from the radiation fields after 45 Gy and the dose to the left ventricle is limited to 40 Gy. Dose-limiting toxicity (DLT) is defined as any grade 3-4 non-hematological toxicity, platelets less than 20,000, and grade 4 neutropenia lasting over 7 days (CALGB Expanded Toxicity Criteria used). For esophageal toxicity grading, we adopted our own toxicity grading scale where grade 3 esophagitis required hospitalization.

Twenty-seven patients with Stage III NSCLC have been entered thus far. Their characteristics include the following: 17 males, 10 females; median age 63 (range 38-68); ECOG PS 0/1/2, 20/6/1; no. with wt. loss exceeding 5%, 6; histology, squamous 8, adenocarcinoma 16, other 3; Stage IIIA/IIIB, 10/17. All patients were required to have an FEV1 of 800 cc.

Twenty-five of 27 patients are assessable for response to the two cycles of induction carboplatin/paclitaxel (C/P). There have been 14 partial responses for a response rate of 56%. Nine patients (36%) have had stable disease. Only two patients (8%) have progressed during initial induction C/P. Toxicity has been tolerable with no dose delays or dose reductions necessary.

Twenty-one of 27 patients have initiated TCRT with concurrent low-dose C/P on day 43. Reasons for failure to begin TCRT have included disease progression(2), early death (2), patient refusal (1), and co-morbid illness (1). Table I depicts the concurrent low-dose C/P and TCRT portion of the protocol.

Sixteen patients are currently assessable for response at least two months following completion of all treatment. The response rate is 81% (all partial) with 19% of patients having stable disease. No progression of disease has been seen during the concurrent low-dose C/P and TCRT phase of treatment. Patients are also assessed six months after completion of all treatment with bronchoscopy to best evaluate the local control rate. Preliminary data on the overall local control rate and survival will be presented.

In conclusion, this treatment strategy is tolerable in Stage III NSCLC. The response rate appears favorable to both induction C/P and the concurrent low-dose C/P and TCRT.

The dose of TRT can be escalated above the standard doses of TRT utilizing three-dimensional treatment planning with acceptable toxicity. Our Phase II dose of TCRT will be either 70 or 74 Gy. Accrual will continue on the Phase II portion of this trial.

References
1. Dillman RO, et al. J Natl Cancer Inst 88:1210-1215, 1996
2. Sause WT, et al. J Natl Cancer Inst 87:198-205, 1995
3. Le Chevalier T, et al. J Natl Cancer Inst 83:417-423, 1991
4. Schaake-Koning C, et al. N Engl J Med 326:524-530, 1992
5. Jeremic B, et al. J Clin Oncol 14:1065-1070, 1996
6. Bonomi P, et al. Proc ASCO 16:454a, 1997
7. Giaccone G, et al. Proc ASCO 16:460a, 1997
8. Choy H, et al. Proc ASCO 16:456a, 1997
9. Belani CP, et al. Proc ASCO 16:448a, 1997
10. Kubota K, et al. J Clin Oncol 12:1547-1552, 1994