Platinum/Etoposide Therapy in Non-Small Cell Lung Cancer Oncology 1992:49(suppl 1):43 50

Section of Medical Oncology . Rush University Medical Center. Chicago, 111.. USA

Key Words Platinum Etoposide Lung cancer

Platinum/Etoposide Therapy in Non-Small Cell Lung Cancer

Abstract Non-small cell lung cancer (NSCLC) is a major health problem in the United States and in many other parts of the world. Identification of systemic therapy that can maintain or improve quality of life and prolong survival is essential because locally advanced disease or distant metastasis is found in the majority of these patients. A variety of combination regimens have produced response rates of 20% or greater in stage IV NSCLC patients in coopertive group trials, including studies conducted within the Eastern Cooperative Oncology Group (ECOG). Although no regimen has emerged as clearly superior, the highest I-year survival rate (25%) in ECOG trials was observed in EP(etoposide cisplatinj-treated patients. Subsequently, a randomized trial in which EP was compared to etoposide carboplatin revealed no significant differences in sur­ vival or response rate, and toxicity was slightly less with etoposide carboplatin. Results from recent phase II trials in which stage 111 NSCLC patients received preoperative EP and concurrent thoracic irradiation have shown response rates o f65 85%, as well as acceptable toxicity and surgical morbidity and mor­ tality. Future stage IV NSCLC trials should include studies of platinum/ etoposide plus new agents. Also a study comparing platinum etoposide versus supportive care should be considered. The objectives of this study would be to compare survival, quality of life, and cost-effectiveness ratio. The results of recent phase II studies in stage III NSCLC patients suggest that preoperative cisplatin etoposide and concurrent thoracic irradiation should be considered for evaluation in a phase III trial in stage Ilia NSCLC patients and that this regimen should also be evaluated in stage 11lb patients.

Lung cancer has been the leading cause of cancer deaths in men in the United States for decades. During the last 5 years, it has also become the leading cause of cancer deaths in women. It isestimated that 85% oftheeasesoflungcancerare caused bycigarettesmoking. Fortunately, the trend toward a decreased incidence of smoking in the United States should eventually result in a declining incidence of lung cancer. However, at present and for decades to come, clinicians will be faced with the difficult problem of at­ tempting to provide palliation and prolong survival for

lung cancer patients. Of the 161,000 new cases expected in 1991. approximately 80% will have nonsmall cell histol­ ogy: 70-80% of these cases will present with distant metastasesor locally advanced disease. In addition, many of the patients who initially proceed to resection will have a re­ currence. Therefore, the majority of non-small cell lung cancer (NSCLC) patients are candidates for systemic therapy. This report will review the results of selected trials of etoposide combined with a platinum compound in NSCLC.

Philip Bonomi. MD Section o f Medical Oncology Rush University Medical Center Room 830. 1725 W. Harrison Chicago. IL 60612 ( USA)

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Philip Bonomi

Single Agents

Table 1. Single-agent chemotherapy for NSCLC

Combination Regimens in Stage IV NSCLC During the latter part of the 1970s. a variety of com­ bination regimens tested at single institutions produced response rates of 40-50% [4], Each of these regimens as well as EP (etoposide cisplatin) were subsequently tested in larger phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Two of the noncisplatin-containing regimens: CAMP (cyclophos­ phamide doxorubicin methotrexate procarbazine) and MACC (methotrexate doxorubicin cyclophosphamide lomustine) produced response rates of < 20% (table 2) [4], When the data from two of these trials were combined, multivariate analyses showed that better performance stal us. absence of bone métastasés, female sex. and absence of weight loss were associated with higher 1-year survival rates [5]. There were no imbalances in these prognostic fac­ tors for any of the regimens tested in these trials: none of the regimens emerged as clearly superior with respect to survival or response rale. However, the highest I-year sur­ vival rate was observed with EP. Of the patients treated with EP, 25% survived for 1 year versus an 18% I-year survival rate for patients treated with other regimens [5]. Toxicity analyses revealed that patients with a worse per­ formance status had a higher rate of lethal toxicity than patients with a better performance status. Comparison of mitomycin cisplatin versus vindesine/cisplatin versus EP showed a slightly lower rate of lethal toxicity for EP [5].

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Bonomi

Drug

Patients, n

Response, %

Range

Ifosfamide Cisplatin Mitomycin Carboplatin Etoposide

326 140 115 159 195

21 20 20 12 11

5-35 6-32 9-40 9-16 3 21

Table 2. Response rates for combination chemotherapy Regimen

CAMP MACC CAP VP EP MVP

Response. % single institution

cooperative group

48 46 39 43 28 53

17 12 23 25 20 28

CAP = Cyclophosphamide doxorubicin cisplatin: VP = vindesine cisplatin: MVP = methotrexate vincristine,cisplatin. Adapted from Bonomi [4],

These observations have led to the exclusion of poor per­ formance status patients from subsequent ECOG NSCLC trials and to the selection of EP as the reference regimen for subsequent ECOG trials. Carboplatin jEtoposide versus EP Recently, carboplatin has been shown to have modest activity in NSCLC. In a randomized ECOG trial [6], treat­ ment with carboplatin alone was associated with longer survival than treatment with several cisplatin-containing combination regimens. Carboplatin is more myelosuppressive than cisplatin. but it has the advantage of produc­ ing less nausea and vomiting. In addition, it can be ad­ ministered easily on an outpatient basis, whereas cisplatin treatment requires hospitalization for administration of additional intravenous fluids and intensive antiemetic reg­ imens. In a randomized Belgian trial [7], 100 patients were treated with EP and 102 patients with carboplatin etopo­ side. The response rate for EP was 27% compared with 16% for carboplatin etoposide; this difference was not sta­ tistically significant. Similarly, there was no appreciable difference in survival for the two regimens. Significantly

Platinum Etoposide for Non-Small Cell Lung Cancer

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Single agents that have been tested in multiple centers and have produced a collective response rate of greater than 10% are listed in table 1. In contrast to small cell lung cancer (SCLC). in which single agents have produced re­ sponse rates of 30-50%, response rates for agents that have shown activity in NSCLC range from 10-20% [I]. A recent report has described eight (44%) responses to etoposide given orally for 21 days in 18 SCLC patients whose disease had progressed previously on shorter cour­ ses of intravenous etoposide [2]. This observation suggests the possibility of significant schedule dependency for etoposide and has led the Vanderbilt group to conduct a phase II trial of a 21-day course of oral etoposide in previously untreated NSCLC patients. A 20% response rale was observed in 25 patients [3], Although this was a small trial, the results suggest that additional NSCLC trials of prolonged administration of etoposide alone or combined with a platinum compound are warranted.

Regimen

Evaluable patients, n

Major responses, %

Median survival. months

Carboplatin Carboplatin cisplatin Carboplatin etoposide Carboplatin vinblastine

70 71 71 54

16 II II 17

6.5 4.0 8.7 6.1

Adapted from Green et al. [9],

Table 4. Ifosfamide etoposide: Regimen I Drug

Dose, mg/nf

Day

Ifosfamide Mesna Carboplatin Etoposide

1.500 2,000 350 60

1.3.5 1.3.5 1 1.3,5

Adapted from Van Zandwijk et al. [15],

Table 5. Ifosfamide etoposide: Regimen II Drug

Dose, mg/nr

Day

1fosfamide Mesna Cisplatin Etoposide

4.000 3.200 25 100

1 1 1.2.3 1.2.3

Adapted from Shepherd et al. [16].

less diarrhea and a trend toward less nausea were noted in patients treated with carboplatin. Surprisingly, the degree of leukopenia was significantly lower with carboplatin compared with cisplatin. Perhaps this might be explained by the fact that the dose of cisplatin was 100 m g/nr while the dose of carboplatin was 300 mg nr. which is ap­ proximately equivalent to 75 mg/nr cisplatin. In a Cancer and Leukemia Group B (CALGB) study [8], carboplatin alone produced a 16% response rate in NSCLC, leading to three phase 11trials in which carbopla­ tin was combined with cisplatin, etoposide, or vinblastine. Response rates ranged from 11-17% and median survival from 4.0-8.7 months (table 3) [9]. Although these regimens were not compared in a randomized trial, the 8.7-month median survival with carboplatin/etoposide suggests a trend toward longer survival with this regimen.

EP versus Single Agents The EP regimen has also been compared with either of the single agents alone. In the first trial, conducted by the Belgium Lung Cancer Study Group [10], EP produced an overall response rate of 26 versus 19% for cisplatin alone. The difference was not statistically significant. In stage 111 patients, there was a trend toward a higher response rate with EP compared with cisplatin alone, with response rates of 43 and 17%, respectively (p = 0.09). In a more recent trial, Italian investigators compared F.P with etopo­ side alone. In this trial, response rate for EP was signifi­ cantly higher - 25 versus 7%. There was, however, no sig­ nificant difference in survival, with median survival for the combination regimen being 8 months and for etoposide alone. 6 months (p = 0.43) [II]. EP Dose The use of higher doses of EP has been addressed by several investigators. First the Belgian group evaluated EP in a randomized trial comparing cisplatin 120 mg n r with cisplatin 60 m g/nr [12]. In this relatively large trial, 125 pa­ tients received the lower dose of cisplatin and 116 patients received the higher dose. Response rates were virtually identical - 25 and 29% for the low- versus high-dose reg­ imen. Again, there was a trend for higher response rates in stage III patients, with a 42% response rate observed at the higher dose of cisplatin and a 30% response rate observed at the lower dose (p = 0.30). Escalation of the etoposide dose has been evaluated in a phase 11trial testing cisplatin 35 mg, n r day x 3 plus etoposide 200 mg/nr day i.v. x 3. This regimen produced a response rate of 45%, suggesting that this more intensive regimen should be considered for further study [13], The Vanderbilt University group has combined a rela­ tively high dose of oral etoposide (50 mg n r over 21 days) with carboplatin in advanced NSCLC and observed a 27% response in 30 patients [14]. Although this response does not appear to be significantly higher than response rales for other regimens, this dose can be administered en­ tirely on an outpatient basis with relatively few visits to the clinic, suggesting that it should be considered for studies in which quality of life and cost analysis are also evaluated. IfosJamide¡Carboplatin Etoposide and Ifosfamide Cisplatin Etoposide lfosfamide’s activity in NSCLC has prompted several groups of investigators to test this agent in combination regimens. Two of these regimens are shown in tables 4 and 5. In the first regimen, ifosfamide was administered on 3 separate days along with a single dose of carboplatin and 3

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Table 3. The CALGH: carboplatin trials in NSCI.C: Summary data

daily doses of etoposidc f 15], In the second regimen, ifosfa­ mide was administered as a single daily dose and etoposide was given over 3 days: these agents were combined with cisplatin rather than carboplatin [16]. The lirst regimen (ifosfamide carboplatin etoposide) produced a 40% re­ sponse rate and an 8.6-month median survival. The second regimen (ifosfamide cisplatin etoposide) was associated with a 44% response rate in a smaller group of patients; median survival was not reached when these data were first reported. Mesna was used in each of the trials in order to protect the bladder epithelium. The high response rates suggest that additional trials of ifosfamide/carboplatin etoposide and ifosfamide cisplatin etoposide are war­ ranted.

rates in two phase II trials. Also, preliminary data indicate that taxol [A Chang, MD, unpubl. data, 1991] and camptothecin [19] compounds are active in NSCLC. Both of these newer agents should be considered for combination with etoposide and a platinum compound. It seems unlikely that higher doses of etoposide/platinum will result in significant benefit in patients with stage IV NSCLC who, in general, are quite ill and frequently have lost significant amounts of weight, therefore making them more susceptible to serious toxicity. If higher doses of these agents are studied, it seems more reasonable to conduct this type of trial in good performance status pa­ tients with less advanced disease.

EP in Stage III NSCLC Conclusions: Stage IV NSCLC

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Bonomi

Response rates for combination chemotherapy are ap­ proximately 50% for stage III disease compared with ap­ proximately 25% for stage IV disease [14], EP was the first regimen for which this phenomenon was observed. Longeval and Klastersky [20] observed a 56% response rate in stage 111 patients given EP compared with a 28% response rate in stage IV patients given the same doses of EP. The apparently higher response rates in stage III NSCLC pa­ tients have led a number of investigators to test the concept in which neoadjuvant combination chemotherapy is given prior to radiation in locally advanced NSCLC [21,22], Subsequently, three phase 111 trials have addressed this question [23-25], Two of them have shown no apparent advantage for sequential chemotherapy and radiation compared with radiation alone [23. 24], However, a third trial conducted by the CALGB has shown a survival ad­ vantage for vinblastine cisplatin followed by radiation compared with radiation alone [25], An ongoing random­ ized trial is attempting to duplicate these results. Based on the preliminary results of phase II trials of se­ quential chemotherapy and radiation, including our own trial, we chose to evaluate concurrent chemotherapy and radiation. Two seccessive phase II trials conducted at Rush University have tested concurrent chemotherapy and split-course radiation therapy [26.27], In the first trial cisplatin 60 mg/nr on day 1 along with 5-fluorouracil (5FU) 800 mg/nr as a continuous 24-hour infusion for 5 consecutive days and radiation therapy 200 cGy/day x 5 were repeated every 4 weeks for a total for 4 cycles [26]. In a second trial etoposide 60 mg/nr/day was added on days 1-4, although the number of days of 5-FU infusion was reduced from 5 to 4. and the cisplatin dose remained the same. Radiation was given on the same schedule, and the

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New agents are clearly needed to treat NSCLC, and clinical investigators should be encouraged to continue their efforts to identify new active agents. However, some patients do not want to participate in phase 11 trials testing new agents, instead preferring treatment with standard therapy. The issue of treating this group of patients in a nontrial setting is controversial. Two of the most widely quoted randomized trials comparing combination che­ motherapy with best supportive care have shown conflict­ ing results [17, 18]. In the Canadian trial [17] treatment with either of two cisplatin combination regimens (cyclophosphamide doxorubicin cisplatin vs. vindesine/ cisplatin) was associated with a modest, but statistically significant, survival advantage. In contrast, in the Austra­ lian trial [18], the same vindesine cisplatin regimen was associated with a trend toward longer survival but a sig­ nificant survival difference was not observed. Additional randomized trials comparing chemo­ therapy with no chemotherapy are needed to assess the effect of cytotoxic treatment on quality as well as quantity of life. Also, these trials should include analyses of cost effectiveness for the different treatments. ECOG is cur­ rently proposing a trial comparing megestrol acetate ver­ sus carboplatin versus carboplatin/etoposide versus carboplatin etoposide/megestrol acetate. Evaluation of quality of life and cost-effectiveness ratio for each treat­ ment will be major objectives of this study. Continued efforts to identify more effective treatment for stage IV NSCLC patients should also involve trials evaluating the addition of a 3rd drug to EP or etoposide/ carboplatin regimens. As mentioned previously, the ad­ dition of ifosfamide produced relatively high response

Table 6. Comparison of response to 5-FU cisplatin RT with and without etoposide Regimen

Clinical responses/ total n patients

Histologic responses, total n patients

5-FU cisplatin RT Etoposide 5-FU cisplatin RT /»value

.54 54 (62)

8/54 (15)

25 29 (86) 0.026

9/29 (31) 0.11

RT = Radiation therapy. Values in parentheses arc percentages.

Table 7. Comparison of hematologic toxicity of 5-FU cisplatin with and without etoposide Toxicity

5-FU/ eisplatin/RT

Leukopenia, x 10!/pl .5.9 Thrombocytopenia, x 10' pi’ 18.5 2 Sepsis. % 0 Bleeding episodes

F.toposide/ 5-FU/ cisplatin/RT .5.2

/»value

0.05

260 0 0

0.001

RT = Radiation therapy.

Table 8. Serum albumin levels of patients treated with 5-FU cisplatin RT with and without etoposide Albumin, g/dl

Pretreatment Posttreatment

5-FU/cisplatin RT

eioposide/5-FU; cisplatin/RT

.5.7 .5.8

3.8 4.1

RT = Radiation therapy.

of surgical planes, 62 of 83 patients underwent resection and 60 of 62 had complete resection. Three patients (5%) died as a result of surgery, which is comparable to the sur­ gical mortality rates for patients undergoing resection without preoperative treatment. Overall, 14 patients ex­ perienced complications, which consisted ofbronchopleu-

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cycles were repeated every 21 days [27]. In both trials, restaging was performed 4 weeks after completion of che­ motherapy and radiation. One hundred and twenty-nine patients were entered into these trials, 83 of whom were considered eligible for surgery at study entry. Each patient was evaluated by a thoracic surgeon, radiation therapist, and medical oncolo­ gist at the start of treatment. Of the 83 patients initially classified as eligible for surgery. 54 were treated with the 2-drug regimen and 29 received the etoposide-containing regimen. Eligibility requirements included histologically confirmed stage 111 NSCLC and performance status of 3 or lower. Results for the 83 patients who were eligible for surgery have been reported separately [28], Comparison of responses for the two regimens is de­ picted in table 6. There was a 62% clinical response with the 2-drug regimen and an 86% response with the etopo­ side-containing regimen. The difference was statistically significant (p = 0.026). Comparison of complete histo­ logic responses shows that 8 of 54 patients (15%) given the 2-drug regimen had complete clearance of tumor in resect­ ed specimen compared with 9 of 29 patients (31%) given the etoposide-containing regimen (table 6). There was a trend toward a higher histologic complete response rate with etoposide (p = 0.11). Comparison of hematologic toxicity for the two re­ gimens (table 7) shows slightly greater leukopenia with etoposide and slightly greater thrombocytopenia with the 2-drug regimen. There was 1 septic death with the 2-drug regimen, but episodes of bleeding or death secondary to infection were not observed with the 3-drug regimen. Vir­ tually all patients experienced some degree of nausea and vomiting but severe esophagitis, dermatitis, or radiation pneumonitis were not observed with either regimen. Comparison of serum albumin levels at the start and completion of therapy for each of the regimens is depicted in table 8. The posttreatment median serum albumin level was slightly higher with both regimens, but the differences between pretreatment and posttreatment levels and be­ tween corresponding levels for the two regimens were not statistically significant. Multi variate analyses indicate that higher posttreatment serum albumin level and higher posttreatment body weight were associated with longer survival. In tact, these two parameters were more strongly related to survival than was clinical response [29]. Perhaps these two parameters provide a more global assessment of the patient's well-being, which is related to tumor burden and oveiall nutritional status. Although surgery following concurrent chemotherapy and radiation is difficult because of dense fibrosis and loss

»=¡9 i . Survival estimates for all eligible patients treated with eisplatin combination therapy and radiation.

Survival (d)

Fig. 2. Survival estimates according to treatment group. RT = Radiation.

Table 9. Surgical complications in patients treated with 5-FU cisplatin RT with and without etoposide Complications

Patients, n

Fistula Tracheostomy Atelectasis Pneumonitis Stroke Total

4 2 5 2 1 14

Resected Surgical mortality

60/62 (97) 3/62 (5)

Values in parentheses are percentages.

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Survival (d)

ral fistula, tracheostomy, persistent postoperative atelec­ tasis. postoperative pneumonia, and cerebrovascular ac­ cident (table 9). The estimated median survival for all 83 patients is 22 months and the 4-year survival rate is 38% (fig. 1). The ad­ dition of etoposide to the regimen resulted in a trend to­ ward longer survival, but this did not reach statistical sig­ nificance (p = 0.22; fig. 2). Comparison of our sequential phase II studies has shown that the addition of etoposide results in a higher clinical response rate and a trend toward a higher histologic complete response rate, as well as a trend toward longer survival. Also, serious toxicity was not increased by the addition of etoposide. Other investigators have studied the use of EP and con­ current radiation therapy. The Mayo Clinic group con­ ducted a small randomized trial in which patients with stage 111 NSCLC were randomized to CAP (cyclophos­ phamide doxorubicin/cisplatin) with or without etopo­ side for two courses, followed by two courses of the same chemotherapy regimen given concurrently with splitcourse radiation therapy [30]. Thirty-eight patients were treated with the 3-drug regimen and 39 patients with the etoposide-containing regimen. Median survival rales were virtually identical. However, the 5-year survival rate for etoposide-treated patients was 18% compared with 3% for patients treated with the 3-drug regimen, and the différ­ ence approached statistical significance (p = 0.08). Al­ though this is a small study, the higher 5-year survival rate with the addition of etoposide is provocative. More recently, Weitberget al. [31] conducted a phase 11 trial in which cisplatin 25 nig n r day w'as given as a con­ tinuous intravenous infusion on days 1-4, and etoposide 100 mg/nr was given on the 2nd and 4th days. This regimen was repeated twice at 28-day intervals. It was given simultaneously with thoracic radiation therapy (5,100-5,400 cGy). Forty-two patients with stage III NSCLC were entered into this study; the clinical response rate was 85% and the median survival was 15.7 months for this group of patients. The Southwest Oncology Group [32] has presented re­ sults of a phase II trial in which cisplatin 50 mg/nr was given on the 1st and 8th days, and etoposide was given at a dose of 50 mg/nr daily for 5 consecutive days. The same regimen was repeated 28 days later and was given concur­ rently with radiation therapy (4,500 cGy). Sixty-five pa­ tients were evaluable when this study was reported, and a response rate of 65% was observed. Similarly, 65% of the patients were able to undergo pulmonary resection. Com­ plete histologic clearance of the tumor was observed in 20% of the 44 patients who underwent resection. The pro­

jected median survival duration for this group of patients is approximately 16 months.

Conclusions: Stage III IMSCLC Additional study of EP and concurrent thoracic radia­ tion therapy for treatment of stage 111 NSCLC should he pursued. Three phase II trials [28. 31, 32] evaluating this type of regimen as preoperative treatment have shown re­

latively high response rates, acceptable toxicity, and rela­ tively low surgical mortality rates. In addition, the survival results are encouraging. If a randomized, prospective trial testing the neoadjuvant concept in stage IIIA NSC'LC is initiated. EP and concurrent radiation therapy should be a leading choice for the experimental arm of the study. Similarly, the encouraging results observed in these trials suggest that this regimen should also be studied in pa­ tients with unresectable, locally advanced (stage IIIB) NSCLC.

References 10 Klastersky J. Seulier J P. Bureau G: Cisplatin versus cisplatin plus ctoposide in the treatment o f advanced non-small cell lungeancer. J. Clin Oncol 1989:7:1087 1092. 11 Rosso R. Salua11 F. Ardizzorti A. et al: F.toposide versus ctoposide plus high-dose cisplatin in the management o f advanced non-small cell lungeancer. Cancer 1990:66:130-134. 12 Klastersky J. Seulier JP. Roue/ P. et al: A randomized study comparing a high and a standard dose o f cisplatin in combination with ctoposide in the treatment o f advanced non­ small cell lung cancer. J Clin Oncol 1986:4: 1780-1786. 13 Muscato J. Clamon G. Perry M. et al: Eloposide and cisplatin at maximum tolerated dose in non-small cell lungeancer: A CALGB study (abstract). Proc Am Soe Clin Oncol 1991:10: 243. 14 Walts J. Devore R. Hainsworth JD. et al: Carboplatin plus prolonged administration o f oral ctoposide in the treatment of nonsmall cell lungeancer: A phase I II trial (abstract). Proc Am Soc Clin Oncol 1991:10:257. 15 Van Zandwijk N. ten Bokkel Huinink W, Wanders J. et al: Dose finding studies with carboplatin. ifosfamide, etoposide and mesna in non-small cell lung cancer. Semin Oncol 1990:17(suppl 2): 16 19. 16 Shepherd FA. Goss PE. Latreille J. et al: A phase II study of ifosfamide, cisplatin. etopo­ side in patients with advanced non-small cell lung cancer. A preliminary report. Semin Oncol 1990:17(suppl 2): 19-23. 17 Rapp E. Paler JL. Willan A. et al: Chemo­ therapy can prolong survival in patients with advanced non-small cell lung cancer Report o f a Canadian multi-center randomized trial. J Clin Oncol 1988:6:633-641. 18 Williams CT. Woods R. Levi J. el at: Chemo­ therapy for non-small cell lung cancer: A ran­ domized trial of cisplatin vindesine chemo­ therapy versus no chemotherapy. Semin Oncol 1988;15fsuppl 7):58-6l.

19 Fukuoka M. Ncgoro S. Niitani H. et al: A phase II study of a new camptothecin deriva­ tive CPTII in previously untreated non-small cell lung cancer (abstract). Proe Am Soc Clin Oncol 1990:9:226. 20 Longcval E. Klastersky J: Combination che­ motherapy with cisplatin and ctoposide in bronchogenic squamous cell and adenocar­ cinoma. A study for the F.ORTC Lung CancelWorking Party (Belgium). Cancer 1982:50: 2751 2756. 21 Fram R. Skarin A. Balikian J. et al: Combina­ tion chemotherapy followed by radiation therapy in patients with regional stage III unrescclablc non-small cell lung cancer. Cancer Treat Rep 1985:69:587-590. 22 Wagner H. Ruckdeschel J. Bonomi P. et al: Treatment of locally advanced non-small cell lung cancer with mitomycin, vinblastine, and cisplatin (MVP) followed by radiation therapy: An ECOG pilot study (abstract). Proc Am Soc Clin Oncol 1985:4:183. 23 Morton R F. Jett J R. Maher L. et al: Random­ ized trial of thoracic radiation therapy with or without chemotherapy for treatment of locally advanced lung cancer of all cell types (ab­ stract). Proc Am Soc Clin Oncol 1988:7:200. 24 Mattson K. Holsti L R. Holsti P. et al: Inoper­ able non-small cell lungeancer: Radiation with or without chemotherapy. EurJ Cancer 1988: 24:477-482. 25 Dillman RO. Scagrcn SL. Proper! K J. et al: A randomized trial o f induction chemotherapy plus high dose radiation versus radiation alone m stage 111 non-small cell lungeancer. N Engl J Med 1990:323:940-945. 26 Taylor SG IV. Trybula M. Bonomi PD. et al: Simultaneous cisplatin 5FU infusion and ra­ diation followed by surgical resection in re­ gionally localized non-small cell lung cancer. AnnTlioracSurg 1987:43:87 91. 27 Recinc D. Rowland K. Reddy S. et al: Com­ bined modality therapy for locally advanced non-small celi lung. Cancer 1990:66:22702278.

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1 F.ttingcr DS: Ifosfamide in the treatment of non-small cell lung cancer. Semin Oncol 1989: I6(suppl 3):31 38. 2 Johnson DH. Greco FA. Strupp .1. el al: Pro­ longed administration o f oral ctoposide in pa­ tients with relapsed or refractory small cell lung cancer: A phase II trial. J Clin Oncol 1990:8:1613-1617. 3 Waits TM. Hainsworth J D. Johnson D ll. el al: Prolonged administration o f oral ctoposide in previously untreated patients with non­ small cell lung cancer (abstract). Proe Am Soe Clin Oncol 1991:10:256. 4 Bonomi P: Brief overview o f combination che­ motherapy in non-small cell lung cancer. Semin Oncol 1986:l3(suppl 3):89-9l. 5 Finkelstein DM. Ettinger DS. Ruckdeschel JC: Long-term survivors in metastatic non­ small cell lung cancer. An Eastern Co-opera­ tive Oncology Group study. J Clin Oncol 1986; 4:702 709. 6 Bonomi P. Finkelstein D. Ruckdeschel JC. et al: Combination chemotherapy versus single agents followed by combination chemo­ therapy in stage IV non-small cell lung cancer: A studv of the Eastern Cooperative Oncology Group. J Clin Oncol 1989:7:1602 1613. 7 Klastersky J. Seulier JP. DabouisG. etahCisplatin plus ctoposide versus carboplatin plus ctoposide in the treatment of advanced non­ small cell lung cancer: A preliminary report: in Bunn PA Jr. Canetta R. Ozols R F. et al (eds): Carboplatin (JM-8): Current Perspectives and Future Directions. Philadelphia. Saunders. 1990. pp 329 338. 8 Kreisman II. Ginsberg S. Proper! K. el al: Carboplatin or iproplatin in advanced non­ smallcell lungeancer. A Cancer and Leukemia Group B study. Cancer Treat Rep 1987:71: 1049-1052. 9 Green MR. Kreisman H. Luikart S. et al: Carboplatin in non-small cell lung cancer: The Cancer and Leukemia Group B experience; in Bunn PA Jr. Canetta R. O /ols R F, cl al (eds): Carboplatin (JM-8): Current Perspectives and Future Directions. Philadelphia. Saunders. 1990. pp 301-306.

28 Kaplan F.H. Bonomi PD. Gale M. el al: Neoadjuvant chemotherapy and concurrent split course radiotherapy in non-small cell lung cancer. Improved response rate when etoposidc is added tocisplatin and infusional 5-fluorouracil: in Salmon S (ed): Adjuvant Therapy of Cancer. VI. Philadelphia. Saunders. 1990. pp 138-144. 29 Thomas C. Bonomi P. Gale M. et al: Treat­ ment related prognostic factors in stage 3 non­ small cell lung cancer patients receiving com­ bined modality treatment (abstract). Proc Am Soc Clin Oncol 1990:9:243.

30 Robinow JS. Shaw FG. Fagan RT. et al: Results of combination chemotherapy and thoracic radiation therapy for unrescclable non-small cell carcinoma of the lung. Int J Ra­ dial Oncol Biol Phys 1989:17:1203-1210. 31 WeitbergT. Posner N. Yanshar J.ct al: Com­ bined modality therapy for stage Ilia non­ small cell lung cancer (abstract). Proc Am Soc Clin Oncol 1990:9:226.

32 AIbain K. Ruseh V. Crowley J. el al: Concur­ rent cisplatin. VPI6. and chest irradiation fol­ lowed by surgery for stages Ilia and II lb non­ small cell lung cancer: A Southwest Oncology Group study (abstract). Proc Am Soc Clin Oncol 1991:10:244.

Discussion

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Dr. Bonomi: I do not know if we can establish universal quality-of-life criteria. I suspect that the forms that we are using, namely, the tO RTC quality-of-life form and a form developed at Rush for specific disease sites, will not be universal. There will be basic functions that apply to every­ one. such as eating, working, and social activities. How­ ever, in some cultures hair loss may not be a problem, whereas in others it may be a major problem.

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Dr. Ariyoshi: Dr. Bonomi. you mentioned that quality of life is very important, espeeially in stage IV non-small cell lung cancer. Do you think that worldwide criteria can be established, because quality of life is different in each coun­ try?

etoposide therapy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a major health problem in the United States and in many other parts of the world. Identification of systemic the...
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