Combined-modality therapies for non-small cell lung cancer

Annals of Oncology 3 (Suppl. 3): S3-S10, 1992. © 1992 Kluwer Academic Publishers. Primed in the Netherlands.

Original article Combined-modality therapies for non-small cell lung cancer C. P. Belani & J. Aisner University of Maryland Cancer Center, Baltimore, Maryland, U.S.A.

irradiation can produce apparently beneficial results with respect to local control and are the subject of ongoing clinical trials. At the University of Maryland Cancer Center, we have combined weekly carboplatin 100 mg/m2 with concurrent chest irradiation. The preliminary results are very encouraging. The toxicity of this treatment program is very manageable, and preliminary data suggest excellent local control and survival. Other pilot studies have suggested that combination chemotherapy with concurrent radiotherapy is also technically feasible. Such combined chemotherapy/radiotherapy programs will be the subject of ongoing clinical trials. Current data favor the use of combined chemotherapy and radiotherapy over radiotherapy alone for stage III NSCLC. This approach offers the possibility of improved survival with the combined-modality therapy, and offers even further potential benefit for earlier-stage disease.

Introduction

chosen to divide stage IIIA into bulky (grossly visible) and microscopic substages, based on potential surgical resectability [3]. A small group of patients who present with T3,N0 disease (stage IIIA) with chest wall invasion but without hilar or mediastinal node involvement have relatively favorable predicted 5-year survivals with surgical therapy and are often considered separately. Stage IIIB includes T4 lesions or tumor involvement in either the contralateral mediastinal lymph nodes or the supraclavicular nodes (N3) and is considered unresectable. The presence of malignant pleural effusion, which defines T4 disease, also tends to preclude radiotherapy. Over the past 30 years, most patients who presented with stage III disease received radiotherapy alone, but the median duration of survival and the frequency of long-term survival have been disappointing. Median survival for patients with unresectable disease is less than 12 months, and 2-year survival frequency is less than 20% [4]. The role of radiotherapy was based in part on the Veterans Administration trial [5], reported in 1968, which compared radiation therapy (35 Gy over 5 weeks) with no irradiation for both small cell lung cancer (SCLC) and NSCLC. Survival at 1 year was 18.2% for the irradiated group and 13.9% for

Non-small cell lung cancer (NSCLC) includes the histologic subforms squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Together these often indistinct subforms of NSCLC comprise 75% to 80% of all lung cancers. The overall cure rate for NSCLC is approximately 10%, and cure is generally achieved by surgery. Unfortunately, however, less than 15% of all patients and less than 25% of those who present with localized disease are candidates for curative surgical resection. Attempts to screen for earlier curable disease in high-risk populations have not met with success [1]. Thus, early diagnosis to increase surgical cure rates is unlikely to improve in the near future. Approximately 40% of patients with NSCLC present with disease that appears clinically confined to the chest but is nonetheless too extensive to warrant surgical resection. This stage of presentation has formerly been classified as stage III disease. The new international staging system [2] that separates stage III into substages IIIA and IIIB has been proposed and widely adopted. Stage IIIA disease encompasses Tl to T3 primary lesions and lymph node involvement not beyond the ipsilateral mediastinum (N2). Some authors have also

Key words: NSCLC, radiotherapy, chemotherapy, cisplatin, carboplatin

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

Summary. Regionally advanced stage III non-small cell lung cancer (NSCLC) accounts for nearly 40% of all presentations of NSCLC. In the past, such patients received radiotherapy alone, but the median and long-term survival durations were disappointingly poor. Past attempts at combining chemotherapy and radiation were also disappointing, and were troubled by low doses of radiation or orthovoltage equipment or both. Recently, cisplatin-containing regimens have shown some efficacy in stage IV disease. The response rate for these combinations in stage III disease is nearly double that in stage IV disease. The greater response in stage III has led to a series of trials of sequenced chemotherapy and radiotherapy for treatment of regionally advanced (unresectable stage IIIA and IIIB) NSCLC. Several randomized trials have now shown a statistically significant advantage for the combined modality over radiation alone regarding time to treatment failure, median survival duration, and percent of long-term survivors. Other trials have focused on the concurrent use of chemotherapy and radiotherapy. Several pilot studies have suggested that concurrent cisplatin plus chest

Table I. Concurrent RT and non-cisplatin chemotherapy for locally advanced NSCLC. Reference

Regimen

19]

5-FU + RT (50 Gy)

mi

5-FU + vincristine + mitomycin + RT (50-56 Gy)

[10]

5-FU + RT (50 Gy) vs. dactinomycin + RT (50 Gy)

No. patients

% Overall response

Median survival (mos)

100

6+

92

9.6

113

19

4.4

114

16

3.4

Bleomycin + RT (50 Gy) vs. RT alone (50 Gy)

15

46

13

15

26

6

(141

5-FU + RT (60 Gy) (continuous, low dose)

30

91 (in 12 previously untreated pts)

NS

|12]

Hydroxyurea + RT (split-course 60 Gy) vs. RT alone (split-course 60 Gy)

28

NS

NS

25

NS

NS

131

53

121

55

[13|

|15[

Levamisole + RT (60 Gy) vs. RT alone (60 Gy)

9.5 12

-

No significant alteration in survival

No significant alteration in 1- and 2-year survival

No significant alteration in survival or differences in patterns of failure

RT = radiotherapy; NS = not stated.

those who did not receive irradiation. Today, these low survival rates suggest inadequate dosing and staging techniques as well as confounded results, caused by the inclusion of patients with SCLC. The Cooperative Oxford Group [6] compared outcomes for asymptomatic patients who received chest irradiation at diagnosis with those whose radiotherapy was delayed until symptoms occurred. In 1971 they reported no survival differences between the groups. This trial also used low-dose orthovoltage radiation and primitive staging methods. Nevertheless, despite improvements in radiotherapy and lung cancer staging techniques, both median and long-term survival for patients with locally advanced NSCLC is disappointingly poor. This is due in part to the high local failure rate and to high rates of distant metastases [7, 8]. These disappointing results have led to attempts to combine treatment modalities such as chemotherapy and radiotherapy in order to improve outcomes.

Concurrent radiation and non-cisplatin chemotherapy in locally advanced NSCLC

Concurrent chemotherapy and irradiation have been used to treat locally advanced NSCLC for nearly 40 years (Table 1). Helsper and Sharp [9] reported a 100% response rate among a small group of patients (n = 8) with inoperable NSCLC who received simultaneous 5-fluorouracil (5-FU) and thoracic irradiation (total dose, 50 Gy), but a subsequent randomized trial by

Hall and Good [10] failed to confirm the results of the earlier trials combining 5-FU with simultaneous chest irradiation. Encouraging results were also reported with the use of 5-FU/mitomycin/vincristine and simultaneous chest irradiation [11]. Hydroxyurea [12] and bleomycin [13] were tested both as potential radiation sensitizers and for their direct cytotoxic activity in patients with locally advanced disease, but neither drug produced any demonstrable survival advantage when added to the chest irradiation. Another study evaluated continuous low-dose 5-FU (300 mg/m2/d) and concurrent thoracic irradiation at 1.8 to 2.0 Gy/d (total dose, 60 Gy) for patients with stage III NSCLC [14] and showed an impressive response frequency (>90%) in previously untreated patients. Among the treated patients, moderate to severe esophagitis occurred in 27% and radiation pneumonitis in 10%. Twelve percent of the patients required parenteral nutrition. These data suggest that continuous 5-FU infusion with simultaneous thoracic irradiation is feasible, but the patient population is too small to substantiate conclusions regarding efficacy. In 1978 the Radiation Therapy Oncology Group (RTOG) began a randomized, single-blind study to evaluate the immunostimulatory effect of levamisole among patients receiving radiotherapy for unresectable NSCLC [15]. Amery and coworkers [16] previously reported that adjuvant postoperative levamisole improved the survival of patients with stage II NSCLC, compared with placebo. In the RTOG study 260 eligible patients received either 60 Gy over 6 weeks plus

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

8 13

Comment

Recent trials with cisplatin and concurrent radiotherapy

ducted a randomized trial in patients with stage III NSCLC, which compared split-course radiotherapy alone with split-course radiotherapy combined with cisplatin given either weekly or daily [26]. Of the first 100 patients, 94 were assessable. Complete responses (CRs) and partial responses (PRs) were observed in 21 of 34 patients in the radiotherapy-alone group, in 20 of 30 patients in the radiotherapy plus weekly cisplatin group, and in 20 of 30 patients in the radiotherapy plus daily cisplatin arm. There was a strong trend toward a survival benefit (P = 0.056 by log-rank analysis) in favor of the patients treated with split-course radiotherapy and daily cisplatin, compared with the radiotherapy-alone group. Grades III and IV nausea and vomiting were seen in 37% of the patients, and severe esophagitis occurred in 4%. Both toxicities were more frequent in the combined-modality arms. Myelosuppression was not a significant problem, and the acute and late forms of toxicity were considered acceptable. However, the numbers of patients in this trial are too small to draw statistically significant conclusions about improved survival or a reduction in local recurrence using weekly or daily low-dose cisplatin with simultaneous thoracic irradiation. These interim results have led to a continuation of this comparison study to arrive at more definitive answers about the possible benefit of combined-modality therapy.

Current evidence suggests that cisplatin is the most effective single agent for treating NSCLC and that cisplatin-containing regimens can improve survival for paAnother approach for combining cisplatin and contients with advanced NSCLC [17]. Cisplatin also potentiates the effects of radiation in mouse tumors and in current chest irradiation was tested by Gandara et al. normal skin when the agent is given either before or [24], predominantly in patients with stage IIIB disease. immediately after irradiation [18, 19]. Preclinical data Radiotherapy (3 separate 10-day courses of 2.0 Gy/d) also suggest that cisplatin and its analogues can effec- was rapidly alternated (i.e. no rest periods) with hightively modulate the mechanisms of radiation cell dam- dose cisplatin. The CR-plus-PR rate was 73% and the age [20, 21]. Platinum coordination complexes are par- median survival duration 14.2 months. Although these ticularly effective as potential hypoxic cell sensitizers findings are better than anticipated for radiotherapy [21]. While the existing information regarding platinum alone, the overall impact of this combined approach recompounds as radiosensitizing agents is interesting and mains uncertain, because there were only 22 eligible somewhat encouraging, their precise role as radiosen- patients and there were substantial hematologic, renal, sitizing or perhaps synergistic agents remains unclear. and radiation-related toxicities. However, these data do Other unresolved issues relate to optimal doses and warrant further clinical studies directed toward develschedules and effects of platinum analogues in relation oping less toxic and more effective combined-modality to the parent compound in this setting. A number of regimens that improve the quality and quantity of surclinical trials have used various doses and schedules vival. of cisplatin in combination with chest irradiation (Table 2) [22-26]. Schaake-Koning et al. [22] showed that 30 mg/m2 of Concurrent carboplatin and radiotherapy for unresectcisplatin was the best tolerated dose when given on the able stage III M0 NSCLC first day of each radiotherapy sequence of 30 Gy over 2 weeks (3 Gy/fraction), followed by a 2-week rest and At the University of Maryland Cancer Center (UMCC) then 25 Gy over 2 weeks. Radiation pneumonitis and we sought to exploit the synergistic potential of platiesophagitis were the major side effects seen with this num analogues and radiotherapy. Carboplatin is essenregimen. Cisplatin 6 mg/m2/d in combination with tially devoid of nephrotoxicity in contrast to the parent radiotherapy was also reported to be feasible [25, 27]. compound and has less pronounced emetic properties. Ansari et al. [25] examined the role of concurrent cis- When given concurrently with irradiation, myelosupplatin and chest irradiation using 70 mg/m2 cisplatin pression is the dose-limiting toxicity [28, 29]. Preclinion days 1, 22, and 43 and showed some improvement cal data suggest that the in vitro synergism between in median survival but no difference in survival at 2 carboplatin and radiotherapy is comparable to that years. The European Organization for the Research seen with cisplatin and radiotherapy [20]. Our experiand Treatment of Cancer (EORTC) subsequently con- ence at UMCC with carboplatin and synchronous con-

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

levamisole (2.5 mg/kg/wk for 2 years or until disease progression) or identical radiation therapy plus placebo. The study did not demonstrate any significant prolongation of overall survival or progression-free survival, or differences in patterns of failure between the two groups. In the levamisole-treated group, intractable vomiting was experienced by 5 patients and 4 had grade III or IV leukopenia. The differences between the trials suggest that levamisole may be beneficial only in the presence of a small tumor burden, as might occur following complete resection of early-stage (e.g. I or II) disease. The earlier combined-modality trials used less effective staging methods and suboptimal doses of radiation, leaving the role of combined-modality therapy for NSCLC open to question. These studies did, however, show that concurrent chemotherapy and chest irradiation was feasible and suggested the need for additional studies with other active drugs or agents with radiopotentiating or radiosensitizing properties.

Table 2. Concurrent cisplatin and RT for locally advanced NSCLC. Reference

Regimen

[22]

Cisplatin 10-35 mg/mVwk + 30 Gy in 2 wk

No. patients

% Overall response

Median survival (mos)

Comment

20

CR45 PR 35 SD 20

NS

Cisplatin 30 mg/m2/wk with concurrent RT

37

CR + PR65

10.5 mos

No treatment delays

22

CR + PR73

14.2 mos

1 -yr survival 64% 2-yr survival 41%

CR9 PR 29 SD 38

41 wks

1 -yr survival 40% 2-yr survival 9%

CR 12 PR 37 SD 35

35 wks

1-yr survival 35% 2-yr survival 15%

1

1

2-wk rest 1

i

[23]

25 Gy in 2 wk Cisplatin 6 mg/m2/d j_

T

3.0 Gy/4 fx/wk x 4 (2-wk rest between 8th & 9th fractions) [24]

Cisplatin 100 mg/m2 weeks 3 & 4, 7 & 8, 11 & 12, 15 & 16 T

RT 60 Gy (3 separate 10-day courses of 2.0 Gy/d weeks 1 &2, 5&6.9&10) [25]

[26]

Cisplatin 70 mg/m2 days 1, 22 & 43 + RT (60 Gy) 1.8-2.0 Gy/d (5 fx/wk) vs. RT alone

209

Cisplatin 30 mg/m2/wk + RT vs. Cisplatin 6 mg/m2/d + RT vs. RT alone 3.0 Gy/d x 10, 2-wk rest, 2.5 Gy/d x 10

100 (94 evaluable)

1-yr survival 49% 2-yr survival 17% 1 -yr survival 50% 2-yr survival 32% 1-yr survival 38% 2-yr survival 14%

RR67 RR67 RR62

SD = stable disease; RR = response rate.

ventional radiotherapy for unresectable head and neck cancer demonstrated that the combination was well tolerated and resulted in appreciable tumor response [29]. Based on this experience and on the prospect of developing a less toxic combined-modality regimen, we initiated a phase II study to evaluate the efficacy of concurrent carboplatin and definitive chest irradiation for patients with unresectable stage III (M0 NSCLC). Eligibility for this pilot study required histologically proven unresectable stage HI disease, Cancer and Leukemia Group B (CALGB) performance status of 2 or better, measurable disease, adequate bone marrow reserve, and appropriate renal and hepatic function. Patients with significant pleural effusions, defined as a reaccumulation of fluid after thoracentesis or visible on conventional chest x-ray, were not eligible. Patients received chest irradiation with 1.8 to 2.0 Gy fractions 5 days per week to a total tumor dose of 60 Gy over 6 to 7 weeks. Carboplatin was administered weekly as intravenous (i.v.) bolus injections, starting at a dose of 75 mg/m2 (Table 3). No grade III or IV toxicity was seen

among the first 6 patients treated at this dose; therefore the dose was increased to 100 mg/m2/wk. All patients were followed to determine survival. Response was evaluated clinically and radiographically at completion of treatment. Table 3. Concurrent carboplatin and RT for unresectable stage III (M0) NSCLC: Treatment regimen. Dose (mg/m2/wk)

No. patients

Carboplatin

75 100

6 16

Concurrent chest RT

5 daily fx of 1.8-2.0 Gy/wk for 6-7 wk

At present, this study has enrolled 35 previously untreated patients with unresectable stage III disease; sufficient follow-up data are available for the first 22 patients (Table 4). Overall, the treatment has been very

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

_i_

alone (same dose). One hundred nineteen patients were treated on each arm of the study. The median survival was 10.3 months in the radiotherapy-alone arm and No. patients Characteristics 11.0 months in the combined-modality arm; there was no significant difference in survival between the two 22 Entered groups. The North Central Cancer Treatment Group Evaluable 20 21/1 Sex: M/F trial [31] administered two cycles of MACC (methoMedian age, yr (range) 61 (47-73) trexate/doxorubicin/cyclophosphamide/lomustine) beMedian Eastern Cooperative Oncology Group fore 60 Gy of chest irradiation, which was then folperformance status (range) 1 (0-2) lowed by two cycles of MACC. Fifty-six patients reHistology ceived combined-modality therapy, and 58 received 11 Squamous cell 7 Adenocarcinoma radiotherapy alone. Myelosuppression was significantly 4 Large cell greater for the combined-therapy group (P = 0.0002), 11 Stage IIIA but the time to progression and the median survival 11 Stage IIIB durations did not differ between the two treatment groups. The 5-year survival was 5% in patients who received radiotherapy alone and 7% in the combinedTable 5. Concurrent carboplatin and RT for unresectable stage III modality group. (MO) NSCLC toxicity. The CALGB compared two cycles of induction No. patients (grade) chemotherapy with cisplatin/vinblastine before definiSevere toxicities" Grades III/IV tive chest irradiation against radiotherapy alone (same dose) [32]. The results are highly provocative (Table 6). 2 (III, IV) Leukopenia Only patients with excellent performance status 1 (IV) Thrombocytopenia (CALGB performance status 0 to 1) were included. 1 (III) Nausea and vomiting 2 (III, III) Fever with sepsis The authors demonstrated that even the brief course of induction chemotherapy before radiotherapy produced Two patients developed acute hypersensitivity reactions. a prolongation of survival when compared with the radiotherapy alone (median durations of survival, 13.8 and 9.7 months, respectively; P = 0.0066 by log-rank well tolerated. Toxicity (Table 5) has included myelo- analysis). At 2 years there were twice as many survivors suppression and mild to moderate nausea and vomit- in the combined-modality arm than in the radiationing. One patient required a platelet transfusion, and 2 alone arm. Several trials are currently under way to patients developed active hypersensitivity reactions confirm these results. presumed to be secondary to carboplatin administraLe Chevalier et al. [33] also tested the effect of comtion. In the first patients the hypersensitivity reaction bined-modality therapies upon both local control and was manifested as hypotension, dyspnea, chest pain, distant metastasis in patients with locally advanced rash, and fever to 105°F, whereas in the second patient NSCLC (Table 6). Three hundred fifty-three patients it manifested as rash, dyspnea, and hyperthermia randomly received either thoracic megavoltage irradia(maximum temperature 105°F). Twenty of the 22 pa- tion alone to a total dose of 65 Gy in 26 fractions over tients entered are assessable for response. There was 1 45 days or the same radiotherapy dose preceded and early death, and 1 patient was removed from study be- followed by 3 monthly cycles of VCPC (vindesine/ cause an anaphylactic reaction developed. One of the cyclophosphamide/cisplatin/lomustine). The 2-year 20 patients achieved a CR, 8 achieved a PR, and 6 had distant metastases rate of 64% in the radiotherapystable disease. The survival range of all patients has alone group was significantly greater than the 43% rate been 1.5 to 39+ months. The study is ongoing, and the in the combined-modality group (P < 0.001). Complanned accrual is 48 patients. bined-modality therapy was also associated with significant improvement in survival (median survival, 10 Randomized trials evaluating the role of sequential vs. 12 months; P < 0.02). Local control at 1 year was chemotherapy and radiotherapy for locally advanced poor in both groups, suggesting that intrathoracic tuNSCLC mor control remains a significant problem for patients with unresectable NSCLC. Within the past 4 years, at least four randomized trials Based on the result of the randomized trials, there of combined chemotherapy and thoracic irradiation vs. appears to be a potential role for combined-modality radiation therapy alone have been reported for local- therapy for regionally advanced NSCLC. The relatively ized, unresectable NSCLC. In the Finnish Group trial high local and systemic failure rates, however, suggest [30] patients with stage III disease as well as some with the need for further studies. For example, it is possible stage II disease were randomized to receive CAP that concurrent schedules of chemoradiotherapy may (cyclophosphamide/doxorubicin/cisplatin) followed by be more effective than sequential therapies for both 55 Gy of thoracic irradiation vs. radiation therapy local and systemic control. Table 4. Concurrent carboplatin and RT for unresectable stage (MO) NSCLC: Patient characteristics.

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

Table 6. Sequential chemotherapy and RT in locally advanced NSCLC. Reference

Regimen

[32]

PV x 2 cycles

% Response

Median survival (mos)

Comment

78

CR 19 PR 37

13.8

2-yr survival 26% 3-yr survival 23%

RT 60 Gy in 6 wk

77

CR 16 PR 27

9.7

2-yr survival 13% 3-yr survival 11 %

VCPC x 3 cycles

176

CR 19 PR 15 SD 16

12

Rate of distant metastases at 2 yr 43%

177

CR 15

10

Rate of distant metastases at 2 yr 64%

No. patients

1

RT 60 Gy in 6 wk vs.

[33|

1

RT 6.5 Gy in 45 d (26 fractions) i i

VCPC x 3 cycles vs.

PV = cisplatin 100 mg/m2 days 1, 29, vinblastine 5 mg/m2 days 1, 8, 15, 22, 29 (RT was begun on day 50); VCPC = vindesine 1.5 mg/m2 days 1, 2, cyclophosphamide 200 mg/m2 days 2-4, cisplatin 100 mg/m2 day 2, lomustine 75 mg/m2 day 3, chemotherapy preceded and followed RT; SD = stable disease.

Concurrent radiotherapy and combination chemotherapy for locally advanced NSCLC

A number of cisplatin-containing combinations have also been used concurrently with thoracic irradiation for locally advanced NSCLC (Table 7) [34-38]. The purpose of using combination chemotherapy with concurrent chest irradiation is presumably to improve upon the local and systemic control obtained with single-agent cisplatin or one of its analogues. Friess et al. [34] evaluated cisplatin/etoposide/thoracic irradiation using 55 to 61 Gy for 20 patients with unresectable stage III NSCLC. They reported an overall response rate (CR and PR) of 80% and a median survival duration of more than 13.5 months at the time of the report. Friess and coworkers also suggested that the toxicity was acceptable, and there were no treatmentrelated deaths. The small number of patients precluded sweeping conclusions, but the authors were able to demonstrate the feasibility of administering combination cisplatin/etoposide/chest irradiation. A number of trials have used the combination of cisplatin/5-FU/thoracic irradiation [35-37]. Elson and colleagues [35] used a 3-day regimen of cisplatin (total dose, 60 mg/m 2 ) and 5-FU (total dose, 3,000 mg/m2), repeated every 28 days with simultaneous thoracic irradiation (total dose, 60 Gy). The median survival for the 24 study patients was 17 months. A moderately high dose of concurrent cisplatin with 5-FU infusion was chosen by Breneman et al. [36]. Overall, the toxicity was acceptable, with nausea, esophagitis, and myelosuppression recognized as the major side effects. Despite radiation doses of 60 Gy and moderately doseintensive chemotherapy, there was a high local and distant recurrence rate and a median survival of 11.6 months.

Response rates as high as 86% have been reported with cisplatin-containing regimens and concurrent thoracic irradiation in patients with locally advanced NSCLC [37]. However, these pilot studies have not as yet indicated any clear survival advantage to adding combination chemotherapy to concurrent irradiation for patients with locally advanced NSCLC. Several randomized trials have shown the potential role of sequential combined-modality therapies; it thus seems reasonable that concurrent combined-modality therapies should also be at least that effective. Ongoing combined-modality trials

There are a multitude of trials of combined-modality treatment in locally advanced NSCLC now in progress. The CALGB has started a trial comparing the regimen of sequential vinblastine and cisplatin followed by radiation with or without concurrent carboplatin based on the prior CALGB study [32] and a feasibility study of cisplatin and vinblastine followed by chest irradiation and concurrent weekly carboplatin [39]. The EORTC is conducting a phase III study, a continuation of their preliminary study [24], comparing radiotherapy alone with radiotherapy plus cisplatin given on the first day of each treatment week, and, with radiotherapy preceded daily by cisplatin in patients with inoperable NSCLC. A three-arm Intergroup study has been started to compare the combined-modality treatment of the CALGB trial [33] with hyperfractionated chest irradiation (total dose, 69.2 Gy) and standard fractionated chest irradiation (total dose, 60 Gy). Recently, new agents such as antifolates (e.g. 10-ethyl-deazaaminopterin, a vinca derivative virorelbine ditartrate [Navelbine] and camptothecin analogue CPT-11) have

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

RT alone 6.5 Gy in 45 d (26 fractions)

Table 7. Concurrent RT and combination chemotherapy for locally advanced NSCLC: Pilot studies. Median survival (mos)

20

80

13.5+

Cisplatin 20 mg/m2 days 1-3 5-FU 1,000 mg/m2 days 1-3 (q28d) + RT 60 Gy

24

NA

17

|36]

Cisplatin 100 mg/m2 5-FU 1,000 mg/mVd CI x 4 (q28d) + RT 60 Gy (split course)

21

67

11.6

[371

Cisplatin 40 mg/m2 Doxorubicin 40 mg/m2 Cyclophosphamide 400 mg/m2 or with Etoposide and triazinate + RT 40 Gy (split course)

102

NA

14.8

[38]

Cisplatin 100 mg/m2 days 1, 29 Vindesine 3 mg/m2 days 1, 8, 29, 36 Mitomycin 8 mg/m2 days 1, 29 + RT 26 Gy/13 fx starting day 2 and RT 24 Gy/12 fx starting day 30

65 (50 evaluable)

86

Regimen

[34]

Cisplatin 50 mg/m2 days 1 & 8 Etoposide 50 mg/m2 days 1-5 (q28d) + RT55 to 61 Gy

|35]

No. patients

NA = not available; CI = continuous infusion.

shown impressive responses in metastatic and recurrent disease, and thus open a new arena for including newer active agents as part of combined modalities for patients with regionally advanced NSCLC. Combined chemotherapy and thoracic irradiation for unresectable locally advanced NSCLC Although locoregional control in unresectable stage III NSCLC is important, most patients die of distant metastases [7]. Therapeutic attempts to control both local disease and micrometastatic disease are therefore important if we are to ultimately improve survival. Combination chemotherapy can produce objective tumor regression in stage IV NSCLC [17], but offers only a small advantage in survival prolongation. The lessons learned from the treatment of advanced disease have already impacted upon regionally advanced unresectable disease and will likely be extended to even earlier disease stages to improve the potential for cure.

References 1. Tockman MS, Frost JK, Stitik FP et al. Screening and detection of lung cancer. In Aisner J (ed): Lung Cancer. New York: Churchill Livingstone; 1985: 25-40. 2. Mountain CF. A new international staging system for lung cancer. Chest 1986; 89: 225S-33S.

3. Martini N, Flehinger BJ. The role of surgery in N2 lung cancer. Surg Clin North Am 1987; 67: 1037-49. 4. Perez CA, Stanley K, Grundy G. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Cancer 1982; 50: 1091-9. 5. Roswit B, Patno ME, Rapp R et al. The survival of patients with inoperable lung cancer. A large scale randomized study of radiation therapy versus placebo. Radiology 1968; 90:688-97. 6. Durrant K, Ellis F, Black J et al. Comparison of treatment policies in inoperable bronchial carcinoma. Lancet 1971; i: 715-9. 7. Cohen MH. Is immediate radiation therapy indicated for patients with unresectable non-small cell lung cancer? Cancer Treat Rep 1986; 67: 333-6. 8. Stanley K, Cox JD, Petrovich Z et al. Patterns of failure in patients with inoperable carcinoma of the lung. Cancer 1981; 47: 2725-9. 9. Helsper JT, Sharp GS. Combination therapy with 5-FU and cobalt-60 for inoperable carcinoma of the lung. Cancer Chemother Rep 1962; 20:4103-6. 10. Hall BE, Good JW. Treatment of far-advanced cancer with 5-fluorouracil, used alone and in combination with irradiation. Incidence and duration of remission and survival time data in 223 patients. Cancer Chemother Kep 1962; 16: 369-86. 11. Farley P, Giri J, Ronquillo A. Treatment of non-small cell lung cancer with simultaneous chemotherapy and radiation therapy. Proc Am Soc Clin Oncol 1984; 3: 211 (Abstract). 12. Landgren RC, Hussey DH, Barkley HT et al. Split course irradiation compared to split course irradiation plus hydroxyurea in inoperable bronchogenic carcinoma - a randomized study of 53 patients. Cancer 1974; 34: 1598-601. 13. Chan PYG, Byfield JE, Kagan AR et al. Unresectable squamous cell carcinoma of the lung and its management by combined bleomycin and radiotherapy. Cancer 1976; 37: 2671-6.

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

% Overall response (CR + PR)

Reference

10

28. 29.

30. 31.

32.

33.

34. 35. 36. 37.

38.

39.

combination with radiotherapy. Radiother Oncol 1984; 1: 227-34. Eisenberger M, Van Echo D, Aisner J. Carboplatin: the experience in head and neck cancer. Semin Oncol 1989; 16(5): 34-41. Belani CP, Egorin MJ, Abrams JS et al. A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide. J Clin Oncol 1989; 7: 1896-902. Mattson K, Holsti LR, Holsti P et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988; 24: 477-82. Morton RF, Jett JR, McGinnis WL et al. Thoracic radiation therapy alone with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. A randomized, phase II trial. Ann Intern Med 1991; 115: 681-6. Dillman RO, Seagreen SL, Propert KJ et al. 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 1990; 323: 940-5. Le Chevalier T, Arriagade R, Quoix E et al. Impact of chemotherapy on survival of locally advanced non-small cell lung cancer: results of a randomized study in 353 patients. Lung Cancer 1991; 7 (suppl): 592 (Abstract). Friess GG, Baikadi M, Harvey WH. Concurrent cisplatin and etoposide with radiotherapy in locally advanced non-small cell lung cancer. Cancer Treat Rep 1987; 71: 681-4. Elson D, Brindle J, Rice B. 5-FU and cisplatin plus radiation therapy for limited inoperable non-small cell lung cancer. Proc Am Soc Clin Oncol 1987; 6: 172 (Abstract). Breneman JC, Mitchell SE, Hawley DK et al. Concurrent radiotherapy and chemotherapy for locally advanced nonsmall cell lung cancer. Am J Clin Oncol 1991; 14:9-15. Robinow JS, Shaw EG, Eagan RT et al. Results of combination chemotherapy and thoracic radiation therapy for unresectable non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1989; 17: 1203-10. Kubota K, Furuse K, Kawahara M et al. Phase II trial of cisplatin (C), vindesine (V), mitomycin-C (M) and concurrent split-course radiotherapy for inoperable locally advanced nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1991; 10: 256 (Abstract). Clamon G, Maurer H, Goutsou M et al. Toxicity and induction chemotherapy response data of combined chemotherapy/ radiotherapy for limited stage III NSCLC. Proc Am Soc Clin Oncol 1990; 9: 239 (Abstract).

Correspondence to: Chandra P. Belani, MD University of Maryland Cancer Center 22 S. Greene St Baltimore, MD 21201, U.S.A.

Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 4, 2015

14. Lokich J, Chaffey J, Neptune W. Concomitant 5-fluorouracil infusion and high dose radiation for stage III non-small cell lung cancer. Cancer 1989; 64: 1021-5. 15. Perez CA, Bauer M, Emami BN et al. Thoracic irradiation with or without levamisole (NSC #177023) in unresectable nonsmall cell carcinoma of the lung: a phase III randomized trial of the RTOG. Int J Radiat Oncol Biol Phys 1988; 15: 1337-46. 16. Amery W for the Study Group for Bronchogenic Carcinoma. Immunopotentiation with levamisole in resectable bronchogenic carcinoma. A double-blind placebo controlled trial. Br MedJ 1975; 3: 461-4. 17. Rapp E, Pater JL, Willan A et al. Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer. Report of a Canadian multicenter randomized trial. J Clin Oncol 1988; 6:633-41. 18. Douple EB, Richmond RC. Enhancement of the potentiation of radiotherapy by platinum drugs in a mouse tumor. Int J Radiat Oncol Biol Phys 1982; 8: 501-5. 19. Douple EB, Eaton WL Jr, Tulloh ME. Skin radiosensitization studies using combined cis-dichlorodiammine platinum II and radiation. Int J Radiat Oncol Biol Phys 1979; 5: 1383-5. 20. Begg AC. Cisplatin and radiation: interaction probability and therapeutic possibilities. Int J Radiat Oncol Biol Phys 1990; 19:1183-9. 21. Douple EB, Richmond RC. Platinum complexes as radiosensitizer of hypoxic mammalian cells. Br J Cancer 1978; 37: 98-102. 22. Schaake-Koning C, Bartelink H, Adema BH et al. Radiotherapy and cis-diammine dichloroplatinum (II) as a combined treatment modality for inoperable non-small cell lung cancer: a dose-finding study. Int J Radiat Oncol Biol Phys 1986; 12: 379-83. 23. van Harskamp G, Boven E, Vermoken JB et al. Phase II trial of combined radiotherapy and low-dose cisplatin for inoperable locally advanced non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1987; 13: 1735-8. 24. Gandara DR, Valone FH, Perez EA et al. Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in stage III B non-small cell lung cancer: results of a phase I/II study. Int J Radiat Oncol Biol Phys 1991; 20: 1047-52. 25. Ansari R, Tokars R, Fisher W et al. A phase III study of thoracic irradiation with or without concomitant cisplatin in locoregional unresectable non-small cell lung cancer (NSCLC): a Hoosier Oncology Group (HOG) protocol. Proc Am Soc Clin Oncol 1991; 10:241 (Abstract 823). 26. Schaake-Koning C, Maat B, van Houtte P et al. Radiotherapy combined with low dose cis-diammine dichloroplatinum (II) (CDDP) in inoperable non-metastatic non-small cell lung cancer (NSCLC): a randomized three arm phase II study of the EORTC lung cancer and radiotherapy cooperative groups. Int J Radiat Oncol Biol Phys 1991; 19: 972-6. 27. Keizer HJ, Karim ABMF, Njo KH et al. Feasibility study of daily administration of cis-diammine dichloroplatinum (II) in