Small cell carcinoma of the lung. A progress report of 15 years' experience

Small Cell Carcinoma of the Lung

A Progress Report of 7 5 Years ' Experience

NOAH C. CHOI, MD,'*t ROBERT W. CAREY, MD,S.§ S. DONALD KAUFMAN, MD,*.§ HERMES C. GRILLO, MD,II.q JERRY YOUNGER, MDJ.9 AND EARLE W. WlLKlNS JR, MDII-7

To assess the results of therapeutic advances in the treatment of small cell carcinoma of the lung (SCCL) achieved during the past 15-year period at a single large institution, 508 patients treated between 1968 and 1982 were divided into two groups: (1) 157 patients (66 in the category of limited-stage disease and 91 in the extensive-stage disease category) treated with low-dose small-volume radiotherapy (RT) (time dose fractionation (TDF] 49-66) and with cyclophosphamide alone or a COPP program during the first period of 7 years (1968-1974); (2) 351 patients (180 in limited and 171 in extensive stage) treated with multidrug chemotherapy (CT) and high-dose large-volume RT (TDF 73-89) during the second period of 8 years (1975-1982). For patients with limited-stage cancer, 5-year actuarial survivals were 3% versus 7% for the periods 1968-1974 versus 1975-1982, respectively, P < 0.01. For patients with extensive- stage cancer, the median survival time (MST) and 2-year actuarial survivals were 5 months and 2% versus 7 months and 4% for the periods 1968-1974 versus 1975-1982, respectively.

To evaluate the outcome of a contemporary approach, i.e., CT alone, with RT reserved for locoregional failure, 180 patients with limited-stage cancer who were treated (1975-1982) were further analyzed for MST, 2- and 5-year actuarial survival figures, and local-tumor control rates according to the therapeutic approaches employed CT + RT (112); CT alone (36); RT alone (17); and surgery (S) ? CT ? RT (15). Although the 36 patients in CT alone seems a small number, 17 of the 36 patients were enrolled in this approach in 1981-1982, reflecting a shift of emphasis from RT to CT. The MST and 2-year actuarial survival figures were 11 months and 0% versus 13 months and 21% for CT alone versus CT + RT respectively, P < 0.05. C T + RT achieved a 5-year cure rate of 8%. S * CT ? RT or RT alone also achieved 5-year cure rates of 8% and 10.5%, respectively, in selected subsets of patients. Local relapse rates were 80% (29/36) versus 25% (28/112) for CT alone versus CT + RT. These data emphasize the importance of thoracic RT given at the early phase of treatment to improve long-term survival for patients with limited-stage SCCL.

Cancer 59:6-14. 1987.

HE TREATMENT OF small cell carcinoma of the lung T (SCCL) is still a difficult problem, as indicated in recent publications. I*' The therapeutic approaches for limited-stage SCCL have evolved from thoracic radiotherapy (RT) alone to a combination of chemotherapy (CT) and thoracic RT. We have witnessed a significant improvement in the median survival time (MST) of patients with the limited stage of SCCL, from 5 to 6 months using thoracic RT alone to 10 to 14 months using CT

From *the Department of Radiation Medicine, .$Medical Services (Hematology-Oncology), 11 Surgical Services (Thoracic Surgery), Mas- sachusetts General Hospital Cancer Center and the Departments of tRa- diation Therapy, §Medicine, SSurgery, Harvard Medical School, Boston, Massachusetts.

Address for reprints: Noah C. Choi, MD, Department of Radiation Medicine, Massachusetts General Hospital Cancer Center, Boston, MA 021 14.

Accepted for publication July 10, 1986.

plus thoracic RT or CT a l ~ n e . ~ - ~ Even when SCCL has reached the extensive stage, a complete remission has been achieved in approximately 20% to 30% of patients, and survival for them can be expected to be similar to that for patients with the limited stage of the tumor. However, despite the earlier optimistic view based on short-term experiences with the current combination CT, reports on long-term survival of these patients have been parse.'^-'^

With the advent of more effective CT, the role of thoracic RT for the limited stage of SCCL has been a subject of debate, and CT alone, with thoracic RT reserved for cases of locoregional failure has become an acceptable a p p r o a ~ h . ~ ~ ' ~ , ~ ~ There have been a few ongoing prospective randomized trials in which patients with the limited stage of SCCL have been treated with either CT alone or a combination of CT and thoracic RT. According to the early results from these studies, thoracic RT seems to be an important component in achieving long-term survival

6

No. 1 SMALL CELL CARCINOMA OF THE LUNG - Choi et d. 7

for patients with the limited stage of the This study evaluates the results of the therapeutic advances achieved during the 15 years from 1968 through 1982 at a single large institution and reassesses the therapeutic strategies for the future.

Materials and Methods

To evaluate the therapeutic advances achieved over the 15 yearsbetween 1968 and 1982,508 of576 patientsseen during this period at the Massachusetts General Hospital were analyzed, with the exception of 37 patients referred elsewhere to be near their homes for further care and 3 1 patients untreated because of the poor general condition. The ages of these patients ranged from 22 to 91 years (median, 63 years); and the ratio of males to females was 2:l (Table 1). Diagnosis of SCCL was made by the same members of the Department of Pathology, with specimens obtained during bronchoscopy, mediastinoscopy, scalene- lymph-node biopsy, or exploratory thoracotomy. A combination of x-rays of the chest showing abnormality com- patible with bronchogenic carcinoma and two to three consecutive cytologic examinations of the sputum positive for small cell carcinoma was also considered sufficient to make a diagnosis of this tumor in 35 patients for whom further diagnostic procedures were judged inadvisable. For confirmation of the diagnoses made before patients were referred to this institution, all biopsy specimens were re- viewed thoroughly.

The patients’ general condition and the extent of tumor were carefully evaluated by detailed history and thorough physical examination with special attention to the sites and organs of frequent metastases. Radiographic studies for delineation of the extent of the primary lesion and the regional lymph nodes included posteroanterior and lateral views of the chest, and tomographic studies of the chest and mediastinum as a supplemental study whenever the x-rays of the chest were judged inadequate. Since 1979, computed tomography of the chest and the upper aspect of the abdomen has been added to the radiographic workup to help delineate the extent of the tumor at the primary site, the mediastinum, and the upper aspect of the abdomen, as well as to assist the planning of thoracic RT. Other work-up included radionuclide scans of the bone, liver and brain. However, computed tomography of the brain has replaced radionuclide brain scan since 1979. Needle aspirations and biopsies of the posterior iliac crest for bone-marrow studies, as well as laboratory evaluation of liver chemistry, serum electrolytes, and blood counts were also included in the initial study. Patients were clas- sified in either the limited or extensive stage, according to the outcome of the workup. The limited stage was defined as disease limited to one lung or the mediastinum excluding malignant pleural or pericardial effusion. Met-

TABLE 1. Small Cell Carcinoma of the Lung; A Progress Report of a 15-Year Period at MGH

1968- I974 1975- 1982

No. patients treated (508) I57 35 1 Tumor stages

Limited stage (246) 66 180 Extensive stage (262) 91 171

Median age (yr) Sex ratio (M:F) 2.3: 1 1.9: 1

61 (22-88) 64 (27-9 1 )

M: male; F: female; MGH: Massachusetts General Hospital.

astatic involvement of the ipsilateral supraclavicular lymph nodes was also considered to be limited disease. The extensive stage was defined as evidence of spread of the tumor beyond the boundary of the one lung, mediastinum, and ipsilateral supraclavicular lymph nodes.

To reflect the advances made by the current therapeutic approaches, the 508 patients were divided into two groups. One hundred and fifty-seven patients (66 with limited and 91 with extensive stages) were treated by the earlier therapeutic approaches consisting of small-volume ( 15 X 10 cm2), low-dose (3000-4000 cGy, TDF 49-66) thoracic RT and CT by means of cyclophosphamide alone ( 1968- 197 1 ) and COPP ( 1972- 1974) during the first period of 7 years ( 1968- l 974)4; and 35 l patients ( 180 with limited and 17 1 with extensive stages) were treated during the second period of 8 years (1975-1982) by multiagent CT (COP, CAV, CCV-AV, MACC, VCE-VCA) and large-volume (22 X 16 cm2), high-dose (4400-5400 cGy, TDF 73-89) thoracic RT (Tables 2 and 3).

The 7-year period from 1968 to 1974 was a develop- mental stage of effective treatments for this tumor. Ther- apeutic approaches employed for patients with limited- stage SCCL during the first 7 years included combined CT and thoracic RT in 43 patients, thoracic RT alone in 17 patients, and surgery (S) followed by CT or thoracic RT or both in six patients. The short-term results of these early therapeutic approaches have previously been re- p ~ r t e d . ~ The second period, the 8 years from 1975 to 1982, represents a progressive stage of an active exploration for more effective multiagent CT and improved thoracic RT. Whereas COP and CAV were the main forms of multiagent CT from 1975 to 1977, CCV-AV and MACC were introduced to replace COP in 1977, and VCE-VCA was added to the existing program in 1980.

The performance status of patients who were treated during the two study periods was very similar. Patients with a Karnofsky performance status score of 70% or greater accounted for 75% of patients with limited stage SCCL (1975-1982) and the remaining 25% of patients had Karnofsky performance status score of 60% or lesser. A similar distribution of patients according to perfor-

8 CANCER January 1 1987 VOI. 59

TABLE 2. Progress in Therapeutic Factors

Study ueriods 1968- 1974 1975- I982

Radiotherapy Energy (photon) Portal arrangements AP-PA POP AP-PA POP plus AP-RPO-LPO (3 fields) Field sizes (average)

2 MeV Van de Graaff generator

15 X 10 cm2 with simple comer blocks

10 MeV Clinac 18

22 X 16 cm2 for AP-PA POP; 22 X 9 cm2 for RPO-LPO; individually tailored shaped blocks

Radiation dose (cGy) 3000-4000 (TDF 49-66) 4400-5400 (TDF 73-89)

Chemotherapy Single agent; early multiagent combination More advanced multiagent combination programs program (COPP)

AP-PA: anteroposterior-posteroanterior; POP parallel opposing portals; TDF time, dose, and fractionation factor; COPP: cyclophosphamide,

mance status was noted in the first 7-year period (1968- 1974). There was a slight change of sex ratio from 2.3: 1 (males to females) for the first 7-year period ( 1968- 1974) to 1.9: 1 (males to females) for the second 8-year period

The therapeutic approaches employed for 180 patients with limited-stage of SCCL treated during the period 1975- 1982 included the combination of CT and thoracic RT in 1 12 patients; CT alone, with thoracic RT reserved for locoregional failure in 36 patients; thoracic RT alone

(1975-1982).

TABLE 3. Chemotherapeutic Regimens Employed in Small Cell Carcinoma (1975-1982)

COP: 28-day cycle (C) cyclophosphamide 500-650 mg/mz, IV day 1 & 7, not to

(0) vincristine (Oncovin) 1.4 mg/m2, IV day 1 & 7; not to exceed

(P) procarbazine 100 mg/m2 for 10 days; maximum daily dose,

exceed 1 g total dose

2 mg

150 mg

CAV: 2 I -day cycle

2000 rng

dose, 365 mg/m2

(C) cyclophosphamide 1000 mg/m2, IV day 1; maximum dose,

(A) Adriamycin (doxorubicin) 40 mg/m2, IV day 1; maximum

(V) vincristine 1 mg/m2, IV; maximum dose, 2 mg day 1

CCV-AV 2 I -day cycle; alternate CCV & AV every 2 1 days (C) cyclophosphamide 700 mg/m2, IV day 1 (C) CCNU 70 mg/m2, day 1; not to exceed 450 mg/m2 (V) vincristine 1.0 mg/m2, IV day 1; not to exceed 2 mg day 1 (A) Adriamycin 50 mg/m2, IV day 1; not to exceed 300 mg/m2

total

MACC: 2 I-day cycle (M) methotrexate 30 mg/m2, IV day 1 (A) Adriamycin 35 mg/m2, IV day 1; maximum dose, 365 mg/m2 (C) CCNU 30 mg/m2 orally day 1 (C) cyclophosphamide 400 mg/m2 IV day 1

then alternates VCA with VCE every other cycle to maximum A dose of 350 mg/m2 (V) vincristine 1.4 mg/m2, IV day 1; not to exceed 2 mg per single

dose. (C) cyclophosphamide 1000 mg/m2 IV day 1 (E) Etoposide (VP-16) 80 mg/m2, infusion over 30-60 min daily (A) Adriamycin 50 mg/m2, IV day 1.

I V intravenously.

VCE-VCA: Note patient receives 6 VCE cycles at 21-day interval,

vincristine, procarbazine, and prednisone.

in 17 patients; and S f CT or thoracic RT or both in 15 patients. Although the number of patients treated with CT alone, according to either the patient’s wishes or the individual physician’s preference, was 36. Seventeen of these 36 patients (48%) were treated during the period 198 1- 1982; this number was equal to the number treated by the combination of CT + thoracic RT during the same period, reflecting a shift of emphasis from the combination of CT + thoracic RT to CT alone. No selection was in- volved in treating the 36 patients by CT alone. Their ages ranged from 44 to 91 years (median, 64 years); the ratio of males to females was 3.5: 1. The performance status of the group treated by CT alone was greater than or equal to 70 on the Karnofsky scale in 3 1 of 36 patients, and 60 on the Karnofsky scale for the remaining five patients. The functional status of CT + thoracic RT group (1 12 patients) was similar to that of CT alone group. For patients with extensive-stage SCCL, CT was the primary form of treatment, and RT was employed for relief of symptoms.

The thoracic RT program had also been expanded from the previous conservative small field ( I 5 X 10 cm2) low- dose (3000-4000 cGy, TDF 49-66) RT delivered by a 2- MeV Van de Graaff generator ( 1968- 1974) to the current large-field (22 X 16 cm2) high-dose (4400-5400 cGy, TDF 73-89) RT by 10-MeV photon ofClinac-18 (1975-1982). Radiotherapeutic technique for thoracic RT has been rel- atively uniform since 1978, and details of this have been described elsewhere. Individually tailored shaped blocks have been used to protect the uninvolved normal tissue in the chest. For patients with a steep slope of the chest, i.e., when the anteroposterior thickness between the central axis at the mid-chest and the suprasternal notch was greater than 3 cm, an anteroposterior compensator individually designed was also employed to achieve a ho- mogeneous dose distribution throughout the treatment volume.

Elective cranial irradiation (ECI) was given to 33% of patients with limited-stage SCCL ( 1975- 1982) as part of a comprehensive treatment program. The entire cranial contents were treated to a total dose of 3000 cGy in 10

No. 1 SMALL CELL CARCINOMA OF THE LUNG * Choi et d.

'U ......... 0 ......... 0 ......... 0 ......... 0 ......... 0

9

to 12 fractions over a period of 2 to 2.4 weeks by parallel- opposing right and left lateral portals. For patients with extensive-stage SCCL, ECI was reserved for those who achieved a complete response.

All patients were followed every 2 to 4 months by one of our group, and dates and sites of failures were docu- mented with appropriate studies. Restaging procediires included previously described radiographic studies, radionuclide scans, computed tomography of the brain and chest, and liver chemistry studies. Bronchoscopy and biopsy were not performed as a routine restaging procedure. Data from autopsy studies were also available for this analysis in 36 patients. Complete response (CR) was defined as complete disappearance of all measurable disease, signs, symptoms, and biochemical changes related to the tumor for more than 4 weeks without the appearance of any new lesions. Partial response (PR) was defined as a 50% or greater reduction in the sum of the products of the perpendicular diameters of all measurable lesions lasting more than 4 weeks.

Statistical Methods

Statistical methods used in this analysis included the life-table method for actuarial survival data and the Man- tel test for the comparison of survival data for the different stages of the tumor according to the different treatment methods. I 9 s 2 O

Results

The minimum follow-up of this study was 2 years, and the survival data were measured from the onset of treatments. A few patients lost to follow-up were considered dead after the time of their last visits.

To evaluate the recent advances in multiagent CT, and CT + thoracic RT, patients treated during the two different periods were compared for their MST and long- term survival. These two groups of patients were comparable with respect to the age, sex, and performance status. For patients with limited-stage SCCL, the 5-year actuarial survival data show improvement from the 3% of the earlier period of 1968- 1974 to the 7% for the recent period of 1975-1982, P < 0.01 (Fig. 1 and 2). The improvement of survival in terms of MST between the two groups was, however, small: 10 months versus 13 months for the periods 1968- 1974 versus 1975- 1982, respectively (Table 4). For patients with extensive-stage SCCL, MST and 2-year actuarial survival rates were 5 months and 2% versus 7 months and 4% for the periods 1968- 1974 versus 1975- 1982, respectively; P > 0.1 (Fig. 3). No patient with extensive-stage SCCL survived beyond 3.5 years.

The stage of cancer and the performance status of patients are known prognostic factors for SCCL. In order to know whether sex is a significant prognostic factor or

0-0 1975 - 1982 (n 180)

o...... 1968 - 1974 ( n= 66)

D<oo1

SURVIVAL fMonths)

FIG. 1. Survival curves for limited-stage small cell carcinoma of the lung. The actuarial method was used, and the minimum follow-up was 2 years.

not, the survival data of patients treated in the recent 8- year period (1975-1982) were further analyzed. Among 180 patients with limited-stage SCCL, there were 105 males and 75 females. The MST were 12 months and 13 months for males and females, respectively. The 2-, 2.5, and 3-year actuarial survival data were 14.7%, lo%, and

*-a LIMITED ( n = 180) 0 ....... 0 EXTENSIVE (n= 171 1

D < 0001

0 12 24 36 48 60

SURVIVAL /Months I

FIG. 2. Survival curves for small cell carcinoma of the lung, 1975- 1982. The actuarial method was used, and the minimum follow-up was 2 years.

10 CANCER January 1 1987 Vol. 59

TABLE 4. Small Cell Carcinoma of the Lung: Survival Data Over a 15-Year Period at MGH

Limited stage Extensive stage

1968-1974 1975-1982 1968-1974 1975-1982 Survival (66 patients) (180 patients) (9 1 patients) (1 7 I patients)

24 mo 9% 19% 2% 4% 36 mo 3% 9% 0% 1 % 60 mo 3% 7% 0% 0% MST 10 mo 13 mo. 5 mo 7 mo

MST: median survival time; MGH: Massachusetts General Hospital.

7.3% versus 23.8%, 13.2%, and 10.5% for males versus females. Among 17 1 patients with extensive-stage SCCL, there were 11 1 males and 60 females. The MST were 6 months for both males and females. The 12- and 18- month actuarial survival data were 15% and 9% versus 23% and 6% for males versus females.

To assess the outcome of the new evolving concept (CT alone with thoracic RT reserved for locoregional failure for patients with limited-stage SCCL), 36 patients treated with this approach during the period 1975-1982 were compared with 1 12 patients treated for the same stage of SCCL in the same time period by the combination of CT + thoracic RT. The MST, the 2-, 3-, and 5-year actuarial survival data, and the control rates for locoregional tumor were evaluated. The two groups were comparable with regard to demographic data and functional status, as de-

o--o 1975 - 1982 ( n = 171 1 0-0 1968- 1974 (n = 91 1

I I I 0 12 24 36 48 60

SURVIVAL (Months)

FIG. 3. Survival curves for extensive-stage small cell carcinoma of the lung. The actuarial method was used, and the minimum follow-up was 2 years.

scribed earlier. The MST were 13 months versus 11 months for CT + thoracic RT versus CT alone respectively. Two-, 3-, and 5-year actuarial survival data were, however, quite different: 21%, 1 1%, and 8% versus 0%, 0%, and 0% for CT + thoracic RT versus CT alone (Fig. 4; Table 5) .

Persistent or recurrent locoregional tumor might have adversely affected the outcome of the treatments. Persis- tent or recurrent locoregional tumor was noted in 29 of 36 patients (80%) treated by CT alone, and in 28 of 112 patients (25%) treated by the combination of CT + thoracic RT (Table 5). Salvage thoracic RT using a median radiation dose of 5000 cGy (TDF 82), with a range of 3000 to 6000 cGy (TDF 49-99), achieved control of local tumor in 9 of 20 patients (45%) without improving the long-term survival when applied to recurrent or persistent SCCL after CT alone.

Twenty-one patients treated initially by surgery during the 15-year period included six patients during the first period (1968-1 974) and 15 patients during the second period ( 1975- 1982), respectively. Patients with peripheral small lesions or central lesions in whom biopsies revealed undetermined histologic types of lung cancer were sub- jected to exploratory thoracotomy and resection. Curative resections included lobectomy in 14 and pneumonectomy in seven patients. Adjuvant treatments employed after surgery were as follows: thoracic RT alone in five patients; thoracic RT plus CT in four patients; CT plus ECI in five patients; CT alone in one patient; and no postoperative adjuvant treatment in six patients. The MST of these 21 patients was 12 months. The long-term survivors among these 21 patients were: one patient, 3.5 years; one patient, 5 years; and one patient, 2.5 years without recurrence. Regional lymph node involvement was noted in nine patients: seven with hilar lymph node involvement (Stage N 1 ), and two with mediastinal lymph node involvement (Stage N2). Regional recurrence was noted in three of seven patients with stage Nl disease; these three and one other did not receive postoperative RT. None of three patients who received postoperative RT for stage N 1 disease had local recurrence. Two patients who received CT after surgery for stage Nl disease had local recurrence. Two patients with stage N2 disease could not be evaluated for local recurrence because of their early death.

Thoracic RT alone was employed during the second period ( 1975-1 982) for limited-stage SCCL in 17 patients because of the following reasons: advanced age in nine patients, poor general condition for CT in six patients, and refusal to accept CT in two patients. The MST for this group of patients was 1.5 years, and 2 of 17 patients, both over 73 years of age, had survived for 5 years and 7 years, respectively.

The brain remains a major site of recurrence without ECI. In the second period (1975-1982), the recurrence

No. 1 SMALL CELL CARCINOMA OF THE LUNG - Choi et a/. 11

TABLE 5. Survival Results after Different Therapies for Limited- Stage Small Cell Carcinoma of the Lung (1975-1982)

Therapeutic methods

5 U"( i

i\ d 0--. CT+RT (n=112)

0 ........ 0 CTolone (n=36)

CT+RT CT RT Surg Survival (112)* (36) (17) (15)

B p < 0 0 5

......... I 'al 1 1 -- L

1 , , 0

0 12 24 36 48 60

SURVIVAL fh4onth.s)

FIG. 4. Survival curves for limited-stage small cell carcinoma of the lung, 1975-1982. The actuarial method was used, and the minimum follow-up was 2 years. CT: multidrug chemotherapy; R T radiotherapy.

rate in the brain in patients with limited-stage SCCL was 22% (25/114) without ECI, and it was 6.7% (4/59) with ECI. When the probability of recurrence in the brain was measured by the life-table method to take into account the duration of survival and the relative-risk period for recurrence in the brain, it was 49% without ECI versus 17% with ECI, P < 0.01 (Fig. 5) . Subsequent recurrence in the brain after the onset of CT + thoracic RT or CT alone was also associated with poor outcome. The MST of patients treated with cranial RT for the subsequent recurrence in the brain was 3 months (0-13 months), compared with the 8 months of those patients who had brain metastasis at the time of diagnosis. Other common sites of recurrences included liver (32%) and bone (30%).

Treatment programs employed during the 15-year pe- nod were associated with moderate toxicities. Compli- cations observed during the first period (1968-1 974) have previously been reported4; and toxicities associated with the second treatment programs (1975- 1982) are described here. All patients experienced a moderate to severe degree of myelosuppression by CT + thoracic RT or the CT alone program. Severe pneumonia was observed in three patients, and this led to death in one patient. Pericarditis was noted in three patients: two patients (CT + thoracic RT) developed moderate pericardial tamponade that was controlled with pericardiocentesis; the third, who developed constrictive pericarditis 7 years after onset of treatments (CT + thoracic RT), died with congestive heart failure after pericardiectomy. Congestive heart failure secondary to cardiomyopathy was observed in two pa-

24 mo 36 mo 60 mo MST

21% 0% 37% 17% 1 1 % 0% 1 1 % 8% 890 0% 10.5% 8%

13mo l l m o 17mo 12mo

Local tumor recurrence rate 25% 80% 20% 20%

CT: multidrug chemotherapy; RT: radiotherapy; Surg: surgery includes

* Numbers in parentheses = number of patients. lobectomy and pneumonectomy; MST: median survival time.

tients who received both thoracic RT and CT including Adriamycin (doxorubicin) (total dose, 450 mg/M2). Moderate to severe radiation pneumonitis was observed in three patients, and contributed to the death of one. Most patients experienced mild to moderate esophagitis during thoracic RT + CT, which was managed well with lidocaine M and antacid preparations. However, severe esophagitis developed in four patients; intravenous hy- dration was given to three of them with good recovery; and a feeding gastrostomy was performed for the fourth patient. Neurotoxicities, i. e., ataxia, memory loss, and decreased intellectual function, were observed in 2 of 31 patients during the second period (1975-1982) who survived 2 years or more after treatments; this represents 20% (2/ 10) of those who received CT + thoracic RT and ECI.

0 WITHOUT ECI fn=114) 0 WITH ECI ( n = 59)

p <0.01

" 6 12 18 24 30 36 42

MONTHS FIG. 5. Limited-stage small cell carcinoma of the lung: the actuarial

method was employed to measure the probability of failure in the brain. ECI: elective cranial irradiation.


Discussion

The main strength that makes our data different from data of others is a long-term follow-up of a large number of patients by one oncology group at a single large institution."-I3 The remarkable initial tumor response rate of 60% to 80%, reported in the literature, a dramatic achievement by current multiagent CT + thoracic RT or CT alone for limited-stage SCCL, has yet to be reflected in long-term survival beyond 2 year.^.^*^-^ Our study showed a gain, albeit modest, by the current treatment program (1 975- 1982) over the previous treatments ( 1968- 1974) (Table 4): MST, 2-year, and 5-year survivals have improved from 10 months, 9%, and 3% in the first 7 years (1968-1974) to 13 months, 19'70, and 7% of the second period (1975- 1982). There was a steady decline of survival even after 2 years, owing to late recurrence, second primary tumor, and treatment-related causes. Patients treated with CT + thoracic RT for limited-stage SCCL (1975-1982) showed a 21% survival rate at 2 years, and there was a further decline of this survival rate to 8% by the end of the fifth year (Table 5).

Therapeutic gain for extensive-stage SCCL during the second period (1975-1982) over the first period (1968- 1974) was also modest. However, long-term survival is still rare, and only one patient survived to 3.5 years in the recent 8-year study period (1975-1982).

Maurer et al. reported that female patients with limited- stage SCCL had a greater chance of achieving a complete remission independent of performance status than male patients and female sex might be an important prognostic factor.6 Indeed, this study showed a trend of better survival for female patients of up to 2 years. However, the differ- ence of survival between male and female patients dis- appeared thereafter.

The diagnosis of some patients might have been changed from the limited to the extensive stage of SCCL as a result of new diagnostic techniques introduced since 1979, i.e., computed tomography of the chest and upper aspect of the abdomen and computed tomography of the head instead of radionuclide brain scan. However, stage migration had taken place only during the last 3 years of the second study period (1975-1982), and its favorable impact on the survival of the patients (1 975- 1982) is likely very small. The fact that there was an improved survival for both stages without net gain in overall survival is a reasonable indication for the absence of stage drift over time from more staging procedures (Figs. 1 and 3)."

CT alone, with thoracic RT reserved for locoregional failure, has been advocated as a therapeutic choice for limited-stage SCCL.'' The data of this study do not sup- port such a concept. Although both approaches were equally effective up to MST, i.e., 13 months by CT + thoracic RT versus 11 months by CT alone, the results after

CT alone were not as good as those after CT + thoracic RT for long-term survival at 2 years and thereafter. There was no long-term survivor in the group who received CT alone. Clear data for this controversial issue will soon be available as a few ongoing randomized trials designed to answer this question will be c~nc luded . '~ , ' ~ A local-failure rate of 80% by CT alone is very alarming, and persistent or recurrent local tumor would certainly affect the outcome of treatment adversely.22

Surgery followed by CT and ECI seems a reasonable treatment for peripheral tumors without metastases to either hilar or mediastinal lymph However, postoperative RT to the ipsilateral hilum and mediastinum might be a valuable adjuvant treatment in addition to CT for surgically treated stage N 1-2 SCCL.

A reasonable inverse relation can be found between radiation dose and local-tumor failure rate in SCCL according to the reports in l i t e r a t ~ r e . ~ . ~ ~ This study achieved a local-tumor control rate of 75% by a combination of CT and thoracic RT (4500-5400 cGy). Every effort should be made to combine CT and thoracic RT to achieve the highest possible CR rate for limited-stage SCCL for the following two reasons: (1) lasting CR is the first step for long-term survival; and (2) currently used CT alone is associated with a high local recurrence rate. Persistent or recurrent SCCL after CT has been associated with a poor response to salvage RT or CT.26-29 This is another reason why thoracic RT should be combined with CT at the early phase of the treatment. Recent in vitro studies of the bi- ology of SCCL demonstrated that chemotherapy-resistant cells might have the characteristics of a radiation-resistant- cell survival curve, i.e., pronounced shoulders and large extrapolation numbers ranging from 5.6 to 14.30

ECI seems an important component of a comprehensive treatment program for limited-stage SCCL for the following reasons: ( 1) the probability of the development of overt metastases in the brain during the course of disease was found to be as high as 49% by the life-table method in this study; and (2) radiotherapy for overt metastases in the brain has been ineffective in achieving a long-term contr01.~'-~~ The assessment of the risk for metastases to the brain by the life-table method takes into account the duration of exposure to the risks, and the 49% rate of brain metastases is close to actual autopsy data.34 ECI is likely to show survival advantage as well as improved quality of life when it is employed for patients who achieved CR, even though routine use of ECI has shown no survival a d ~ a n t a g e . ~ ~ - ~ ~ The currently used RT program for ECI along with multiagent CT has been associated with significant late neurotoxicitie~.~' Ten of 3 1 patients who survived 2 years or more (1975-1982) had received ECI, and two of ten patients showed significant neurotoxicities. This high incidence of neurotoxicities should be reduced by employing a total radiation dose

No. 1 SMALL CELL CARCINOMA O F THE LUNG - Choi el al. 13

and fraction sizes smaller than the currently used program of 3000 cGy in 10 fractions over a period of 2 weeks and also by omitting or reducing the dosage of neurotoxic drugs, i.e., procarbazine, lomustine, and high doses of methotrexate from the multiagent CT pr~gram.~’

The recent slowdown in achieving better survival by multiagent CT regimens has been attributed to the development of tumor cell clones resistant to drugs and, possibly, to radiation, accounting for over 90% of the treatment failure^.^' Attempts made to date to overcome this problem in current oncology include the alternating of schedules of non-cross resistant CT regimen^,^,^^-^* the sequencing of drugs and radiation>34s high-dose CT and autologous bone marrow tran~plantation,~~ and systemic hemibody irradiation.4749 However, the results from these studies have been mixed. Until a new breakthrough is found in systemic approaches, patients with SCCL will continue to be served best by judicious use of CT and RT.S0,5’

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Small cell carcinoma of the lung. A progress report of 15 years' experience