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Keywords:

  • limited-stage small cell lung carcinoma;
  • combined-modality therapy;
  • age;
  • elderly;
  • radiotherapy;
  • chemotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

A Phase III trial was conducted by the North Central Cancer Treatment Group to determine whether chemotherapy (etoposide and cisplatin) plus either twice-daily radiotherapy (BIDRT) or once-daily radiotherapy (QDRT) resulted in a better outcome for patients with limited-stage small cell lung carcinoma (LD-SCLC). No difference in survival was identified between the two arms. The current analysis examined the relation between age and outcome for patients treated during this trial.

METHODS

The current study included 263 patients with LD-SCLC and an Eastern Cooperative Oncology Group performance status of ≤ 2 who were randomized to receive QDRT or split-course BIDRT. The outcomes of the 209 (79%) younger patients (age < 70 years old) were compared with the 54 (21%) elderly patients (age ≥ 70 years old).

RESULTS

Elderly patients presented with significantly greater weight loss and poorer performance status. The 2-year and 5-year survival rates were 48% and 22% for younger patients compared with 33% and 17% for older patients (P = 0.14). One specific toxicity (i.e., Grade ≥ 4 pneumonitis [according to National Cancer Institute Common Toxicity Criteria]) occurred in 0% of those patients age < 70 years compared with 6% of older patients (P = 0.008). Grade 5 toxicity occurred in 1 of 209 (0.5%) patients age < 70 years compared with 3 of 54 (5.6%) older patients (P = 0.03).

CONCLUSIONS

Despite having more weight loss, poorer performance status, increased pulmonary toxicity, and more deaths due to treatment, survival was not found to be significantly worse in older individuals. Fit elderly patients with LD-SCLC can receive combined-modality therapy with the expectation of relatively favorable long-term survival. Future research should focus on ways to decrease toxicity especially in the elderly. Cancer 2005. © 2005 American Cancer Society.

During 2004, lung carcinoma was diagnosed in an estimated 173,770 patients and caused an estimated 169,440 deaths in the U.S.1 Approximately 20% of patients with lung carcinoma have small cell lung carcinoma (SCLC) and of these, 30% have limited-stage disease (LD-SCLC).2 The median age of patients diagnosed with lung carcinoma is 70 years.3 Because one-half of the patients are ≥ 70 years, it is important to understand the effects of modern combined-modality therapy in the elderly.

SCLC is a rapidly proliferating tumor that is responsive to chemotherapy. Radiotherapy (RT) also has a central role in the treatment of patients with LD-SCLC. In 1992, 2 metaanalyses were published regarding the role of thoracic RT in addition to chemotherapy.2, 4 They were based on randomized prospective studies that compared chemotherapy alone with chemotherapy plus thoracic RT. Both reported a significant (5.4%) increase in survival associated with the use of thoracic RT. In addition, prophylactic cranial irradiation (PCI) has been shown to positively influence survival in patients who achieve a complete response (CR). Auperin et al.5 published a metaanalysis that included data from seven randomized prospective studies comparing PCI with no PCI after a CR was achieved. The 3-year survival rate was 5.4% greater for those who received PCI (P = 0.01). These studies emphasize the importance of combined-modality therapy in treating LD-SCLC.

Mayo Clinic investigators performed a pilot study for patients with LD-SCLC which included etoposide and cisplatin (EP) for a total of six cycles.6 During Cycles 4 and 5, split-course, twice-a-day RT (BIDRT) was administered, which included the delivery of 24 gray (Gy) in 16 fractions followed by a 2.5-week break and an additional 24 Gy in 16 fractions. A treatment break was included to lessen the severe esophagitis anticipated with a program that included 1.5 Gy twice per day and concurrent radiosensitizing chemotherapy. They reported a median survival of 26 months and a 2-year survival rate of 55%. These results appeared to be promising, and consequently a Phase III trial was launched by the North Central Cancer Treatment Group (NCCTG) to compare EP plus either once-daily RT (QDRT) or split-course BIDRT. When compared with QDRT, the split-course BIDRT approach offered no advantage with regard to survival, disease control, or toxicity.7, 8

The current study examined the relation between age and outcome in patients treated during this Phase III trial. The goal was to determine whether elderly patients did worse than their younger counterparts in terms of tolerance, disease control, and survival after combined-modality therapy. The current study addresses the toxicity and survival concerns that limit enthusiasm for offering aggressive potentially curative therapy to older patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The following studies were performed before treatment: history and physical examination, complete blood cell count (CBC), serum chemistry levels (bilirubin, aspartate aminotransferase, alkaline phosphatase, creatinine, calcium), computed tomography scans of the head, chest, and upper abdomen, pulmonary function tests, bone scan, and bone marrow biopsy. Patients participating in this study met the following eligibility criteria: pathologic confirmation of SCLC, limited-stage disease, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and adequate organ function.7, 8 Limited disease was defined as SCLC limited to a hemithorax, the ipsilateral supraclavicular fossa, and was encompassed within a reasonable RT field. There were no age restrictions for participation.

The current study was reviewed and approved by each participating institution's institutional review board. The experimental nature of the study was explained and informed consent was obtained from each patient before treatment.

All patients received six cycles of EP. Each cycle lasted 3 days and was separated by 28 days. Each day of chemotherapy was comprised of 30 mg/m2 of cisplatin given intravenously (i.v.) over 30–60 minutes followed by 130 mg/m2 of etoposide given i.v. over 45 minutes. The etoposide dose was reduced to 100 mg/m2 for Cycles 4–6. Chemotherapy doses were modified based on renal, hematologic, or neurologic toxicity.7, 8

After the initial three cycles of EP, all patients were restaged and patients were randomized to receive QDRT or BIDRT if they met the following requirements: thoracic disease encompassed within reasonable RT ports, ECOG performance status ≤ 2, and no distant metastases other than brain metastases.

Thoracic RT was delivered with 4–10 megavolt X-rays using custom blocks. QDRT included the delivery of 50.4 Gy in 28 fractions delivered on weekdays. The initial 39.6 Gy was delivered with anterioposterior/posteroanterior (AP/PA) fields. The final 10.8 Gy was delivered with oblique fields that excluded the spinal cord. The EP regimen was continued during RT for Cycles 4–5 and began on the first day of RT. BIDRT included the delivery of 48 Gy in 32 fractions. After the initial 24 Gy, RT was held for 2.5 weeks and subsequently resumed 28 days after beginning RT to coincide with the 5th cycle of EP. AP/PA fields were used for the first 33 Gy followed by oblique fields, which excluded the spinal cord for the last 15 Gy. The spinal cord was limited to a maximum dose of 37 Gy with BIDRT and 45 Gy with QDRT. RT was administered to postchemotherapy volumes including the primary tumor, ipsilateral hilar, mediastinal, and supraclavicular volumes.

After the thoracic RT, the sixth cycle of EP was given, followed by restaging. PCI (30 Gy in 15 fractions) was administered to all patients having a CR.

Follow-up was performed at 4-month intervals for the first year and at 6-month intervals thereafter. These evaluations included a history and physical examination, chemistry panel, CBC, and chest X-rays.

Patients were divided into 2 groups: elderly patients (age ≥ 70 years) versus younger patients (age < 70 years). There were no significant differences in outcome based on treatment arm (BIDRT vs. QDRT);, therefore the two treatment arms were combined in each age group for the current analysis. The survival and disease recurrence rates were calculated using the Kaplan–Meier method and differences between these rates were calculated using the log-rank test.9, 10 Only the 263 randomized patients who received chemotherapy plus thoracic RT were included because the intent was to evaluate patients who received combined-modality therapy. The incidence and severity of hematologic, nonhematologic, and overall toxicity was determined using the National Cancer Institute Common Toxicity Criteria (version 1). The incidences of Grade ≥ 3 and Grade ≥ 4 toxicity were compared across groups using the chi-square test or the Fisher exact test when appropriate. Statistical significance was declared at P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

The trial was open for accrual from September 1990 to November 1996. Of the 324 patients enrolled, 14 patients were ineligible, leaving 310 evaluable patients. After the first 3 cycles of EP, randomization to EP and QDRT or EP and BIDRT was performed in the 263 patients who met the previously described requirements. These 263 patients were evaluated. They had a median age of 63 years (range, 37–81 years). PCI was administered to the 154 patients that achieved a CR. The two age groups were balanced regarding initial characteristics except that performance score and weight loss were significantly worse in the elderly patients (Table 1). The median follow-up period for survivors was 8.1 years (range, 4.6–11.9 years). Of the 263 patients, 209 (79%) were age < 70 years and 54 (21%) were age ≥ 70 years (elderly patients).

Table 1. Patient Characteristics by Age Group
CharacteristicsAge < 70 yrs (n = 209) (%)Age ≥ 70 yrs (n = 54) (%)Total (n = 263) (%)P value
  • QDRT: once-daily radiotherapy; BIDRT: twice-daily radiotherapy.

  • a

    P value determined using the Fisher exact test.

Median age (yrs) (range)61.0 (37.0–69.0)73.0 (70.0–81.0)63.0 (37.0–81.0) 
Gender   0.54
 Female91 (43.5)21 (38.9)112 (42.6) 
 Male118 (56.5)33 (61.1)151 (57.4) 
Arm   0.19
 QDRT110 (52.6)23 (42.6)133 (50.6) 
 BIDRT99 (47.4)31 (57.4)130 (49.4) 
Performance score   0.007
 0–1201 (96.2)46 (85.2)247 (93.9) 
 28 (3.8)8 (14.8)16 (6.1) 
Weight loss since registration   0.01a
 ≤5191 (91.4)42 (77.8)233 (88.6) 
 5–1017 (8.1)11 (20.4)28 (10.6) 
 ≥101 (0.5)1 (1.9)2 (0.8) 
Response to chemotherapy   0.32a
 Better than stable disease196 (93.8)51 (94.4)247 (93.9) 
 Stable11 (5.3)2 (3.7)13 (4.9) 
 Local progression2 (1)0 (0)2 (0.8) 
 Brain metastasis0 (0)1 (1.9)1 (0.4) 
Race   1.0
 Other13 (6.2)3 (5.6)16 (6.1) 
 White196 (93.8)51 (94.4)247 (93.9) 

Tumor Control and Patient Survival

There was no significant difference in tumor progression rates based on patient age. The 2-year and 5-year freedom-from-disease progression rates were 32% and 21%, respectively, in patients age < 70 years compared with 30% and 17% in elderly patients (P = 0.19). The 2-year and 5-year distant disease recurrence rates were, respectively, 32% and 35% in patients age < 70 years compared with 39% and 44% in elderly patients (P = 0.14). Local control was not found to be influenced by patient age (P = 0.10) (Fig. 1). There was no significant difference noted in survival based on patient age. The 2-year and 5-year survival rates were 48% and 22%, respectively, in patients age < 70 years compared with 33% and 17% in elderly patients (P = 0.14) (Fig. 2).

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Figure 1. Incidence of local disease recurrence by age group (age < 70 vs. age ≥ 70 years) (P = 0.101).

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Figure 2. Overall survival by age group (age < 70 vs. age ≥ 70 years) (P = 0.139).

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Toxicity

The occurrence of overall, hematologic, and nonhematologic toxicity was compared between the treatment arms, and no significant differences were found. Therefore, the following analyses use toxicity data pooled across the treatment arms (BIDRT vs. QDRT).

The most common Grade ≥ 3 nonhematologic toxicity was nausea followed by emesis, esophagitis, and pneumonitis (Table 2). The most common Grade ≥ 3 hematologic toxicity was leukopenia followed by thrombocytopenia and anemia. The overall occurrence of severe toxicity (including both hematologic and nonhematologic toxicity) was examined by age group. The overall rates of Grade ≥ 3 or Grade ≥ 4 toxicity were not greater in elderly patients. Grade ≥ 3 toxicity occurred in 91% of patients age < 70 years compared with 94% of elderly patients (P = 0.58). Grade ≥ 4 toxicity occurred in 46% of patients age < 70 years compared to 50% of elderly patients (P = 0.65).

Table 2. Toxicity for Patients Treated with EP + Either BID-RT or QD-RT Based on Age Groupa
CharacteristicsAge < 70 (yrs) (n = 209) (%)Age ≥ 70 (yrs) (n = 54) (%)P value
  • EP: etoposide and cisplatin; BIDRT: twice-daily radiotherapy; QDRT: once- daily radiotherapy.

  • a

    Toxicity was determined according to version 1 of the National Cancer Institute Common Toxicity Criteria.

Grade ≥ 3 toxicity   
 All toxicity190 (90.9)51 (94.4)0.58
 Hematologic toxicity186 (89)49 (90.7)0.81
  Leukopenia179 (85.6)48 (88.9)0.66
  Thrombocytopenia111 (53.1)25 (46.3)0.45
  Anemia13 (6.2)6 (11.1)0.24
 Non-hematologic toxicity95 (45.5)28 (51.9)0.45
  Nausea37 (17.7)7 (13)0.54
  Emesis30 (14.4)5 (9.3)0.38
  Esophagitis20 (9.6)3 (5.6)0.43
  Pneumonitis11 (5.3)3 (5.6)1.0
  Renal3 (1.4)0 (0)1.0
Grade ≥ 4 toxicity   
 All toxicity96 (45.9)27 (50)0.65
 Hematologic toxicity86 (41.1)27 (50)0.28
  Leukopenia71 (34)23 (42.6)0.27
  Thrombocytopenia43 (20.6)14 (25.9)0.46
  Anemia0 (0)1 (1.9)0.21
 Non-hematologic toxicity24 (11.5)6 (11.1)1.0
  Nausea1 (0.5)0 (0)1.0
  Emesis14 (6.7)2 (3.7)0.54
  Esophagitis001.0
  Pneumonitis0 (0)3 (5.6)0.008
  Renal1 (0.5)0 (0)1.0

Neither Grade ≥ 3 nor Grade ≥ 4 hematologic toxicity rates were found to be significantly greater in the patients age > 70 years (Table 2). The severity of nonhematologic toxicity was evaluated for the two age groups (Table 2). Grade ≥ 3 nonhematologic toxicity occurred in 46% of those age < 70 years compared with 52% of elderly patients (P = 0.45). Grade ≥ 4 nonhematologic toxicity occurred in 12% of those age < 70 years compared with 11% of elderly patients (P = 1.0). Of the nonhematologic toxicities, only Grade ≥ 4 pneumonitis (respiratory insufficiency requiring ventilation or continuous oxygen) was more frequent in elderly patients. This was a relatively uncommon toxicity occurring in no patients age < 70 years compared with 6% of elderly patients (P = 0.008). Grade ≥ 3 esophagitis occurred in 10% of those patients age < 70 years compared with 6% of elderly patients (P = 0.43).

Four of the 263 patients (2%) died of treatment-related toxicity (Grade 5 toxicity). Grade 5 toxicity occurred in 3 of 54 (5.6%) of those patients age ≥ 70 years compared with 1 of 209 (0.5%) younger individuals (P = 0.03). These deaths occurred due to pneumonitis in the 3 elderly patients and infection in the patient age < 70 years.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Recent studies have confirmed the value of combined-modality therapy for LD-SCLC. Both thoracic RT and PCI have been found to be advantageous for LD-SCLC. Although the NCCTG trial could not detect a survival advantage for BIDRT, the Intergroup trial 0096 reported by Turrisi et al. did observe better survival.7, 8, 11

The age cutoff used to define the elderly is open to debate. The median age of patients diagnosed with lung carcinoma is 70 years, which appears to be a reasonable cutoff for defining the elderly. In addition, this age cutoff was used by other investigators exploring the results of therapy for LD-SCLC in the elderly.12–14

Quon et al.12 reviewed the experience of 608 patients with LD-SCLC who participated in 2 Phase III trials (BR.3 and BR.6) performed by the National Cancer Institute of Canada. Both trials included the same chemotherapy regimen, consisting of cyclophosphamide, doxorubicin, plus vincristine (CAV), and EP delivered either in a sequential or alternating sequence. In BR.3, thoracic RT was given after chemotherapy with randomization to 25 Gy in 10 fractions or 37.5 Gy in 15 fractions. In BR.6, thoracic RT (40 Gy in 15 fractions) was given concurrently with EP with randomization to either the early (with Cycle 2, Week 4) or late (with Cycle 6, Week 16) RT arm. Eighty-eight (14%) patients were age ≥ 70 years and 520 (86%) were younger. There was no statistical difference noted with regard to the rates of RT-related toxicities, response, local control, or survival between the young and older age groups. Within the dose range examined, age did not have an impact on the delivery, tolerance, or efficacy of thoracic RT for LD-SCLC. This cohort of patients was also evaluated by Siu et al.13 with more emphasis placed on systemic management. There was no significant difference based on age noted when comparing the incidence rates of hematologic and most nonhematologic toxicities. Siu et al. concluded that potentially curative combined-modality treatment should not be withheld on the basis of age.

Intergroup Trial 0096 was a Phase III trial that compared EP plus QDRT with EP plus BIDRT for patients with LD-SCLC.11 Yuen et al.14 reevaluated this trial to determine the effects of patient age on outcome. Of 381 patients, 50 (13%) were age ≥ 70 years. The elderly group did not differ significantly from those age < 70 years with respect to gender distribution, performance status, or weight loss. Severe hematologic toxicity (Grade 4–5: 61% vs. 84%; P = 0.01) and fatal toxicity (1% vs. 10%; P = 0.01) occurred more often in older patients. There were no differences in the frequency of nonhematologic toxicities. Age was not found to be associated with response or local control rates. The 5-year survival rates were 16% for elderly patients compared with 22% for younger individuals (P = 0.051). Yuen et al. recommended that selected older patients, such as those with a good performance status, should be considered for optimum treatment approaches.

The results of these studies were generally consistent, finding that age alone did not significantly impact survival.12–14 Both the Intergroup and NCCTG trials compared chemotherapy plus QDRT versus BIDRT. Grade 5 toxicity was significantly more frequent among patients age ≥ 70 years. This was due to hematologic toxicity in the Intergroup trial and pneumonitis in the NCCTG trial. The results were quite similar to our findings in elderly patients treated with concurrent chemotherapy (EP) and thoracic RT for Stage III nonsmall cell lung carcinoma.15

One strength of the current study was a consistent treatment approach with concurrent chemotherapy and thoracic RT followed by PCI. This approach achieved relatively favorable long-term results with a 5-year survival rate of 17% in elderly patients. Some degree of caution is warranted in extrapolating these data to all elderly patients. Elderly patients selected to participate in aggressive therapy trials may not represent ordinary patients as they are probably more physically fit.16

To our knowledge there are very little data available regarding the treatment of patients age > 80 years. At the time of last follow-up, our oldest patient was age 81 years. Therefore, one can only speculate on the results and treatment tolerance of these individuals.

Elderly patients may experience greater toxicity due to preexisting illnesses, decreased clearance of chemotherapy, and limited bone marrow reserve. Therefore, physicians should be more cautious when monitoring the effects of therapy in elderly patients. In spite of the increase in specific toxicities that accompanied combined-modality therapy in elderly patients, they had disease control and survival rates similar to those of younger patients.

Fit elderly patients with locally advanced LD-SCLC should be encouraged to receive combined-modality therapy, preferably in clinical trials. Future research should focus on ways to decrease toxicity especially in the elderly. Toxicity may be lessened with the use of protective agents, bone marrow-stimulating agents, and some of the newer targeted therapies. Modern RT planning systems may also be used to better spare normal tissues. Investigators are now designing trials specifically for elderly patients.17, 18

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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    Turrisi AT, Kyungmann K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999; 340: 265271.
  • 12
    Quon H, Shepard FA, Payne DG, et al. The influence of age on the delivery, tolerance and efficacy of thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys. 1999; 43: 3945.
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    Siu LL, Shepherd FA, Murray N, Feld R, Pater J, Zee B. Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol. 1996; 14: 821828.
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    Yuen AR, Zou G, Turrisi AT, et al. Similar outcome of elderly patients in Intergroup Trial 0096: cisplatin, etoposide and thoracic radiotherapy administered once or twice daily in limited stage small cell lung cancer. Cancer. 2000; 89: 19531960.
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    Schild SE, Stella PJ, Geyer SM, et al. The outcome of combined-modality therapy for stage III non–small-cell lung cancer in the elderly. J Clin Oncol. 2003; 21: 32013206.
  • 16
    Perrone F, Gallo C, Gridille C. Re: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst. J Natl Cancer Inst. 2002; 94: 10291030; author reply 1030-1. No abstract available.
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    The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999; 91: 6672.
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    Jatoi A, Stella P, Hillman S, et al. Weekly carboplatin and paclitaxel in elderly non-small-cell lung cancer patients (≥65 years of age): a phase II North Central Cancer Treatment Group Study. Am J Clin Oncol. 2003; 26: 441447.