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Limited-Stage SCLC Treatment

Limited-Stage SCLC Treatment



·         Standard Treatment Options for Patients With Limited-Stage SCLC
o    Chemotherapy and radiation therapy
o    Combination chemotherapy alone
o    Surgery followed by chemotherapy or chemoradiation therapy
o    PCI
o    Neurologic sequelae
o    Treatment options for older patients
·         Treatment Options Under Clinical Evaluation
·         Current Clinical Trials

Standard Treatment Options for Patients With Limited-Stage SCLC

Standard treatment options for patients with limited-stage small-cell lung cancer (SCLC) include the following:
  1. Chemotherapy and radiation therapy.
  2. Combination chemotherapy alone.
  3. Surgery followed by chemotherapy or chemoradiation therapy.
  4. Prophylactic cranial irradiation (PCI).

Chemotherapy and radiation therapy

Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.
Evidence (combined modality treatment):
  1. Survival. The following results have been reported in clinical trials:
    1. Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1-3][Level of evidence: 1iiA]
    2. Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[3-7][Level of evidence: 1iiA]
    3. No consistent survival benefit has resulted from the following:[8-16]
§  Increased dose intensity.
§  Increased dose density.
§  Administration of additional drugs or other (non–etoposide-containing) platinum-based combination regimens.
§  Altered modes of administration of various chemotherapeutic agents.
§  Maintenance chemotherapy.
  1. Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.[8-15][Level of evidence: 1iiA]
  2. Dose and timing. The optimal dose and timing of TRT remain controversial.
    1. Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3-6,8,9,15,17-20][Level of evidence: 1iiA]
    2. The amount of time from start to completion of TRT in LD SCLC may also effect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval, 0.49–0.80; P = .0003).[20][Level of evidence: 1iiA]
    3. Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).[17][Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[21-25][Level of evidence: 3iiiA]

Combination chemotherapy alone

Patients with a contraindication to radiation therapy could be treated with chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation.[26,27] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Surgery followed by chemotherapy or chemoradiation therapy

The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy.[28-32][Level of evidence: 3iiiDii] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery.[32][Level of evidence: 3iiiDii] Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and risk from the surgical procedure.
Evidence (role of surgery):
  1. A randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[33][Level of evidence: 1iiA]

PCI

Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[32,34,35] The majority of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% by the administration of PCI.[34]
Evidence (role of PCI):
  1. A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[34][Level of evidence: 1iiA
  2. A randomized study (RTOG-0212) of 720 patients with LD SCLC in complete remission after chemoradiation therapy demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as and less toxic than higher doses of brain radiation.[36]
  3. Randomized trials such as EORTC-22003-08004 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.[36-38]

Neurologic sequelae

Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[32,35,39-41] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[41] The majority of patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI.[41] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[39-41] Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Treatment options for older patients

The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity.[42] Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.
No specific phase III trial in older patients with LD SCLC has been reported; however, three secondary analyses of two cooperative group trials have been published evaluating outcomes in patients aged 70 years or older.[43-45] The survival outcomes for the older patients were identical to their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in theEST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged ≥70 years; P = .01).[44] Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation for patients with LD SCLC include the following:
·         New drug regimens.
·         Surgical resection of the primary tumor.
·         New radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation).

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients withlimited stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.

References

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