Phase III trial of concurrent thoracic radiotherapy (TRT) with either the first cycle or the third cycle of cisplatin and etoposide chemotherapy to determine the optimal timing of TRT for limited-disease small cell lung cancer

Reporter: Annemarie Fernandes
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 4, 2012

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Presenter: Keunchil Park, MD, PhD
Presenter's Affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Background

  • About 20% of all lung cancers are small cell lung cancer (SCLC) and about 1/3 of SCLC patients present with limited stage disease that is confined to the thorax
  • Patients with limited-stage (LS) SCLC are treated with concurrent chemotherapy and thoracic radiation therapy (TRT).
  • Turrisi et al. (NEJM, 1999) demonstrated that chemotherapy (cisplatin and etoposide) with concurrent thoracic radiation therapy with twice-daily 1.5 Gy fractions to a total dose of 45 Gy improves overall survival compared to concurrent once-daily radiation therapy to 45 Gy. In this study, TRT was initiated during the first cycle of chemotherapy.
  • Prior studies (Murray, JCO, 1993 and Jeremic, JCO, 1997) have evaluated the role of early (week 1-4) vs. late (week 6-9) initiation of concurrent TRT to determine the value of shrinking bulky disease with chemotherapy to reduce the size of the radiation portal and ultimately radiation toxicity
    • These studies found that late initiation of concurrent TRT (week 6-9) did not impact toxicity and actually increased the rates of local failure, development of brain metastasis and even overall survival
    • As a result early initiation of concurrent TRT within 1-4 weeks was recommended and remains the standard of care.
  • Given the high risk of systemic failure of SCLC, prompt initiation of chemotherapy upon diagnosis is important. However, the complexity of radiation therapy planning and coordination of care practically limits the feasibility of initiation of TRT during week 1 of chemotherapy. As a result, initiation of chemotherapy is sometimes delayed.
  • This study is a non-inferiority study that evaluates the timing of TRT and the impact on outcome and toxicity with a 2 cycle (6 week) delay in initiation of TRT

Materials and Methods

  • This randomized, phase III trial enrolled patients with limited-stage SCLC from July 2003 to June 2010.
  • Inclusion Criteria: histologically confirmed SCLC, limited stage disease, a measurable lesion, age >18 years
  • Treatment:
    • Patients were randomly assigned to receive concurrent TRT:
      • With the first cycle (initial arm) of chemotherapy or
      • With the third cycle (delayed arm) of chemotherapy.
    • Chemotherapy: Patients received four cycles of cisplatin plus etoposide (cisplatin 70 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1 to 3 every 3 weeks).
    • Radiation Therapy: In both arms, patients received 2.1 Gy once-daily in 25 fractions over a period of five weeks, with a total dose of 52.5 Gy. Patients with partial or complete response were recommended to receive prophylactic cranial irradiation (PCI).
  • The primary study objective was to demonstrate non-inferiority of delayed (cycle 3) TRT compared to initial (cyce 1) TRT in terms of CR rate.

Results

  • A total of 222 patients were enrolled and 219 were evaluated (111 initial, 108 delayed).
  • Median follow-up was 4.9 years (range, 1.2 – 8.1 years)
  • Baseline patient and tumor characteristics were well balanced between both arms
  • Completion of Treatment:
    • Approximately 82% of patients completed planned four cycles of chemotherapy with 52.5 Gy TRT (81.1% and 82.4% in the initial and delayed arm, respectively).
    • PCI was given to 49.5% and 55.6% of patients in the initial and delayed arms, respectively (P = 0.37).
  • Survival rates and Outcomes: There was no difference in PFS, OS or CRR between the two arms.
    • Median overall survivals were 24.1 (initial) and 26.8 months (delayed) (P=0.60)
    • Progression-free survival was 12.2 (initial) vs. 12.1 months (delayed) (P=0.94)
    • Complete response rates 36.0% (initial) vs. 38.0% (delayed) (P=0.77)
  • Patterns of Failure- there was no statistically significant difference in patterns of failure (local-regional or distant failure), however the cumulative incidence failure curves demonstrated a trend to increased local-regional failure in the delayed arm (about 60% in the delayed arm and about 50% in the initial arm, p= 0.014).
  • Toxicity: The initial arm had higher rates of febrile neutropenia
    • Febrile neutropenia was significantly more frequent in the initial arm, occurring in 21.6% of patients, as compared with 10.2% in the delayed arm (P = 0.02). There were 5 treatment-related deaths related to febrile neutropenia and sepsis. Three of these deaths were in the initial groups and 2 were in the delayed group.
    • Esophagitis (any grade) occurred in 45.0% and 37.0% of the initial and delayed arms, respectively (p = 0.23).
    • No difference in other hematologic side effects or radiation pneumonitis.

Author's Conclusions

  • The authors conclude that TRT beginning with the third cycle of chemotherapy showed comparable survival outcomes and complete response rates with TRT beginning with the first cycle of chemotherapy, with a lower frequency of febrile neutropenia.
  • The authors support the use of delayed TRT given concurrently with the 3rd cycle of chemotherapy

Clinical Implications

  • This study is an interesting comparison of initial vs. delayed initiation of thoracic radiation therapy with concurrent chemotherapy in limited-stage SCLC.
  • This question is relevant to current treatment practice given the practical limitations of initiating TRT during week 1 of chemotherapy, as recommended from prior studies comparing early vs. late initiation of TRT. Given the high risk of systemic failure of SCLC, prompt initiation of chemotherapy upon diagnosis is important. However, the complexity of radiation therapy planning and coordination of care practically limits the feasibility of initiation of TRT during week 1 of chemotherapy.
  • The study used an unconventional approach to radiation therapy: 52.5 Gy in 2.1 Gy daily fractions. The standard of care from the Turrisi regimen is 45 Gy in twice daily 1.5 Gy fractions. Currently, the CALGB 30610 protocol is investigating daily-fractionated radiation therapy with 2 Gy fractions to a total dose of 70 Gy and the EORTC 08072 is evaluating daily fractions of 2 Gy to a total dose of 66 Gy. These regimens use more appropriate biologically effective dosing regimens with daily fractioned therapy than the one utilized here.
  • It is unclear why the patients in the initial arm experienced higher rates of febrile neutropenia. Of note, there were similar rates of death from febrile neutropenia and sepsis in the initial arm (N=3) and delayed arm (N=2). These deaths occurred during the concurrent phase of treatment.
  • It is interesting that the authors used complete response rate as the primary endpoint, as survival and disease control are more conventional end points. The authors noted that they used complete response as a surrogate for long term control.
  • Although the authors support the use of delayed TRT initiation with cycle 3 of chemotherapy, there is still concern for increased failures as demonstrated in previous studies. Although not statistically significant, there was a trend to higher local-regional failure rates in the delayed arm.
  • In contrast to the author's conclusions, early initiation of thoracic radiotherapy should still be attempted in all patients with limit-stage SCLC, when feasible. Because delayed TRT was not demonstrated to be inferior in terms of complete response, PFS and OS, delay of therapy due to technical or practical reasons is acceptable. In keeping with this, the current CALGB 30610 and EORTC 08072 protocols allow initiation of TRT with cycle 1 or 2 of chemotherapy.


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