Study of Paclitaxel, Etoposide, and Cisplatin Chemotherapy Combined with Twice-Daily Thoracic Radiotherapy for Patients with Limited Stage Small Cell Lung Cancer: An RTOG 96-09 Phase II Study
Reviewer: Drew Moghanaki, MD The Abramson Cancer Center of the University of Pennsylvania
Authors: David S. Ettinger, et. al. Authors' Affiliations: Radiation Therapy Oncology Group Journal: J Clin Onc 2005; August 1, 23(22):4991-98
Although Small Cell Lung Cancer (SCLC) is responsive to either chemotherapy or radiation, it carries a very poor prognosis, as most patients present with advanced or metastatic disease at the time of diagnosis. The 30-40% of SCLC patients who present with only limited-stage disease (LS-SCLC) are candidates for potentially curable treatment.
The most effective treatment regimen currently available for LS-SCLC was demonstrated in an Intergroup phase III randomized trial, which involved the use of cisplatin and etoposide given together and concurrently with twice-daily thoracic radiotherapy.
While the Intergroup regimen of twice-daily concurrent thoracic radiotherapy with combination chemotherapy has provided the largest benefit demonstrated in LS-SCLC, the outcomes still remain poor. Investigators from the RTOG (Radiation Therapy Oncology Group) sought to determine if adding a third chemotherapeutic agent, paclitaxel, to this regimen might improve outcomes.
The rationale for adding paclitaxel was based upon evidence of a 34-51% response rate when used as a single-agent in extensive stage SCLC, and there was also data to suggest it may be a radiosensitizer. Additionally, two separate phase I toxicity studies had established the safety of this 3-drug regimen.
The goals of this study were to conduct a single-arm multi-institutional phase II trial to assess the safety and efficacy of cisplatin, etoposide, and paclitaxel given concurrently with twice-daily thoracic radiotherapy.
Inclusion and exclusion criteria were similar to the prior Intergroup study. Patients were screened with a standard workup including CT of the brain/chest/abdomen/ pelvis, as well as a bone scan and BM aspiration with biopsy. Only patients with limited-stage disease and good performance status were enrolled. It is notable that patients with ipsilateral supraclavicular disease were allowed entry, whereas the Intergroup study had not.
Treatment consisted of 3 cycles of cisplatin (60 mg/m 2), etoposide (60-80 mg/m 2), and paclitaxel (135-175 mg/m 2) given every 4 weeks, starting with week 1 of radiation.
Thoracic radiotherapy replicated the technique used in the Intergroup study with variations only in treatment volume. Fractionation consisted of 150 cGy given twice daily for 3 weeks, Monday through Friday. The irradiated volumes included tumor visible on CT in addition to adjacent portions of mediastinal lymph nodes and ipsilateral hilar lymph nodes. Unlike the Intergroup study, ipsilateral supraclavicular lymph nodes were allowed to be treated if directly involved by tumor, in the presence of upper lobe tumors, or with bulky pre- or paratracheal nodes on CT measuring > 5cm.
Patients achieving a complete or partial response were offered prophylactic cranial irradiation within 6 weeks following the last cycle of chemotherapy.
Progression-free survival was defined as time to local, regional, or distant progression or any cause of death, while overall survival was defined as time to any cause of death.
Between 1996-98, 55 patients were enrolled and data was available for 53 at time of analysis.
75% successfully completed the chemotherapy protocol and 94% completed the radiation protocol. 17% received prophylactic cranial irradiation.
Complete and partial response rates were 75% and 17%, respectively.
With a maximum follow-up of 71 months, survival ranged from 29-71 months.
Median survival was 24.7 months, and median progression-free survival was 13 months. 2 year survival rate was 54.7% and 2 year progression-free survival was 26.4%.
Patterns of first failure were mostly distant (63%), and included 13% with brain metastasis as the first site of failure among those who had not received prophylactic cranial irradiation. Another 22% of patients progressed in the original primary tumor, and 7% progressed in locoregional lymph nodes.
Compared to the results of the Intergroup regimen, the authors of this study concluded that the addition of paclitaxel would be unlikely to improve survival and discontinued the study.
While the current study allowed treatment of the ipsilateral supraclavicular nodes in certain situations, it is unclear how this may have impacted the results of this study when compared to the Intergroup trial, which excluded treatment of supraclavicular nodes.
The authors briefly discuss current and future direction of studies for LS-SCLC, and highlight the ongoing phase-II RTOG 97-12 study in which concurrent cisplatin and etoposide is being used with escalating total radiation dose by using once-daily treatment to large fields followed by cone-down boost technique with twice-daily radiation treatment.
Nonetheless, the regimen used in the Intergroup study remains the most effective regimen for LS-SCLC
Turrisi AT III, Kim 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 340:265-271, 1999