Analysis of a Novel Protocol of Combined Induction Chemotherapy and Concurrent Chemoradiation in Unresected Non–Small-cell Lung Cancer: A Ten-year Experience with Vinblastine, Cisplatin, and Radiation Therapy

Eugenie Waters; Brian Dingle; George Rodrigues; Mark Vincent; Robert Ash; Rashid Dar; Richard Inculet; Walter Kocha; Richard Malthaner; Michael Sanatani; Larry Stitt; Brian Yaremko; Jawaid Younus; Edward Yu

Disclosures

Clin Lung Cancer. 2010;11(4):243-250. 

In This Article

Discussion

This retrospective analysis presents the outcomes of a large cohort though highly selected subset of stage IIIA/IIIB NSCLC patients, all of whom initiated treatment with VCRT, a unique concurrent chemoradiation regimen in use at the LRCP. Many other platinum based chemotherapy regimens with sequential or concurrent radiation have been reported in the literature, and should serve as a standard by which our VCRT protocol is judged.

In that regard, Table 4 provides both reasonable comparators, and historical interest in the development of treatment for this disease over the last 2 decades. The addition of chemotherapy (either sequential or concurrent) to radiation for treatment of unresectable stage IIIA/IIIB NSCLC has been well established, yielding MSTs ranging from 12 to 22 months.[5,9–14]

The studies by Curran, Furuse, and Zatloukal et al[10,15,16] demonstrate improvements of concurrent over sequential chemotherapy, although the studies by Fournel and Huber et al,[17,18] while suggestive of improvements, did not achieve statistical significance.[30]

The highest survival outcomes to date have been reported by the Southwest Oncology Group (SWOG S9504) study using concurrent chemoradiation with cisplatin and etoposide followed by 3 cycles of Docetaxel as consolidation chemotherapy in patients with IIIB NSCLC.[19] Although the phase III Hoosier Oncology Group trial, which used the same chemotherapy platform, did not confirm benefit from the addition of consolidation Docetaxel, both their study and the SWOG 9504 trial demonstrate improved survival compared with others.[20]

Attempts to determine the superiority of induction or consolidation treatment, in addition to concurrent therapy, have been unsuccessful,[21,22] and while Vokes et al reported improvements with up front concurrent therapy in the SWOG 39801 study, the survival statistics with Carboplatin and Paclitaxel were disappointing, showing only a 14-month MST.[23]

The Locally Advanced Multi-Modality Plan (LAMP) trial is interesting, suggesting a trend for concurrent first treatment followed by consolidation as opposed to the reverse.[24]

By comparison, our VCRT protocol's MST of 18 months and overall 5-year survival of 20% compares favorably with all the above.

Our results are especially interesting because: (1) the VCRT protocol administered the total dose of cisplatin for each cycle over the course of 3 days, thus potentially reducing acute toxicity, while the traditional schedules involved the total dose of cisplatin per cycle to be administered on 1 day,[5,10,15–17,21,22] or alternatively at a diminished pulse of daily or weekly.[13,19,20,26] When the VCRT protocol was first initiated, it was not known how these changes in dosing and scheduling would affect efficacy; (2) The VCRT protocol administered 2 cycles of induction chemotherapy followed by 2 cycles of concurrent chemoradiation. Biologically this arrangement helps to eliminate circulating microscopic tumor cells before the consolidation with the chemoradiation phase. This retrospective study suggests that the VCRT protocol is not detrimental, in this regard.

In summary, the VCRT protocol's MST of 18 months and overall 5-year survival of 20% is comparable to the reported survival for stage IIIA/IIIB NSCLC using other concurrent chemoradiation protocols.

In addition to achieving OS outcomes that are in keeping with the results of other trials, the number of patients who died during the VCRT therapy for IIIA/IIIB NSCLC was moderately low. In their phase III trial comparing sequential and concurrent chemoradiation with cisplatin and vinorelbine in unresectable stage 3 NSCLC, Fournel et al documented 10 toxic deaths out of 102 patients (9.8%) enrolled in the concurrent arm of their trial in addition to 13 deaths as a result of progressive disease.

In the SWOG S9504 trial,[19] which examined IIIB NSCLC and the use of consolidation Docetaxel following concurrent chemoradiation, 4 patients died on treatment out of a total of 83 patients in the trial (4.8%).

Of note, the large majority of patients in the SWOG S9504 trial had a performance status of 0-1 at the outset of treatment and the trial rigorously excluded patients who were found to have stage 4 disease or who had inadequate staging to document IIIB NSCLC or rule out stage 4 disease. In contrast, the decision to offer treatment with VCRT over the past 10 years at the LRCP was based solely on clinical judgment and patient preference in a nonclinical trial setting. Consequently, a formal, quantitative assessment of performance status is simply not available for our patients. Despite this, we feel the relatively low treatment related death rate observed in our study implies that our patients were functioning at an appropriate performance level before initiation of treatment.

As demonstrated in Table 2, only 11% of patients in this cohort had a positron emission tomography (PET) scan for staging. This reflects the limited access to PET scanning in Ontario and the 10-year nature of this retrospective review, dating back to 1996.[31]

In this retrospective analysis, 25% of patients experienced at least 1 grade 4 toxicity. Nevertheless, there was no significant difference in survival between those with and without grade 4 toxicity, suggesting that VCRT is a clinically tolerable therapy. Grade 3–4 neutropenia was present in 39% of patients who had VCRT and of those, 23% had grade 4 neutropenia. This is significantly less than the 48%–58% of patients who experienced grade 4–5 neutropenia in the concurrent arms of the RTOG 94-10 trial. Grade 3–4 neutropenia rates with VCRT are also significantly less than those reported from the concurrent arm of the Furuse et al. trial (99%) and the concurrent arm of the trial conducted by Zatloukal et al (53%).[16] Rates of grade 3–4 thrombocytopenia were also comparable between VCRT (4%) and other reports of concurrent chemoradiation such as the RTOG 94-10 trial, which reported 4%–8% thrombocytopenia, and Zatloukal et al, who documented 6% thrombocytopenia. Although 61% of patients experienced esophagitis, only 3% of those patients had grade 3–4 esophagitis. This result is similar to the 2% who experienced such toxicity in the trial by Furuse et al, but significantly less than the 25% and 18% who were reported to have grade 3–4 esophagitis in the concurrent chemoradiation arms of the RTOG 94-10 trial and the trial by Zatloukal et al, respectively. It is important to note that Furuse et al used a split-course radiation schedule, as opposed to the continuous radiation schedule used in the VCRT protocol, potentially accounting for the lower rate of esophagitis noted by that group.

The observation that patients receiving more cisplatinum had a better prognosis is not surprising, and may simply reflect that chemotherapy plus radiotherapy is better than radiotherapy alone. The choice of 500 mg total dose is quite arbitrary; many factors such as treatment delivery, body size, organ function and host metabolic activities may alter subsequent functional levels of drug delivery to the target.

There was a trend toward improved survival with smaller tumor size and both radiation and chemotherapy were shown to have dose dependent responses. A proportion of patients received < 60 Gy or did not undergo any radiation therapy because of disease progression, patient's decision, or early death. From these groups, a dose dependent relationship for treatment response with radiation therapy dose was demonstrated (Figure 2). This result is limited because it was determined retrospectively and the patients who received less radiation may have had poorer prognosis, declined further therapy, or switched to a palliative radiation therapy. Nevertheless, the improved survival with increased radiation dose is hypothesis generating and biologically reasonable.

This study did not identify a survival difference between stage IIIA and IIIB disease (nor did the CALGB 913021), but this could easily reflect the small numbers, the lack of surgical staging inherent in unresectable tumors, the lack of mediastinoscopy, and the fact that radiation treatment targeted the mediastinum in both groups.

Finally, this study demonstrates that a pathologic complete remission of IIIA/IIIB NSCLC is possible in the small subset of patients who underwent completion surgery after VCRT. It is impossible to make conclusions regarding these outcomes because of this cohort's small size, and the retrospective nature of the analysis. This study, as with all retrospective analyses, has inherent limitations. The OS may be an underestimate because it was determined by including all patients deemed unresectable (but in whom a radiation treatment plan could be safely developed), regardless of whether they completed VCRT, had a poor performance status, or were subsequently found to have metastases after beginning treatment. Current trials focusing on patients with locally advanced NSCLC generally include mediastinoscopy for staging but this analysis was retrospective and only 35% of patients had mediastinoscopy. The retrospective nature of the review limits information surrounding the patient deaths during treatment. In addition, the data spans 10 years, during which time there have been significant advances in cancer diagnosis and care. Admittedly, it was difficult to grade some of the toxicities accurately because of the limited information found in the assessment notes and consultant notes, especially concerning the more subjectively reported toxicities of esophagitis, mucositis, neuropathy, and nausea/vomiting. Lastly, the small number of patients involved, and the possibility that numerous confounders may have impacted their survival, limits the applicability of the completion surgery cohort.

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