Etoposide

We treated 27 patients with regionally advanced non-small-cell lung cancer (NSCLC) with two cycles of neoadjuvant chemotherapy with etoposide, vindesine, and cisplatin. Twenty-three patients were evaluable for response; 13 had a partial response while ten patients had stable disease or disease progression. Subsequent local therapy consisted of surgery followed by radiotherapy in four patients and of radiotherapy alone in 14 patients. Five patients did not receive local therapy. At completion of local therapy, seven patients were considered free of disease including all four who had undergone surgery. Median time to disease progression for the 13 patients who had a partial response to neoadjuvant chemotherapy was eight months (three to 51+ months). The median survival for all patients registered on study was eight months (three days to 53+ months). Chemotherapy induced toxicities included moderate myelosuppression, nausea and vomiting in all patients, and occasional ototoxicity, neurotoxicity, and wasting syndrome. One patient died of intracerebral hemorrhage due to thrombocytopenia. This trial shows that administration of neoadjuvant chemotherapy to patients with locoregionally advanced NSCLC is feasible and may yield an increased response rate compared to patients with stage IV disease. While no clearly beneficial effect of the use of chemotherapy on patient survival is apparent in this study, further studies utilizing neoadjuvant chemotherapy in patients with NSCLC are warranted and should attempt to identify more active combinations of drugs. (Chest 1989; 96:110-13)

The prognosis for patients with locoregionally advanced (stages IIIA and IIIB) NSCLC remains poor. The majority of patients die of either local and/or distant disease; five-year survival rates of less than 10 percent have been reported for patients with mediastinal or supraclavicular lymph node involvement.[1] Thus, despite apparent locoregional confinement of the disease, aggressive therapy with surgery and/or radiotherapy will result in cure for the occasional patient only. Efforts at improving this grim prognosis of NSCLC have most recently focused on the combined use of multiple therapeutic modalities including neoadjuvant chemotherapy or concomitant chemotherapy and radiotherapy.[2,3]

Neoadjuvant chemotherapy has been applied in a number of solid tumor malignancies.[4,5] It is hoped that the initial administration of chemotherapy will lower the locoregional tumor burden and allow for subsequent curative local therapy. In addition, the early use of systemic therapy may eradicate micrometastases and prevent distant failure. For this concept to be successful, effective systemic chemotherapy is essential. In general, response rates of patients with stage IV NSCLC to chemotherapy have been disappointing.[6,7] On the other hand, the experience with neoadjuvant chemotherapy in patients with head and neck cancer suggests that higher overall response rates including complete responses can be achieved when administering chemotherapy at an earlier stage in the natural history of the disease. Therefore, in 1983, we decided to study the feasibility of administering neoadjuvant chemotherapy with vindesine, etoposide, and cisplatin to patients with locoregionally advanced NSCLC. This analysis represents the final report of this phase II trial.

PATIENTS AND METHODS

Between March 1983 and June 1985, 30 patients were entered into this study. Follow-up is available through July 1988. Eligible patients had histologically or cytologically confirmed NSCLC with T2 or T3 primaries and clinically apparent mediastinal or ipsilateral supraclavicular lymph node involvement. A performance status of 0-3 (ECOG), and a 24-hour urine creatinine clearance of 50 ml per minute were also required. All patients were previously untreated and signed informed consent.

Initial staging procedures for all patients consisted of a complete history and physical examination, complete blood count, routine serum chemistries, 24-hour urine creatinine clearance, split pulmonary function studies, chest x-ray film, a CT-scan of the chest including the upper abdomen to the level of the adrenal glands, a bone scan, a liver spleen scan, and a whole body gallium scan. Bronchoscopy was performed in all patients; mediastinoscopy or supraclavicular lymph node biopsy was performed to confirm clinically suspicious-appearing mediastinal supraventricular lymph nodes as malignant.

The treatment plan called for two cycles of neoadjuvant chemotherapy followed by response evaluation usually consisting of a repeat chest x-ray film and a CT-scan. Subsequent local therapy consisted of surgery followed by radiotherapy when the disease was considered resectable by the attending surgeon. Patients with unresectable disease received radiotherapy alone. A flexible number of additional cycles of chemotherapy were administered following local therapy unless prohibited by disease progression or cumulative toxicity. Chemotherapy consisted of vindesine, 3.0 mg/[m.sup.2] by intravenous bolus, and etoposide, 300 mg/m[2] intravenous infusion over 30 to 45 minutes, both administered on days 1, 8, 15, 22, 29, and 36. Cisplatin was given intravenously at a dose of 120 mg/[m.sup.2] on days 1 and 22. Standard hydration and antiemetic schedules were applied.

Radiotherapy was delivered at daily fractions of 200 cGy for a total dose of 5,400 cGy by a 4 Mv or 6 Mv linear accelerator. Included in the radiotherapy field were the primary tumor, the ipsilateral hilum, the mediastinum, and the supraclavicular fossae. Prophylactic cranial irradiation consisting of 3,000 cGy in ten fractions was administered to patients with adenocarcinoma who were clinically free of disease following completion of local therapy. Response criteria defined a complete response as complete disappearance of all evidence of disease, a partial response as average decrease of measurable or evaluable disease by at least 50 percent of pretreatment size, stable disease as reduction of pretreatment tumor size by less than 50 percent or no decrease in size, and progressive disease as increase in average tumor size.

RESULTS

Thirty patients signed informed consent for this study. However, three of these patients were found to be ineligible on review. One patient refused chemotherapy after signing informed consent and was lost to follow up; one patient was found to have metastatic pancreatic cancer while being worked up for complications during cycle 2 of chemotherapy; one patient had received prior chest irradiation with 4,800 cGy.

The true study cohort consists of 27 patients. The patient characteristics, including performance status and tumor histology, are summarized in Table 1.

The response to two cycles of neoadjuvant chemotherapy is as follows: four patients were not evaluable for response; one patient died 24 hours after initiation of his chemotherapy, presumably from compression of his mainstem bronchus by tumor; one patient died of acute pulmonary embolism prior to reevaluation following cycle 2; one patient died of progressive atypical pneumonia following cycle 1; one patient died of an acute intracerebral hemorrhage while thrombocytopenic during cycle 1. Of 23 patients who were evaluated for response, 13 had a partial response to chemotherapy. Ten patients had stable disease or progressive disease. Therefore, 13 of 27 patients responded in this study for an overall response rate of 48 percent (95 percent confidence intervals 28 to 68 percent).

Following neoadjuvant chemotherapy, local therapy consisted of surgery followed by radiotherapy in four patients; all four had experienced a partial response to chemotherapy and had residual disease in the resected specimens. Fourteen patients received radiotherapy alone. Five patients received no local therapy on protocol; all had failed to respond to initial chemotherapy and received either no further therapy at all (three patients) or additional chemotherapy with other drugs (two patients). At completion of local therapy, seven patients were considered free of disease, including all four who had undergone surgical resection, and three who had received radiotherapy alone.

Eighteen patients who completed local therapy on protocol were eligible to receive additional cycles of chemotherapy. However, in eight patients, no additional chemotherapy was administered because of either cumulative toxicity, disease progression, or patient refusal. Four patients received one cycle of additional chemotherapy, and only six patients received more than one cycle.

The median survival for all 27 patients in this study was eight months (range three days to 53+ months) as shown in Figure 1. The median time to disease progression for patients responding to neoadjuvant chemotherapy was eight months (range three to 51 + months). Overall, disease progression was documented in 20 patients. The site of progression was local in eight patients, distant only in six patients (including two patients who developed brain metastases only), and both local and distant in six patients. The cause of death was considered to be the underlying malignancy in 21 patients, while five patients died of intercurrent disease (one of myocardial infarction while clinically free of disease). One patient whose therapy included surgery is currently alive and free of disease at 53 months of follow-up.

The toxicities of neoadjuvant chemotherapy on this protocol are summarized in Table 2. The predominant toxicity of this regimen was myelosuppression, which affected the great majority of patients. In order to ameliorate this side effect, dose reductions of etoposide and of vindesine had to be performed regularly. Therefore, the mean dose administered for etoposide was 71 percent (range 29 to 96 percent) and for vindesine, 70 percent (range 33 to 92 percent) of the ideal dose for those drugs in this regimen. Cisplatin, on the other hand was administered at a mean dose of 91 percent (range 50 to 100 percent) of the ideal dose in this regimen reflecting an overall low incidence of renal toxicity. Only two patients developed a serum creatinine level exceeding 2.0 mg/dL. Other toxicities observed included neuropathy (five patients), an allergic reaction to vindesine (one patient), nausea and vomiting, and alopecia. One patient died of intracerebral hemorrhage while thrombocytopenic, four patients had documentation of neutropenic fever, and one patient developed a wasting syndrome and died after completion of neoadjuvant chemotherapy and chest radiotherapy in the absence of clinical disease progression.

Discussion

We have presented the long-term results of a pilot trial utilizing neoadjuvant chemotherapy in a group of patients with regionally advanced NSCLC. Thirteen of 27 evaluable patients had an objective response. This is lower than in our initial report;[8] however, the confidence intervals overlap and this figure is compatible with other recent reports involving similar combinations of drugs.[2,9-12] Our results support the feasibility of neoadjuvant chemotherapy in NSCLC, as tumor shrinkage prior to local therapy can be achieved. Although many patients did not respond, it is unlikely that their prognosis was adversely affected by the use of neoadjuvant chemotherapy, given the poor results

achieved with standard radiotherapy alone.

While a median survival figure of eight months is profoundly disappointing, most patients entered on this trial had advanced locoregional disease and were considered unresectable at the time of diagnosis. Many of these patients would currently be staged as III B.[13] Such patients may represent a suboptimal group in which to test neoadjuvant chemotherapy, as their tumor burden may exceed the limited activity of currently available chemotherapeutic agents.

The toxicities encountered in this study clearly exceeded those of radiotherapy alone, and at least one patient died as a direct consequence of

having received chemotherapy. In the great majority of patients, however, toxicities consisted primarily of moderate myelosuppression and did not result in severe morbidity. Furthermore, a large portion of this chemotherapy was given on an outpatient basis.

Neoadjuvant chemotherapy continues to be investigated in many solid tumors. Only recently, however, have studies been published that involve patients with NSCLC.[2,9-12] Spain et al[2] treated 22 inoperable patients with three to four cycles of mitomycin C, cisplatin, and vinblastine. Seventy-three percent of patients responded including 23 percent who achieved complete response. At a median follow-up of 39+ months, the median survival is 19 months. Osoba et al[9] treated 30 patients with unresectable stage II or III disease with two cycles of bleomycin, etoposide, and cisplatin prior to split course radiotherapy. Of 25 patients evaluable for response to chemotherapy, one had a complete response, and ten, a partial response. The median survival had not been reached at 52 weeks of follow-up.

Other authors have also reported high response rates to neoadjuvant chemotherapy, although an increase in patient survival was not apparent.[10,11] Eagan et al[10] reported on 39 patients with regionally advanced NSCLC. Although 20 patients (51 percent) had an initial response to chemotherapy, the median survival for all patients was 11 months only. For 19 patients who underwent subsequent thoractomy (all 19 had responded to neoadjuvant chemotherapy), the median survival was 15 months and the two-year survival rate 10 percent. These patients who underwent thoracotomy were noted to have a low local recurrence rate; however, a high distant failure rate, presumably due to inability of the chemotherapy to eradicate distant micrometastases, was also observed.

These conflicting survival data that contrast with the consistently high initial response rates of NSCLC to neoadjuvant chemotherapy call for further evaluation of this concept in randomized studies. The preliminary results of a randomized study conducted by the CALGB were recently presented by Dillman et al.[12] There were 180 patients with unresectable stage III NSCLC were randomized to receive radiotherapy alone, or two cycles of vinblastine and cisplatin followed by radiotherapy. At a median follow-up of 19 months, the median survival was 16.5 months for the group receiving both treatment modalities vs 8.5 months for the group treated with radiotherapy alone.

There is increasing evidence for a role of chemotherapy in the treatment of patients with NSCLC. Randomized trials have shown a survival advantage as a result of the use of chemotherapy in patients with metastatic disease,[14] patients receiving adjuvant chemotherapy following incomplete resection and radiotherapy,[15] and patients receiving neoadjuvant chemotherapy.[12] Pilot trials such as reported here have identified the feasibility of administering neoadjuvant chemotherapy to patients with regionally advanced NSCLC, and documented that response rates exceeding those observed in patients with metastatic disease can be obtained. Future trials should aim at identifying more active combinations of drugs to be administered in this setting, as well as address questions regarding the optimal number of cycles to be given, the need for additional adjuvant chemotherapy, and the administration of concomitant chemoradiotherapy.

ACKNOWLEDGEMENTS: We wish to thank Dr. Charles M. Brown for treating his patients with this protocol and Helena Fleming for preparation of the manuscript.

References

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