Teniposide

Treatment for small cell lung cancer has not improved substantially in the past 15 years. Some advances are being made in supportive care and by use of more intense concurrent thoracic radiotherapy. New agents such as the taxanes and the topoisomerase I inhibitors hold promise and are currently in phase III evaluation. The question whether dose intensity can improve the outcome of patients with small cell lung cancer has been raised for many years. Improving supportive care enhances our ability to test this question more thoroughly. This paper reviews the historical and current experience using high-dose therapy with hematopoietic stem cell support for the treatment of small lung cancer. Future directions are identified.

(CHEST 1999; 116:531S-538S)

Abbreviations: ABMT = autologous bone marrow transplantation; G-CSF = granulocyte colony-stimulating factor; SCLC = small cell lung cancer

Lung cancer is the leading cause of death from cancer in both men and women,[1] and it is epidemic throughout the world due to increased tobacco consumption. Approximately 15 to 25% of all bronchogenic carcinomas are small cell lung cancer (SCLC). Excellent immediate palliation from combination chemotherapy is achieved. Many chemotherapeutic agents have a major amount of activity against SCLC. The most active of these agents are the following: cisplatin (and carboplatin), etoposide (and teniposide), ifosfamide, cyclophosphamide, vincristine, and doxorubicin. Combination regimens constructed from the established agents remarkably achieve almost identical short- and long-term results. A reasonable consensus treatment consists of 4 to 6 cycles of etoposide and platinum with concurrent chest radiation therapy, for the third of patients with limited-stage disease[2] and combination chemotherapy alone for those with extensive-stage disease. Only 20 to 40% of patients with limited-stage disease and [is less than] 5% of those with extensive-stage disease remain alive after 2 years.[3,4] About half of the patients who are alive at 2 years are alive at 5 years. A number of new agents appear to have at least equivalent activity compared with these established drugs, including taxanes (paclitaxel and taxotere), gemcitabine, and the topoisomerase I inhibitors (topotecan, irinotecan). Trials to define the role of the new active agents as well as resistance modulators in first-line therapy are ongoing. A median age of 60 to 65 years, underlying smoking-related cardiovascular and pulmonary co-morbidity, and enhanced risk of secondary smoking-related malignancies contribute to an increased risk when applying dose-intensive therapy to lung cancer patients.

Preclinical in vitro and in vivo experiments indicate near log-linear dose-response relationships for many agents, particularly for the alkylating agents and radiation.[5-8] Cohen et al[9] in 1977 were among the first to demonstrate higher response rates, both complete and partial, and a modestly longer median survival time when administering higher rather than lower doses of cyclophosphamide, lomustine, and methotrexate.

DOSE INTENSITY

Without Cellular Support

The contribution of the dose or dose intensity of chemotherapy to response and survival remains controversial. Klasa et al[10] analyzed numerous SCLC trials using the methodology of Hryniuk and Bush[11] to determine whether the dose intensity (expressed in a drug dose administered per square meter per week) of individual agents or regimens correlated with response or survival. Longer median survival times in patients with extensive disease receiving higher dose intensities of cyclophosphamide/ doxorubicin/vincristine and cyclophosphamide/adriomycin/etoposide, but not etoposide/cisplatin, were observed, but the effects and the dose ranges analyzed were small.[10] This analysis makes the assumptions that all drugs are therapeutically equivalent and that cross-resistance (or synergy) between drugs, peak drug concentrations, or schedule and duration of drug exposure have no effect.

Seven randomized trials have evaluated dose intensity in SCLC, almost exclusively in the extensive-stage setting.[9,12-17] The planned dose intensity differences between the high and lower dose arms of the study ranged between 1.2- and twofold, although the differences in actual delivered doses were less. Three of the seven randomized trials showed a modest survival advantage for the higher dose therapy. Two of these three trials compared less than standard dose therapy with full-dose therapy. The trials without evident benefit generally compared full dose to a small incremental dose intensity between one- and two-fold times the full conventional dose. Currently established cytokines (eg, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor [G-CSF]) shorten chemotherapy-induced myelosuppression and consequent febrile neutropenia.[18] Dose intensities can be increased by only 1.5- to twofold with cytokine use due to cumulative thrombocytopenia. Survival advantages have not been described. The effectiveness of various thrombopoietins or other cytokines in increasing the achievable dose intensity remains to be demonstrated.

Arriagada et al[17] randomized patients to six cycles of conventional-dose chemotherapy with or without a modestly intensified first cycle. In my view, it was surprising to observe a complete response and survival advantage for the patients receiving the intensified chemotherapy, since the relative difference between the two groups was so small. While this result could reflect chance, it is possible that dose intensity, particularly if the dose is given early in the course of treatment, may be more likely to impact on outcomes in the limited-stage setting rather than the extensive stage setting. Both of these themes, early intensification and treatment of an earlier stage of disease, are important in considering new trial designs.

Multidrug cyclic weekly therapy was designed to intensify the number of drugs to which the cancer was exposed with less compromise of the dose, given the differing toxicities of the weekly agents. Early phase II results were quite promising,[19,20] although patient selection effects were evident. The randomized trials evaluating these regimens did not demonstrate response or survival advantage.[21,22] Unfortunately, in actual practice in the randomized trials,[23,24] the weekly schedules had greater dose reductions and delays compared with conventional therapy on a schedule of every 3 weeks, thus the actual delivered dose intensities were not that different. Not only did dose and schedule differ, but so did the regimens, which led to interpretation obstacles. In these studies, follow-up is also too short to observe late disease-free survival plateau differences.

With Cellular Support

Patients with SCLC undergoing autologous bone marrow transplantation (ABMT) were analyzed if sufficient details were provided about their response status (relapsed or refractory, untreated, or responding to first-line chemotherapy; partial or complete response) and the extent of their disease (limited or extensive stage) and were pooled for aggregated relapse-free and overall survival characteristics.

Fourteen studies (median of 3 patients; maximum of 8 patients) described outcomes of 52 patients who had either relapsed disease or refractory disease.[25-38] Complete and partial responses were observed in 19% and 37% of patients, respectively. The median response durations and survival times were approximately 2 to 3 months. Combination chemotherapy regimens, especially those containing multiple alkylating agents, were slightly more effective (response rate, 58%; complete response, 26%), but were more toxic (18% vs 6% deaths). The observed high complete response rate supports a dose-response relationship but was insufficient to improve survival.

Overall and complete response rates of 84% and 42% were achieved in 103 patients with SCLC (71% with limited disease) receiving high-dose therapy as the initial treatment.[39-46] Relapse-free, 2-year, and overall survival rates in these patients were comparable to those in patients treated with conventional multicycle regimens. Transplantation in the newly diagnosed SCLC setting may not be optimal because of the frequency of life-threatening complications from uncontrolled disease and the potential for tumor cell contamination in untreated autografts.

Approximately 334 patients responding to first-line chemotherapy received high-dose chemotherapy with autologous bone marrow support as intensification.[47] Of those patients achieving partial responses only to induction therapy, the conversion to complete response occurred in 40 to 50%, but without durable effect. The best results (35% of patients progression free, with a median follow-up time of [is greater than] 3 years at the time of publication) were reported in patients with limited disease in complete response at the time of high-dose therapy.

Much of the experience with patients receiving high-dose treatment for SCLC that was reviewed took place during the initial developmental phase of high-dose therapy for solid tumors. Therefore, many of these high-dose trials employed either single chemotherapeutic agents (with or without low-dose agents in addition; 6 series, 2 with chest radiotherapy),[41,42,48-53] single alkylating agents (6 series, 4 with chest radiotherapy),[42,44,47,54-57] or combination alkylating agents (10 series, 6 with chest radiotherapy).[29,32,43,58-64] There was higher treatment-related morbidity and mortality than is currently expected.

Humblet et al[60] designed a randomized trial of five cycles of conventional therapy with prophylactic cranial irradiation followed by one further cycle of either high-dose or conventional-dose therapy using cyclophosphamide, etoposide, and carmustine. No chest radiotherapy was given. Of 101 SCLC patients entered in the study, only 45 were eligible for randomization due to disease progression and morbidity of treatment. A clear dose response was demonstrated. Conversion from partial to complete response occurred in 77% of patients capable of being evaluated after high-dose therapy compared with 0% after conventional-dose treatment. Disease-free survival was significantly enhanced, and a trend toward improved survival was observed. However, an 18% toxic death rate on the ABMT arm led the investigators to conclude that dose-intensive therapy should not be considered a standard therapy in SCLC. Moreover, since chest radiotherapy was not performed in this thai, almost all patients who relapsed had the disease recur in the chest.

High rates of relapse in sites of prior tumor involvement[41,56] may be explained by greater tumor burden in the chest, by the possible presence of drug-resistant clones or non-SCLC elements, by poorer drug delivery, or by intratumoral resistance factors such as hypoxia, or, in the ease of autograft contamination, by the possibility of homing and microenvironmental support for the tumor in local-regional sites. By 3 years, chest relapse is expected in 90% of individuals following chemotherapy alone and in 60% after conventional-dose radiotherapy. Thus, radiotherapy to sites of bulk disease is likely to represent an essential component in curative treatment approaches.

Newer Reports Using Cellular Support

A number of experiences have been reported since transplantation for SCLC was last reviewed.[46] Jennis et al[53] treated 10 extensive-stage patients with partial responses to ifosfamide/cisplatin/etoposide chemotherapy with high-dose cyclophosphamide for mobilization. Six patients underwent transplantation along with administration of high-dose methotrexate and etoposide. Near complete response was obtained in all patients, however, all relapsed after a median time of 4 months later. Of note, half the patients had documented tumor contamination of their peripheral blood progenitor cells.

In this Polish experience, 6 patients with limited-stage disease and 20 with extensive-stage disease were treated with two cycles of high-dose cyclophosphamide and etoposide as induction, followed by administration of the same drugs in 6 patients or bischloroethyl-nitrosourea in 20. Seven of 18 patients converted from partial to complete responses. Seven patients were already in complete response. Five patients remain progression free 3 to 89 months later. Of the patients with overall complete responses, 29% remained disease free after [is greater than] 2 years.[64] Brugger et al[65] reported on 18 patients with limited-stage disease who received two cycles of vincristine/ifosfamide/ cisplatin/etoposide with mobilization of peripheral blood progenitor cells. Thirteen patients (72%) received high-dose ifosfamide/carboplatin/etoposide with epirubicin; three were nonresponders and two with poor performance status were not considered candidates. With a median of 14 months follow-up, event-free survival is 69%. Nine patients remain progression free.

At the Dana Farber Cancer Institute and Beth Israel Hospital, [is greater than] 50 patients with limited-stage SCLC and [is greater than] 25 patients with extensive-stage SCLC have been treated with a high-dose combination of alkylating agents following response to conventional-dose induction therapy. Of the original cohort of 36 patients with limited-stage SCLC (all had stage N2 or N3 disease), 29 were in or near complete response prior to treatment with high-dose cyclophosphamide, carmustine, and cisplatin with bone marrow support (plus support with peripheral blood stem cells in some patients) followed by chest and prophylactic cranial radiotherapy,[62-63] with a minimum follow-up of 36 months after completion of high-dose chemotherapy (range, 36 months to 10 years; 5-year event-free survival, 52%). Of the extensive-stage patients, 15 to 20% remain progression free [is greater than] 2 years after high-dose chemotherapy (A. Elias, MD; unpublished data; January, 1999). Local regional relapse represents about 50% of all relapses.

FUTURE DIRECTIONS

Intensify Involved Field Radiotherapy

As summarized by meta-analyses of randomized trials, chest radiotherapy provides a 25% improvement in local-regional control and a 5% increase in long-term progression-free survival for limited-stage SCLC.[66-67] With the commonly used 45- to 50-Gy thoracic radiotherapy, chest relapse remains unacceptably high (an approximately 60% actuarial risk of local relapse by 3 years)[68-70] and may be underestimated due to the competing risk of systemic relapse.[71] Since chest-only relapse is observed in about 40% of patients, further enhancement of local-regional control may increase the proportion of long-term survivors. This concept recently has been supported by the survival benefit of chest radiotherapy after mastectomy for breast cancer. If systemic control is improved by high-dose chemotherapy, initial failure in local-regional sites may become more prevalent.

The dose intensity of chest radiotherapy has not been well studied. The Eastern Cooperative Oncology Group/ Radiation Therapy Oncology Group recently reported a comparison of 45-Gy chest radiotherapy given daily over 5 weeks with that given twice daily over 3 weeks, with concurrent cisplatin and etoposide chemotherapy.[72] Intensified chest radiotherapy reduced actuarial risk of chest failure from 61% to 48% at 2 to 3 years (p [is less than] 0.05). Further follow-up indicates that the daily radiotherapy had 75% local failure, with or without distant failure, whereas the twice-daily radiotherapy had a 42% overall local failure rate. There is now a survival advantage for the more intensive radiotherapy. Choi[73] escalated the dose of radiotherapy in cohorts of 5 to 6 patients with limited-stage SCLC. Thoracic radiotherapy was given concurrently with cisplatin and etoposide chemotherapy either as daily 180-cGy fractions or as twice-daily 150-cGy fractions. The maximal tolerated doses with respect to acute esophagitis appear to be 45 Gy for twice-daily administration and 70 Gy once daily administration, using a shrinking field technique. Thus, marked intensification of the radiotherapy dose appears to be possible and should be evaluated in a randomized setting.

The Cancer and Leukemia Group B and Southwest Oncology Group activated a phase II feasibility trial stemming from the Dana Farber Cancer Institute/Beth Israel Hospital experience. Patients [is less than] 60 years old with limited-stage disease were treated with four cycles of cisplatin and etoposide with concurrent twice-daily chest radiotherapy to 45 Gy (150-cGy fractions). Those patients achieving complete or near complete responses received high-dose cyclophosphamide, cisplatin, and carmustine with autologous stem cell support. On recovery, prophylactic cranial irradiation is given. It is hoped that this will lead to a phase III trial that tests the concept of dose during intensification in patients with excellent initial response.

Intensify Induction

Induction therapy reduces tumor burden and allows the selection of patients possessing chemosensitive tumors for subsequent dose intensification. Rapidly progressive systemic and local symptoms from SCLC can be controlled with marked improvement of performance status. Moreover, reduction of micrometastases in the marrow and/or circulating buffy coat, as discussed below, should be achieved. On the other hand, during induction, chemoresistant tumor cells might proliferate or even be induced by induction. Several strategies have been explored to intensify the close early in treatment. As previously discussed, the weekly multidrug regimens had greater planned dose intensity, but required enough dose reduction and delay due to unacceptable toxicity such that the actual delivered dosing was not substantively enhanced.[23,24] Similar findings were noted in cytokine-supported trials.[74]

As suggested by the trial of Arriagada et al,[17] initial intensification of induction may improve overall disease-free survival and overall survival. A logical extension of this concept would be to administer multicycle, dose-intensive combination therapies supported by cytokines and peripheral blood progenitor cells using either repeated cycles of the same regimen[75-78] or a sequence of different agents.[79-82] Increasing experience with sequential cycles of stem cell-supported therapy have been reported for the treatment of SCLC patients with good performance status. The doses delivered in individual cycles ranged from the conventional dose, but given more frequently, to moderately intensified doses (about two thirds of the usual doses given to transplant patients). Pettengell et al[77] have explored ways to achieve greater dose intensity with the ICE regimen. In a phase I trial, 25 patients received conventional-dose ICE for six cycles. Autologous hematopoietic cell support was given on day 3 of chemotherapy. The cycle length was 3 weeks using cryopreserved pheresis products or 2 weeks using either pheresis products or 750 mL of whole blood stored at 4 [degrees] C. By repeating cycles when platelets levels had recovered to [is greater than] 30,000/[micro]L, the full planned dose intensity for each of the study arms was achieved over the first three cycles, although only 56% of patients completed all six cycles. The mortality rate was 12%, the complete response rate was 64%, and the median follow-up was 10 months, and, thus, the longer-term outcomes are unknown. The authors note that the collection of whole blood without cryopreservation reduced the cost and complexity of treatment substantially.[77] In a subsequent randomized phase II study, Woll et al[76] treated 50 "good prognosis" patients with ICE given either every 2 or 4 weeks. The median dose intensity delivered over the first three cycles was 0.99 (range, 0.33 to 1.02) vs 1.8 (range, 0.99 to 1.97), respectively, on the 4-week cycle vs the 2-week cycle. More hematopoietic and infectious toxicity was encountered on the standard-dose 4-week arm of the study.

Perey et al[78] reported an European Bone Marrow Transplant Group experience with 47 patients, of whom 35 were able to be evaluated at the time of this report. Mobilization was achieved with epirubicin and G-CSF followed by three cycles of moderately intensive ICE. Radiation therapy to the chest and head was recommended. The overall complete or near-complete response rate was observed in 69% of patients, and the mortality rate was 14%.

Humblet et al[78] treated 37 limited-stage patients with four intensive alternating cycles of ifosfamide with etoposide, and carboplatin with etoposide.[78] Patients received 10-Gy thoracic radiotherapy in five fractions concurrently with each chemotherapy administration. The median follow-up was 16 months and the median event-free survival time was 18 months, and 80% remain alive at 30 months. Perhaps because no prophylactic cranial irradiation was performed, 8 of 13 relapses occurred in the brain. The mortality rate was 3%.

Minimal Residual Tumor/Autograft Involvement

Tumor contamination of stem cells may be a source of relapse, particularly since stem cells must be protected from the high-dose therapy. As demonstrated by gene-marking studies, residual tumor cells contribute to relapse in certain hematologic malignancies and neuroblastomas.[82-84] It is less clear whether these cells are the sole cause for relapse or whether their presence indicates that the patient has increased systemic chemotherapy-resistant tumor burden. Gene-marking experiments in solid tumors have not yet been informative.[85]

In SCLC, the bone marrow is one of the most common metastatic sites. Of patients with untreated SCLC who have negative results of histologic examinations of their bone marrow at diagnosis, small trials have demonstrated that subclinical micrometastatic disease is detected in bone marrow in 13 to 54% of patients with limited-stage SCLC and in 44 to 77% of patients with extensive-stage SCLC by immunohistochemical techniques that have a sensitivity of detection of 1 in 104 cells.[86-90] Two small series suggest that two thirds of patients with excellent chemotherapy response had residual contamination.[91,92] Leonard et al[92] suggested that residual tumor predicted relapse. In patients with metastatic SCLC or breast cancer, peripheral blood cells that were mobilized with G-CSF during the first cycle of vinblastine, ifosfamide, and cisplatin chemotherapy had demonstrable circulating tumor cells, although their viability was not established.[93] The mobilization of tumor cells after the second cycle of chemotherapy was apparently not observed, supporting the contention that in vivo chemotherapy induction can "purge" the patient and the autologous stem cell source. In our own unpublished data, up to 85% of our patients with limited disease in or near complete response prior to high-dose chemotherapy have detectable tumor cells in their bone marrow, as shown by keratin staining.

Numerous chemotherapeutic agents have major clinical activity against overt SCLC, although the uniformly dismal clinical outcomes suggest that differing systemic drugs fail to eradicate a central core of tumor stem cells, presumably enriched for in vivo resistance mechanisms. Identification and characterization of these residual cancer cells may guide therapeutic strategies to specifically target these cells. Minimal residual tumor characterization then could be employed to determine additional treatment. Thus, the detection of heterogeneity and the analysis of patterns of coexpression of various markers are the focus of our effort to detect rare cells. We are utilizing a confocal fluorescence microscope with automated computerized scanning that uses one set of fluorescent probes for detection and a second set with different fluorophores for biological characterization.[94] Prospective trials to evaluate the clinical significance of bone marrow or peripheral blood tumor contamination and the impact of novel stem cell sources to support high-dose therapy are being started.

CONCLUSION

The two major strategies for administering high-dose chemotherapy for SCLC are the multicycle approach and the "later" intensification. The advantages of each approach are evident. The multicycle approach can achieve early dose intensity and maintain it for about three to four cycles. The disadvantages of this approach include lower-than-transplant doses, high mortality rates, general inability to deliver chest radiotherapy early (except for the Humblet et al[82] trial, which uses a relatively low-dose thoracic radiotherapy), and the collection of stem cells early in treatment when they are highly likely to be contaminated with tumor cells. On the other hand, the later intensification can take advantage of initial therapy to control the tumor-related symptoms with consequent improved performance status for the patients, the partial purge of stem cell sources, the ability to give thermoradiotherapy early during intense induction therapy. The major disadvantage is the later administration of the dose-intense cycle, although this drawback can be surmounted in part by intensification and shortening of induction chemoradiotherapy.

High-dose therapy kills more tumor cells. In the situations in which toxicity is acceptable, it will result in prolonged progression-free survival. An additional group of patients may achieve minimal residual tumor burden (near-cure). If additional targets of residual tumor cells can be identified for novel treatment strategies and modalities, high-dose therapy may have an increased value. Most biological strategies, such as replacement of the retinoblastoma gene and/or p53 function, interference with autocrine or paracrine growth loops, or immunologic therapy (interleukin 2, interleukin 12, immunotoxins, or tumor vaccines), work best against minimal tumor burden.

(*) Median follow-up was 3 years, with wide variability between studies.

CR = complete response;

ED = extensive-stage disease;

LD = limited-stage disease;

PR = partial response;

SD = stable disease.

Table 2--Consolidation of Responding SCLC With High-Dose Chemotherapy With ABMT(*)

(*) RT = radiotherapy.

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(*) From the Dana-Farber Cancer Institute, Harvard Medical School Boston, MA.

Supported in part by a grant from the Public Health Service by grant CA13849 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

Correspondence to: Anthony Elias, MD, Harvard Medical School, Department of Medicine, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115

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