Phase II Study of 9-Nitro-Camptothecin in Patients With Advanced Chordoma or Soft Tissue Sarcoma
http://www.100md.com
《临床肿瘤学》
the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
ABSTRACT
PURPOSE: The purpose of this trial was to assess the objective clinical response, toxicity, and time to progression of treatment with 9-Nitro-Camptothecin (9-NC) in patients with advanced chordoma, soft tissue sarcoma (STS), and gastrointestinal stromal tumor (GIST).
PATIENTS AND METHODS: Patients with locally advanced and/or metastatic chordoma, STS, or GIST received 9-NC 1.25 mg/m2 orally for 5 consecutive days followed by 2 days of rest. Patients continued on therapy until disease progression, uncontrollable toxicity, or withdrawal of consent.
RESULTS: From January 2000 to May 2003, 51 patients (15 chordoma, 23 STS, 13 GIST patients) enrolled. One patient (7%) with chordoma and one patient (4%) with STS had an objective response. Median time to progression was 9.9, 8.0, and 8.3 weeks for chordoma, STS, and GIST patients, respectively. Three- and 6-month progression-free survival rates were 47% and 33% for chordoma patients, 26% and 22% for STS patients, and 31% and 23% for GIST patients, respectively. Ten patients (10%) stopped study drug before disease progression secondary to toxicity. Common adverse events included anemia (42 patients, seven with grade 3/4 toxicity), leukopenia (33 patients, nine with grade 3/4 toxicity), fatigue (30 patients, three with grade 3/4 toxicity), nausea (34 patients, six with grade 3/4 toxicity), and diarrhea (28 patients, five with grade 3/4 toxicity).
CONCLUSION: 9-NC has modest activity in delaying progression in patients with unresectable or metastatic chordoma. 9-NC is associated with moderate toxicity and shows little benefit in patients with advanced STS and GIST.
INTRODUCTION
Chordoma is a relatively slow-growing primary bone tumor that is derived from embryonic notochord remnants and accounts for 1% to 4% of primary malignant bone tumors.1 Because all other primary bone cancers are sarcomas, chordoma is often considered a sarcoma. However, chordoma is of ectodermal origin and it cannot technically be considered a sarcoma.2 It occurs along the axial spine in the sacral (60%), spheno-occipital/nasal (25%), cervical (10%), and thoracolumbar regions (5%).1 Although chordoma has often been thought to be of low metastatic potential, spread of disease to lung, bone, soft tissue, lymph node, liver, and skin has been described in up to 43% of patients.1,3-5
Standard therapy consists of radical or subtotal surgical resection, depending on feasibility.6 Due to tumor friability and proximity to vital structures, residual disease is common and local recurrence is the norm. Various modalities of radiation therapy may improve progression-free survival and local control rates.7-12 Effective options for systemic therapy for chordoma are limited. We could not identify any published prospective therapeutic trials in chordoma patients, and there is no accepted standard of care.6,13
Sarcoma is an uncommon mesenchymal malignancy that encompasses many tumors of both the soft tissue and bone. Systemic therapy for soft tissue sarcoma (STS) centers on a few chemotherapeutic agents. Single-agent response rates for doxorubicin and ifosfamide vary, but have been reported at median rates of 26%.14 In combination, doxorubicin and ifosfamide is a commonly used first-line therapy and has reported response rates ranging from 7% to 57%.14 The combination of gemcitabine and docetaxel has recently been reported to have significant activity as well, with response rates of 43%.15 Studies of additional investigational agents, especially in the metastatic setting, are ongoing with variable success.
Gastrointestinal stromal tumor (GIST) is a subtype of STS that resembles the interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract.16,17 The pathogenesis of this tumor involves a gain-of-function mutation in the KIT proto-oncogene leading to a constitutively active tyrosine kinase.17 An important feature distinguishing GIST from other STS is their poor response to conventional chemotherapy.18 In this trial of cytotoxic therapy, STS patients were stratified into GIST and non-GIST STS patients so that their response rates could be assessed independently.
Nine-nitro-camptothecin (9-NC, 9-nitro-20(S)-camptothecin, rubitecan; SuperGen Inc, Dublin, CA) is derived from the Asian tree Camptotheca acuminata, and has been found to have antineoplastic activity in a number of tumors.19 The mechanism of anticancer activity is inhibition of topoisomerase 1, an enzyme that breaks and reseals single-stranded DNA allowing supercoiled DNA to relax and replicate.19-21 Preclinical studies of 9-NC revealed tumor growth inhibition in human myeloid leukemia, melanoma, breast and ovarian carcinoma cell lines and xenograft models.22-25
A phase I trial of 9-NC in 34 patients showed activity in a variety of malignancies and suggested a phase II dose for previously untreated or minimally treated patients of 1.5 mg/m2/d for 5 consecutive days followed by a 2-day rest period.26 Dose-limiting toxicities were hematologic and gastrointestinal, and chemical cystitis was also seen in 23% of patients. Subsequent studies produced lower rates of cystitis with recommended oral hydration.
We conducted a phase II trial of 9-NC in GIST and non-GIST STS patients. During the trial, we treated a patient with chordoma and noted a clinical response. Acknowledging that chordomas are distinct from STS, the trial was amended to formally include patients with chordoma, and in this article we report on each of these groups.
PATIENTS AND METHODS
Eligibility Criteria
Patients older than 18 years with a confirmed pathologic diagnosis of chordoma, non-GIST STS (intermediate or high grade), or malignant GIST were eligible. Patients had incurable locally advanced or metastatic disease and bidimensional measurable disease. Other eligibility criteria included: Eastern Cooperative Oncology Group performance status of 0-2, adequate bone marrow function (WBC count > 2,500 cells/mm2, hemoglobin > 10 g/dL, platelet count > 100,000/mm2), hepatic function (AST 3x normal, serum bilirubin 2.0 mg/dL), and renal function (serum creatinine 2.0 mg/dL). Patients with child-making potential agreed to use an accepted contraceptive method. There was no limit on previous therapies. Although there was no specification regarding the need for prior therapy, in chemotherapy-naive patients, the option of treatment with a regimen containing doxorubicin and ifosfamide was discussed. Patients also could not have a history of pleural or pericardial effusions for at least one year before enrollment, no prior therapy for at least 3 weeks, and no prior treatment with 9-NC or other camptothecin analogs. Patients who were pregnant or nursing were also excluded. The protocol was approved by the institutional review board and all patients were required to provide written informed consent.
Statistical Considerations
The trial was originally developed to study patients with STS, stratified by GIST or non-GIST tumor designation. A patient with a chordoma was treated with clinical response, and the trial was formally amended to include patients with chordoma. All strata had identical study designs. In each cohort, the Minimax two-stage accrual design was used, with accrual of 13 eligible patients in the first stage.27 If one or more responses were seen in the first 13 patients, an additional 14 patients were to be accrued. Further study with 9-NC would be proposed if four or more responses were achieved in the 27 eligible patients. This design provided 80% power at the 5% significance level to detect a difference between a response rate of 5% and one of 20%. Accrued patients were to receive 8 weeks of 9-NC administered orally for the first 5 consecutive days of a week at 1.5 mg/m2/d followed by 2 days rest. This dose was later modified to 1.25 mg/m2/d due to toxicity. One cycle consisted of 4 weeks of treatment. Patients with disease stabilization or regression after 2 cycles received additional courses of treatment until disease progression, symptomatic progression, uncontrollable toxicity, or withdrawal of consent.
Estimates of the time from study registration to treatment failure and death were produced using the Kaplan-Meier technique. The relationship between toxicities and patient characteristics (disease type, age, sex, number of prior systemic treatments, prior radiation therapy status, and prior surgery status) was also assessed. The rate of toxicity was calculated for five major toxicity categories (hematologic, gastrointestinal, renal, constitutional, and hepatic). Within each toxicity category, one rate was calculated for any toxicity grade and a separate rate was calculated for grade 3 or 4 toxicities only. For categoric patient characteristic variables (eg, disease type), Fisher's exact test was used to assess the relationship with toxicity, and the Kruskal-Wallis test was used to test the relationship between toxicity and continuous patient variables (eg, age). All tests were performed at the 5% significance level and using the SAS System (SAS/STAT User's Guide, Version 6, 1990; SAS Institute, Cary, NC).
Dose Modification
Dose level increases or reductions were based on weekly blood counts and assessments of toxicity from the baseline dose level of 0 (Table 1). Dose level 0 was initially 1.5 mg/m2/daily but this was decreased to 1.25 mg/m2/daily because of excessive toxicity. For WBC nadirs higher than 2,000 cells/mm2 and platelet nadirs higher than 150,000 cells/mm2 for 4 weeks without other drug toxicity, the dose level was increased by one level. For WBC nadirs of 500 to 1,000 cells/mm2 and platelet nadirs of 50,000 to 100,000 cells/mm2, therapy was held and decreased by one level on restarting therapy, once parameters returned to baseline levels. For WBC nadirs lower than 500 cells/mm2 and platelet nadirs lower than 50,000 cells/mm2, therapy was held and decreased by two levels on restarting therapy, once parameters returned to baseline levels. The use of granulocyte-colony–stimulating factor was allowed in cases of granulocyte levels of less than 500 cells/mm2 or neutropenic fever, but was not given concurrently with 9-NC. Except for alopecia or emesis, patients experiencing nonhematologic toxicities of grade 3 severity were decreased 1 dose level or held treatment, based on the discretion of the physician/investigator. For grade 4 toxicities, treatment was held until recovery and was restarted at a two-level decrease.
Pretreatment Evaluation and Follow-Up
Pretreatment evaluation consisted of a complete medical history, physical examination including measurement of any palpable masses, assessment of performance status, vital signs, weight, identification of disease-related symptoms, blood chemistries, complete blood cell count and imaging (chest x-ray, computed tomography scan, or ultrasound). All evaluations were repeated after each 4-week cycle except for complete blood cell counts which were performed every 7 days, and imaging which was performed every 8 weeks.
Response Assessment
Measurable disease was assessed at baseline and every 8 weeks using the same modality. For patients attaining a clinical response, confirmation was obtained at least 4 weeks later using the same imaging technique. Complete response was defined as the complete disappearance of evident disease on physical exam and imaging. Partial response was defined as a greater than 50% shrinkage of measurable disease and no evidence of progression of any lesion or new lesions. The amount of measurable disease was determined by summing the product of each lesion's largest diameter times its perpendicular diameter. Stabilization of disease was defined as a change in measurable disease too small to meet the requirement for partial response or disease progression and appearance of no new lesions for a period of at least 4 weeks. Progressive disease referred to an unequivocal increase of at least 50% in the size of any measurable lesion, worsening of assessable disease, new lesions, reappearance of a lesion that had previously disappeared, or a significant deterioration in symptoms, weight, or performance status (unless the deterioration was clearly unrelated to the cancer).
RESULTS
Patient Characteristics
Fifty-one patients were enrolled from January 2000 to May 2003 (15 patients with chordoma, 23 patients with non-GIST STS, 13 patients with GIST). Due to lack of response in GIST patients, accrual to the second stage was not pursued. Both chordoma and non-GIST STS patients were advanced to the second stage, however, both arms of the trial were closed before meeting second stage accrual goals.
Patient characteristics are listed in Table 2. The median age for chordoma patients was 50 years (range, 24 to 79 years), non-GIST STS patients was 56 years (range, 27 to 74 years), and GIST patients was 62 years (range, 29 to 74 years). Patients with chordoma were treated with a median of zero prior systemic therapy regimens, compared with two previous regimens in patients with STS, and one previous regimen in GIST patients. The majority of patients were treated with surgical resection of their primary lesion (chordoma patients, 80%; STS patients, 87%; GIST patients, 92%), and most chordoma patients were also treated with radiation therapy (87%), compared with STS patients (65%) and GIST patients (8%). The patients' primary sites of disease is shown in Table 3.
Efficacy
Patients were evaluated for response after two cycles of therapy. Twelve of 15 chordoma patients, 14 of 23 non-GIST STS patients, and 10 of 13 GIST patients completed two cycles of therapy. Patients who did not complete 8 weeks of therapy were considered to have disease progression at the time of treatment discontinuation.
Chordoma patients received a median of four cycles of therapy (range, 1 to 10). The median time to progression in chordoma patients was 9.9 weeks (range, 4 to 36) with a 3-month progression-free survival (PFS) of 47% and a 6-month PFS of 33% (Table 4). One patient with recurrent chordoma of the clivus and cerebellar and dural metastases achieved a partial remission (Fig 1). The patient remained on therapy for 251 days with continued response but withdrew from therapy due to adverse effects. Stable disease was the best response achieved in the remainder of the chordoma patients that were assessed for efficacy.
Both non-GIST and GIST STS patients received a median of two cycles of therapy (range, 0 to 30). One patient with a leiomyosarcoma of the uterus achieved a partial remission; other patients had stable or progressive disease. The median time to progression among all non-GIST subtypes was 8.0 weeks (range, 1 to 133); the 3-month PFS was 26% and 6-month PFS was 22% (Table 4). Patients with GIST had similar outcomes with a median time to progression of 8.3 weeks (range, 2 to 47), 3-month PFS of 31%, and 6-month PFS of 23% (Table 4).
Among the subtypes of non-GIST STS, patients with fibrosarcoma fared most favorably, however only three patients with this histology were enrolled. One 29-year-old patient with a fibrosarcoma of the abdominal wall metastatic to the lungs had progressive disease on prior doxorubicin, ifosfamide, and dacarbazine combination chemotherapy. This patient had stable disease on 9-NC for 2.5 years. Some patients with leiomyosarcoma also appeared to have clinical benefit. Two patients with leiomyosarcomas of the retroperitoneum and uterus had PFS for more than 1 year.
Kaplan-Meier curves demonstrating the failure-free and overall survival rate of the three groups are presented in Figure 2. There is a noticeably superior overall survival rate for the GIST patients, despite a similar failure-free survival rate, when compared with the chordoma and non-GIST STS patients. This difference is best explained by the introduction of imatinib in the therapy of GIST patients shortly after the initiation of this trial.
Safety
One hundred twenty-nine grade 3 or 4 adverse events occurred in 36 patients (71%). Ten patients (20%) discontinued treatment because of toxicity. In six patients, treatment discontinuation was felt to be medically necessary, whereas in the remaining four patients it was because of patient preference. Reasons for treatment discontinuation included diarrhea, nausea, vomiting, myelosuppression, febrile neutropenia, recurrent urinary infections, and severe constitutional symptoms.
Common treatment related toxicities of any grade were anemia, leukopenia, and nausea, and these are elaborated further in Table 5. One patient required a platelet transfusion and three others required blood transfusions. Five patients (10%) were treated for febrile neutropenia. The relationship between patient characteristic variables and major toxicities was assessed. The only significant relationship was found in patients who experienced grade 3 or 4 hematologic toxicities. Fifty-two percent of patients with prior radiation therapy had this toxicity as compared with 6% of patients without prior radiation therapy (P = .0073).
DISCUSSION
Topoisomerase I inhibitors are being used with increasing frequency in clinical practice. 9-NC is an appealing agent given its oral bioavailability and preclinical activity.
Following recognition of clinical benefit in a patient with chordoma treated with 9-NC, we felt that it was important to formally amend the trial to recognize this tumor as an entity distinct from sarcoma, increase efforts to attract patients with this disease, and describe the outcome with chordoma separately. Propelled by experiences with imatinib in GIST, we are increasingly aware that sarcoma subtypes are indeed distinct from each other. This trial presents an early attempt to separate outcomes based on tumor types. This concept has since been further developed by Thall et al28 by proposing a hierarchical Bayesian trial design in treating sarcoma subtypes.
This is the first prospective phase II trial of systemic therapy in chordoma patients that we could identify in the literature. Retrospective series have shown little utility to using cytotoxic chemotherapy. Only case reports have shown chemotherapy to be of benefit.29,30 Recently, Casali et al31 described clinical benefit in treating patients with advanced chordoma with imatinib mesylate. Success to date has otherwise been mostly limited to dedifferentiated chordomas.32
Although the objective response rate was low in this small sample of patients, 9-NC did appear to delay progression in some chordoma patients. Unfortunately, there are no adequate historical controls or survival curves of patients with progressive chordoma for comparison identified in the literature. The fact that the median overall survival in this group of patients was 24 months, as compared with reported mean survivals of all chordoma patients of up to 73 months, implies fairly advanced disease.13,33,34
The chordoma arm was closed before reaching the accrual goal of 27 patients. Because of early success of 9-NC and the rarity of chordoma, there was a commitment to expand this trial to two additional sites. However, due to financial constraints this was not possible. Despite a relatively large influx of chordoma patients to our center from across the country, enrollment to the trial was limited due to patients' comorbidities and geographic constraints. We recognized we could not complete accrual as a single institution and reluctantly closed the trial.
In this study, 9-NC did not show significant disease activity in STS. Because of our experience and the recently published M.D. Anderson series by Patel et al,35 the non-GIST STS arm was closed early after 23 patients. Specifically, Patel et al treated 17 and 39 patients with gastrointestinal leiomyosarcomas (mostly GIST) and other STS, respectively, also with minimal clinical benefit. Although our target study accrual was 27 patients, it did not appear reasonable to continue this trial in consideration of both experiences, as well as the introduction of other promising agents in this patient population.
Topoisomerase I inhibitors have also been shown to have synergistic anticancer activity when administered with alkylating agents in human cell lines and xenografts.36,37 In pediatric rhabdomyosarcomas, topotecan, a topoisomerase I inhibitor also derived from the parent compound 20(S)-camptothecin, is efficacious when used sequentially with cyclophosphamide.38 This may be a rationale for using 9-NC in a combination setting, especially in this patient population. Additional dose reductions may be necessary due to toxicity concerns.
Consistent with the lack of efficacy of other cytotoxic agents, 9-NC was not active in GIST patients. Since the initiation of this trial, the advent of the tyrosine kinase inhibitor imatinib mesylate has revolutionized the treatment of GIST patients.39,40 Additional therapy in these patients will likely continue to be directed at inhibiting the mutated KIT tyrosine kinase.
9-NC exhibited moderate toxicity in this trial with 20% of patients withdrawing because of toxicity by protocol mandate or personal preference. This was in excess of what was expected based on phase I and II data, and prompted a midtrial amendment to decrease the starting dose from 1.5 mg/m2/d to 1.25 mg/m2/d for 5 days on, 2 days off. The high number of dropouts due to toxicity may be related to extensive pretreatment of patients. The majority of treatment discontinuations were in STS patients. Forty-four percent of STS patients had been treated with two or more previous therapies. In a phase I study, the greatest toxicity was seen in patients who were heavily pretreated, and the recommended phase II dose in this patient population was 1.0 mg/m2/d.41
In conclusion, although a few patients with STS appeared to derive benefit from treatment with 9-NC, a large majority did not. Thus, we believe that further investigation of 9-NC as a single agent in STS is not warranted. As some minimal activity was noted, there may be benefit by combining 9-NC with novel or other cytotoxic agents.
Although activity was limited, we do believe that 9-NC may be a promising agent in patients with progressive chordoma. Given the lack of an otherwise effective systemic agent in treating this disease, the desire to further investigate 9-NC is increased. This study may serve as a basis of comparison for future trials in chordoma. Due to the rarity of this disease, accrual to clinical trials is difficult and may best be pursued on a multi-institutional and perhaps on an international level.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Laurence H. Baker, Ascentia, Kinisia, Novartis. Honoraria: Laurence H. Baker, Ascentia, Kinisia, Novartis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank Jacqueline Williamson for her assistance with data management.
NOTES
Supported by SuperGen Inc.
Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
PURPOSE: The purpose of this trial was to assess the objective clinical response, toxicity, and time to progression of treatment with 9-Nitro-Camptothecin (9-NC) in patients with advanced chordoma, soft tissue sarcoma (STS), and gastrointestinal stromal tumor (GIST).
PATIENTS AND METHODS: Patients with locally advanced and/or metastatic chordoma, STS, or GIST received 9-NC 1.25 mg/m2 orally for 5 consecutive days followed by 2 days of rest. Patients continued on therapy until disease progression, uncontrollable toxicity, or withdrawal of consent.
RESULTS: From January 2000 to May 2003, 51 patients (15 chordoma, 23 STS, 13 GIST patients) enrolled. One patient (7%) with chordoma and one patient (4%) with STS had an objective response. Median time to progression was 9.9, 8.0, and 8.3 weeks for chordoma, STS, and GIST patients, respectively. Three- and 6-month progression-free survival rates were 47% and 33% for chordoma patients, 26% and 22% for STS patients, and 31% and 23% for GIST patients, respectively. Ten patients (10%) stopped study drug before disease progression secondary to toxicity. Common adverse events included anemia (42 patients, seven with grade 3/4 toxicity), leukopenia (33 patients, nine with grade 3/4 toxicity), fatigue (30 patients, three with grade 3/4 toxicity), nausea (34 patients, six with grade 3/4 toxicity), and diarrhea (28 patients, five with grade 3/4 toxicity).
CONCLUSION: 9-NC has modest activity in delaying progression in patients with unresectable or metastatic chordoma. 9-NC is associated with moderate toxicity and shows little benefit in patients with advanced STS and GIST.
INTRODUCTION
Chordoma is a relatively slow-growing primary bone tumor that is derived from embryonic notochord remnants and accounts for 1% to 4% of primary malignant bone tumors.1 Because all other primary bone cancers are sarcomas, chordoma is often considered a sarcoma. However, chordoma is of ectodermal origin and it cannot technically be considered a sarcoma.2 It occurs along the axial spine in the sacral (60%), spheno-occipital/nasal (25%), cervical (10%), and thoracolumbar regions (5%).1 Although chordoma has often been thought to be of low metastatic potential, spread of disease to lung, bone, soft tissue, lymph node, liver, and skin has been described in up to 43% of patients.1,3-5
Standard therapy consists of radical or subtotal surgical resection, depending on feasibility.6 Due to tumor friability and proximity to vital structures, residual disease is common and local recurrence is the norm. Various modalities of radiation therapy may improve progression-free survival and local control rates.7-12 Effective options for systemic therapy for chordoma are limited. We could not identify any published prospective therapeutic trials in chordoma patients, and there is no accepted standard of care.6,13
Sarcoma is an uncommon mesenchymal malignancy that encompasses many tumors of both the soft tissue and bone. Systemic therapy for soft tissue sarcoma (STS) centers on a few chemotherapeutic agents. Single-agent response rates for doxorubicin and ifosfamide vary, but have been reported at median rates of 26%.14 In combination, doxorubicin and ifosfamide is a commonly used first-line therapy and has reported response rates ranging from 7% to 57%.14 The combination of gemcitabine and docetaxel has recently been reported to have significant activity as well, with response rates of 43%.15 Studies of additional investigational agents, especially in the metastatic setting, are ongoing with variable success.
Gastrointestinal stromal tumor (GIST) is a subtype of STS that resembles the interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract.16,17 The pathogenesis of this tumor involves a gain-of-function mutation in the KIT proto-oncogene leading to a constitutively active tyrosine kinase.17 An important feature distinguishing GIST from other STS is their poor response to conventional chemotherapy.18 In this trial of cytotoxic therapy, STS patients were stratified into GIST and non-GIST STS patients so that their response rates could be assessed independently.
Nine-nitro-camptothecin (9-NC, 9-nitro-20(S)-camptothecin, rubitecan; SuperGen Inc, Dublin, CA) is derived from the Asian tree Camptotheca acuminata, and has been found to have antineoplastic activity in a number of tumors.19 The mechanism of anticancer activity is inhibition of topoisomerase 1, an enzyme that breaks and reseals single-stranded DNA allowing supercoiled DNA to relax and replicate.19-21 Preclinical studies of 9-NC revealed tumor growth inhibition in human myeloid leukemia, melanoma, breast and ovarian carcinoma cell lines and xenograft models.22-25
A phase I trial of 9-NC in 34 patients showed activity in a variety of malignancies and suggested a phase II dose for previously untreated or minimally treated patients of 1.5 mg/m2/d for 5 consecutive days followed by a 2-day rest period.26 Dose-limiting toxicities were hematologic and gastrointestinal, and chemical cystitis was also seen in 23% of patients. Subsequent studies produced lower rates of cystitis with recommended oral hydration.
We conducted a phase II trial of 9-NC in GIST and non-GIST STS patients. During the trial, we treated a patient with chordoma and noted a clinical response. Acknowledging that chordomas are distinct from STS, the trial was amended to formally include patients with chordoma, and in this article we report on each of these groups.
PATIENTS AND METHODS
Eligibility Criteria
Patients older than 18 years with a confirmed pathologic diagnosis of chordoma, non-GIST STS (intermediate or high grade), or malignant GIST were eligible. Patients had incurable locally advanced or metastatic disease and bidimensional measurable disease. Other eligibility criteria included: Eastern Cooperative Oncology Group performance status of 0-2, adequate bone marrow function (WBC count > 2,500 cells/mm2, hemoglobin > 10 g/dL, platelet count > 100,000/mm2), hepatic function (AST 3x normal, serum bilirubin 2.0 mg/dL), and renal function (serum creatinine 2.0 mg/dL). Patients with child-making potential agreed to use an accepted contraceptive method. There was no limit on previous therapies. Although there was no specification regarding the need for prior therapy, in chemotherapy-naive patients, the option of treatment with a regimen containing doxorubicin and ifosfamide was discussed. Patients also could not have a history of pleural or pericardial effusions for at least one year before enrollment, no prior therapy for at least 3 weeks, and no prior treatment with 9-NC or other camptothecin analogs. Patients who were pregnant or nursing were also excluded. The protocol was approved by the institutional review board and all patients were required to provide written informed consent.
Statistical Considerations
The trial was originally developed to study patients with STS, stratified by GIST or non-GIST tumor designation. A patient with a chordoma was treated with clinical response, and the trial was formally amended to include patients with chordoma. All strata had identical study designs. In each cohort, the Minimax two-stage accrual design was used, with accrual of 13 eligible patients in the first stage.27 If one or more responses were seen in the first 13 patients, an additional 14 patients were to be accrued. Further study with 9-NC would be proposed if four or more responses were achieved in the 27 eligible patients. This design provided 80% power at the 5% significance level to detect a difference between a response rate of 5% and one of 20%. Accrued patients were to receive 8 weeks of 9-NC administered orally for the first 5 consecutive days of a week at 1.5 mg/m2/d followed by 2 days rest. This dose was later modified to 1.25 mg/m2/d due to toxicity. One cycle consisted of 4 weeks of treatment. Patients with disease stabilization or regression after 2 cycles received additional courses of treatment until disease progression, symptomatic progression, uncontrollable toxicity, or withdrawal of consent.
Estimates of the time from study registration to treatment failure and death were produced using the Kaplan-Meier technique. The relationship between toxicities and patient characteristics (disease type, age, sex, number of prior systemic treatments, prior radiation therapy status, and prior surgery status) was also assessed. The rate of toxicity was calculated for five major toxicity categories (hematologic, gastrointestinal, renal, constitutional, and hepatic). Within each toxicity category, one rate was calculated for any toxicity grade and a separate rate was calculated for grade 3 or 4 toxicities only. For categoric patient characteristic variables (eg, disease type), Fisher's exact test was used to assess the relationship with toxicity, and the Kruskal-Wallis test was used to test the relationship between toxicity and continuous patient variables (eg, age). All tests were performed at the 5% significance level and using the SAS System (SAS/STAT User's Guide, Version 6, 1990; SAS Institute, Cary, NC).
Dose Modification
Dose level increases or reductions were based on weekly blood counts and assessments of toxicity from the baseline dose level of 0 (Table 1). Dose level 0 was initially 1.5 mg/m2/daily but this was decreased to 1.25 mg/m2/daily because of excessive toxicity. For WBC nadirs higher than 2,000 cells/mm2 and platelet nadirs higher than 150,000 cells/mm2 for 4 weeks without other drug toxicity, the dose level was increased by one level. For WBC nadirs of 500 to 1,000 cells/mm2 and platelet nadirs of 50,000 to 100,000 cells/mm2, therapy was held and decreased by one level on restarting therapy, once parameters returned to baseline levels. For WBC nadirs lower than 500 cells/mm2 and platelet nadirs lower than 50,000 cells/mm2, therapy was held and decreased by two levels on restarting therapy, once parameters returned to baseline levels. The use of granulocyte-colony–stimulating factor was allowed in cases of granulocyte levels of less than 500 cells/mm2 or neutropenic fever, but was not given concurrently with 9-NC. Except for alopecia or emesis, patients experiencing nonhematologic toxicities of grade 3 severity were decreased 1 dose level or held treatment, based on the discretion of the physician/investigator. For grade 4 toxicities, treatment was held until recovery and was restarted at a two-level decrease.
Pretreatment Evaluation and Follow-Up
Pretreatment evaluation consisted of a complete medical history, physical examination including measurement of any palpable masses, assessment of performance status, vital signs, weight, identification of disease-related symptoms, blood chemistries, complete blood cell count and imaging (chest x-ray, computed tomography scan, or ultrasound). All evaluations were repeated after each 4-week cycle except for complete blood cell counts which were performed every 7 days, and imaging which was performed every 8 weeks.
Response Assessment
Measurable disease was assessed at baseline and every 8 weeks using the same modality. For patients attaining a clinical response, confirmation was obtained at least 4 weeks later using the same imaging technique. Complete response was defined as the complete disappearance of evident disease on physical exam and imaging. Partial response was defined as a greater than 50% shrinkage of measurable disease and no evidence of progression of any lesion or new lesions. The amount of measurable disease was determined by summing the product of each lesion's largest diameter times its perpendicular diameter. Stabilization of disease was defined as a change in measurable disease too small to meet the requirement for partial response or disease progression and appearance of no new lesions for a period of at least 4 weeks. Progressive disease referred to an unequivocal increase of at least 50% in the size of any measurable lesion, worsening of assessable disease, new lesions, reappearance of a lesion that had previously disappeared, or a significant deterioration in symptoms, weight, or performance status (unless the deterioration was clearly unrelated to the cancer).
RESULTS
Patient Characteristics
Fifty-one patients were enrolled from January 2000 to May 2003 (15 patients with chordoma, 23 patients with non-GIST STS, 13 patients with GIST). Due to lack of response in GIST patients, accrual to the second stage was not pursued. Both chordoma and non-GIST STS patients were advanced to the second stage, however, both arms of the trial were closed before meeting second stage accrual goals.
Patient characteristics are listed in Table 2. The median age for chordoma patients was 50 years (range, 24 to 79 years), non-GIST STS patients was 56 years (range, 27 to 74 years), and GIST patients was 62 years (range, 29 to 74 years). Patients with chordoma were treated with a median of zero prior systemic therapy regimens, compared with two previous regimens in patients with STS, and one previous regimen in GIST patients. The majority of patients were treated with surgical resection of their primary lesion (chordoma patients, 80%; STS patients, 87%; GIST patients, 92%), and most chordoma patients were also treated with radiation therapy (87%), compared with STS patients (65%) and GIST patients (8%). The patients' primary sites of disease is shown in Table 3.
Efficacy
Patients were evaluated for response after two cycles of therapy. Twelve of 15 chordoma patients, 14 of 23 non-GIST STS patients, and 10 of 13 GIST patients completed two cycles of therapy. Patients who did not complete 8 weeks of therapy were considered to have disease progression at the time of treatment discontinuation.
Chordoma patients received a median of four cycles of therapy (range, 1 to 10). The median time to progression in chordoma patients was 9.9 weeks (range, 4 to 36) with a 3-month progression-free survival (PFS) of 47% and a 6-month PFS of 33% (Table 4). One patient with recurrent chordoma of the clivus and cerebellar and dural metastases achieved a partial remission (Fig 1). The patient remained on therapy for 251 days with continued response but withdrew from therapy due to adverse effects. Stable disease was the best response achieved in the remainder of the chordoma patients that were assessed for efficacy.
Both non-GIST and GIST STS patients received a median of two cycles of therapy (range, 0 to 30). One patient with a leiomyosarcoma of the uterus achieved a partial remission; other patients had stable or progressive disease. The median time to progression among all non-GIST subtypes was 8.0 weeks (range, 1 to 133); the 3-month PFS was 26% and 6-month PFS was 22% (Table 4). Patients with GIST had similar outcomes with a median time to progression of 8.3 weeks (range, 2 to 47), 3-month PFS of 31%, and 6-month PFS of 23% (Table 4).
Among the subtypes of non-GIST STS, patients with fibrosarcoma fared most favorably, however only three patients with this histology were enrolled. One 29-year-old patient with a fibrosarcoma of the abdominal wall metastatic to the lungs had progressive disease on prior doxorubicin, ifosfamide, and dacarbazine combination chemotherapy. This patient had stable disease on 9-NC for 2.5 years. Some patients with leiomyosarcoma also appeared to have clinical benefit. Two patients with leiomyosarcomas of the retroperitoneum and uterus had PFS for more than 1 year.
Kaplan-Meier curves demonstrating the failure-free and overall survival rate of the three groups are presented in Figure 2. There is a noticeably superior overall survival rate for the GIST patients, despite a similar failure-free survival rate, when compared with the chordoma and non-GIST STS patients. This difference is best explained by the introduction of imatinib in the therapy of GIST patients shortly after the initiation of this trial.
Safety
One hundred twenty-nine grade 3 or 4 adverse events occurred in 36 patients (71%). Ten patients (20%) discontinued treatment because of toxicity. In six patients, treatment discontinuation was felt to be medically necessary, whereas in the remaining four patients it was because of patient preference. Reasons for treatment discontinuation included diarrhea, nausea, vomiting, myelosuppression, febrile neutropenia, recurrent urinary infections, and severe constitutional symptoms.
Common treatment related toxicities of any grade were anemia, leukopenia, and nausea, and these are elaborated further in Table 5. One patient required a platelet transfusion and three others required blood transfusions. Five patients (10%) were treated for febrile neutropenia. The relationship between patient characteristic variables and major toxicities was assessed. The only significant relationship was found in patients who experienced grade 3 or 4 hematologic toxicities. Fifty-two percent of patients with prior radiation therapy had this toxicity as compared with 6% of patients without prior radiation therapy (P = .0073).
DISCUSSION
Topoisomerase I inhibitors are being used with increasing frequency in clinical practice. 9-NC is an appealing agent given its oral bioavailability and preclinical activity.
Following recognition of clinical benefit in a patient with chordoma treated with 9-NC, we felt that it was important to formally amend the trial to recognize this tumor as an entity distinct from sarcoma, increase efforts to attract patients with this disease, and describe the outcome with chordoma separately. Propelled by experiences with imatinib in GIST, we are increasingly aware that sarcoma subtypes are indeed distinct from each other. This trial presents an early attempt to separate outcomes based on tumor types. This concept has since been further developed by Thall et al28 by proposing a hierarchical Bayesian trial design in treating sarcoma subtypes.
This is the first prospective phase II trial of systemic therapy in chordoma patients that we could identify in the literature. Retrospective series have shown little utility to using cytotoxic chemotherapy. Only case reports have shown chemotherapy to be of benefit.29,30 Recently, Casali et al31 described clinical benefit in treating patients with advanced chordoma with imatinib mesylate. Success to date has otherwise been mostly limited to dedifferentiated chordomas.32
Although the objective response rate was low in this small sample of patients, 9-NC did appear to delay progression in some chordoma patients. Unfortunately, there are no adequate historical controls or survival curves of patients with progressive chordoma for comparison identified in the literature. The fact that the median overall survival in this group of patients was 24 months, as compared with reported mean survivals of all chordoma patients of up to 73 months, implies fairly advanced disease.13,33,34
The chordoma arm was closed before reaching the accrual goal of 27 patients. Because of early success of 9-NC and the rarity of chordoma, there was a commitment to expand this trial to two additional sites. However, due to financial constraints this was not possible. Despite a relatively large influx of chordoma patients to our center from across the country, enrollment to the trial was limited due to patients' comorbidities and geographic constraints. We recognized we could not complete accrual as a single institution and reluctantly closed the trial.
In this study, 9-NC did not show significant disease activity in STS. Because of our experience and the recently published M.D. Anderson series by Patel et al,35 the non-GIST STS arm was closed early after 23 patients. Specifically, Patel et al treated 17 and 39 patients with gastrointestinal leiomyosarcomas (mostly GIST) and other STS, respectively, also with minimal clinical benefit. Although our target study accrual was 27 patients, it did not appear reasonable to continue this trial in consideration of both experiences, as well as the introduction of other promising agents in this patient population.
Topoisomerase I inhibitors have also been shown to have synergistic anticancer activity when administered with alkylating agents in human cell lines and xenografts.36,37 In pediatric rhabdomyosarcomas, topotecan, a topoisomerase I inhibitor also derived from the parent compound 20(S)-camptothecin, is efficacious when used sequentially with cyclophosphamide.38 This may be a rationale for using 9-NC in a combination setting, especially in this patient population. Additional dose reductions may be necessary due to toxicity concerns.
Consistent with the lack of efficacy of other cytotoxic agents, 9-NC was not active in GIST patients. Since the initiation of this trial, the advent of the tyrosine kinase inhibitor imatinib mesylate has revolutionized the treatment of GIST patients.39,40 Additional therapy in these patients will likely continue to be directed at inhibiting the mutated KIT tyrosine kinase.
9-NC exhibited moderate toxicity in this trial with 20% of patients withdrawing because of toxicity by protocol mandate or personal preference. This was in excess of what was expected based on phase I and II data, and prompted a midtrial amendment to decrease the starting dose from 1.5 mg/m2/d to 1.25 mg/m2/d for 5 days on, 2 days off. The high number of dropouts due to toxicity may be related to extensive pretreatment of patients. The majority of treatment discontinuations were in STS patients. Forty-four percent of STS patients had been treated with two or more previous therapies. In a phase I study, the greatest toxicity was seen in patients who were heavily pretreated, and the recommended phase II dose in this patient population was 1.0 mg/m2/d.41
In conclusion, although a few patients with STS appeared to derive benefit from treatment with 9-NC, a large majority did not. Thus, we believe that further investigation of 9-NC as a single agent in STS is not warranted. As some minimal activity was noted, there may be benefit by combining 9-NC with novel or other cytotoxic agents.
Although activity was limited, we do believe that 9-NC may be a promising agent in patients with progressive chordoma. Given the lack of an otherwise effective systemic agent in treating this disease, the desire to further investigate 9-NC is increased. This study may serve as a basis of comparison for future trials in chordoma. Due to the rarity of this disease, accrual to clinical trials is difficult and may best be pursued on a multi-institutional and perhaps on an international level.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Laurence H. Baker, Ascentia, Kinisia, Novartis. Honoraria: Laurence H. Baker, Ascentia, Kinisia, Novartis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank Jacqueline Williamson for her assistance with data management.
NOTES
Supported by SuperGen Inc.
Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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