Clinical Trials in Bone Sarcomas |
An ESUN Article
Introduction
Dramatic progress has been made in the treatment of bone tumors over the last several decades in both the rates of survival and the quality of life of surviving patients. These improvements can be attributed to a variety of factors including identification of effective chemotherapy, improvements in surgical procedures and radiation delivery as well as improvements in supportive care, the recognition of the value and widespread utilization of multimodality therapy and a greater emphasis on multidisciplinary approaches to cancer care, among other reasons. Critical in making this progress, has been organized clinical trials, which have validated the efficacy of the various new modalities and approaches that have been incorporated into treatment and have defined what is now considered the standard of care. Clinical trials in bone tumors in North America have been conducted by a variety of institutions, multi-institutional groups and cooperative groups. The pediatric cooperative groups, the Children’s Cancer Study Group and the Pediatric Oncology Group, which have merged to form the Children’s Oncology Group, have been very active in studying bone tumors. Clinical trials participation is viewed as the standard of care by pediatric oncologists with over 90% of pediatric patients receiving their treatment as part of a clinical trial. This is in marked contrast to adult patients of which only a minority receive their treatment as part of clinical trials. This is believed by many to account in part for the improved outcomes of younger as compared to older oncology patients.
It is important to note that in most Children’s Oncology trials in bone tumors participation is not limited to patients less than 18 or 21, the traditional separation between pediatric and adult services, with patients up to the third or fourth decade of life eligible for enrollment. The Children’s Oncology Group is not the only group involved in bone sarcoma clinical trials. The adult oncology cooperative groups, such as the South West Oncology Group, have sponsored clinical trials in this area. More recently several cooperative efforts more specifically focused on sarcoma clinical trials have begun to emerge. These include groups such as the Sarcoma Alliance for Research through Collaboration (SARC) consortium developed in association with the Connective Tissue Oncology Society (CTOS). As this clinical trials effort is a critical part of defining bone sarcoma standard of care and identifying new potentially effective therapies, this review will briefly describe the nature of clinical trials, review several completed clinical trials which have been critical in defining the present standard of care and discuss several clinical trials which are underway. The description of ongoing clinical trials can not be complete, nor is every patient appropriate for participation in a particular trial and therefore a treating oncologist is essential for identifying what or may not be appropriate for consideration.
General Principles of Clinical Trials
Clinical trials are generally described as being conducted in a series of phases, I through III. The various phases, represent in order, the steps that a new drug needs to take in order to become approved as a standard treatment. In general, from the standpoint of a patient, their interest would be best served by being treated in the opposite order of that taken by drugs, so that they receive the most proven therapy possible for their tumor. Therefore, in considering participation in a clinical trial, first preference would generally be given to a phase III study.
Most phase III studies are performed in patients with newly diagnosed tumors, in which a standard treatment exists. Although study designs vary, in general, in a phase III study a randomized comparison is being made between treatment that is considered standard and an experimental arm which is hypothesized to be superior to that treatment. Although the experimental arm is hypothesized to be superior, that may not prove to be the case, hence the arms are viewed by the treating physicians as being equivalent. This equivalence is necessary to ethically be able to subject a patient to their treatment being decided randomly. In a well designed phase III study, the standard arm would be the treatment used by the majority of physicians for patients who did not elect to be part of the phase III study. The experimental arm would test something new and promising. In designing a clinical study the number of patients that will be permitted to participate is specified initially. The size of the study is defined so that it is likely to answer the question that is being asked. The parameters that influence the size of the study include the predicted outcome of the patients and the magnitude of the difference the intervention is believed possible of making, among others. The smaller the magnitude of difference anticipated, the larger the number of patients that are necessary for the clinical trial.
In phase III studies a comparison is being made between a proven therapy and something which is postulated to provide an incremental benefit, hence by definition, the anticipated difference in outcomes for the treatment arms can not be large. Phase III studies therefore require large numbers of patients and because of the rarity of bone sarcomas necessitate their conduct as part of multi-institutional or cooperative groups over several years. Their performance in this manner mandates review by a large number of institutions and regulatory bodies, ensuring a high level of consideration of patient protection and safety.
Phase II trials are intended to obtain information on the efficacy of a new agent or treatment regimen. Of the three phases of clinical trials the greatest variability exists in the design of phase II studies, as multiple approaches can be utilized to obtain information on efficacy. In the most traditional phase II study design, a new treatment is given as a single therapy to a patient for whom no standard therapy exists. Typically this occurs in the setting of diseases that have recurred after standard therapy. The lack of standard therapy makes use of novel agents or treatment approaches ethically acceptable providing a treatment option, that otherwise would not have existed. In this setting, patients typically have a poor prognosis and therefore the likelihood that a new agent will prove to be effective is low. Phase II trials are also performed of new treatment regimens to pilot their feasibility and obtain a preliminary estimate of their efficacy. These pilot studies can be performed in different patient groups and are conducted for a variety of reasons. Some pilot phase II studies are conducted to demonstrate the feasibility of a regimen that is believed to be more efficacious than standard therapy, in anticipation of it becoming the experimental arm of a phase III study. In many of these studies, standard therapy is felt in some way to be inadequate justifying the use of a new treatment approach. These pilot phase II studies may be conducted in newly diagnosed patients, sometimes selecting patient subgroups which may be anticipated to have a worse prognosis, such as those presenting with metastatic disease. Numerous other phase II trial designs exist including window studies and randomized trials, a full description of which would be beyond the scope possible in this review. As these studies typically are not comparing treatments, these studies are typically smaller and therefore can be performed by single institutions as well as larger groups. It is not uncommon that a single patient may be eligible for more than one phase II trial. Frequently little data exists to provide a rational basis for selecting treatment on a particular phase II trial over other phase II trials or standard therapy. A treating oncologist can usually obtain additional information from the physicians leading each of the clinical trials among other sources and therefore is an invaluable resource in making these decisions.
Phase I trials are intended to demonstrate the safety of a new therapy or combination of therapies. These studies are virtually always performed in patients who have exhausted standard treatment options with alternatives to this therapy usually being other phase I trials or symptom directed care. Most phase I studies are performed with successive small groups of patients being treated at increasing doses to define what side effects occur and at what dose level. Given the nature of the patients being treated and that a proportion of patients will not be treated at the optimal dose of the new agent, the probability of having a response is relatively low, although a theoretical potential for benefit does exist. Similar to phase II trials, patients may be eligible for more than one trial and selecting between them is frequently difficult.
Clinical Trials Resources on the Internet
Considering A Cancer Clinical Trial (SARC)
Clinical Trials: What You Need to Know (American Cancer Society)
An Introduction to Clinical Trials (ClinicalTrials.gov)
Clinical Trial Myths vs. Facts (the Seattle Cancer Care Alliance)
Should I enter a clinical trial? from the ECRI Institute
Osteosarcoma
Before the identification of effective chemotherapy, the only treatment available for osteosarcoma was surgery. Approximately 85 to 90% of patients who presented with only what appeared to be localized disease and underwent radical surgery, such as an amputation for an extremity lesion, rendering them grossly free of disease had recurrences of disease (1-3). This high probability demonstrates that the majority of patients with apparently localized disease have radiographically non-detectable metastases. Given this poor outcome, in the 1970’s several investigators reported using agents such as doxorubicin, cisplatin, high-dose methotrexate with leucovorin rescue, and ifosfamide and reported that chemotherapy had activity against osteosarcoma (4-14). All of these trials were non-randomized phase II treatments employing adjuvant chemotherapy, comparing results against historical control. Not all investigators were convinced that chemotherapy was appropriate for all patients, as these studies can be flawed. To clarify the issues surrounding the value of adjuvant chemotherapy, the Multi-Institution Osteosarcoma Study, a phase III randomized trial of chemotherapy versus observation alone, was initiated (15). Patients were eligible for study entry after tumor resection if they did not have clinically detectable metastatic disease. Patients who did not receive chemotherapy after surgery had a probability of disease free survival of 11% as compared to 66% for those who received chemotherapy unequivocally demonstrating chemotherapy was of benefit (15). Around the same time investigators introduced the concept of giving chemotherapy before carrying out definitive surgery on the primary tumor (16,17). This concept of induction chemotherapy arose from the need for time to make the custom endoprosthesis required for limb salvage procedures, creating an interval during which chemotherapy could be administered. In addition, theoretical advantages of chemotherapy prior to definitive surgery included early treatment of micro-metastatic disease and facilitation of the eventual surgical procedure. It also became possible to examine the histologic response of the tumor to this initial period of chemotherapy to assess the effectiveness of therapy. A strong correlation between the degree of necrosis observed in the tumor at the time of definitive surgery and the probability of subsequent disease free survival was observed which has been confirmed in multiple clinical trials (16-21). Numerous trials have been conducted to clarify the role of the various chemotherapeutic agents and approaches in the treatment of osteosarcoma. Not all of these trials can be reviewed, but the most recently published North American phase III study performed by the Children’s Oncology Group will be briefly described. This study addressed the questions of whether the addition of ifosfamide and/or muramyl tripeptide – phosphatidyl ethanolamine to the three other agents used in the standard treatment of osteosarcoma (doxorubicin, cisplatin, and high dose methotrexate) would improve the probability of disease free survival. This study unfortunately produced confusing results showing when combined with standard therapy no improvement with either agent alone but some benefit when the two were used together (21). This suggested an interaction may have been occurring between these two experimental agents, which had not been expected at trial initiation and therefore will require further study to properly interpret the results. Until this confusion is resolved standard therapy for newly diagnosed osteosarcoma remains a three drug regimen comprised typically of cisplatin, doxorubicin and high dose methotrexate both preceding and following definitive surgery. In osteosarcoma although patients presenting with metastatic disease have a worse prognosis, the principles of therapy, including the chemotherapy are generally the same.
Ewing Sarcoma Family Tumors
Similar to what is described for osteosarcoma the survival of patients with Ewing Sarcoma Family Tumors (ESFT) prior to chemotherapy was poor; with studies reporting a 5-year survival of 10%. Options for local control for ESFT includes both radiation therapy and surgery, a discussion of which is beyond the scope of this review. The first chemotherapeutic agents shown to be effective in ESFT were cyclophosphamide, actinomycin-D, and vincristine, with these agents used individually in the early 1960s and in combination by the late 1960s. The majority of prospective, randomized phase III clinical trials in ESFT in North America were conducted as Intergroup Ewing Sarcoma Studies by the Children’s Cancer Group and Pediatric Oncology Group beginning in 1973. Numerous important findings were made in these studies including the identification of high risk subgroups of patients including those with large and pelvic primaries, and the additional optimization of the chemotherapy regimens (22,23). The last published phase III study from this group randomized patients to receive standard chemotherapy with doxorubicin, vincristine, cyclophosphamide and dactinomycin to those four dugs along with courses of ifosfamide and etoposide. The experimental arm significantly enhanced the survival of patients with apparently localized ESFT (24). Hence; standard chemotherapy for patients with localized ESFT would be comprised of a regimen comprised of vincristine, cyclophosphamide, doxorubicin, dactinomycin, ifosfamide and etoposide. Unfortunately in patients presenting with metastatic disease the experimental arm did not improve the known poor prognosis of this subgroup of patients. In ESFT a series of phase II trials have been reported using high dose chemotherapy followed by autologous stem cell transplant (bone marrow or peripheral stem cells) for patients with recurrent and/or metastatic disease in an attempt to improve upon the poor outcomes (25,26). These studies were driven by the hypothesis that the dose response curves for ESFT cells is very steep, and that, therefore, increasing the dose of these agents would kill adequate numbers of ESFT cells to ensure patient survival. In this strategy the high dose chemotherapy is the therapeutic portion of the treatment and the autologous stem cell (bone marrow or peripheral stem cells) transplant is merely a means of rescuing the patient from the toxic effects of the treatment. Without stem cell rescue with the doses of chemotherapy and/or radiation typically employed in these regimens the patients bone marrow would become aplastic and they would not survive. It may be worthwhile to note that this strategy generally has not been utilized in osteosarcoma because the chemotherapy that is most effective in this disease, does not have myelosuppression as its major side effect and bone marrow transplantation would therefore not allow higher dosing than used routinely. These phase II studies in ESFT demonstrated the feasibility of high dose regimens requiring stem cell support despite being associated with significant toxicity. However, the impact of these regimens upon improving outcome have been very mixed and controversial (25-27).
Recently Completed and Ongoing Chemotherapy Trials in Osteosarcoma and Ewing Sarcoma Family Tumors
A significant lag exists between the completion of a clinical study and its publication. Some of this lag is necessary so that patient outcomes are sufficiently mature so that confidence exists in the data. Others are a result of other lags such as the time to produce a manuscript, have it accepted by a medical journal and published, among others. Preliminary results are frequently presented at Scientific Meetings prior to their publication to disseminate the information to the medical community. Treating oncologists are a valuable resource for access to this information. Other studies that have been completed by the Children’s Oncology Group but have not been published include the following: a series of pilot phase II studies investigating intensifying doxorubicin with dexrazoxane, ifosfamide/etoposide or both to patients with newly diagnosed osteogenic sarcoma, a phase II study of trastuzumab (Herceptin®) along with standard chemotherapy to patients with newly diagnosed metastatic osteosarcoma, a phase III randomized study of a 30-week dose intensive regimen of alkylators to the previous 48 week regimen in ESFT and a phase III randomized study in ESFT of compressing the time between chemotherapy cycles to two weeks. For some of these studies the results have been presented at scientific meetings but none will be described in detail in this review, as these trials are neither available for participation nor to this point of time have they defined a new standard of care.
Perhaps the most important issue being discussed is ongoing clinical trials. Although they do not define care at present, the majority of these studies are active and patients meeting specific criteria can be enrolled in them. This review can not cover all of the active trials and will discuss only selected studies. One of the best resources for identifying clinical trials in oncology in North America is a website directory of active clinical trials maintained by the National Cancer Institute. This website lists trials from cooperative groups as well as institutions, and by nature of its government affiliation is relatively unbiased. At present the website list approximately thirty osteosarcoma therapeutic studies and about thirty ESFT therapeutic studies. Representative studies for the treatment of osteosarcoma are presented in Table 1 and for ESFT in Table 2. Several of these studies will be discussed briefly in the subsequent section.
Please check our Clinical Trials Resources for a listing of clinical trial websites and organizations.
The difficulty in describing ongoing clinical trials, particularly for the Phase I and II studies, is their availability changes rapidly and information frequently is relevant only for limited periods of time. Therefore the descriptions of the individual studies will be kept very brief. In osteosarcoma, the Children’s Oncology Group has just embarked on a phase III randomized trial for patients with newly diagnosed localized osteosarcoma. This study will be conducted throughout North America and in collaboration with European Clinical Trials Groups. Patients up until the age of 40 are permitted to participate. All patients will receive the same therapy prior to definitive surgery. Following this therapy post-operative chemotherapy will be based on the histological response observed at the time of definitive surgery. Patients with a greater degree of necrosis will be randomized to standard therapy (cisplatin, doxorubicin, methotrexate) with/or without pegylated interferon. Patients with an inferior degree of necrosis will be randomized to standard therapy with/or without high-dose ifosfamide and etoposide. These studies are intended to definitively establish the relative merit of the experimental versus standard treatment arms.
A number of institutions and groups are exploring new treatment options for patients with recurrent osteosarcoma in phase II and I studies. Of particular interest is developing targeted therapies which are more selectively directed towards osteosarcoma than present treatments with their significant side effects. In some tumors this has been achieved by identifying agents that target molecular alterations exclusively present in the tumors. Thus far, this has been elusive for osteosarcoma. An alternative means of targeting tumors is to deliver the anti-cancer agent selectively to the site where it resides. In osteosarcoma the vast majority of metastatic disease appears in the lungs, with other bones being a much rarer metastatic site. Therapy is therefore being developed to specifically accumulate in the lungs or bones. To have drug preferentially accumulate in the lungs, the chemotherapy can be given as an aerosol. This will result in a higher concentration in the lungs than in the systemic circulation. This approach is being used to deliver a cytokine as part of a Children’s Oncology Group trial and cisplatin encapsulated in a liposome as part of a trial at the Children’s Hospital at Montefiore. Similarly a bone seeking isotope, samarium, is being used to selectively deliver radiation to bone metastases as a part of a trial being conducted at the John’s Hopkins Medical Center. Numerous other chemotherapy trials are being conducted in osteosarcoma of a variety of agents with a partial list summarized in Table 1.
The Children’s Oncology Group for patients with ESFT presenting with lung metastases is collaborating with the European Cooperative groups, as they are for osteosarcoma, in performing a Phase III trial. This trial is intended to more definitively address whether patients with ESFT presenting with metastases benefit from high dose chemotherapy with stem cell rescue. The patients treated on this trial all receive standard chemotherapy which is followed by a randomization to high dose chemotherapy with stem cell transplant versus continuation chemotherapy. This trial should help clarify the potential benefit of high dose chemotherapy with stem cell rescue approaches for high risk ESFT. One of the innovative phase II trials being conducted for recurrent ESFT is a study of transplant re-infusing stem cells from a donor rather than the patient, being conducted at the National Cancer Institute. This approach has several potential advantages. One potential cause of relapse following use of the patient’s stem cells is contamination of the stem cells themselves with tumor cells because ESFT can metastasize to that site. Use of donor cells avoids that risk. More importantly, engrafted stem cells from a donor will form the patient’s immune system. Use of stem cells from a donor enhances the likelihood that the patient’s newly reconstituted immune system will recognize residual ESFT cells, if they exist, as foreign and kill them. Hence, the stem cells themselves in this transplant may be therapeutic. Balancing these potential benefits, stem cell transplantation from a donor is associated with much greater risk than an autologous procedure. This trial will begin to provide evidence of the potential benefits of this treatment strategy. Numerous other chemotherapy trials are being conducted in ESFT of a variety of agents with a partial list summarized in Table 2.
Conclusion
In this review, the various phases of clinical trials have been described. The progress that has been made in osteosarcoma and ESFT through chemotherapy clinical trials was described. The progress has been significant with these studies defining the present standard of care. Several ongoing trials were briefly described. All patients with osteosarcoma and ESFT should consider participation in a clinical trial if they are eligible. Resources exist for helping a patient identify active oncology clinical trials. Additional information can be provided, on these and other studies, by treating oncologists that can help to determine which if any trial should be considered for participation.
Reference
1. Marcove RC, Mike V, Hajek JV, et al. Osteogenic sarcoma under the age of twenty-one. A review of 145 operative cases. J Bone Joint Surg [Am] 1970;52:411-423.
2. Gehan EA, Sutow WW, Uribe-Botero G, et al. Osteosarcoma: The M.D. Anderson experience, 1950-1974. Prog Cancer Res Ther 1978;6:271-282.
3. Uribe-Botero G, Russell W, Sutow W, Martin R. Primary osteosarcoma of bone: A clinicopathologic investigation of 243 cases, with necropsy studies in 54. Am J Clin Pathol 1977;67:427-435.
4. Cortes EP, Holland JF, Wang JJ, Sinks LF. Doxorubicin in disseminated osteosarcoma. JAMA 1972;221:1132-1138.
5. Jaffe N, Farber S, Traggis D, et al. Favorable response of metastatic osteogenic sarcoma to pulse high dose methotrexate with citrovorum rescue and radiation therapy. Cancer 1973;31:1367-1373.
6. Pratt C, Howarth C, Ransom J, et al. High dose methotrexate used alone and in combination for measurable primary and metastatic osteosarcoma. Cancer Treat Rep 1980;64:11-20.
7. Nitschke R, Starling KA, Vats T, Bryan H. Cis-diamminedichloroplatinum (NSC-119875) in childhood malignancies: A Southwest Oncology Group Study. Med Pediatr Oncol 1978;4:127-132.
8. Baum ES, Gaynon P, Greenberg L, et al. Phase II study of cis-dichlorodiammineplatinum (II) in childhood osteosarcoma: Children's Cancer Study Group Report. Cancer Treat Rep 1979;63:1621-1627.
9. Marti C, Kroner T, Remagen W, et al. High-dose ifosfamide in advanced osteosarcoma. Cancer Treat Rep 1985;69:115-117.
10. Jaffe N, Frei E, Traggis D, Bishop Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med 1974;291:994-997.
11. Cortes EP, Holland JF, Glidewell O. Adjuvant therapy of operable primary osteosarcoma--Cancer and Leukemia Group B experience. Rec Results Cancer Res 1979;68:16-24.
12. Goorin A, Delorey M, Gelber R, et al. The Dana-Farber Cancer Institute/The Children's Hospital adjuvant chemotherapy trials for osteosarcoma: Three sequential studies. Cancer Treat Rep 1986;3:155-159.
13. Sutow WW, Sullivan MP, Fernbach DJ, et al. Adjuvant chemotherapy in primary treatment of osteogenic sarcoma. A Southwest Oncology Group Study. Cancer 1975;36:1598-1602.
14. Sutow WW, Gehan EA, Dyment PG, et al. Multidrug adjuvant chemotherapy for osteosarcoma: Interim report of the Southwest Oncology Group Studies. Cancer Treat Rep 1978;62:265-269.
15. Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314:1600-1606.
16. Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma. The rationale for preoperative chemotherapy and delayed surgery. Cancer 1979;43:2163-2177.
17. Winkler K, Beron G, Kotz R, et al. Neoadjuvant chemotherapy for osteogenic sarcoma: Results of a Cooperative German/Austrian Study. J Clin Oncol 1984;2:617-624.
18. Rosen G, Murphy ML, Huvos AG, et al. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 1976;37:1-11.
19. Bacci G, Picci P, Ruggieri P, et al. Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities. The Instituto Rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin. Cancer 1990;65:2539-2553.
20. Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: A report from the Children's Cancer Group. J Clin Oncol 1997;15:76-84.
21. Meyers PA, Schwartz CL, Krailo ML, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin and high-dose methotrexate. J Clin Oncol 2005:23:2004-2011.
22. Nesbit ME, Gehan EA, Burgert EO, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol 1990;8:1664-1674.
23. Evans RG, Nesbit ME, Gehan EA, et al. Multimodal therapy for the management of localized Ewing's sarcoma of pelvic and sacral bones: A report from the second intergroup study. J Clin Oncol 1991;9:1173-1180.
24. Grier HE, Krailo MD, Tarbell NJ, et al: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s Sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694-701.
25. Pinkerton CR, Bataillard A, Guillo S, Oberlin O, Fervers B, Philip T. Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 2001;37:1338-1344.
26. Hawkins D, Barnett T, Bensinger W, Gooley T, Sanders J. Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing- Sarcoma-Family tumors. Med Pediatr Oncol 2000;34: 328-337.
27. Kushner BH, Meyers PA. How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 2001;19:870-880.
V3N2 ESUN Copyright © 2006 Liddy Shriver Sarcoma Initiative.