High-dose chemotherapy and bone marrow transplantation ( HDC/BMT ), also high-dose chemotherapy with autologous bone marrow transplantation ( HDC/ABMT or just ABMT ), was a treatment regimen for metastatic breast cancer, and then high-risk breast cancer, which was considered promising during the 1980s and 1990s. It was ultimately determined to be no more effective than normal treatment, and had significantly higher side effects, including treatment-related deaths.
From its inception in the 1980s to its denial in the late 1990s, HDC/BMT changed clinical practice, health insurance coverage, public health policy, and encouraged entrepreneurial oncology for two decades. This also raises one of the most serious cases of erroneous research in the 20th century.
Video High-dose chemotherapy and bone marrow transplant
Sejarah Perawatan
High-dose chemotherapy (HDC) with autologous bone marrow transplant (ABMT) is a treatment for advanced breast cancer developed in the 1980s, but the idea for HDC/ABMT is based on the earlier leukemia treatment that emerged in 1950 when E. Donnall Thomas has shown that the bone marrow can be taken from a person and transplanted into the same person or another person. High-dose chemotherapy treatments with autologous bone marrow transplant have serious side effects for the patient, including cardiac toxicity, sepsis, lung failure, and nephrotoxicity, among others. The chronic consequences of treatment include the development of leukemia and lymphoma and increased susceptibility to infection immediately after transplantation. Randomized clinical trials reported a treatment mortality rate from 0% to 7% for women receiving HDC/BMT treatment, compared with no such deaths in the control group receiving a typical chemotherapy regimen.
In HDC, bone marrow transplantation is used to maximize the dose of chemotherapy. By harvesting and freezing the bone marrow, then implanting the marrow after HDC, doctors are theoretically able to penetrate the toxicity limit; the so-called "red ceiling". Early supporters of this technique were George Canellos and Emil Frei of Dana-Farber Cancer Institute, and William Peters, who had been recruited by Frei to the institute in 1982. Howard Skipper and Frank Schabel demonstrated efficacy in the rat model for megadose therapy in 1983.
Frei and Peters developed a Solid Tumor Autologous Marrow Program (STAMP) regimen. Researchers at the National Cancer Institute (NCI) do not believe that care will be effective and careful about the consequences of this treatment. For example, George Canellos, one of the original members of NCI, has noticed that the long-term side effect of a megadotic chemotherapy regimen is myelodysplasia, a condition that tends to develop into leukemia. During the early stages of STAMP clinical trials, the first patients were those who had no hope - women with advanced stage metastatic breast cancer who had received, and did not respond, to existing treatments. However, about half way through the experiment, a woman who was previously untreated with metastatic breast cancer was enrolled in the STAMP program, and many Peters colleagues began to notice. The treatment results are unprecedented - tumors and metastatic deposits have shrunk significantly. From then until the end of this initial clinical trial, Peters has transplanted and treated more cases and also obtained significant remissions similar to those of this woman. They then believe that STAMP produces a more durable remission compared to conventional chemotherapy, and therefore Peters went on to make a randomized clinical trial at Duke University.
By December 1984, 32 women had completed a phase I study of the regimen, designed to investigate safety. The researchers proceeded with a Phase II trial, which showed very promising results. However, only women who are healthier and respond better to conventional chemotherapy who are eligible for Phase II studies. Problems with the Phase II study are described as follows:
If you have a hundred patients and you give them a treatment that applies to all 100, and two live after 10 years, it is an absolute 2% survival rate. If you have 100 patients and you have treatments that apply to 20 out of 100, and 20% of those 20 are alive after 10 years, it's just an absolute 4% survival rate, not a 20% survival rate.
This selection bias makes the treatment look better, because the candidates who will fare better under any conditions are selected. To improve Hortobagyi's further point, using data from the MD Anderson University Cancer Center in Texas, it was reported in May 1995 that those eligible for high-dose chemotherapy survived 65% longer on conventional chemotherapy than those who did not will qualify for the protocol. Subsequent research on protocols containing doxorubicin for the treatment of metastatic breast cancer, found that mean progression-free survival (PFS) was 16 and 8 months and the median overall survival (OS) was 30 and 17 months, respectively for women meet eligibility criteria versus those who do not, when all receive conventional treatment.
Randomized controlled trials of stage III are required to confirm the benefits of HDC/BMT. In 1985, William Peters left the National Cancer Institute to establish a trial at Duke University in North Carolina. He persuaded Group B Cancer and Leukemia (CALGB) to sponsor a multicenter, randomized controlled trial.
Clinical use of this treatment is encouraged by women with breast cancer and advocacy groups, such as ACT UP; they believe that the FDA treatment approval process is too slow. Health Net's Nelene Fox transplant rejection - a case involving the coverage of HDC/ABMT insurance - triggered a public reaction and prompted a change of access to treatment. Unlike new drugs, which are evaluated and approved by the Food and Drug Administration (FDA), medical procedures are not officially regulated by any agency nor are there any legal requirements to serve similar functions. Approximately 30,000 women received the HDC/ABMT procedure in the period 1989-2002; the medical profession is divided into its commitment to clinical trials and approves procedures as better than existing treatments before there is evidence from the scientific community - of women receiving the procedure, only about 1000 of them are enrolled in randomized clinical trials in the United States. In contrast, repeated assessments concluded that existing data did not support the HDC/ABMT effectiveness claim, leading to high priority phase 3 clinical trials in 1990-1991, supported by efforts by the National Cancer Institute (NCI), skeptical scientists, health insurance companies, and cancer groups.
The results of clinical trials ending show that HDC/BMT for breast cancer is not an effective treatment and does not improve survival rates compared with existing treatments. This conclusion is drawn from a combination of studies, including Peters studies and a large study conducted by the Dutch Cancer Institute, both of which conclude that HDC/BMT is not superior to standard breast cancer treatments. Another study, conducted by researcher Werner Bezwoda, reached the conclusion that the treatment was effective, but his studies were later discredited for scientific misconduct, including data forgery. Treatment is stopped for breast cancer, although it is still used to combat other types of cancer, such as leukemia and lymphoma.
Maps High-dose chemotherapy and bone marrow transplant
Funding mechanism and litigation
With the increasing popularity of this treatment, more and more women with breast cancer want it available to the public - not only offered in clinical trials. Inspired by HIV/AIDS activism, several cancer advocacy groups began lobbying for general availability of HDC/BMT. This attracts prospective patients away from clinical trials, such as Peters. As a result, in the late 1980s, most private hospitals and clinics had a transplant space to provide HDC/BMT for women looking for it.
Treatment remains exclusive of most women due to high costs; $ 50,000 to $ 400,000 per patient. As long as HMO regards the regime as experimental or investigation , there is no contractual obligation to cover it. Meanwhile, in the mid-1980s, less than 100 bone marrow transplants a year were performed in breast cancer patients, HDC/BMT uptake increased sixfold between 1 January 1989 and 30 June 1995. Between 19,291 the autotransplant was reported to Autologous Blood and Marrow Transplant Registry; 5.886 is for breast cancer. After 1992, breast cancer was the most common indication for autotransplant. Only 11% of women with stage 2/3 disease and less than one percent of those with stage 4 disease participated in a randomized trial. The International Bone Marrow Transplant Registry estimates that at least 4,000 women were treated with HDC/BMT, from 1989 to 1993, with less than 10% doing it in trials. Based on unfounded beliefs on the success of HDC/BMT, women refuse to be randomized to conventional treatment conditions, and doctors are not replaced for the additional time spent on protocol administration. At the same time, this treatment is very beneficial for hospitals which, in 1995, conducted billing procedures at $ 80,000 to $ 100,000, with hospital admissions of less than $ 60,000. Hospitals, such as Beth Israel in Boston, devote entire floors to the transplant unit.
In 1993, a landmark court case, Fox v. Health Net . change existing HMO policies to pay for maintenance. A public school teacher named Nelene Hiepler Fox (January 9, 1953 - April 22, 1993) was diagnosed with breast cancer in 1991. She asked her HMO to pay for High-Dose Chemotherapy and Bone Marrow Transplant (HDC/BMT) to treat her cancer. His health maintenance organization, Health Net, refused his request, stating this therapy is an unproven experimental therapy. Fox's brother Mark Hiepler took his HMO, the Health Net, to court to force them to pay for HDC/BMT, which they refused. Despite raising $ 220,000 himself and receiving a treatment regime, Fox died on April 22, 1993. Mark Hiepler sought damage from Health Net for delaying the care of his sister. On December 28, the Fox family got $ 89 million by a California jury, including $ 12.1 for bad faith and careless emotional suffering, and $ 77 million in damages. Jim Fox and Nelene Fox plantations v. Health Net is considered a watershed case where most health insurance companies then begin to approve HDC/BMT for advanced breast cancer.
Between 1988 and 2002, 86 cases were filed to force HMOs to pay for transplants, 47 of which were successful. The Massachusetts, New Hampshire, Virginia and Minnesota legislatures mandated insurance coverage for all high-dose chemotherapy with ABMT or peripheral blood stem cell transplant (PBSCT) for women with breast cancer.
The media, both newspapers and television, play an important role in promoting HDC/ABMT to people, especially through their portrayal of women with breast cancer, sparking public protests and encouraging legislative changes that mandate the coverage of HDC/ABMT insurance. For example, Boston Globe published a story about Charlotte Turner, a woman with breast cancer that HMO would not pay for her treatment, which pushed the state's legislative lobby of Massachusetts. In response to the lobby and public pressure generated by the story, the state legislature of Massachusetts passed a law requiring HMOs to cover HDC/BMT treatment by the end of 1993. Journalists describe HDC/ABMT as a miracle treatment, with patients playing victims, , and breast cancer and health insurance criminals. Most articles make three main points: one, HDC logical because if small chemotherapy can treat early cases, then more clear chemotherapy is needed for more advanced cases; two, HDC/ABMT is the only hope for someone with advanced breast cancer; three, the main barrier between a person and their potential drug is money, which the health insurance company does not want to cover for treatment. This causes many people to mistakenly think that HDC/ABMT, in fact, is a treatment not supported by clinical trials. As a result, patients encourage that treatment is given more widely and is covered by insurance companies.
The reluctance of insurance organizations to pay for HDC/BMT treatment comes from differences of opinion of patients/doctors and researchers on treatment. Academic researchers want to wait for the results of clinical trials, while breast cancer oncologists and bone marrow transplants support this procedure. At that time, the clinical trials on the effectiveness and benefits of these treatments were very different: trials by Peters in the US and other major research hospitals in Europe reached the conclusion that the treatment had the simplest results - even negative results - about the superiority of this high-dose chemotherapy with autologous bone marrow transplantation. However, a study by researcher Werner Bezwoda shows the promising benefits of this treatment - although his studies were later confirmed to falsify the data. In addition, there has been a lot of positive publicity surrounding treatment, and 79% of oncologists believe that HDC/BMT is the right treatment for women with advanced breast cancer. In fact, the number of women receiving this treatment increased by about 8,000 between 1990 and 1999. This gap is one reason why HMOs refrain from including high-dose chemotherapy with autologous bone marrow transplantation; if care is expensive and not clinically proven to be beneficial, health organizations may refuse to pay for treatment, regardless of patient protests.
The general strategy for the plaintiff includes arguing that HDC/BMT is the only chance of the patient to survive, the patient's choice of a doctor's recommendation, and describes the HMO in terms that are unfavorable to the jury. General strategies for defendants, or insurers, include stating that coverage plans do not believe HDC/BMT is in the patient's best interest because of high mortality and declining quality of life; states that treatment has not been clinically proven to be beneficial and more effective than existing treatments - clinical trial results have not been reported.
Randomized controlled trial
In May 1992, researchers from the University of Witwatersrand (Wits) in South Africa presented preliminary results from a randomized controlled trial (RCT) at the annual meeting of the American Society of Clinical Oncology (ASCO) in San Diego. The principal investigators are Werner Bezwoda, professor of hematology and oncology at Wits. This is the first scientific evidence of the emerging clinical benefits.
Bezwoda published the first randomized controlled trial of high-dose chemotherapy versus conventional dose chemotherapy as first-line treatment for metastatic breast cancer in October 1995. Ninety patients were randomly assigned to compare two high-dose cyclophosphamide cycles, mitoxantrone, and etoposide (HD-CNV) versus six to eight conventional doses of cyclophosphamide, mitoxantrone, and vincristine (CNV). The overall response rate for HD-CNV is 95%, with 23 of 45 patients achieving a complete response (remission).
The real success of the 1995 study drew immediate attention to the authors; As of February 2001, the 1995 article has been cited 354 times. Patients are also in demand; in the Autologous Blood and Marrow Transplant Registry (ABMTR) database, the number of patients treated with high-dose therapy increased rapidly after Bezwoda's study was published. Many centers in the United States are offering HDC/BMT on the basis of Bezwoda's work. In 1999/2000 perhaps as many as 35,000 women had been treated with the regime. However, Bezwoda's research work is completely flawed, and the audit concludes that the results are basically made.
The Annual Meeting of the American Society of Clinical Oncology (ASCO) 1999
During May 15-18, 1999, the American Society of Clinical Oncology (ASCO) held its 35th annual meeting in Atlanta. At the plenary session, held on May 17, four HDC/BMT studies were presented to approximately 20,000 participants.
The Philadelphia Intergroup Study (PBT-1) is the largest randomized HDC trial compared with conventional dose chemotherapy in response to metastatic breast cancer. This study shows no difference in overall survival and no substantial toxicity differences between groups.
The largest randomized trial of bone marrow transplantation in metastatic breast cancer showed no improvement in overall survival by transplantation, no increase in time for progression-free development or survival with transplantation, no substantial difference in lethal toxicity. A serious non-lethal toxicity is greater in the transplant arm, particularly haematology, infection, nausea and diarrhea. Of course, from the survival curve, these results will not change with more follow-up in this study.
William Peters presented the preliminary results of his CALGB research (fully described as CALGB 9082/SWOG 9114/NCIC MA-13). Peters found "there was no significant difference in event-free or overall event-free survival between randomized groups.31 There were 31 deaths associated with therapy in the high-dose arm, the rate of 7.4%." The study design calls for an additional three years of follow-up before final conclusions can be drawn.
The Scandinavian Breast Cancer Study Group 9401 randomly assigned 525 high-risk breast cancer patients between 1 March 1994 to 4 March 1998. The principal investigator Jonas Bergh reported no overall survival benefit for high-dose therapy compared with the adjusted regimen, after a median follow-up time 27 months.
Finally, Werner Bezwoda presented a randomized and controlled clinical trial of 154 patients.
Most of the patients were black, and all were under 55 years of age. Research differs from others because no induction therapy is used; patients are promptly randomized to high-dose or standard therapy. After five years, 21 of 75 patients in the high-dose group experienced recurrence, compared with 55 of 79 patients in the standard dose group. Relapse-free survival and overall survival are significantly better in high-dose arms. High-dose chemotherapy using a combination of CMVP was found to be safely administered to younger patients with high-risk breast cancer. High-dose chemotherapy results in very low recurrence rates, and high-dose chemotherapy is associated with significantly greater disease-free survival and overall in this patient population.
Doing research on errors
At the time of the 1999 ASCO meeting, Bezwoda's 1995 and 1999 studies were the only trials supporting the use of HDC/BMT. While still at the meeting, Gabriel Hortobagyi has called for a replication of South African research. Raymond Weiss from Georgetown University, who has also seen the presentation, and Roy Beberidge helps organize the South African research audit.
The audit team found that Bezwoda had patient records for only 62 patients out of 154 patients. Many of the notes are undocumented, handwritten entries and there is no evidence that Bezwoda has randomly assigned patients. There is no record showing that every patient has received standard care. The audit team informed the ethics committee in Wits about possible ethical issues with Bezwoda's research on January 28, 2000.
On January 31, 2000 the head of the Department of Medicine gave the chairman an ethics committee statement signed, dated January 30, from Bezwoda, acknowledging "serious violations of honesty and scientific integrity in a presentation made at the American Society for Clinical Oncology (ASCO) in May 1999". The disciplinary hearing is set for March 10. Max Price, dean of the Faculty of Health Sciences, was appointed as head of hematology and oncology. Bezwoda was dismissed by the university on 11 March.
Peter Cleaton-Jones, chair of the University's Institutional Review Board, responded to findings in the March 18, 2000 edition of The Lancet. He affirmed that research should be approved by the Research Committee on Human Subjects (Medical) in Wits, and can not be done unless the agreement is obtained. The ethics committee in Wits does not have a Bezwoda clinical trial record. Lancet editor Richard Horton questioned whether Bezwoda could act alone to make the study without the knowledge of his colleagues. Weiss and his team concluded:
Bezwoda's study should not be used as a basis for further trials to test the efficacy of cyclophosphamide, mitoxantrone, etoposide regimens for high-dose chemotherapy in women with high-risk primary breast cancer.
George Canellos, editor-in-chief of the Journal of Clinical Oncology raised further concerns about Bezwoda's previous research. The 1995 paper was audited in 2001, along with reviews of other published studies to determine whether they have been subject to necessary institutional scrutiny.
The researchers found only 61 of 90 patients. Only 27 have sufficient information recorded to evaluate eligibility for trials with published criteria. Of these 27, 18 did not meet one or more eligibility criteria. Only 25 patients appeared to have been treated with therapy assigned to them around the time of their enrollment, and only three of these 25 did not receive HDC (ie could be in the control group). The treatment details are slightly similar to the published data. In addition, nine other Bezwoda trials are not reviewed or approved by the appropriate institutional committee and contain at least one major lie.
The Journal of Clinical Oncology retracted the 1995 paper on April 26, 2001, concluding: "The trial was not conducted in a scientifically acceptable way." The protocol was apparently written 9 years after the study began and only after another study by the same investigator will be audited.No patient signed the consent form, and there is little evidence of randomization. "The ASCO President Lawrence H. Einhorn called the scam a" shocking public treachery. "
Status on breast cancer
The utilization of HDC/ABMT for breast cancer declined sharply after a negative report was revealed at the ASCO meeting in 1999. In addition, a mixture of winnings and losses from litigation lawsuits over coverage of health insurance companies from treatment affects the decline in treatment, since the judicial technology assessed in court has concluded that the data do not support the claim that HDC/ABMT is better than conventional therapy. Due to the decline in quality of life during and after HDC/BMT compared with conventional breast cancer treatment as well as minimal life extension, many doctors and the majority of people believe that the treatment is ineffective and too toxic. In addition, the findings that Bezwoda's research incorrectly further pushed the point that the treatment was not significantly beneficial compared to standard treatment, therefore the only study that suggests a recurrence-free survival rate benefit of HDC/BMT. Other randomized trials conducted in the Netherlands and the United States, for example, all support the opposite point: that this treatment is not a significant improvement over conventional breast cancer treatment today. High dose therapy is also associated with increased second malignancy, including myelodysplastic syndrome and leukemia. While reflecting on the story of HDC/ABMT, especially in widespread treatment and lack of scientific data, many researchers and medical professionals claim that HDC/ABMT should never be accessible to the public without logical scientific data and conclusions; they see it as a period of embarrassment for cancer drugs.
The 2011 picture of six randomized trials concluded:
Overall survival of patients with metastatic breast cancer in six randomized trials did not increase significantly with high-dose chemotherapy; any benefit of small high doses. No subset was identified from patients who appeared to benefit from high-dose chemotherapy.
While HDC/ABMT has been discontinued, an increased therapy for cancer similar to HDC/BMT is CAR-T cell therapy, which is a type of immunotherapy. CAR T therapy collects the patient's own immune cells to treat their cancer, which is a similar idea behind HDC/BMT. Currently, there is FDA-approved T-cell therapy for children with acute lymphoblastic leukemia and adults with advanced lymphoma, but clinical trials are still under development whether T cell-cell therapy can be effective against solid tumor cancers, such as breast cancer.. In a similar way to HDC/BMT, this treatment was first introduced to people whose treatments had stopped working. The first women to participate in the Peters clinical trial were also those with advanced breast cancer and for whom other treatments stopped working.
High-dose chemotherapy and bone marrow transplant for other cancers
While high-dose chemotherapy and bone marrow transplant treatment is known for its effects on breast cancer, current treatments are used to treat other types of cancer, including testicular cancer, neuroblastoma, multiple myeloma, and various types of leukemia and lymphoma, such as Hodgkin's and non-Hodgkin's lymphoma.
There are two types of stem cell transplantation: an autologous stem cell transplant, in which the person's own stem cells are collected, frozen, and stored before chemotherapy regimens and transfused back into their body by IV after chemotherapy, and transplanted allogeneic stem cells , in which stem cells come from donors that match a person's HLA type to prevent the risk of graft-versus-host disease.
Source of the article : Wikipedia
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