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© 2003 American Society for Clinical Oncology Biologic and Immunologic Therapies for Ovarian CancerFrom the David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; AltaRex Corp, Waltham, MA; and Unither Pharmaceuticals, Inc, Wellesley Hills, MA. Address reprint requests to Jonathan S. Berek, MD, David Geffen School of Medicine at UCLA, Division of Gynecologic Oncology, 24-137 UCLA Center for the Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095-1740; e-mail: jberek{at}mednet.ucla.edu.
Biologic therapy of ovarian cancer has been conducted using nonspecific biologic response modifiers, cytokines, monoclonal antibodies (MAbs), vaccines, and gene therapy. Antibodies directed toward her2/neu have also been studied. Phase I and II gene therapy trials using adenoviral vectors containing a wild-type or modified p53 have shown that the treatment is well tolerated. Phase II and III trials are ongoing with MAbs directed against CA-125 (MAb B43.13) and an antibody directed against HMFG1 (anti-HMFG1–yttrium-90–labeled antibody). The trials have shown that these agents are well tolerated and that immunologic responses occur, although the ultimate clinical value of these agents remains to be determined. Prolonged survival after MAb B43.13 treatment has been correlated with changes in several immune parameters, including human antimurine antibody, Ab2, anti–CA-125 antibody development, and induced T-cell immunity. Clinical trials using a MAb directed toward the encoded products of her2/neu have shown minimal activity against ovarian cancer in a phase I and II trial conducted by the Gynecologic Oncology Group. Cytokine therapies have been administered systemically and intraperitoneally. Intracavitary interferon alfa, interferon gamma, and interleukin-2 alone or in combination with cytotoxic therapy in phase I and II trials demonstrated intraperitoneal lymphoid cell stimulation and produced antitumor responses. A randomized trial of chemotherapy with or without interferon gamma in primary treatment produced a response and a progression-free survival advantage in the arm that incorporated the interferon gamma, without a statistically significant benefit in overall survival. A phase III study of interferon gamma in combination with first-line chemotherapy is currently ongoing.
EPITHELIAL OVARIAN cancer is responsive to many chemotherapeutic agents, but despite improvements in surgery and chemotherapy, the 5-year survival rate remains approximately 20% to 30% for advanced-stage disease.1 Because the disease typically eludes early detection techniques, most patients present in advanced stage. Innovative approaches to the control of metastatic residual epithelial ovarian cancer are being sought. Biologic therapies for ovarian cancer are being developed. Ovarian cancer represents an attractive target for these therapies because of the biology of the disease and the means by which it disseminates. The bulk of ovarian cancer occurs in the peritoneal cavity, making the regional administration of biologic therapy theoretically attractive. Although initial studies with nonspecific immunotherapy, such as bacille Calmette-Guérin and Corynebacterium parvum, have demonstrated tumor regression in some circumstances, these therapies have not been shown to prolong survival when combined with cytotoxic chemotherapy in randomized trials.1 Phase II and III trials with monoclonal antibodies (MAbs) directed toward CA-125 (Oregovomab, MAb B43.13; AltaRex Corp, Waltham, MA, and Unither Pharmaceuticals, Wellesley Hills, MA) and toward human milk fat globulin membrane (HMFG1; anti-HMFG1–yttrium-90 [90Y]–labeled antibody; Antisoma, Inc, London, United Kingdom) are ongoing. These trials have shown that these agents are well tolerated and that immunologic responses occur. When recombinant technology made large quantities of purified cytokines available for clinical testing, trials were soon initiated that were based on the preclinical data showing that interferon alfa, interferon gamma, and interleukin-2 possessed some antitumor activity. Studies of the intraperitoneal administration of interferon alfa, alone and in combination with cisplatin, and interferon gamma revealed surgically documented complete response rates in women with minimal residual epithelial ovarian cancer at second-look laparotomy. Intraperitoneal interleukin-2, alone or in combination with lymphokine-activated killer cells, also has shown an antitumor response, but the toxicity was too great for this approach to be practical. The initial experience with gene therapy using adenoviral vectors to replace mutated p53 tumor suppressor gene has shown this therapy to be well tolerated.
A recent innovative approach to immunologic cancer therapy, pioneered by researchers at AltaRex, Unither, and their collaborators, involves administration of low-dose murine MAbs that are designed to target tumor-specific antigens circulating in the bloodstream, in addition to antigens on tumor cells themselves. MAb B43.13 is a murine MAb to the tumor-specific antigen CA-125, which is found in more than 90% of patients with late-stage ovarian cancer. MAb B43.13 binds to circulating CA-125 antigens with high affinity to form complexes that the body recognizes as foreign because the complex includes the (foreign) antibody. These immune complexes are believed to enhance the processing of the autologous CA-125 antigen, leading to induction of CA-125–specific antibodies, T-helper cells, and cytolytic T cells. The antigen processing of the autologous antigen–xenotypic antibody complex is altered relative to the processing of either component alone, and immune responses, both cellular and humoral, directed to the tumor antigen and tumor have been demonstrated to be induced in a treatment-emergent fashion. Administered via 20-minute intravenous infusion, low-dose MAbs such as MAb B43.13 are better tolerated compared with previous high-dose murine antibody approaches. The possible therapeutic value of the low-dose MAb approach was serendipitously discovered in a diagnostic study with MAb B43.13, which was first developed as a tumor-imaging agent for nuclear medicine because of its high affinity for the ovarian cancer marker CA-125. In a study using technitium-99m–radiolabeled MAb B43.13 for the immunoscintigraphic detection of recurrent ovarian cancer, it was noted that a large group of patients exhibited unexpectedly long survival times.2–4 Efforts are under way to corroborate and extend these findings by assessing the therapeutic efficacy of nonradiolabeled MAb B43.13 in a series of prospective placebo-controlled and open-label studies in patients with ovarian cancer. The therapeutic objectives are to extend the period of disease stabilization while maintaining quality of life and to supplement surgical and chemotherapeutic approaches so that greater survival with extended quality of life is achieved. The utility of MAb B43.13 is being explored in several clinical applications combined with the standard treatments of ovarian cancer, either alone or in conjunction with chemotherapy. Furthermore, basic science research characterizing the immune-altering properties of the MAb B43.13–CA-125 complex in both animal tumor models and in vitro models of antigen processing and lymphocyte stimulation continues to refine the understanding of the therapeutic approach. The relationship of serum CA-125 kinetics, clinical disease burden, characteristic immune response, and therapeutic outcome continues to be refined.5
In Vitro and Preclinical Studies More recently, the group in collaboration with Dean Mann at the University of Maryland and Theresa Whiteside at the University of Pittsburgh studied antigen processing and T-cell stimulation both in vitro and using blood samples from treated patients.8,9 The group demonstrated that MAb B43.13 modifies antigen processing of CA-125 by dendritic cells in vitro. Preliminary data reveal a selective shifting of lymphocyte response from a solitary CD4 phenotype to a balanced CD4 and CD8 interferon gamma–producing phenotype. This finding is consistent with altered antigen processing and the selective presentation of CA-125 peptide fragments in the context of both HLA classes I and II.
The Use of MAb B43.13 in Consolidation Three protocols involving more than 500 patients have been conducted in this consolidation period. Ehlen et al10 recently reported on the initial results of their randomized, placebo-controlled, multicenter study of 342 patients with stage III to IV disease and no assessable disease after first-line treatment. A 2-mg, 20-minute infusion or placebo control was provided for one treatment each month for 3 months and then quarterly until relapse. Time to relapse, quality of life, immune response, survival, and safety have been followed up, and follow-up is continuing. More than half of the treated patients generated a vigorous immune response as measured by human antimurine antibody (HAMA) or anti-B43 idiotype (Ab2), and these immune responses are significantly associated with favorable clinical outcome. These immune responses are direct humoral antibody responses to the administered antibody, the former to the isotype murine IgG and the latter to the variable antigen binding region of the clone B43.13; neither is related to the CA-125 level. For the population as a whole, a significant difference was not measured between MAb B43.13 treatment and placebo; however, in the subpopulation defined by more successful response to first-line surgery and chemotherapy, a significant advantage for MAb B43.13–treated patients was evidenced. In this subset, the progression-free survival was 20.2 months for MAb B43.13 versus 10.3 months for placebo (P = .029). MAb B43.13 treatment did not adversely affect quality of life during this period when the patient was free of evident tumor and provided a safety profile similar to that of placebo. Because these observations were derived from a subset analysis, the ultimate effect of MAb B43.13 treatment on chemotherapy remains unclear. This result must be validated in confirmatory studies (Immunotherapy Pivotal Ovarian Cancer Trial [IMPACT] I and IMPACT II), which are currently being undertaken in the United States. The population eligible for these studies must have small-diameter (≤ 2 cm) or microscopic residual disease and a favorable CA-125 decline to 65 U/mL or less before the third cycle of chemotherapy, with normalization by the end of chemotherapy (35 U/mL). Available CA-125 in the measurable range is important for pharmacologic activity. Bookman et al11 studied MAb B43.13 in a randomized, double-blind, placebo-controlled study of 55 patients with no clinical or radiographic evidence of disease but with elevated CA-125 levels (> 35 U/mL) after first-line therapy. Patients relapsed rapidly in this clinical population, which limited the value of the study because treatment was discontinued on clinical relapse. Immune responses were induced at a frequency consistent with other studies, and in a subpopulation of patients who had time to mount an immune response and had small-diameter residual disease, a trend similar to that observed in the study by Ehlen et al10 was evidenced, with a 6-month progression-free survival of 75% for the MAb B43.13 group and 35% for the placebo cohort (P = .1). Method et al12 studied the effect of dose frequency and schedule in a cohort of patients with stage III and IV ovarian cancer who have completed first-line therapy with no evidence of disease. This 102-patient study involved a random assignment of patients into three dosing groups. The study is ongoing; however, the results as reported by Method et al indicated that optimal immune response requires more than two doses. However, increasing the dosing intensity to one injection per month for 6 months at initiation did not boost the frequency or magnitude of induced immunity. Consistent with preclinical data, this study indicates that the use of a MAbs to induce immunity to a tumor antigen follows a characteristic bell-shaped dose-response curve and that increasing the dose or dose number can in fact flatten the desired response analogous to the dose versus immune responses encountered in studies of tolerance induction.
Several phase II studies of MAb B43.13 have been completed in patients with known recurrent ovarian cancer. Ehlen13 conducted an open-label trial of 13 patients with recurrent ovarian cancer with CA-125 levels exceeding 35 U/mL, multiple prior regimens of chemotherapy, and poor prognosis. Importantly, an interferon gamma enzyme-linked immunoassay spot test was used and treatment-emergent induction of T-cell responses to the tumor antigen was first demonstrated in this study. A second study,14 which enrolled 20 patients with recurrent ovarian cancer, assessed the clinical and immunologic effects of immunotherapy before and concurrent with salvage chemotherapy. Tumor samples for immunologic studies were collected from patients who underwent surgery before first treatment with MAb B43.13 (available for eight patients). Humoral and cellular immune responses were monitored at baseline, at two time points before chemotherapy, and after chemoimmunotherapy. The study demonstrated that MAb B43.13 is well tolerated and that immune induction was feasible in this patient population. Induction of CA-125–specific T-cell immunity has been demonstrated in seven (39%) of 18 patients. Of the eight patients with available tumor samples, five (63%) showed a significant increase compared with baseline. Subsequent chemotherapy did not abrogate the induced immune responses, and interestingly, T-cell responses to autologous tumor increased in three patients and remained stable in the other two patients who were treated with combined chemoimmunotherapy.15 Patients with T-cell response to CA-125 to autologous tumor (N = 22) showed a highly significant benefit in time to progression and survival compared with nonresponders (P < .01). The third study is a long-term follow-up of a cohort of German patients who underwent imaging with radiolabeled MAb B43.13.16 Data from 44 patients with suspected or established recurrent disease who underwent initial antibody exposure between 1989 and 1996 were compiled for long-term follow-up and analysis to assess survival times and immunologic correlates of therapeutic effects. Data from these patients demonstrate that MAb B43.13 is associated with prolonged survival times, which are correlated with induction of humoral responses, including HAMA, anti-B43.13 idiotype, and induced anti–CA-125.17 Several patients have demonstrated prolonged survival despite stage III disease, and tumor regression as assessed by positron emission tomographic scan has been documented in several patients. Considered together, these findings indicate that MAb B43.13 is safe and may have activity in the recurrent disease setting, although confirmatory studies are necessary.
The use of MAb B43.13 has not yet been studied in conjunction with first-line therapy. Traditional thinking has discouraged this approach because the immunosuppressive properties of first-line therapy may ablate the immunostimulatory effects of the antibody treatment. An increasing number of reports, however, have indicated that chemotherapy may beneficially alter the characteristics of an immune response, perhaps through selective elimination of immune-suppressive lymphocyte populations.18 The phase II data generated with MAb B43.13 in patients with recurrent disease and concurrent chemoimmunotherapy indicate that study of first-line chemoimmunotherapy should be considered.19 Not only has selective cytolytic T-cell induction been suggested with concomitant therapy but also combination therapy has altered neither the safety profile of MAb B43.13 nor the chemotherapeutic agents studied. Future study of antibody-based immunostimulation with MAb B43.13 in conjunction with first-line treatment is anticipated. The data collected to date regarding effects of MAb B43.13 administered for recurrent ovarian cancer or during the watchful waiting stage of disease after surgery or chemotherapy indicate that MAb B43.13 prolongs survival and increases the time to relapse in selected patients with ovarian cancer. These clinical benefits are reproducibly associated with induction of tumor-specific T-cell responses (clearly demonstrated in the prospective recurrent disease studies) and to production of standard humoral markers, such as HAMA and Ab2.20 Used to treat more than 500 patients thus far, MAb B43.13 has been demonstrated to have a benign safety profile, particularly in the context of currently used chemotherapies. CA-125, the ovarian cancer marker to which MAb B43.13 binds, is also found in patients with other cancer types. CA-125, therefore, may be medically relevant to multiple tumor types. In addition to MAb B43.13, several other monoclonal antibody products directed against tumor-specific antigens are being explored in preclinical and clinical applications. The potential to treat ovarian cancer with multiple antibodies specific to multiple tumor antigens expressed in a given patient may result in a more vigorous therapeutic response.
HMFG1 is a murine immunoglobulin G1 monoclonal antibody developed at the Imperial Cancer Research Fund (London, UK) with specificity to an epitope of polymorphic epithelial mucin, which is expressed by more than 90% of epithelial ovarian cancers and many other carcinomas.21 Phase I and II trials of an antibody directed toward HMFG1 that is radiolabeled with 90Y have shown that this agent is generally well tolerated when administered intraperitoneally.22 The survival of patients with microscopic residual disease after induction chemotherapy who received the intraperitoneal agent seems to be prolonged compared with survival of historical controls.23 Antisoma (London, UK) has conducted a multicenter, randomized, prospective phase III trial of 90Y-labeled HMFG1 MAb in women with no evidence of disease. The radiolabeled MAb was used as consolidation therapy at the completion of their primary chemotherapy as demonstrated by a negative second-look laparoscopy, and we await the results of this trial.
An important MAb in breast cancer therapy is the anti-HER2/neu MAb (Herceptin, Genentech, South San Francisco, CA). This MAb has established itself as an active agent in conjunction with paclitaxel chemotherapy in relapsed breast cancer patients who express the HER2/neu protein product. The Gynecologic Oncology Group has conducted phase I and II trials of Herceptin in ovarian cancer. Among patients with recurrent ovarian cancer who were screened for participation in the trial, the rate of HER2/neu overexpression was less than 12% (ie, lower than expected). In a trial of 41 patients, the overall response rate seems to be less than 10% (Gynecologic Oncology Group data, Society of Gynecologic Oncologists, 2000). The drug is undergoing testing in combination with platinum- and taxane-based chemotherapy to determine its activity in that setting.
Interferon Alfa and Interferon Gamma Interferon alfa and interferon gamma have been shown to be active against ovarian cancer both in vitro and in vivo.24–27 The earliest clinical trials of interferon alfa administered intraperitoneally were conducted in women with persistent ovarian cancer at second-look laparotomy.28–30 In several confirmatory second-line trials in women with minimal residual disease, the surgically documented response rates were 30% to 50%.31–34 This outcome was shown to be similar in women treated with intraperitoneal interferon gamma as second-line therapy,35–37 with surgically documented responses in the range of 30% to 45% in patients with minimal residual disease. Although there is in vitro evidence that interferon gamma can increase the sensitivity of cancer cells to cisplatin,25 second-line intraperitoneal interferon alfa in combination with cisplatin does not seem to offer any advantage to interferon alone in these patients.31,32 Adverse effects, such as lethargy, fatigue, and flu-like symptoms, are common with the administration of the interferons.
Randomized Trial of Interferon Gamma With Primary Chemotherapy Although this represents the first trial of its kind, one of the limitations of the trial is that the chemotherapy used was a combination of cisplatin and cyclophosphamide. These drugs have now been supplanted by drugs that seem to be more efficacious and less toxic (eg, carboplatin and paclitaxel). The use of this interferon and possibly others should be added to current treatment regimens in a comparative trial to determine whether they would also have a similar advantage when combined with carboplatin and paclitaxel. Although a mechanism of action for interferon gamma in patients with ovarian cancer is unknown, the authors have speculated that this may inhibit the expression of dysregulated oncogenes (eg, HER-2/neu), improving the response of cisplatin-resistant cells. Evidence for this is mixed.39–41 Cytokine administration intraperitoneally seems to be necessary to augment local and cytotoxic effector cells where presumably most of the residual cancer was located. The presumption is that the direct contact with the cytokine through regional administration is necessary to induce the cytostatic or cytotoxic effect in the peritoneal cavity. However, in this randomized trial by Windbichler et al,38 systemic administration confers the survival benefit. Most likely, one should attribute this to the modulatory effects of interferon gamma on cells of the immune system, including stimulation of natural killer cells and macrophages, both of which are known to have antitumor properties.30 The induction of macrophages and other cytotoxic effector T cells may have a nonspecific immunomodulatory effect in these patients that favors responsiveness to chemotherapy or that has direct antitumor effects. Intriguingly, the interferons, including interferon gamma, have been shown to have not only an antiproliferative effect but also antiangiogenic effects. Theoretically, the effects have their highest probability of success in women who also receive chemotherapy for treatment of their disease. The combination of agents such as gamma interferon, thalidomide, or anti-vascular endothelial growth factor and cytotoxic therapy is a new opportunity for the development of innovative pharmacologic agents in solid tumors. This trial indicates that the combination of interferon and other related compounds with cytotoxic therapy should be further explored in phase II and III trials conducted in epithelial ovarian cancer patients.
p53 Gene Replacement Mutation of the p53 tumor suppressor gene is the most common known defect associated with solid tumors and is seen in more than half of ovarian cancers.42 Mutation of this gene is associated with a compromised survival in ovarian cancer. Several trials have been conducted using an approach that seeks to replace a mutated or defective p53 gene with replication-deficient adenovirus encoding human, recombinant, wild-type p53.42–44 Using this approach with rAd/p53 (SCH 58500) administered via the intraperitoneal route, Buller et al documented that the administration of this vector in 36 patients was generally well tolerated and could be combined with platinum chemotherapy. A phase I and II trial of single-dose therapy was followed by a multidose regimen. The median survival in these patients was 12 to 13 months, similar to the survival observed in historical controls. Although a multi-institutional, phase III, placebo-controlled trial was initiated, it was discontinued after accrual of nearly 80 patients because no apparent benefit was seen in those patients who received the rAd/p53 (Pegram M, personal communication, October 2001). Another group of researchers performed a phase I trial in 16 women of intraperitoneal administration of the adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted.44 E1A gene expression has been shown to increase cellular sensitivity to chemotherapy in a p53-independent manner. This adenovirus allows selective replication in and lysis of p53-deficient tumor cells and has been shown to have activity in a preclinical model against p53-deficient nude mouse–human ovarian carcinomatosis xenografts. The study demonstrated that this replication-competent and selective virus can be safely administered and was generally well tolerated, although no responses were observed. Biologic and immunologic therapy of ovarian cancer currently remains experimental. It would seem that for many of these therapeutic approaches, exquisite attention to surgical outcome may enhance the clinical effect to be garnered by the biologic therapy. Biologic and immunologic therapies seem to augment what can be accomplished with optimal chemotherapy and thus could provide an incremental improvement in patient management compared with current standards when results of currently ongoing studies establish definitive treatments as a standard of care.
DR. CANNISTRA: In GOG-182, maintenance therapy is specifically prohibited, and yet in other studies it’s being allowed. How do you reconcile these two different approaches given the data from GOG-178? DR. MARKMAN: It’s very difficult. There are the clinical trials questions and there are the questions of what you do in standard care for your patients. Ultimately, patients need to be presented with all the information that’s available as clearly and honestly as one can present it. My patients routinely ask me about clinically defined complete responses, because they look at the Internet. They want to know, since 80% of the patients recur, if there is something they can do to prevent recurrence? The bottom line is that one needs to provide patients with appropriate explanations of current therapies and the doctor’s own interpretation of these therapies. When you get into the question of clinical trials, it becomes complicated because then the question is whether clinical trials are mandated to have a consolidation arm, and if they don’t, do you have to tell the patients at the beginning that there’s an option that they’re being denied. DR. CANNISTRA: Implicit in what you said is the possibility that there still could be a survival advantage associated with the strategy of prolonged maintenance paclitaxel, but you can’t determine this from your study because of crossover issues after the results were made known to patients in the control arm of GOG-178. DR. MARKMAN: Unfortunately, that can never be addressed. One can say that this study may have had a positive impact on survival, but unfortunately we’ll never know. Therefore, we should negate the study because the endpoint should have been overall survival. My take on the progression-free survival in a disease like this in the front-line or second-line setting is whether the patient has good quality of life. These are two different questions. Is survival the only endpoint of front-line therapy? If so, then it is fair to say that we should ignore the results of this trial? If we say that this is a chronic disease, we’re prolonging the time to development of evidence of disease, it has a positive psychological endpoint, and it is going to prevent the patient from developing symptoms, then it’s a valid endpoint. You have to separate the questions. DR. CANNISTRA: Do you discuss with your patients the fact that you will be using a dose of 135 mg/m2, which was really not shown to be associated with the prolonged progression-free survival? DR. MARKMAN: I do, because I believe there is neurotoxicity in this regimen, and obviously if I had known the results of the trials and the toxicity, I probably would have suggested we start out with a lower dose than 175 mg/m2. I think there is significant neurotoxicity in this trial and that there are patients who become very uncomfortable from it. DR. McGUIRE: You’re the principal investigator for the industry-sponsored trial of polyglutamulated paclitaxel versus paclitaxel with carboplatin, and there are 12 cycles of paclitaxel versus polyglutamulated paclitaxel. How do you justify 12 additional cycles of polyglutamulated paclitaxel in that study with absolutely no data to suggest that that does anything? DR. MARKMAN: The goal is to see if you can have the same outcome but with less toxicity. The hypothesis is that this new taxane is less toxic than paclitaxel. DR. BAST: But, if you look at time off of treatment, you get a different story, don’t you? If I did the mathematics correctly, for 9 months of additional treatment, you get 7 months of progression-free survival. DR. BEREK: Also, wasn’t the response and relapse a CA-125 relapse? DR. MARKMAN: Thirty percent of the patients fell into that category. The CA-125 relapse is far more reliable than clinical relapse under any criteria. The clinical criteria of measurable disease or symptoms are very poor. So all the CA-125 does is make sure it’s a quantitative measurement in both arms. The issue is that CA-125 ultimately leads to symptoms. It may be that symptoms occur several months later, but they’re going to occur several months later with either arm. All it does is give you a better measurement of this. Regarding the issue of additional therapy, I believe we’ve got to start looking at not whether they’re on therapy, but what is the quality of life while on that therapy. DR. BAST: In the absence of quality-of-life data, the issue is whether being on chemotherapy is associated with a worse quality of life, prima facie, than being off chemotherapy. DR. MARKMAN: If you had done a quality-of-life analysis on GOG-178, you would have found that probably the patients who were getting this toxicity were not very happy about it. On the other hand, they wouldn’t have known why they were on the study because there were no data supporting the value of it at that point. If you asked a patient whether she was willing to accept 12 months of this therapy even though we have data that show that it might impact on survival, the paradigm within the patient’s head may be different in terms of her perceptions of why she’s doing it. She might say that the toxicity isn’t so bad because now I actually know why I’m doing it. So quality of life may be a moving target in a particular trial relative to what patients would say when we actually have the data. DR. BAST: As we plan additional trials that are likely to become the standards against which all other trials must be judged, quality of life or overall survival ought to be the hard endpoints. We want to avoid the situation where we prolong progression-free survival in the absence of data regarding quality of life.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
