Controversy still surrounds combining IP chemotherapy with IV chemotherapy for ovarian cancer.
Determining whether or not intraperitoneal chemotherapy should become the standard of care for ovarian cancer following initial cytoreductive surgery is among the more controversial topics in the field of gynecologic oncology. Some experts question whether the topic should be debated at all.
“There should be no controversy,” said David S. Alberts, MD, Regents’ Professor of Medicine and Pharmacology at the University of Arizona College of Medicine and director of the Arizona Cancer Center.
“Never in the annals of cancer research have the results of three consequent, positive phase-3 trials not led to a complete change in therapeutic approaches to common cancers,” Alberts told HemOnc Today, referring to the studies conducted by the Gynecologic Oncology Group (GOG).
David S. Alberts, MD, at the Arizona Cancer Center, supports the use of IP chemotherapy for the treatment of ovarian cancer.
Photo by Arizona Cancer Center
“Of course, this is why we performed well-designed phase-3 trials,” Alberts said. “Otherwise, we are turning our backs on our wonderful patients who participate in these studies and turn to us for knowledge and unbiased honest decision process.”
In January 2006, the results of the third study in the GOG series, which were consistent with the previous two, prompted the National Cancer Institute to issue a clinical announcement encouraging physicians to follow surgery with a combination of IV and IP therapy. It stated the approach, although more toxic, extended overall survival for women with advanced ovarian cancer by about a year compared to IV delivery alone.
Maurie Markman, MD, vice president for clinical research, M.D. Anderson Cancer Center, and member of the GOG, agreed.
“There really is no controversy,” Markman said. “Three evidence-based cooperative group randomized phase-3 trials have revealed that the IP administration of cisplatin as primary treatment of small-volume residual stage III ovarian cancer improves survival, [with a] 20% to 30% relative reduction in the risk of death.”
Even though the majority of experts interviewed were in favor of IP chemotherapy for ovarian cancer, said Robert F. Ozols, MD, PhD, that is not the general consensus.
“The controversy about IP chemotherapy relates to both toxicity and efficacy,” said Ozols, senior vice president for medical science at Fox Chase Cancer Center. “Many investigators feel there is no definitive proof that IP chemotherapy is superior to IV carboplatin plus paclitaxel.”
Robert F. Ozols
The American Cancer Society estimates that 21,650 women will be diagnosed with ovarian cancer this year, with more than 15,500 women estimated to die from the disease. The best method to bring these numbers down is still under dispute.
The use of IP chemotherapy for treating ovarian cancer has been an option in many institutions for decades. Memorial Sloan-Kettering Cancer Center, for example, has been using IP chemotherapy as part of its standard protocol for battling ovarian cancer since the mid-1980s. Still, IP chemotherapy was not considered the standard of care. In fact, according to an article in the Journal of Clinical Oncology by Gore et al, some experts believe that it is experimental.
The GOG trials are what many consider the most important trials on IP chemotherapy. In the first study, the GOG and Southwestern Oncology Group (SWOG) randomly assigned patients to IV cisplatin plus cyclophosphamide or IP cisplatin combined with IV cyclophosphamide.
The second (GOG-114), led by Markman, found an experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. The researchers also concluded that because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm was not recommended for routine use.
Results from another GOG study (GOG-158) was then released. GOG-158 analyzed carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer. Led by Ozols, the researchers concluded that the regimen of carboplatin plus paclitaxel resulted in less toxicity, was easier to administer and is not inferior when compared with cisplatin plus paclitaxel.
The third IP study (GOG-172) compared an IP regimen (135 mg/m2 paclitaxel IV) over 24 hours on day one, plus 100 mg/m2 cisplatin IP on day two, plus 60 mg/m2 paclitaxel IP on day eight, to an IV regimen (135 mg/m2 paclitaxel) over 24 hours IV on day one, plus 75 mg/m2 cisplatin IV on day two administered every three weeks for six cycles.
In the multicenter study, led by Deborah K. Armstrong, MD, associate professor of oncology, gynecology and obstetrics at Johns Hopkins Kimmel Cancer Center, Baltimore, overall survival for 205 women with surgically debulked stage III ovarian cancer who received both IP and IV chemotherapy was a median of 65.6 months. This was 25% longer than that of 210 women treated with IV only chemotherapy (49.7 months). Also, women who received IP chemotherapy had 20% longer progression-free survival.
Despite this, many still argued many of the study’s results were not all positive.
“The largest issues that remain are the complexity and toxicity of the IP therapy,” said Armstrong. “Some feel that the toxicities are too great to recommend it, and others feel that the IP approach is too complicated to use routinely,” Armstrong said.
According to Ozols, the major concern with the results of the GOG-172 study is the “alleged” improved median survival of 15 months for IP therapy compared to IV chemotherapy.
Ozols said that the Armstrong study, published in The New England Journal of Medicine, which sparked the NCI’s clinical announcement, used the wrong control arm.
“In that study, IV cisplatin plus paclitaxel was used as a control arm,” Ozols said. “The previous study [GOG 158] used the same eligibility criteria to compare IV carboplatin plus paclitaxel versus IV cisplatin plus paclitaxel. The results of that study were not known to the investigators at the time the IP study was begun and hence they used the control arm of IV cisplatin and IV paclitaxel,” Ozols said.
However, Ozols said, GOG-158 demonstrated that IV carboplatin plus paclitaxel was superior to IV cisplatin plus paclitaxel with an improvement in median survival of approximately nine months.
“Consequently, in a cross-trial comparison of the IP treatment in GOG-172 vs. the IV results of carboplatin plus paclitaxel in GOG-158 — there would be no statistically significant improvement in survival for the IP arm,” Ozols said.
Ozols said that although a cross-trial comparison is not proof, it is hypothesis-generating and the results are informative because in both GOG-172 and -158 the same control arm of IV cisplatin plus paclitaxel produced identical results.
“It strongly suggests that if IV carboplatin plus paclitaxel had been the control arm, there would not have been any significant improvement in survival for the IP arm,” Ozols said.
Lari Wenzel, PhD, associate professor in the department of medicine at the University of California, Irvin, was an investigator in the GOG-172 study. She said that those arguing against IP therapy understand the study design complexities associated with it.
“However, these arguments should not obfuscate the promise of compelling results and the opportunities to further study and adopt IP therapy,” she said.
Markman also noted that it is not just one study that justifies the use of IP therapy.
“It is the overwhelming data, confirmed in several meta-analyses, that IP cisplatin improves survival in this specific clinical setting,” Markman said.
“Although there are no definitive data about how many patients are receiving IP chemotherapy, it is my belief that the majority of patients are not receiving IP chemotherapy due to the questions about efficacy and the concerns about the toxicity,” Ozols said.
Ozols said that the large number of patients in the Armstrong study could not tolerate the chemotherapy and, in fact, 18% of patients randomized to the IP arm received IV carboplatin plus paclitaxel after they stopped IP treatment.
“However, these patients continue to be followed on the survival curve for IP therapy. The IP arm in GOG-172 had differences in dose and schedule that may have also accounted for differences in efficacy,” Ozols said.
“Finally, the toxicity of therapy is unacceptable,” he added. “In GOG-172, only 42% of patients could complete six cycles of chemotherapy due to a variety of grade-3 and -4 toxicities.”
Although a lot was made of the toxicity of the Armstrong regimen and the high percentage of patients who did not complete the six full courses of therapy, Alberts said the careful quality-of-life evaluation performed at 12 months after therapy completion revealed no difference between the IV and IP therapy groups.
“With respect to quality of life, although it was clear that patients randomized to the IP/IV arm experienced greater quality-of-life disruption and toxicities during and shortly after treatment, two additional points are worth nothing,” Wenzel said. “Only neurotoxicity remained as a significant difference subsequent to treatment, and in general quality of life improved for women in both treatment groups over time.”
“Yes, these are reversible toxicities and the quality-of-life measurers indicate that after completing therapy, quality of life is equivalent, in spite of the more toxic regimen,” Armstrong said.
Alberts said that the one major problem with the safe administration of IP chemotherapy has been the relative lack of in-depth training available in the setting of medical oncology and gynecologic oncology fellowships.
“Without such in-depth training concerning both the proper surgical catheter placement and type of IP catheter, as well as important details on supportive care, IP therapy toxicity issues will continue to impede real progress. This is true for the introduction of any new medical technology; for example, minimal surgery for hip replacements,” Alberts said. “Without strong training, the complications can be devastating.”
In early 2006, on the heels of the release of the Armstrong study, the GOG sponsored a workshop in which the trials were discussed in detail. In addition, SWOG sponsored a training workshop during its semiannual meeting to further educate oncologists about IP therapy.
Armstrong said that like any new or more detailed treatment approach, it is unlikely to be successful unless the health care provider is dedicated to making it work. “Those of us at teaching hospitals have a lot of support to help manage patients on IP therapy, but a community physician may not have such support.”
Alberts said he “would like to see the cooperative clinical trials groups, with the help of NCI-DCTD-CTEP, sponsor a series of IP therapy workshops for oncologists and nurses at their bi-annual or quarterly meetings. In fact, I would volunteer my time to accomplish this essential training effort.”
There is virtually no standard of care for any of the common cancers in metastatic stages, Alberts said. In concept, the experimental arms of well-designed phase-3 trials should always out-perform the control study arms.
“So, the issue is not the Armstrong (GOG-172) regimen,” Alberts said. “The real issue is that IP therapy must be offered to women who have optimally debulked stage III epithelial-type ovarian cancer.
“No other conclusion can be drawn after the IP experimental arms on three consecutive Gynecologic Oncology Group studies were associated with dramatic survival advantages compared to the IV platinum-containing regimens,” Alberts said.
Markman said the objections to IP therapy are clear. They relate to the toxicity, which he thinks can be minimized the lack of experience, which he thinks can be overcome, often by referring a patient to an oncology group that is willing and able to employ this strategy; and the cost of treatments.
But, he said, individual physicians and practices will need to determine if it is appropriate for them to treat patients in this manner, and it is rational that they may objectively decide it is not appropriate for them to undertake this method of treatment.
“However, what absolutely should not be criticized is the validity of the very solid evidence demonstrating the survival benefits of this strategy,” Markman said.
Ozols said that with all of these considerations, he does not feel that any potential benefits of intraperitoneal therapy clearly outweigh the risks.
“Patients and physicians are willing to accept increased toxicity if there is clear-cut evidence that survival is improved, but it clearly has not been established that the IP route of administration leads to improved survival compared to treatment with IV carboplatin plus paclitaxel, which is a generally well-tolerated regimen,” Ozols said.
Wenzel believes the potential of IP absolutely outweighs the risk. “Substantial evidence, including the Armstrong study, exists to support the promise associated with IP therapy.”
However, Wenzel said that there are several considerations to minimizing risk, and these should be evident in the design of many new trials.
“It is important that proper training and standardization of administration be available to health care practitioners to assist in minimizing risk,” Wenzel said. “In addition, measures should be in place to avoid, anticipate or mitigate associated toxicities. It is likely that new studies will address these issues through careful design and treatment administration considerations, in addition to a greater role for supportive care measures during treatment.”
“I must emphasize that there is an extreme human factor involved with oncologist decisions not to offer, or half-heartedly offer, IP therapy to their optimally debulked, stage III patients,” Alberts said. “These women deserve to benefit from evidence-based medicine; their lives depend on us.” – by Angelo Milone
Should intraperitoneal chemotherapy become the standard of care for ovarian cancer?
For more information:
- Alberts DS, Markman M, Muggia F, et al. Proceedings of a GOG workshop on intraperitoneal therapy for ovarian cancer. Gynecol Oncol. 2006; 103: 783-792.
- Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006; 103: 783-792.
- Gore M, du Bois A, Vergote I. Intraperitoneal chemotherapy in ovarian cancer remains experimental. J Clin Oncol. 2006; 24: 4528-4530.
- Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group and Eastern Cooperative Oncology Group. J Clin Oncol. 2001; 19: 1001-1007.
- Ozols R, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol. 2003; 21: 3194-3200.
- Vergote I, Amant F, Leunen K, et al. Intraperitoneal chemotherapy in patients with advanced ovarian cancer: The con view. The Oncologist. 2008; 13: 410-414.
- Wenzel L, Huang H, Armstrong D, et al. Health-Related Quality of Life During and After Intraperitoneal Versus Intravenous Chemotherapy for Optimally Debulked Ovarian Cancer: A Gynecologic Oncology Group Study. J Clin Oncol. 2007;25: 437-443.