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Consider the following analyses involving previously published data in the peer-reviewed medical literature comparing outcomes across 1) ovarian cancer trials and 2) retrospective institutional experiences in this malignancy:

Analysis 1

  1. Top of page
  2. Analysis 1
  3. Analysis 2
  4. Analysis 3
  5. Reanalysis 1
  6. Reanalysis 2
  7. Reanalysis 3
  8. REFERENCES

Several institutions have reported their individual data regarding long-term (>5 years) risk for recurrence in patients with advanced ovarian cancer who previously had achieved a surgically confirmed complete response to primary chemotherapy.1–3 Table 1 shows that, after cisplatin-based treatment, this rate exceeded 50%,1, 2 whereas for patients who received alkylating agent chemotherapy, the risk of recurrence was <20% (even with follow-up >8 years).3 These data would appear to support the conclusion that alkylating agent therapy is the superior primary chemotherapy strategy in advanced ovarian cancer. Why is this class of antineoplastic agents not the “standard of care” in the management of the malignancy?4

Table 1. Risk of Recurrence After Either Primary Cisplatin-Based or Alkylating Agent Chemotherapy in Patients With Advanced Ovarian Cancer Who Achieved a Pathologically Negative Second-Look Surgical Assessment
ChemotherapyPatients with recurrence, %
  • *

    See Rubin et al., 19991 and Copeland and Gershenson, 1986.2

  • See Cain et al., 1986.3

Cisplatin-based chemotherapy*≥50
Alkylating agent chemotherapy<20

Analysis 2

  1. Top of page
  2. Analysis 1
  3. Analysis 2
  4. Analysis 3
  5. Reanalysis 1
  6. Reanalysis 2
  7. Reanalysis 3
  8. REFERENCES

In a randomized Phase III trial that was conducted by the Gynecologic Oncology Group (GOG) exploring the clinical utility of primary platinum-based chemotherapy in large-volume, residual, advanced ovarian cancer (stage IV disease and stage III disease with at least a single residual tumor nodule >1 cm in maximum dimension), the median progression-free and overall survival of patients who received cisplatin plus paclitaxel were 14 months and 26 months, respectively, which clearly was not different from the GOG experience in an identical patient population that received cisplatin plus cyclophosphamide (Table 2).5, 6 Based on this analysis, what was the justification for the GOG, other cooperative groups, and practicing oncologists to consider cisplatin plus paclitaxel the new “standard of care” in this clinical setting?4

Table 2. Comparison of the Impact of Cisplatin and Paclitaxel Versus Cisplatin and Cyclophosphamide as Primary Treatment for Suboptimal Residual Advanced Ovarian Cancer
VariableCisplatin and cyclophosphamideCisplatin and paclitaxel
  1. PFS indicates progression-free survival; OS, overall survival.

Median PFS, mo1314
Median OS, mo2426

Analysis 3

  1. Top of page
  2. Analysis 1
  3. Analysis 2
  4. Analysis 3
  5. Reanalysis 1
  6. Reanalysis 2
  7. Reanalysis 3
  8. REFERENCES

Two independent investigative groups reported objective response rates of >40% associated with the administration of a cisplatin plus gemcitabine combination chemotherapy regimen to a group of patients with ovarian cancer who were defined by the researchers as having platinum-resistant disease (Table 3).7, 8 It is noteworthy that previously published Phase II and Phase III trials that involved multiple antineoplastic agents delivered in this setting have revealed objective response rates of <20%.9, 10 One interpretation of the cisplatin plus gemcitabine data is that they represent a substantial improvement in activity compared with alternative programs in this clinical setting.

Table 3. Response Rates of Cisplatin and Gemcitabine Compared With Alternative Chemotherapy Regimens in Platinum-resistant Ovarian Cancer
VariableORR, %
  1. ORR indicates objective response rate.

Phase II agents (multiple)5–20
Phase II trials of cisplatin and gemcitabine>40

Although the specific “facts” in the 3 “analyses” presented above are stated accurately, the profoundly flawed conclusions result from inappropriate comparisons made between patient populations outside the setting of a well-designed, prospective, randomized trial. Now, consider the following “reanalyses” of each of the 3 scenarios.

Reanalysis 1

  1. Top of page
  2. Analysis 1
  3. Analysis 2
  4. Analysis 3
  5. Reanalysis 1
  6. Reanalysis 2
  7. Reanalysis 3
  8. REFERENCES

The stated recurrence rates noted in Table 1 after platinum-based and alkylating agent therapy reflect the observed institutional experiences with these agents.1–3 However, they do not represent an appropriate evaluation of patients who received the specific regimens that differed only in the drugs employed. “Standard” cisplatin-based treatment generally has included from 5 to 8 months of drug delivery with a second-look surgical evaluation (if this management approach is employed) performed approximately 1 or 2 months after the completion of chemotherapy.5, 11 In sharp contrast, in the past, patients who were administered alkylating agent-based therapy who did not experience disease progression typically received the drug for ≥18 months before surgical reassessment was undertaken (Table 4),3, 12 Thus, during this more prolonged observation phase, a far larger proportion of individuals with persistent disease had the opportunity to exhibit biologic progression that became clinically evident or that, at least, was of sufficient quantity/volume to become detectable (e.g., biopsy-positive, second-look procedure) in contrast to the much shorter time interval from diagnosis to the second surgery associated with cisplatin treatment. Consequently, the overall smaller numbers of patients who had a “negative” reassessment after alkylating agent chemotherapy (both because of the inferiority of nonplatinum-based regimens13, 14 and because of the timing of the evaluation3, 12) appeared to have a superior ultimate prognosis. It is highly likely (although only actual data can address the issue definitively) that, if second-look surgeries were performed routinely in platinum-treated ovarian cancer patients from 18 to 24 months after the initiation of primary chemotherapy, then those individuals found to be “without documented disease” would experience a similarly low risk of recurrence (from that point onward), as noted in the alkylating agent-treated population.

Table 4. Risk of Recurrence After Either Primary Cisplatin-Based or Alkylating Agent Chemotherapy in Patients With Advanced Ovarian Cancer Who Achieved a Pathologically Negative Second-Look Surgical Assessment: The Impact of a Modification in a Major Clinical Parameter
VariablePatients with recurrence, %Approximate timing of second-look assessment (from initiation of chemotherapy), mo
Cisplatin-based chemotherapy≥506–9
Alkylating agent chemotherapy<20>18

Reanalysis 2

  1. Top of page
  2. Analysis 1
  3. Analysis 2
  4. Analysis 3
  5. Reanalysis 1
  6. Reanalysis 2
  7. Reanalysis 3
  8. REFERENCES

The analysis (Table 2), although it involved the management of patients by the same group of gynecologic oncologists employing identical eligibility criteria, represents a cross-trial comparison of populations treated with the 2 chemotherapy programs on consecutive GOG studies (cisplatin/cyclophosphamide on GOG 111 and cisplatin/paclitaxel on GOG 132).5, 6 In fact, the actual differences between the 2 regimens in progression-free survival (P < .001) and overall survival (P < .001) within the same trial (Table 5) were substantial5 and led (along with the results of a second Phase III randomized study15) to an appropriate change in the management paradigm for advanced ovarian cancer.4 What caused the major difference between the outcomes associated with the same cisplatin/paclitaxel study regimens in the 2 studies, in what appear to be “identical” entry criteria for the consecutive trials? Although it is not possible to provide a definitive answer to this provocative question, it is logical to assume that there were unanticipated and unappreciated differences in the patient populations that participated in the 2 specific trials. One hypothesis is that the legitimate concern for “sudden death” and “severe cardiac toxicity” that surrounded the very early experience with paclitaxel led to a relative decrease in participation in the initial randomized trial of women with clinically relevant comorbidities in addition to known cardiac dysfunction (which was an exclusion criteria for the trial).16, 17 When this Phase III study revealed the absence of serious cardiac events5 and it became clear that paclitaxel-associated hypersensitivity was a manageable drug-related toxicity, it is possible that the subsequent trial (with the lower survival in the paclitaxel-containing arm) included women with a spectrum of comorbid conditions that were not evident (at least in the same proportion) in the first study and that had a negative influence on the outcome.6 It is important to state again that this is only a hypothesis and nothing more.

Table 5. Comparison of the Impact of Cisplatin and Paclitaxel Versus Cisplatin and Cyclophosphamide as Primary Treatment of Suboptimal Residual Advanced Ovarian Cancer: The Impact of Cross-Trial Analysis
VariableCisplatin and cyclophosphamideCisplatin and paclitaxel*(Cisplatin and paclitaxel)*
  • PFS indicates progression-free survival; OS, overall survival; GOG, Gynecologic Oncology Group.

  • *

    GOG 111 and GOG 132 were sequential trials conducted by the Gynecologic Oncology Group with the same entry criteria.

Median PFS, mo131418
Median OS, mo242638
GOG trialGOG 111GOG 132GOG 111

Reanalysis 3

  1. Top of page
  2. Analysis 1
  3. Analysis 2
  4. Analysis 3
  5. Reanalysis 1
  6. Reanalysis 2
  7. Reanalysis 3
  8. REFERENCES

It is well recognized in oncology that the objective response rates in small Phase II, antineoplastic drug studies frequently are not replicated when the identical regimens are examined in multicenter, randomized trials.18 Differences in the extent of disease and prior therapy, location and size of the tumor(s), the presence or absence of significant comorbidity, and the criteria employed for determining a response all may play an important role in this common observation. Thus, it should not come as a surprise to learn that, when the GOG conducted its own Phase II trial of the combination of cisplatin plus gemcitabine in platinum-resistant ovarian cancer, the observed objective response rate was substantially lower than that noted in the noncooperative group setting19 and was within the range reported for agent-single agent gemcitabine20, 21 and other cytotoxic agents employed in this clinical setting (Table 6).9, 10

Table 6. Response Rates of Cisplatin and Gemcitabine Compared With Alternative Chemotherapy Regimens in Platinum-Resistant Ovarian Cancer: The Impact of Cross-Trial Analysis
VariableORR, %
  1. ORR indicates objective response rate; GOG, Gynecologic Oncology Group.

Phase II agents (multiple)5–20
Phase II trials of cisplatin and gemcitabine>40
(Phase II GOG trial of cisplatin and gemcitabine)(16)

This commentary has not been written to suggest that an examination of differences in outcomes between individual trials or institutional experiences is always without merit. On the contrary, such efforts may lead to provocative hypotheses that subsequently may result in the initiation of prospective, randomized, Phase III studies. For example, the rather prolonged survival of a subset of women with platinum-resistant ovarian cancer who were treated with single-agent paclitaxel on a National Cancer Institute-sponsored Phase II trial, compared with an “expected outcome” that was suggested by historic data in this clinical setting,22 led to the development of a Phase III study exploring this agent as a “maintenance” strategy in patients with advanced ovarian cancer.23

However, it is absolutely critical that the substantial limitations (this type of analysis can be only hypothesis-generating) and inherent dangers (profoundly inappropriate claims for the validity of the results of such comparisons) of this academic exercise be understood clearly. Furthermore, an appreciation for the importance of this issue must be shared by journal editors, peer-reviewers, and all who attempt to evaluate the objectivity and relevance of articles that appear in the oncology literature. Finally, it is essential that the education and mentoring of our clinical (and clinical research) trainees include thorough discussions regarding the fundamental concerns associated with “cross-trial” and “cross-retrospective experience” comparisons as well as the potential role of such efforts in the generation of novel hypotheses to be tested in future, well-considered investigative initiatives.

REFERENCES

  1. Top of page
  2. Analysis 1
  3. Analysis 2
  4. Analysis 3
  5. Reanalysis 1
  6. Reanalysis 2
  7. Reanalysis 3
  8. REFERENCES
  • 1
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    Copeland LJ, Gershenson DM. Ovarian cancer recurrences in patients with no macroscopic tumor at second-look laparotomy. Obstet Gynecol. 1986; 68: 873874.
  • 3
    Cain JM, Saigo PE, Pierce VK, et al. A review of second-look laparotomy for ovarian cancer. Gynecol Oncol. 1986; 23: 1425.
  • 4
    Covens A, Carey M, Bryson P, et al. Systematic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol. 2002; 85: 7180.
  • 5
    McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996; 334: 16.
  • 6
    Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2000; 18: 106115.
  • 7
    Rose PG, Mossbruger K, Fusco N, et al. Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma. Gynecol Oncol. 2003; 88: 1721.
  • 8
    Nagourney RA, Brewer CA, Radecki S, et al. Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol. 2003; 88: 3539.
  • 9
    Conte PF, Gadducci A, Cianci C. Second-line treatment and consolidation therapies in advanced ovarian cancer. Int J Gynecol Cancer. 2001; 11( Suppl 1): 5256.
  • 10
    Markman M. Ovarian carcinoma: management after first-line therapy. J Pelvic Surg. 2000; 6: 2733.
  • 11
    Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004; 96: 16821691.
  • 12
    Katz ME, Schwartz PE, Kapp DS, et al. Epithelial carcinoma of the ovary: current strategies. Ann Intern Med. 1981; 95: 98111.
  • 13
    Advanced Ovarian Cancer Trialists' Group. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. BMJ. 1991; 303: 884893.
  • 14
    Aabo K, Adams M, Adnitt P, et al. Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group. Br J Cancer. 1998; 78: 14791487.
  • 15
    Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000; 92: 699708.
  • 16
    Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med. 1995; 332: 10041014.
  • 17
    McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989; 111: 273279.
  • 18
    Zia MI, Siu LL, Pond GR, Chen EX. Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. J Clin Oncol. 2005; 23: 69826991.
  • 19
    Brewer CA, Blessing JA, Nagourney RA, et al. Cisplatin plus gemcitabine in platinum-refractory ovarian or primary peritoneal cancer: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2006; 103: 446450.
  • 20
    D'Agostino G, Amant F, Berteloot P, et al. Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer. Gynecol Oncol. 2003; 88: 266269.
  • 21
    Shapiro JD, Millward MJ, Rischin D, et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol. 1996; 63: 8993.
  • 22
    Markman M, Hakes T, Barakat R, et al. Follow-up of Memorial Sloan-Kettering Cancer Center patients treated on National Cancer Institute Treatment Referral Center Protocol 9103: paclitaxel in refractory ovarian cancer. J Clin Oncol. 1996; 14: 796799.
  • 23
    Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003; 21: 24602465.