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Phase III trials in oncologySetting standards of care? Survival data from phase III trials can be very misleading because patients are not offered the best follow-up therapy argue Siegfried Seeber and Ada Braun in CancerWorld’s new Forum section. Emma Mason canvassed clinical trial leaders, and presents their responses in the Debate section that follows.
For many years, oncologists enrolled patients have not received (4.0 and 2.8 months), it is against * S Seeber is the Director of the West German Cancer Centre, and AH Braun is a Clinical Fellow at the West German Cancer Centre, University of Duisburg-EssenMedical School, Essen, Germany. AH Braun is also Research Instructor at Vanderbilt University, Nashville, Tennessee.
This article was first published in Nature Clinical Practice Oncology, vol 2, no. 9, and is reproduced with permission. www.nature.com/clinicalpractice;doi:10.1038/ncponc0284. 2005 Nature Publishing Group – some for over eight years. In manycases, clinical responses wereobserved even in the sixth or seventhline (see Case Report, opposite).
These patients require close monitor-ing, early intervention at progression,and individualised multimodal thera-py employing effective drugs eithersingly or in adequate combinations,irrespective of their registration sta-tus. Dose-dense regimens should beused in critical phases and ‘softer’interims involving oral maintenancetherapy as well as locoregional treat-ment options (e.g. surgery, interven-tional radiology or hepatic artery infu-sions). Experienced physicians arenot impressed by studies claiming asurvival advantage of 15.4 vs 12.7months for docetaxel versus paclitaxelin metastasised breast cancer,4 aresult advertised as a ‘highlight’ of the2003 ECCO. that combining paclitaxel with carbo-platin is as effective as vinorelbine plus cisplatin,5 with equally poormedian survival (8 months), and one- and S Seeber, unpublished data). in platinum-refractory patients, and taxotere failure? Albeit active, the lat- Unsatisfactory post-study access to active agents may account for the unacceptable median survival Representative case report: breast cancer
57-year-old female patient with metastatic breast cancer; history of 15 lines of chemotherapy; now good performance status Note that the patient has been treated off-label since the 2nd line of chemotherapy; alopecia was induced only under EC-(epirubicin/cyclophosphamide) and taxane-based treatment; response to treatment was assessed at least every 3 weeks usingultrasonography and serum markers (including CA 15-3 and LDH) or at least every 9–12 weeks using CT, MRI and/orX-rays; pulmonary metastases remained in good partial remission throughout treatment; any attempt to ascribe the relativecontribution of individual drugs to the overall survival of the patient appears absurd.
First diagnosis of breast cancer (invasive ductal adenocarcinoma; left breast) T1 N1 (2/11) M0; G2; oestro-gen/progesterone receptor (ER/PR) negative; HER2+++ (immunohistochemistry) breast-conserving surgery,adjuvant radiotherapy left breast, 6 cycles of adjuvant chemotherapy (CMF; cyclophosphamide, methotrexate,5-fluorouracil) in a peripheral hospital Increase in CA 15-3 tumour marker, indicative of relapse Total mastectomy on local recurrence; tumour now ER+, PR-; adjuvant tamoxifen therapy Once again increase in CA 15-3 tumour marker; first diagnosis of pulmonary metastases; treatment with thearomatase inhibitor formestane Progression of pulmonary metastases; first diagnosis of liver and bone metastases Treatment with the progestin medroxyprogesterone acetate (MPA) to no avail Chemotherapy with epirubicin and cyclophosphamide (EC; 1st line chemotherapy for metastatic disease);clinical response for more than 6 months Upon patient request of hair-sparing therapy, treatment with vinorelbine and 5-fluorouracil within a clinical trial(2nd line; until 09/1999); good clinical response Radiotherapy of right ileosacrum for pain control (30 Gy) Increase in CA15-3; docetaxel (3rd line) results in partial remission of hepatic lesions Bridging therapy with the aromatase inactivator exemestane proved to be ineffective Raf kinase inhibitor (BAY 43-9006; 4th line; phase I clinical trial); minor response for 5 months with excellentquality of life Fulminant hepatic disease progression (CA 15-3 increase up to 18,750); 3x monthly locoregional therapy(hepatic artery infusions) with mitomycin C plus 5-fluorouracil (5th line); major response and recoveredperformance status Oral maintenance therapy using capecitabine (6th line) Progressive disease (liver); oral chemotherapy with CMP (cyclophosphamide, methotrexate, prednisone; 7thline) induces partial response for 2 months Increase in CA 15-3; mitoxantrone therapy (8th line); clinical response for 3 months Increase in CA 15-3; combination therapy with vinorelbine and epirubicin (9th line) Although minor remission of hepatic lesions, due to toxicity therapy is continued with gemcitabine (10th line);time to disease progression is 3 months Trastuzumab (11th line) induces regression of hepatic and pulmonary lesions Tumour marker turnaround; treatment with vinorelbine (12th line) Oral capecitabine maintenance therapy (13th line) Upon marker progression, treatment with oral CMP (cyclophosphamide, methotrexate, prednisone; 14th line) Progressive disease (liver, pelvis, ascites); treatment with paclitaxel single-agent (15th line) Despite clinical response, change of therapy due to toxicity (polyneuropathy); docetaxel (16th line) inducesminor response Since 12/2004, treatment paused; ultrasonography shows continued response but evidence of developing livercirrhosis; good performance status (WHO 1) bicin for platinum-resistant tumours.
References1. O'Shaughnessy J et al. (2002) Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breastcancer: phase III trial results. J Clin Oncol 20:2812– 2. Albain KS et al. (2004) Global phase III study ofgemcitabine plus paclitaxel (GT) vs paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival. Proc Am Soc Clin Oncol22:a510 3. Bell R et al. (2004) Maximizing clinical benefit with trastuzumab. Semin Oncol 31: 35–444. Ravdin P et al. (2003) Phase III comparison of docetaxel (D) and paclitaxel (P) in patients with metastatic breast cancer (MBC). Eur J Cancer Suppl1:S201 5. Kelly K et al. (2001) Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine pluscisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19:3210–3218 6. Schneider A et al. (2004) Weekly irinotecan in patients with advanced non-small-cell lung cancer (NSCLC) after failure of cisplatin, taxane andgemcitabine based chemotherapy. Onkologie 27 7. Du Bois A et al. (2004)Epirubicin/paclitaxel/carboplatin (TEC) vs paclitaxel/carboplatin (TC) in first-line treatment of ovarian cancer (OC) FIGO stages IIB-IV. An AGO-GINECO Intergroup phase III trial [abstract]. Proc Am 8. Tannock IF et al. (2004) Docetaxel plus prednisoneor mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512 9. Goldberg RM et al. (2004) A randomized controlledtrial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol22:23–30 10. Tournigand C et al. (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advancedcolorectal cancer: a randomized GERCOR study. The central charge of the quate other therapies, although time ure in the trials. I cannot imagine eth- that ‘only’ two thirds of the patients “The situation Seeber is referring to is and I don’t see why a patient in a clin- ical trial would have less access to sal- patients with advanced breast cancer.
been in a trial; so participation in tri- Seeber told CancerWorld: “We … Siegfried Seeber: A drug has to be helpful, Aron Goldhirsch: Phase IIIs tell us which treatment but it is nearly impossible to relate overall is better overall. The care of individuals must as an endpoint may fail to take proper account predictive features are identified (i.e.
robust, randomised phase III trials.
it is nearly impossible to relate overall second, third or more lines of thera-pies, Therasse said: “There are manytrials addressing these questions oftreatment sequence and indications –probably too many as compared toother important questions which willremain unanswered, because there isno drug or no company behindthem.” quoted above all disagree with Seeberand Braun that current phase III trialpractice offers patients insufficientaccess to the best follow-up thera-pies. There is a general consensusthat overall survival is not necessarilythe best primary endpoint for a trial Monica Castiglione: The fact that ‘only’ two thirds of the patients received a third-line participation in a trial decreased access to best salvage treatment, no patients would be entered sensitive endpoints. However,Therasse and Castiglione believe that survival for adjuvant trials. So I do not The Debate was compiled by Emma Mason
drugs for metastatic disease should beregistered on the basis of results from trials using endpoints of improvedrelapse-free survival or improved time would like to know what your thoughts or experiences are on these Kaye that this is no longer an issue.
issues. Is there a problem with the way phase III trials are run and their effect on the way drugs are licensed? Do patients suffer from lack of proper follow-up treatment at the end of their trials? Contact us at editor@esoncology.org and let us know.
*The European Medicines Agency’s Guideline On The Evaluation Of Anticancer Medicinal Products In Man, which gives details about their policy on crossover and use of overallsurvival versus disease-free or progression-free survival as a primary endpoint, can be found at www.emea.eu.int/pdfs/human/ewp/020595en.pdf

Source: http://www.cancerworld.net/pdf/7308_27_33_cw11_Forum%20dx%20.pdf