NSABP PROTOCOL B-34. Date Opened to Randomization: December 1, 2000 Date Closed to Randomization: March 31, 2004 Number of Patients Randomized: 3,323

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1 NSABP PROTOCOL B-34 A Clinical Trial Comparing Adjuvant Clodronate Therapy versus Placebo in Early-Stage Breast Cancer Patients Receiving Systemic Chemotherapy and/or Tamoxifen or No Therapy Date Opened to Randomization: December 1, 2000 Date Closed to Randomization: March 31, 2004 Number of Patients Randomized: 3,323 Protocol Chair: Protocol Officer: Protocol Statistician: Protocol Pathologist: Alexander Paterson, MD Barry Lembersky, MD Stewart J. Anderson, PhD Soomyoung Paik, MD

2 NSABP PROTOCOL B-34 I. SPECIFIC AIMS This study is a prospective, randomized, double-blind, phase III, adjuvant clinical trial to assess administration of clodronate in early-stage breast cancer patients who may or may not be receiving concurrent chemotherapy or hormonal therapy. Patients must have invasive adenocarcinoma of the breast and have previously undergone either a total mastectomy or a lumpectomy with either an axillary dissection or sentinel node biopsy. For women undergoing sentinel node biopsy, only those participating in NSABP B-32 will be eligible. If sentinel node biopsy is performed outside of the B-32 protocol, completion of axillary dissection is required. Eligible patients for this trial may be nodenegative or node-positive. The primary aim of this study is to determine whether clodronate, given to patients with early-stage breast cancer for a period of three years, either alone or in addition to adjuvant chemotherapy or hormonal therapy, will improve disease-free survival. The secondary aims of this study are to determine whether the addition of adjuvant clodronate will: reduce the incidence of skeletal metastases, improve overall survival, improve relapse-free survival, reduce the incidence of non-skeletal metastases, and reduce the incidence of skeletal morbidity (skeletal fractures, hypercalcemia, skeletal pain, need for skeletal radiation therapy, spinal cord compression). An additional secondary aim is to investigate the relevance of serum markers of bone turnover as a prognostic factor for the development of bone metastasis. NSABP B-34 SCHEMA Stratification Age (<50, > 50 Number of Positive Nodes (0, 1-3, 4+) ER/PgR Status (negative [ER- and PgR-], positive [ER+ and/or PgR+]) Randomization Group 1 Clodronate mg/day x 3 years Group 2 Placebo 1 x 3 years 1 At the discretion of the investigator, patients may receive adjuvant systemic chemotherapy and/or Tamoxifen, or no adjuvant therapy.

3 II. PATIENT ENTRY AND CHARACTERISTICS This protocol was opened for accrual on December 1, The first patient was accrued to the study on January 22, 2001, and accrual was terminated on March 31, During that period, 3,323 patients were accrued to the study, 154 of which were accrued in March The average accrual in the last year was nearly 98 patients per month. The projected accrual was 50 patients per month. As of January 5, 2010, 54 patients (1.6%) have been declared ineligible: 23 in group A and 31 in group B. Due to the blinded nature of the study, the treatment arms are only identified as Group A and Group B. As of December 31, 2009, the average time on study for all patients with follow-up on B- 34 was 86.2 months. Patient characteristics are summarized in Table 1. The characteristics, as expected, appear to be reasonably balanced by arm. III. TOXICITY As of December 27, 2009, adverse event information had been received for 3,235 patients [see Tables 2a-3b]. Seventeen deaths have been reported while patients were on protocol therapy via the adverse event or Form ALERT mechanisms. No toxicity deaths were reported in The most recent toxicity death occurred in 2007 and was described in the 2007 Progress Report. One hundred and ninety five (195; 6.0%) cases of patients having at least one Grade 4 toxicity have been reported and another 469 (15.0%) had at least one highest toxicity grade of 3. The grade 4 toxicities included two allergic reactions, three hemoglobin toxicities, 35 cases of leukocytopenia, 104 cases of low counts of neutrophils/granulocytes, three cases of low platelet counts, one diarrhea, one bilirubin, two patients with SGOT values > 10 times the normal value, two patients with SGPT values > 10 times the normal value, one creatinine toxicity, one hematologic toxicity, one prolonged Qtc interval, one cardiac arrhythmia toxicity, nine cases of myocardial infarction, one cardiac troponin I, one cardiac troponin T, 17 emboli, one circulatory toxicity, one fatigue, one infectious wound, two cases of colitis, one rectal fistula, four cases of CNS hemorrhaging, one hemorrhage associated with surgery, one infection with neutropenia, five infections without neutropenia, one amylase, two cases of creatinine phosphokinase toxicity, four cases of hyperglycemia, two cases of hypokalemia, four lipase toxicities, ten cerebrovascular ischemias, one case of cognitive disturbs, one case of confusion, two cases of anxiety, three depressions, one seizure, one bone pain, one chest pain, two cases of myalgia, one ARDS toxicity, two sleep apnea, six cases of rest dyspnea, four cases of hypoxia, two cases of pneumonitis, eight cases of ureteral obstructions, one case of secondary malignancy, and one case of bowel obstruction. In addition to the acute toxicities listed above, two myeloproliferative disorders and one myelomatosis have been reported. All three of these patients have died. It should be noted that some patients have had concomitant adverse conditions which may result in these individuals appearing in several toxicity categories.

4 IV. DISCONTINUATION OF PROTOCOL THERAPY As of January 5, 2010, 74 patients did not start protocol therapy. One thousand three hundred and eight (1,308) others withdrew prior to completion of their therapy for a variety of reasons. Forty two (42) patients of the 1,308 had skeletal metastases prior to or during protocol therapy, that is, withdrew according to protocol guidelines. Nineteen (19) others died while they were on study and another 38 discontinued due to other disease. Forty-nine (49) patients discontinued because they preferred an alternative therapy. Two hundred and sixty-nine (269) patients discontinued because of toxicity. Seven hundred and twenty-one (721) discontinued for unspecified reasons after starting on protocol therapy, while one hundred and seventy (170) patients discontinued due to other reasons. Finally, 1,908 patients discontinued therapy after completion of their three years of therapy. A Kaplan-Meier analysis based on a January 5, 2010, cutoff indicates that the dropout rate on B-34 is 41.4% at three years. The May 2003 revision of the protocol projected a roughly 32% dropout rate over three years so that a higher proportion of patients have discontinued therapy than was originally projected. In addition, 191 individuals have withdrawn consent to be followed in this study. V. DATA DELINQUENCY As of December 31, 2009, 18.7% [574/3,065] of the Entry forms, 100% [17/17] of T forms, 100.0% [7/7] of AT, 0.6% [17/2,776] AE forms, 7.6% [214/2,804] of FA (followup) forms, and 7.6% [214/2,804] of FB (follow-up) forms were three or more months delinquent.

5 NSABP Protocol B-34 Table 1. Patient Entry and Characteristics* Characteristic* Group A Group B Number randomized Number ineligible Number who withdrew consent Number without follow-up Number with follow-up Mean time on study (mos) ** Age at entry 49 years 50 years Race White Hispanic Black Pacific Islander Asian American Indian Other Unknown Number of positive nodes Negative or more ER/PgR status Both Negative ER and/or PgR Positive * Values are based on all patients entered into the study unless otherwise specified ** As of December 31, As reported at the time of randomization.

6 TABLE 2a. GREATEST TOXICITY GRADE PER PATIENT FREQUENCY DISTRIBUTION TOXICITY: AE FORMS Overall Toxicity TOXICITY: ADVERSE EVENT FORM Allergic Reaction Hemoglobin Leukocytes Neutrophils/granulocytes Platelets Rash/desquamation Anorexia Constipation Diarrhea w/o prior colostomy Nausea Vomiting Alkaline phosphatase Bilirubin Hypoalbuminemia SGOT SGPT Hypocalcemia Creatinine Other

7 TABLE 2b. GREATEST TOXICITY GRADE PER PATIENT PERCENT DISTRIBUTION TOXICITY: AE FORMS Overall Toxicity TOXICITY: ADVERSE EVENT FORM Allergic Reaction 100 <1 <1 0 Hemoglobin 100 <1 <1 0 Leukocytes Neutrophils/granulocytes Platelets 100 <1 <1 0 Rash/desquamation 100 <1 0 0 Anorexia 100 <1 0 0 Constipation 100 <1 0 0 Diarrhea w/o prior colostomy 99 1 <1 0 Nausea Vomiting Alkaline phosphatase 100 <1 0 0 Bilirubin 100 <1 <1 0 Hypoalbuminemia 100 <1 0 0 SGOT 100 <1 <1 0 SGPT 99 1 <1 0 Hypocalcemia 100 <1 0 0 Creatinine 100 <1 <1 0 Other

8 TABLE 3a. GREATEST TOXICITY GRADE PER PATIENT FREQUENCY DISTRIBUTION Middle ear/hearing Lymphopenia Transfusion: platelets Hematologic-other Conduction abnormality Prolonged QTc interval Sinus bradycardia Sinus tachycardia Supraventricular arrhythmias Ventricular arrhythmia Arrhythmia-other Cardiac-ischemia/infarction Cardiac-left ventricular fn Cardiac troponin I (ctnl) Cardiac troponin T (ctnt) Hypertension Hypotension Pericrdl. effusn./pericarditis Peripheral arterial ischemia Thrombosis/embolism Visceral arterial ischemia Circulatory or cardiac-other Fatigue Fever Weight gain Constitutional symptoms-other Partial thromboplastin time Prothrombin time Thrombotic microangiopathy Coagulation-other Prutitus Radiation dermatitis Wound-infectious Wound-non-infectious Colitis

9 TABLE 3a. GREATEST TOXICITY GRADE PER PATIENT FREQUENCY DISTRIBUTION Dehydration Dyspepsia Dysphagia Fistula-rectal/anal Gastric ulcer Ileus Mucositis due to radiation Pancreatitis Stomatitis/pharyngitis

10 TABLE 3a. GREATEST TOXICITY GRADE PER PATIENT FREQUENCY DISTRIBUTION GI-other Hemorrhage w thrombocytopenia CNS hemorrhage/bleeding Hematemesis Hematuria Hemorrhage assoc. w surgery Melena/GI bleeding Petechiae/purpura Vaginal bleeding Hemorrhage-other GGT Liver dysfunction/failure Hepatic-other Catheter-related infection Febrile neutropenia Infection, gr. 3/4 neutropenia Infection w/unknown ANC Infection w/o neutropenia Infection-other Acidosis Amylase Creatinine phosphokinase Hypercholesterolemia Hyperglycemia Hypokalemia Hyponatremia Hypophosphatemia Lipase Arthritis Muscle weakness Myositis Joint, muscle, bone-other CNS cerebrovascular ischemia Cognitive disturb./lrning. prb Confusion

11 TABLE 3a. GREATEST TOXICITY GRADE PER PATIENT FREQUENCY DISTRIBUTION Delusions Dizziness/lightheadedness Involuntary move./restlessness Insomnia Memory loss Mood alter.-anxiety/agitation Mood alteration-depression Neuropathy-cranial Neuropathy-motor Neuropathy-sensory Seizure(s) Syncope (fainting) Vertigo Cataract Glaucoma Keratitis Tearing (watery eyes) Ocular-other Abdominal pain or cramping Arthralgia Bone pain Chest pain Dyspareunia Headache Myalgia Neuropathic pain Pelvic pain Pleuritic pain Pain-other ARDS Apnea Cough Dyspnea Hypoxia Pleural effusion

12 TABLE 3a. GREATEST TOXICITY GRADE PER PATIENT FREQUENCY DISTRIBUTION Pneumonitis/pulm. infiltrates Pneumothorax Pulmonoary-other Renal failure Ureteral obstruction Urinary frequency/urgency Renal/GU-other Secondary malginancy-other Irregular menses Sexual/reproductive fn-other Bowel Obstruction Death, Cause Unknown

13 TABLE 3b. GREATEST TOXICITY GRADE PER PATIENT PERCENT DISTRIBUTION Middle ear/hearing 100 <1 0 0 Lymphopenia 100 <1 0 0 Transfusion: platelets 100 <1 0 0 Hematologic-other 100 <1 <1 0 Conduction abnormality 100 <1 0 0 Prolonged QTc interval <1 0 Sinus bradycardia 100 <1 0 0 Sinus tachycardia 100 <1 0 0 Supraventricular arrhythmias 100 <1 0 0 Ventricular arrhythmia 100 <1 0 <1 Arrhythmia-other 100 <1 <1 0 Cardiac-ischemia/infarction 99 <1 <1 <1 Cardiac-left ventricular fn. 100 <1 0 0 Cardiac troponin I (ctnl) <1 0 Cardiac troponin T (ctnt) 100 <1 <1 0 Hypertension Hypotension 100 <1 0 0 Pericrdl. effusn./pericarditis <1 Peripheral arterial ischemia 100 <1 0 0 Thrombosis/embolism Visceral arterial ischemia 100 <1 0 0 Circulatory or cardiac-other 100 <1 <1 <1 Fatigue 100 <1 <1 0 Fever 100 <1 0 0 Weight gain 100 <1 0 0 Constitutional symptoms-other <1 Partial thromboplastin time 100 <1 0 0 Prothrombin time 100 <1 0 0 Thrombotic microangiopathy 100 <1 0 0 Coagulation-other 100 <1 0 0 Prutitus 100 <1 0 0 Radiation dermatitis 100 <1 0 0 Wound-infectious 99 1 <1 0 Wound-non-infectious 100 <1 0 0 Colitis <1 0 Dehydration 100 <1 0 0 Dyspepsia 100 <1 0 0 Dysphagia 100 <1 0 0 Fistula-rectal/anal 100 <1 <1 0 Gastric ulcer 100 <1 0 0

14 TABLE 3b. GREATEST TOXICITY GRADE PER PATIENT PERCENT DISTRIBUTION Ileus 100 <1 0 0 Mucositis due to radiation 100 <1 0 0 Pancreatitis 100 <1 0 0 Stomatitis/pharyngitis 100 <1 0 0

15 TABLE 3b. GREATEST TOXICITY GRADE PER PATIENT PERCENT DISTRIBUTION GI-other 100 <1 0 0 Hemorrhage w thrombocytopenia 100 <1 0 0 CNS hemorrhage/bleeding 100 <1 <1 0 Hematemesis 100 <1 0 0 Hematuria 100 <1 0 0 Hemorrhage assoc. w surgery <1 0 Melena/GI bleeding 100 <1 0 0 Petechiae/purpura 100 <1 0 0 Vaginal bleeding 100 <1 0 0 Hemorrhage-other 100 <1 0 0 GGT 100 <1 0 0 Liver dysfunction/failure <1 Hepatic-other Catheter-related infection 100 <1 0 0 Febrile neutropenia 100 <1 0 0 Infection, gr. 3/4 neutropenia 100 <1 <1 <1 Infection w/unknown ANC 100 <1 0 0 Infection w/o neutropenia 99 1 <1 0 Infection-other 100 <1 0 0 Acidosis <1 Amylase 100 <1 <1 0 Creatinine phosphokinase <1 0 Hypercholesterolemia 100 <1 0 0 Hyperglycemia 99 1 <1 0 Hypokalemia 100 <1 <1 0 Hyponatremia 100 <1 0 0 Hypophosphatemia 100 <1 0 0 Lipase <1 0 Arthritis 100 <1 0 0 Muscle weakness 100 <1 0 0 Myositis 100 <1 0 0 Joint, muscle, bone-other 100 <1 0 0 CNS cerebrovascular ischemia 100 <1 <1 0 Cognitive disturb./lrning. prb <1 0 Confusion 100 <1 <1 0

16 TABLE 3b. GREATEST TOXICITY GRADE PER PATIENT PERCENT DISTRIBUTION Delusions 100 <1 0 0 Dizziness/lightheadedness 100 <1 0 0 Involuntary move./restlessness 100 <1 0 0 Insomnia 100 <1 0 0 Memory loss 100 <1 0 0 Mood alter.-anxiety/agitation 100 <1 <1 0 Mood alteration-depression 100 <1 <1 <1 Neuropathy-cranial 100 <1 0 0 Neuropathy-motor 100 <1 0 0 Neuropathy-sensory 100 <1 0 0 Seizure(s) 100 <1 <1 0 Syncope (fainting) 100 <1 0 0 Vertigo 100 <1 0 0 Cataract 100 <1 0 0 Glaucoma 100 <1 0 0 Keratitis 100 <1 0 0 Tearing (watery eyes) 100 <1 0 0 Ocular-other 100 <1 0 0 Abdominal pain or cramping 100 <1 0 0 Arthralgia 100 <1 0 0 Bone pain 100 <1 <1 0 Chest pain 100 <1 <1 0 Dyspareunia 100 <1 0 0 Headache 100 <1 0 0 Myalgia 100 <1 <1 0 Neuropathic pain 100 <1 0 0 Pelvic pain 100 <1 0 0 Pleuritic pain 100 <1 0 0 Pain-other 100 <1 0 0 ARDS <1 0 Apnea 100 <1 <1 0 Cough 100 <1 0 0 Dyspnea 99 <1 <1 0 Hypoxia 100 <1 <1 0 Pleural effusion 100 <1 0 0

17 TABLE 3b. GREATEST TOXICITY GRADE PER PATIENT PERCENT DISTRIBUTION Pneumonitis/pulm. infiltrates 100 <1 <1 0 Pneumothorax 100 <1 0 0 Pulmonoary-other 100 <1 0 0 Renal failure 100 <1 0 0 Ureteral obstruction <1 0 Urinary frequency/urgency 100 <1 0 0 Renal/GU-other 100 <1 0 0 Secondary malginancy-other <1 0 Irregular menses 100 <1 0 0 Sexual/reproductive fn-other 100 <1 0 0 Bowel Obstruction <1 0 Death, Cause Unknown <1