Robert B. Catalano

Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer Therapy

For 50 years the dosing of anticancer drugs has been empirical— small phase I trials predict a tolerable dose, and subsequent studies refine the accuracy of that prediction. Because of population variability, however, a proportion of patients will inevitably experience more severe toxicity at doses selected for general use. Phase III trials routinely report grade 4 myelosuppression rates of up to 80% in certain solid tumors, without a recommendation for a dose adjustment. Historically, this risk has been regarded as acceptable, compared with the greater risk of treating the greater part of the population with ineffective doses. Approaches to individualizing therapy have been sought through pharmacokinetic analyses, but recommendations to the community have never been practical. In recent years, the potential of pharmacogenetic analyses to improve the therapeutic index of cancer therapy in pediatric malignancies has been described. For example, thiopurines are subject to variable metabolic disposition through single nucleotide polymorphisms (mutations in a gene sequence that have a prevalence of at least 1%). Clinical studies have shown that identification of the variant population has the potential to ameliorate toxicity while enhancing therapeutic outcome. Similar genetic signatures have long been sought in adult solid tumors. In colorectal cancer, several candidate genes have been identified that have the potential to determine risk of toxicity and possibly efficacy of fluoropyrimidines and oxaliplatin. Such approaches have two distinct goals: to minimize toxicity and to maximize the effectiveness of therapy. In 2005, the US Food and Drug Administration (FDA) took two actions that may be perceived as an advance regarding how pharmacogenetic approaches might permit us to reduce the risk of chemotherapy. First, it was determined that a fraction of the population at higher risk for adverse effects associated with the use of standard doses of irinotecan can be identified prospectively. These are patients who, by virtue of a genetic polymorphism, have a lower than normal capacity to metabolize SN-38, the active metabolite of irinotecan. The polymorphism is found in the gene encoding uridine diphosphate glucuronosyltransferase (UGT) 1A1, which facilitates the excretion of SN-38. This risk was emphasized by a warning added to the package insert of irinotecan. The text added to the label states that “individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele.” Second, the FDA approved a test to identify these individuals. The genetic test (Invader UGT1A1 Molecular Assay; Third Wave Technologies Inc, Madison, WI), conducted on genomic DNA isolated from peripheral blood, identifies patients homozygous for the UGT1A1*28 allele. Such patients clear irinotecan and its metabolites more slowly than the rest of the population, and so have greater exposure to active drug after a standard dose. The FDAapproved label for the test states that “a reduced initial dose [of irinotecan] should be considered for patients known to be homozygous for the UGT1A1*28 allele.” What are practicing oncologists to do with this information?

An effective low-dose adriamycin regimen as secondary chemotherapy for metastatic breast cancer patients

Sixty breast cancer patients with hormone‐resistant metastatic disease who had progressed after chemotherapy with low‐dose cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) or with L‐phenylalanine mustard underwent treatment with a low‐dose Adriamycin regimen, i.e., 20 mg/m2, intravenously on days 1 and 8 every 28 days. Two percent of patients had complete responses; 25%, partial responses; 38%, stabilization; and 35%, progression. The time to progression for the responders was similar to that of the stabilized patients, while the responders and stabilized patients survived significantly longer than did the progressors. Responses were seen in nodal, hepatic, dermal/subcutaneous, bone, pulmonary, and peritoneal metastases. The toxicity was mild: 18% of patients had leukocyte counts of less than 3,000/mm3; 10% had platelet counts of less than 90,000/mm3; 22% experienced vomiting; and 33% had hair loss. No patient experienced local venous/subcutaneous toxicity or heart failure. Since this regimen of low‐dose Adriamycin appears to be as effective as, but less toxic than, the secondary standard‐dose of Adriamycin at 60–75 mg/m2 every three weeks, a randomized trial of low‐dose Adriamycin vs. standard‐dose Adriamycin should be conducted in metastatic breast cancer patients who have previously undergone chemotherapy. Cancer 46:433–437, 1980.

An effective low‐dose intermittent cyclophosphamide, methotrexate, and 5‐fluorouracil treatment regimen for metastatic breast cancer

A low‐dose, three‐drug regimen, C.M.F. (cyclophosphamide 50 mg, p.o., days 1–14; methotrexate, 25 mg, and 5‐fluorouracil, 500 mg, i.v., days 1 and 8; cycled every 28 days) was used in 46 consecutive chemotherapy‐eligible women (41 previously hormonally treated) with recurrent breast cancer. Thirteen percent of the patients had complete regressions (C.R.); 33% had partial regressions (P.R.); 26% stabilized; and 28% progressed. In evaluating response by sites of metastases, lymph nodes (30%), lung nodules (22%), and subcutaneous deposits (2/3) had the highest incidence of C.R.; 46–71% of patients with lymph node, lung, subcutaneous, liver, breast, or peritoneal disease showed C.R. or P.R. Skin and pleural disease responded in 30% of patients whereas no patients had radiographic healing of bony metastases. The toxicity was minimal: 7% gastrointestinal, 26% marrow‐suppressive, and 7% infectious. This low‐dose C.M.F. regimen resulted in regression rates similar to higher dose C.M.F. protocols, which use approximately twice these drug dosages with commensurate toxicity.

Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, adriamycin, methotrexate, 5‐fluorouracil (CAMF) versus sequential cyclophosphamide, methotrexate, 5‐fluorouracil (CMF) and adriamycin

Seventy‐eight advanced breast cancer patients with hormone‐resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5‐fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF → A). C was given at 50 mg/m2, po, days 1‐14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28‐day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses‐62% vs. 49%; stabilizations‐23% vs. 31%). Responses by site of metastasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.

Half-body and local chest irradiation as consolidation following response to standard induction chemotherapy for disseminated small cell lung cancer: An Eastern Cooperative Oncology Group Pilot Report

Abstract A two-institution Phase 11 Pilot Study for the Eastern Cooperative Oncology Group (ECOG) used standard induction chemotherapy (cyclophosphamide and CCNU) followed by consolidation radiation therapy (RT) (600 rad of upper half-body irradiation plus 2000 rad in one week of localized chest irradiation) followed by maintenance chemotherapy in patients with extensive small cell bronchogenic carcinoma (SCBC). Nineteen patients were entered and 9 (47%) had partial responses (PR) after induction chemotherapy. No complete responses (CR) were seen. The 10 patients whose disease progressed were ineligible for consolidation RT and died with a short median survival time (MST) of 15 weeks. Of the 9 patients who were consolidated, 7(78%) had complete responses in the chest; five (63%) became overall complete responders. The MST of all consolidated responders was 44 weeks. At this writing, two of the 5 patients who achieved CR after RT consolidation were alive without disease for more than one year; another patient was alive with disease for almost one year. A control group consisting of patients with extensive SCBC was used for comparison; these patients were treated by the two participating institutions in an earlier ECOG protocol with the same chemotherapy regimen but without RT consolidation.

Report of phase II trial of concurrent chemoradiotherapy with radical thoracic irradiation (60 Gy), infusional fluorouracil, bolus cisplatin and etoposide for clinical stage IIIB and bulky IIIA non-small cell lung cancer.

PURPOSE To assess the response rate, median and long-term survival of patients (pts) with locally advanced, initially inoperable non-small cell lung cancer (NSCLC) treated on a phase II study of radical thoracic radiotherapy (TRT) and concurrent radiosensitizing chemotherapy. METHODS AND MATERIALS From 3/87 to 7/90, 41 previously untreated patients at Fox Chase Cancer Center with locally advanced non-small cell lung cancer, 24 with bulky clinical Stage IIIA, and 17 with IIIB disease, received concurrent thoracic radiotherapy (60 Gy/2.0 Gy/d in 6 weeks) and 2 cycles of infusional 5FU (640-800 mg/m2/24 hrs x 5 d); cisplatin (20 mg/m2 qd x 5); and etoposide (50 mg/m2 d 1, 2, 5) administered days 1 and 28 of TRT. RESULTS Forty of 41 were evaluable. Response rate was 90%, with radiographic CR in 20%. Thirteen pts (33%) underwent thoracotomy and complete resection with clinical downstaging in 10, including three pathologic CRs. Overall median survival was 14 months and 2-year survival was 38% with no difference between CS IIIA and IIIB pts (p = 0.2224). At median potential follow-up of 42 months, 8/40 pts. (20%) are alive and progression-free, including 4 of 13 resected pts. The chief toxicity was esophagitis, occurring in 32 pts. (80%), Grade 3-4 in 21 (52%), with 13 (33%) requiring hospitalization and 7 (18%) needing TPN. Grade 3-4 granulocytopenia was noted in 20 pts. (50%) with ten episodes of fever mandating intravenous antibiotics. Cardiac ischemia was documented in 2 (5%). Of 13 thoracotomy pts, six underwent lobectomy without perioperative mortality; 3 of 7 pneumonectomy pts died post-operatively, two from broncopleural fistula, and one from ARDS. CONCLUSION This aggressive regimen produced a 2-year survival (38%) comparable to the best arm of cancer and leukemia groups B study 8433, which administered radical thoracic radiotherapy after protoadjuvant vinblastine and cisplatin in similar and earlier stage non-small cell lung cancer patients. Toxicity, particularly esophagitis, was severe, but of short duration. An unacceptably high complication rate was seen following pneumonectomy, but not lobectomy.

An effective low‐dose mitomycin regimen for hormonal‐ and chemotherapy‐refractory patients with metastatic breast cancer

Ninety evaluable metastatic breast cancer patients refractory to hormonal therapy and combinations of cyclophosphamide, methotrexate, 5‐fluorouracil, and doxorubicin were treated with a low‐dose mitomycin regimen, i.e., 10 mg/m2 intravenously every 28 days. In order to minimize thrombocytopenia, dose de‐escalations related to platelet counts were made. One patient (1%) had a complete response and 17% had partial responses for a median duration of 4 months. The time to progression for the responders and stabilized patients was similar; however, the responders and stabilized patients lived significantly longer than did the progressors. Hematologic toxicity was minimized because of planned de‐escalations in mitomycin dosage. Perivenous ulceration, both immediate and delayed (8%), congestive heart failure (2%), and heart‐renal failure with malignant hypertension (2%) resulted in significant morbidity, including two drug‐related deaths. Although mitomycin dosages were successfully titrated according to platelet counts in this group of chemotherapy‐refractory patients, prolonged use of this drug in adjuvant or early metastatic breast cancer patients is not recommended because of potentially irreversible thrombocytopenia.

Tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal patients with advanced breast cancer: A randomized trial

Eighty‐nine postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low‐dose cyclophosphamide‐methotrexate‐5‐fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12 week treatment with tamoxifen alone, 59% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs. 28% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. As yet, no benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders. Cancer 45:735‐741, 1980.

Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer

SummaryEighty-eight postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12-week treatment with tamoxifen alone, 60% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs 31% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. No benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders.

Intraperitoneal cisplatin and etoposide in peritoneal mesothelioma: favorable outcome with a multimodality approach

Ten patients with histologically documented peritoneal mesothelioma were treated with intraperitoneal cisplatin 200 mg/m2, sodium thiosulfate rescue and etoposide 65–290 mg/m2 every 4 weeks for a maximum of six cycles. All had epithelial or mixed epithelial-fibrous histology. Toxicity was tolerable, with 50% sustaining grade 3 or 4 granulocytopenia. There was one episode of neutropenic fever. Grade 2 peripheral neuropathy occurred in one patient, grade 1 in five patients. Complete remission occurred in one of five patients with measurable disease. Median survival for patients whose tumors were surgically debulked to <2 cm residua prior to treatment was 22 months, while it was 5 months for those with measurable, surgically inaccessible disease (P=0.0731 by Cox regression proportional hazard model). These data suggest that patients who present with resectable disease may benefit from an aggressive adjuvant approach. This possibility warrants prospective testing in a randomized clinical trial.