Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR Dental PBRN.

Case reports and cohort studies have linked bisphosphonate therapy and osteonecrosis of the jaws (ONJ), but neither causality nor specific risks for lesion development have been clearly established. We conducted a 1:3 case-control study with 3 dental practice-based research networks, using dentist questionnaires and patient interviews for collection of data on bisphosphonate therapy, demographics, co-morbidities, and dental and medical treatments. Multivariable logistic regression analyses tested associations between bisphosphonate use and other risk factors with ONJ. We enrolled 191 ONJ cases and 573 controls in 119 dental practices. Bisphosphonate use was strongly associated with ONJ (odds ratios [OR] 299.5 {95% CI 70.0-1282.7} for intravenous [IV] use and OR = 12.2 {4.3-35.0} for oral use). Risk markers included local suppuration (OR = 7.8 {1.8-34.1}), dental extraction (OR = 7.6 {2.4-24.7}), and radiation therapy (OR = 24.1 {4.9-118.4}). When cancer patients (n = 143) were excluded, bisphosphonate use (OR = 7.2 {2.1-24.7}), suppuration (OR = 11.9 {2.0-69.5}), and extractions (OR = 6.6 {1.6-26.6}) remained associated with ONJ. Higher risk of ONJ began within 2 years of bisphosphonate initiation and increased 4-fold after 2 years. Both IV and oral bisphosphonate use were strongly associated with ONJ. Duration of treatment >2 years; suppuration and dental extractions were independent risk factors for ONJ.

Dental risk factors for osteonecrosis of the jaws: a CONDOR case-control study.

BACKGROUND: Reports of osteonecrosis of the jaw (ONJ) have associated this lesion to treatment with bisphosphonates (BPs) and dental procedures. In this study, we investigated the association of specific dental diagnoses and procedures with ONJ among patients with past BP use. METHODS: Dentists from three practice-based research networks provided ONJ cases and controls (1:3). Data gathered from patients and dental offices with two respective standard questionnaires included demographic, medical, pharmaceutical, and dental information. Diagnoses and procedures up to 3 years prior to ONJ (prior to interview for controls) were analyzed within risk strata, defined by BP use and cancer status, using interaction terms within conditional logistic regression models. RESULTS: We enrolled 191 ONJ cases and 573 controls from 119 dental offices. Among participants who had used only oral BP, extraction was the only dental risk factor for ONJ (odds ratio (OR) = 12, p = 0.01). Suppuration was also more prevalent in cases (18 %) than in controls (9 %), but not statistically significant (OR = 9, p = 0.06). Among participants who had not used either oral or IV BP (a majority of whom received radiation therapy to the head and neck), suppuration was the only dental risk factor for ONJ (prevalence = 34 % for cases and 8 % for controls; OR = 7, p = 0.01). The prevalence of extractions in this group was also higher, but not statistically significant (44 vs 10 %; OR = 3). Limited power precludes definitive findings among participants exposed to IV BP. CONCLUSIONS: Among patients taking oral BP, extraction was the only dental procedure associated with subsequent ONJ development CLINICAL RELEVANCE: Results of this study suggest that routine dental procedures are not associated with development of ONJ in patients exposed to BPs.

Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN.

Case reports and cohort studies have linked bisphosphonate therapy and osteonecrosis of the jaws (ONJ), but neither causality nor specific risks for lesion development have been clearly established. We conducted a 1:3 case-control study with three dental Practice-based Research Networks, using dentist questionnaires and patient interviews for collection of data on bisphosphonate therapy, demographics, co-morbidities, and dental and medical treatments. Multivariable logistic regression analyses tested associations between bisphosphonate use and other risk factors with ONJ. We enrolled 191 ONJ cases and 573 controls in 119 dental practices. Bisphosphonate use was strongly associated with ONJ (odds ratios [OR] 299.5 {95%CI 70.0-1282.7} for intravenous [IV] use and OR = 12.2 {4.3-35.0} for oral use). Risk markers included local suppuration (OR = 7.8 {1.8-34.1}), dental extraction (OR = 7.6 {2.4-24.7}), and radiation therapy (OR = 24.1 {4.9-118.4}). When cancer patients (n = 143) were excluded, bisphosphonate use (OR = 7.2 {2.1-24.7}), suppuration (OR = 11.9 {2.0-69.5}), and extractions (OR = 6.6 {1.6-26.6}) remained associated with ONJ. Higher risk of ONJ began within 2 years of bisphosphonate initiation and increased four-fold after 2 years. Both IV and oral bisphosphonate use were strongly associated with ONJ. Duration of treatment > 2 years; suppuration and dental extractions were independent risk factors for ONJ.

Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias.

PURPOSE: The nucleoside analogs fludarabine, 2'-deoxycoformycin (DCF), and 2-chlorodeoxyadenosine (CdA), commonly used in the treatment of patients with indolent lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL), are associated with myelosuppression and profound and prolonged immunosuppression. These complications raise the possibility of an increase in secondary malignancies in patients whose disease already places them at greater risk. The purpose of the present study was to assess the frequency of second tumors in patients with CLL who are treated with fludarabine and in patients with HCL who are treated with DCF and CdA. PATIENTS AND METHODS: We reviewed the long-term follow-up data for 2,014 patients treated on National Cancer Institute Group C protocols with fludarabine for relapsed and refractory CLL and with DCF and CdA for HCL using a Second Cancer Report. The numbers of observed and expected secondary tumors were compared. RESULTS: Median follow-up periods for the DCF (n = 409), fludarabine (n = 724), and CdA (n = 979) studies were 6.9, 7.4, and 5.1 years, respectively. The 111 malignancies were most commonly lymphoma (25 patients), prostate (19), lung (15), colorectal (nine), bladder (six), and breast (six), but also CNS, stomach, ovary, head and neck, melanoma, sarcoma, testicular, and myeloid leukemias. Compared with age-adjusted 1994 Surveillance and Epidemiology End-Results rates for the general population, the observed/expected frequencies for DCF, fludarabine, and CdA were 1.43 (95% confidence interval [CI], 0.93 to 2.10), 1.65 (95% CI, 1.04 to 2.47), and 1.50 (95% CI, 1.14 to 1.93), respectively, indicating a significant (at P =.05) increase in risk for patients treated on the latter two protocols compared with a normal population. However, these values are consistent with the increase already associated with these diseases. CONCLUSION: Despite their immunosuppression, nucleoside analogs can be safely administered to patients with CLL or HCL without a significantly increased risk of secondary malignancies.

Measuring response in solid tumors: unidimensional versus bidimensional measurement.

BACKGROUND: Tumor shrinkage is a common end point used in screening new cytotoxic agents. The standard World Health Organization criterion for partial response is a 50% or more decrease in the sum of the products of two measurements (the maximum diameter of a tumor and the largest diameter perpendicular to this maximum diameter) of individual tumors. However, theoretically, the simple sum of the maximum diameters of individual tumors is more linearly related to cell kill than is the sum of the bidimensional products. It has been hypothesized that the calculation of bidimensional products is unnecessary, and a 30% decrease in the sum of maximum diameters of individual tumors (assuming spherical shape and equivalence to a 50% reduction in the sum of the bidimensional products) was proposed as a new criterion. We have applied the standard response and the new response criteria to the same data to determine whether the same number of responses in the same patients would result. METHODS: Data from 569 patients included in eight studies of a variety of cancers were reanalyzed. The two response criteria were separately applied, and the results were compared using the kappa statistic. The importance of confirmatory measurements and the frequency of nonspherical tumors were also examined. In addition, for a subset of 128 patients, a unidimensional criterion for disease progression (30% increase in the sum of maximum diameters) was applied and compared with the standard definition of a 25% increase in the sum of the bidimensional products. RESULTS: Agreement between the unidimensional and bidimensional criteria was generally found to be good. The kappa statistic for concordance for overall response was 0.95. CONCLUSION: We conclude that one dimensional measurement of tumor maximum diameter may be sufficient to assess change in solid tumors.

Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins.

PURPOSE: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment. METHODS: Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (<1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (> or =3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group. RESULTS: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. CONCLUSION: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients.

PURPOSE: To provide cladribine (CdA) to physicians for the treatment of patients with previously treated or untreated hairy cell leukemia (HCL), and to determine the response rate, response duration, survival, and toxicity with this agent. PATIENTS AND METHODS: This Group C phase II study was open to all eligible patients whose primary physician obtained written permission from the National Cancer Institute (NCI) to register patients onto this protocol. Of 979 patients registered, 861 were assessable for response and 895 for toxicity. RESULTS: The complete remission (CR) rate was 50% and the partial remission (PR) rate was 37%. At a median follow-up of 52 months, 12% of patients were reported to have progressed and 62 (7%) have died of disease. CONCLUSION: This large experience confirms the excellent response rates and remission duration of CdA in patients with HCL. Nevertheless, the response rates in this setting, which approximates general clinical practice, were lower than in other series. In general, CdA was well tolerated, but the potential increased risk for secondary malignancies requires additional follow-up evaluation. CdA can now be considered as one of the best agents for the treatment of HCL.

Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia.

PURPOSE: To quantify the incidence and severity of tumor lysis syndrome (TLS) as a consequence of fludarabine therapy in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: A retrospective review and questionnaire follow-up of clinical and laboratory data were performed on patients with intermediate or high-risk CLL on the National Cancer Institute Group C protocol or special exception mechanisms, or phase II trials of fludarabine, for whom adverse drug reports of TLS were available. Fludarabine was administered at a dose of 20 to 40 mg/m2 per day for 5 days at monthly intervals. RESULTS: Among the 6,137 patients, TLS was suspected in 26 (0.42%), with clinical and laboratory features consistent with TLS present in 20 (0.33%). Prophylaxis against TLS had been administered to 60% of these patients. Clinical or laboratory features were similar to patients who did not develop TLS. Of the patients with TLS, 90% had high-risk CLL, 60 months of prior disease duration, with a median pretreatment WBC of 109 x 10(9)/L, two prior regimens, lymphadenopathy in 89%, splenomegaly and/or hepatomegaly in 90%. TLS developed on approximately day 7 and lasted a median of 9.5 days. Dialysis was required in 30% during the TLS episode; 20% of patients died during cycle one of fludarabine therapy with renal failure, and another 20% died of infection or congestive heart failure. Six patients were retreated with fludarabine without recurrent TLS. CONCLUSION: TLS after fludarabine therapy is extremely uncommon, but may be associated with significant morbidity and mortality.

Treatment of refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C protocol mechanism of the National Cancer Institute: five-year follow-up report.

PURPOSE: To provide fludarabine to physicians for the management of patients with advanced refractory chronic lymphocytic leukemia (CLL) and to determine the response rate and duration, toxicity, and survival with this agent. PATIENTS AND METHODS: This phase II protocol was open to all eligible patients whose local physicians obtained written permission from the National Cancer Institute (NCI) to register patients onto this protocol. Of 791 national and international enrolled patients, 724 with a median age of 65 years received fludarabine, of which 703 were assessable for response. RESULTS: Thirty-two percent of assessable patients responded (95% confidence interval [CI], 29% to 36%), with 21 patients (3%) obtaining a complete response and 205 (29%) a partial response. The median duration of response was 13.1 months and the median survival time from registration was 12.6 months. Age, performance status (PS), and Rai stage correlated with survival (P < .01). Grade 4 hematologic toxicity was reported in 43% and was associated with infection in 22%. Neurotoxicity (primarily grade 1 motor dysfunction) was reported in 14% patients and correlated with age. CONCLUSION: This study describes the toxicity and activity of fludarabine in refractory CLL in a setting that more closely resembles clinical practice than most published trials. The low response rate may be related to advanced stage (89% Rai high-risk), disease-related symptoms (63% had B symptoms), and/or degree of prior treatment. Other contributing factors inherent in a group C treatment protocol included lack of central pathology review, variable supportive care, and a tendency to use this mechanism at a later stage in the disease.

Paclitaxel activity in heavily pretreated breast cancer: a National Cancer Institute Treatment Referral Center trial.

PURPOSE: To provide paclitaxel, an investigational drug at the inception of this study, to women with chemotherapy-refractory metastatic breast cancer and to evaluate response and toxicity in these patients. PATIENTS AND METHODS: Two hundred sixty-seven patients with progressive disease (PD) following at least two chemotherapy regimens for metastatic breast cancer and a contraindication to further doxorubicin treatment received paclitaxel either at 175 mg/m2 intravenously (IV) over 24 hours or at 135 mg/m2 if they had prior irradiation to 30% of marrow-bearing bone or a cumulative dose of mitomycin > or = 20 mg/m2. RESULTS: In a subgroup of patients (n = 172) with measurable disease, four complete responses (CRs) and 36 partial responses (PRs) occurred, for an overall response rate of 23% (95% confidence interval [CI], 17% to 30%). No differences in response rates were noted according either to the number of prior chemotherapy regimens received or to whether patients were considered refractory to doxorubicin. The dose and schedule used in this trial resulted in febrile neutropenia in 45% of patients and a hospitalization rate of 49%. CONCLUSION: Paclitaxel's activity in this multiinstitutional trial in heavily pretreated patients confirms the encouraging results attained in single-institution trials. Although at this dose and schedule paclitaxel may be considered too myelosuppressive for palliative care, supportive measures such as colony-stimulating factors and antibiotics were not used prophylactically. Current research efforts are focusing on whether paclitaxel's activity against breast cancer is dose- and/or schedule-dependent, and on what role it has in patients with less advanced disease.

Neurotoxicity of purine analogs: a review.

PURPOSE: The purine analogs, fludarabine, cladribine, and pentostatin, are active against a broad spectrum of indolent lymphoid malignancies. They also have similar toxicities, including myelosuppression, immunosuppression, and sporadic neurotoxicity. This review compares the spectrum of neurotoxicity of each of these agents. Now that these drugs are commercially available and are being widely used, physicians should be aware of potentially serious side effects that may be encountered. METHODS: The literature was searched using MedLine and Cancerline, as well as the bibliographies of published reports through the fall of 1993. In addition, case records from National Cancer Institute (NCI) Group C protocols were reviewed for fludarabine in chronic lymphocytic leukemia (CLL), and cladribine and pentostatin in hairy cell leukemia (HCL), as well as adverse drug reactions reported to the NCI from January 1980 through September 1993. RESULTS: At higher than recommended doses, life-threatening and fatal neurotoxicity were encountered with all three drugs. At the recommended doses, each agent induced neurotoxicity in approximately 15% of patients, mostly mild and reversible. However, severe neurologic complications were reported; these were occasionally delayed, sometimes fatal, but often at least partially reversible. CONCLUSION: The doses of these three agents should not be increased above the recommended levels. Development of moderate or worse neurotoxicity should result in discontinuation of that drug.

Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103.

PURPOSE: To provide an investigational drug, paclitaxel, now commercially available, to women with refractory ovarian cancer and to evaluate response and toxicity in these patients. PATIENTS AND METHODS: Patients with platinum-refractory ovarian cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3, at least three prior chemotherapy regimens, adequate hepatic and renal function, and no significant cardiac history were eligible. Patients were treated with paclitaxel 135 mg/m2 administered by 24-hour continuous intravenous infusion every 3 weeks. RESULTS: Leukopenia was the most frequent toxicity, with 78% of patients experiencing grade 3 or 4 toxicity. Other grade 3 and 4 toxicities were less common: fever (33%), infection (12%), thrombocytopenia (8%), vomiting (7%), cardiac (2%), neurologic (2%), and mucositis (1%). Fifteen treatment-related deaths (1.5%) were reported. The objective response rate was 22% (4% complete response [CR], 18% partial response; 95% confidence interval [CI] for overall response, 19% to 25%). The median time to progression from treatment initiation was 7.1 months in responding patients and 4.5 months for all patients. The median survival duration was 8.8 months. CONCLUSION: Paclitaxel has shown activity in women with platinum-refractory ovarian cancer, and it can be administered with an acceptable safety profile. Further research is needed to determine the optimal role of paclitaxel in the primary and salvage treatment of ovarian cancer.

Preoperative and postoperative combination chemotherapy for potentially resectable gastric carcinoma.

BACKGROUND: Median survival of patients with local-regional gastric carcinoma is 10 months. Resection of the primary tumor and regional lymph nodes, with tumor-free margins (curative resection), has been the most effective treatment for local-regional gastric carcinoma. However, median survival of patients with curative resection of gastric carcinoma is 24 months, and the 5-year survival rate is about 20%. A single institution pilot study has established the feasibility of administering two courses of chemotherapy preoperatively and three courses postoperatively. In another study, a 15% pathologically documented complete response (pathologic complete response) has been reported in unresectable gastric carcinoma treated with etoposide, doxorubicin, and cisplatin. PURPOSE: Our purpose was to increase the curative resection rate in potentially resectable gastric carcinoma and to delay or eliminate micrometastases and thus improve survival. We also evaluated clinical and pathologic response to chemotherapy. METHODS: Forty-eight previously untreated patients with potentially resectable gastric carcinoma received a chemotherapy regimen (EAP) consisting of etoposide (120 mg/m2 intravenously over a 2-hour period on days 4, 5, and 6), doxorubicin (20 mg/m2 as a 10-minute intravenous infusion on days 1 and 7), and cisplatin (40 mg/m2 as a 1-hour intravenous infusion on days 2 and 8). Patients received three courses of chemotherapy before resection, and responding patients received two courses postoperatively. Clinical and pathologic response rates, toxicity, patterns of treatment failure, and survival times were assessed. RESULTS: A median of three courses (range, 1-5) of preoperative therapy was administered; six (12%) of the 48 patients had clinical complete response, and nine (19%) had partial response. Forty-one (85%) underwent surgery; 37 (90%) of these 41 (77% of the 48 patients) had a curative resection. There were no pathologic complete responses. Median survival for all patients is 15.5 months (range, 2-29+ months). Therapy was discontinued because of the toxic effects in one patient before surgery and in six patients after surgery. Doses were reduced in 37 patients (77%), mainly because of hematologic toxicity. Nineteen (40%) were hospitalized because of toxic effects, including 15 patients who developed fever with neutropenia. Grade 3 or 4 nausea and vomiting occurred in 15 patients and grade 3 or 4 diarrhea in seven patients. One death was directly related to chemotherapy. CONCLUSIONS: These data support that administration of preoperative and postoperative chemotherapy for local-regional gastric carcinoma is feasible in a multi-institutional setting. Our findings demonstrate that this EAP regimen is modestly active but is associated with substantial toxicity. IMPLICATIONS: Use of preoperative chemotherapy in resectable gastric carcinoma merits further evaluation, but more effective drug regimens will be required before a controlled trial is initiated.

Current Status of U.S. Clinical Trials in Chronic Lymphocytic Leukemia.

Current therapies for chronic lymphocytic leukemia (CLL) have not substantially improved the survival of these patients (pts). As a result treatment has been primarily palliative. One major obstacle in designing innovative therapies has been a lack of new and effective agents. Recent interest in clinical trials has been stimulated by the impressive activity in pts with CLL of three unique purine analogues; fludarabine (FLUDARA), 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (CDA). Of the three, the largest experience in CLL is with FLUDARA. More than 1200 CLL patients have received FLUDARA either on clinical trials or through the NCI-Group C protocol mechanism. In contrast to the published data, preliminary analysis of the first 87 evaluable Group-C patients revealed only 2% complete and 37% partial responses; this discrepancy can be explained by the fact that most patients were still receiving treatment at the time of the analysis, and many were continuing to respond (9 of 12 patients who received treatment for > 6 cycles responded); there was no central pathology review to confirm the diagnosis, 89% were Rai "high risk", and most patients had received extensive prior therapy. An updated analysis of response in the first 300 cases is underway. Of 497 pts evaluable for toxicity, 41% developed infections which were serious in 17%, and there were episodes of serious neurotoxicity in 9%. Based on the high level of activity and relative tolerability of FLUDARA, a national U.S. phase III trial is underway comparing chlorambucil (CLB) vs FLUDARA vs CLB + FLUDARA in untreated patients with advanced disease. A comparison of FLUDARA vs CDA in relapsed/refractory pts is being planned. Combination regimens are being piloted in relapsed/refractory CLL including DCF + FLUDARA, DCF + CLB, FLUDARA + CDA, FLUDARA + interferon-alpha, FLUDARA + gallium, FLUDARA + cyclophosphamide. Since FLUDARA achieves true complete responses in a substantial number of previously untreated pts, it is being considered as part of an induction program prior to autologous bone marrow transplantation. FLUDARA has a high degree of bioavailability in dogs, and an oral preparation is being evaluated in clinical trials. Hopefully, new purine analogue-based combination regimens will improve the response rate and survival in patients with CLL.