To determine prognostic factors to select high-risk men receiving dose-escalated radiation therapy (RT) who will have favorable outcomes with short-term (ST) or no androgen deprivation therapy (ADT).
Medical records of 458 men treated with definitive RT for high-risk, nonmetastatic prostate cancer at 3 academic referral centers from 1988 to 2009 were examined. Median dose was 76.4 Gy. Men received no ADT (n=105), STADT (<12 mo, n=194), or long-term ADT (LTADT: ≥12 mo, n=160). Univariate and multivariable analysis for freedom from distant metastases (FFDM) and cause-specific survival (CSS) were performed. Median follow-up was 71 months.
Seven-year FFDM was 83% and CSS was 91%. Multivariable analysis demonstrated that prostate-specific antigen (PSA) nadir ≤0.2 (HR=0.36; 95% CI, 0.20-0.64) and Gleason score (GS) were associated with FFDM and CSS (all P<0.05). ADT duration was not associated (P>0.05). Those with PSA nadir ≤0.2 ng/mL had improved outcomes. Men with GS 9 disease did poorly despite a PSA nadir ≤0.2 ng/mL and had improved CSS with LTADT (95% vs. 71%, P<0.05).
Select men with high-risk disease treated with dose-escalated RT may not require LTADT. In men treated with ADT, PSA nadir ≤0.2 is an independent prognostic factor associated with FFDM and CSS. Men without GS 9 may have acceptable outcomes with STADT if PSA nadir is ≤0.2 ng/mL. Further investigation is necessary to elucidate the role of PSA nadir in determining the optimal length of adjuvant ADT.
The aim of the present study was to evaluate the efficacy and safety of carboplatin plus paclitaxel versus gemcitabine plus vinorelbine in patients with advanced nonsmall cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group performance status (PS) of 2.
Chemotherapy-naive patients with NSCLC of stage IIIB or IV and a PS of 2 were eligible. The patients received 3-week cycles of carboplatin (area under the curve of 6) plus paclitaxel (200 mg/m(2)) on day 1 (CP) or gemcitabine (1000 mg/m(2)) plus vinorelbine (25 mg/m(2)) on days 1 and 8 (GV). The primary end point was 1-year survival rate for selection of the better treatment arm for further study.
Of the 89 patients enrolled, 84 were assessable (41 in the CP arm, 43 in the GV arm). The overall response rate, median survival time, and 1-year survival rate were 29.3%, 5.9 months, and 22.0%, respectively, for the CP arm and 20.9%, 6.0 months, and 27.9% for the GV arm. Common toxicities of grade 3 or 4 included neutropenia (67.5% for the CP arm vs. 65.1% for the GV arm), febrile neutropenia (20% vs. 14%), and infection (25.0% vs. 23.2%). The frequency of nausea of grade 3 was greater for the CP arm (17.5% vs. 2.3%), whereas that of anemia of grade 3 or 4 (30.2% vs. 12.5%) or treatment-related death (7.0% vs. 2.4%) was greater for the GV arm.
The 1-year survival rate did not exceed 30% for either doublet chemotherapy. Furthermore, each treatment was associated with a substantial degree of toxicity.
To determine the optimal daily dose of the new antiestrogen droloxifene for the treatment of breast cancer, a multinational, multicenter, randomized, double-blind, phase II trial was initiated. Postmenopausal women with progressive advanced breast cancer (distant metastatic cancer, inoperable recurrent or primary tumor) with positive or unknown hormone receptor status (estrogen or progesterone) were entered in the study. Droloxifene was administered in a double-blind randomized design with daily doses of either 20, 40, or 100 mg once daily as first-line systemic therapy. None of the patients had received previous systemic antitumor therapy with the exception of adjuvant chemotherapy terminated at least one year before the patient's recruitment. Response was determined according to Union Internationale Contre le Cancer/World Health Organization criteria. Only patients with at least one measurable lesion were entered into the trial. The highest quality of data was achieved in two ways: source verification in the hospitals through monitors and peer review with subgroups of investigators determining the tumor response of each patient at adjudication meetings (evaluating parameters obtained from physical examination and reviewing X-rays and computer tomography scans). To date, 254 patients have been enrolled. Results from all these groups, without breaking the randomization code, based on 131 patients whose data have been verified are as follows: 10 complete responses (CR), 37 partial responses (PR), 47 no change, 29 progressive disease, 8 patients too early to evaluate. Thus, the overall response rate (CR + PR) was 38%. Droloxifene was well tolerated.
To compare 2 different strategies of chemotherapy for elderly metastatic colorectal cancer patients.
This randomized, multicenter phase II study involved 80 metastatic colorectal cancer patients aged 70 years and above (performance status [PS] 0-2) or 65 years and above (PS 2), randomly assigned to arm A (capecitabine 1250 mg/m twice daily on days 1-14) or arm B (capecitabine 1000 mg/m twice daily on days 1-14, oxaliplatin 100 mg/m on day 1 initially, 130 mg/m for subsequent cycles). Primary endpoint was response rate, and secondary endpoints were toxicity, progression-free survival, overall survival, and quality of life (QoL), which was assessed with the EORTC QLQ-C30 questionnaire.
Confirmed response rates were 22.5% and 35.0% (P=0.217), progression-free survival were 4.4 and 6.6 months (P=0.335), and overall survival were 14.2 and 11.0 months (P=0.106). Hematologic toxicities were frequently observed in arm B, but grade ≥3 toxicities were not different. Patients in arm A tended to present more favorable preservation of QoL in global health status, physical and role functioning, fatigue, and appetite loss.
Initial aggressive treatment strategy would not be recommended for this patient population because QoL appeared more preserved, treatments were better tolerated, and survivals did not differ in patients treated with initial capecitabine monotherapy.
A phase II study of stent therapy for unresectable malignant colorectal obstruction was conducted to ascertain the clinical efficacy, safety, and procedural feasibility.
Inclusion criteria comprised unresectable obstruction of the rectum or sigmoid colon; no other apparent stenosis; performance status by Eastern Cooperative Oncology Group ≤3; and maintained major organ function. The treatment protocol was to place an uncovered metal stent through the anus in an obstructive portion under x-ray fluoroscopic guidance. The patients were followed for 4 weeks after therapy, and the degree of improvement in subjective symptoms lasting ≥2 weeks was assessed as effective when the patient was decompressed with stent, or ineffective when not decompressed. Rate of clinical efficacy was defined as the proportion of effective cases.
The participants of the study comprised 33 patients (13 men and 20 women; mean age, 60 y). Rate of procedure completion was 97.0% (32/33). Treatment was effective in 27 patients, ineffective in 4, and unassessable in 1, yielding a clinical efficacy rate of 81.8% (27/33). Death owing to underlying disease (n=3), stent removal owing to anal pain (n=1), and occlusion at another location (n=1) were noted. No recurrences were seen among clinically effective cases. Adverse reactions included grades 2 to 3 diarrhea (n=12), pain (n=5), bleeding (n=1), and dysuria (n=1), but no grade 4 adverse reactions or treatment-related deaths were identified.
Stent therapy for unresectable malignant colorectal obstruction is effective, safe, and feasible.
To assess whether microvessel density (MVD), an immunohistochemical marker for tumor vascularity, predicts for radiotherapy (RT) outcome in locally advanced HNSCC patients.
A total of 459 patients, enrolled on the RTOG 90-03 trial, had biopsy specimens submitted, and a value for MVD determined, prior to definitive RT. 450 patients were analyzable for this study. Tumor microvessels were stained for factor VIII-related antigen using a standard immunoperoxidase method. The mean number of stained microvessel profiles, from three x200 fields containing the highest MVD (hot spot), was recorded as the MVD. A prospective value of >or=60 was chosen as the threshold for high MVD, tumor vascularity.
The median follow-up for the analyzable patients with MVD assessment was 22.0 months and 79.1 months for all living patients. There were no differences concerning the pretreatment characteristics between those RTOG 90-03 patients with a value for MVD and those without a value for MVD. Thus, the present study cohort possessed comparable characteristics with the entire RTOG 90-03 population. MVD values ranged from 5 to 80, with a median value of 30. Only 37 of 450 (8.2%) patients possessed an MVD >or=60. There were no outcome differences for patients with MVD <60 versus >or=60 on multivariate analysis for time to local-regional failure (P = 0.89), time to distant metastasis (P = 0.80), disease-free survival (P = 0.46), and overall survival (P = 0.39).
In this large, correlative study, a MVD >or=60, ie, high tumor vascularity, did not predict for outcome in locally advanced head and neck squamous cell carcinoma patients treated with radiotherapy.
No established therapy exists for unresectable intrahepatic cholangiocarcinoma (ICC). We conducted a phase I/II study to ascertain the recommended dose (RD) of hepatic arterial infusion using gemcitabine (GEM) for ICC and to assess the efficacy and safety.
For patients with unresectable ICC, GEM was administered through the hepatic artery via the port system as a 30-minute infusion on days 1, 8, and 15 every 4 weeks for 5 cycles. In phase I, dosage for levels 1, 2, and 3 was set at 600, 800, and 1000 mg/m, respectively, and was increased in 3 to 6 patients at a time. Maximum tolerated dose was defined as a dosage resulting in dose-limiting toxicity in 2 of 3 patients or 3 of 6 patients, and RD was estimated during the first cycle. In the phase II, more RD patients were added to assess tumor response and toxicity.
During the phase I, 16 patients were enrolled. Maximum tolerated dose was not reached. Assuming RD at 1000 mg/m, the phase II enrolled a total of 13 patients. The following Grade 3 toxicities were observed: neutropenia 20%, increased gamma-glutamyl transpeptidase 8%, increased aspartate aminotransferase 4%, increased alanine aminotransferase 4%, increased bilirubin 4%, nausea 4%, and fatigue 4%. The tumor response rate was 7.7% (complete response 0, partial response 1, stable disease 8, and progressive disease 4).
Whereas the toxicity of hepatic arterial infusion with 1000 mg/m GEM for ICC was tolerable, expected efficacy could not be obtained, thus suggesting only minimal activity.
Encouraging results of several clinical trials utilizing combination chemotherapy and irradiation in unresectable non-small-cell lung cancer have been reported. A recent report from a cooperative group study suggested that preirradiation vinblastine and cisplatin improved survival over irradiation alone. In an attempt to enhance the possible effectiveness of combination chemotherapy and irradiation, the Radiation Therapy Oncology Group embarked on a Phase II trial utilizing preirradiation vinblastine (5 mg/m2 weekly x 5) and cisplatin (100 mg/m2) on days 1 and 29 prior to irradiation and on days 50, 71, and 92 during irradiation. The irradiation began on day 50 and consisted of 6300 cGy in 7 weeks. Between May 20, 1988 and May 1, 1989, 30 patients were entered on study. Seventy-two percent of patients had Karnofsky status greater than 90, and 76% had weight loss less than 5%. Forty-eight percent of the patients were younger than 60 years of age. Forty-five percent of the patients had Stage IIIA disease. Eighty-three percent of the patients received at least four courses of vinblastine, and 59% received at least four courses of cisplatin. Seventy-eight percent of the patients received at least 95% of the prescribed irradiation. The major toxicity was hematologic, and there were two fatal complications in the study group. The preliminary survival figures are encouraging. This combination of chemotherapy and irradiation appears to be tolerable and may merit further investigation.
To analyze factors that influence the timing of adjuvant chemotherapy in patients who are candidates for breast-conservation therapy (BCT) but elect mastectomy with immediate reconstruction (M-IR).
We identified 35 consecutively treated patients with stage I or II breast cancer between 2004 and 2009 who underwent M-IR and adjuvant chemotherapy from the University of Louisville Cancer Registry. We matched these patients for age and AJCC stage to 35 controls who underwent BCT and adjuvant chemotherapy. We examined the timing and delay of initiation of chemotherapy using univariate logistic regression and McNemar test for matched pairs.
For the 70 patients evaluated, the median age was 46 years (range, 30 to 65 y), and the distribution for stage I, IIA, and IIB was 22.9%, 65.7%, and 11.4%, respectively. The 2 groups were well balanced in terms of race, rural/urban status, smoking, diabetes, insurance coverage, and histology. For BCT and M-IR, the median time to chemotherapy initiation was 38 days (range, 25 to 103 d) and 55 days (range, 30 to 165 d), respectively. Patients undergoing M-IR were more likely to experience any delay (>45 d; 54.3% vs. 22.9%; P<0.001) and/or significant delay (>90 d; 20.0% vs. 2.9%; P<0.001). On univariate logistic regression analysis, surgery type had a major impact on delay of chemotherapy (odds ratio=8.35; 95% confidence interval, 2.86-24.4; P<0.001).
The use of M-IR in breast-conservation candidates independently predicts for delay in initiation of adjuvant chemotherapy. Further study is needed to qualify the causes and clinical significance of these delays.
Superficial and measurable tumors were treated with hyperthermia and radiation therapy according to RTOG protocol 78-06. This study focuses on a subset of patients who were heated with microwaves. Eighty patients representing 88 lesions were treated between 1978 and 1981 with a schedule which allowed 48-96 hours to elapse between treatment sessions. The mean value of the average temperatures for individual lesions was 42.3 degrees C. The mean total radiation dose was 33.95 Gy. Skin reaction was examined in terms of the maximum score reported, using a modified Fowler scale. Erythema, the most common finding, was reported as the maximum skin reaction in 24% of the cases. Ulcerations and blisters occurred with frequencies of 18% and 7%, respectively. No reaction or desquamation was reported in 19% and 17% of the cases. Complete regression was noted in 48% of the treated lesions, partial regression in 17%, and no change in 24%. Twenty-five percent of the patients enjoyed sustained response for greater than 180 days. Refinement of hyperthermia treatment equipment and technique may result in less normal tissue reaction and improved clinical responses. In view of the encouraging initial results, we recommend aggressive pursuit of hyperthermia as a new treatment modality.
The purpose of this study was to determine if radiographic response correlates with survival for patients treated patients with malignant gliomas treated on Radiation Therapy Oncology Group (RTOG) protocol 90-06. This study compared patients treated with hyperfractionated radiation and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to standard fractionation and BCNU.
There were 453 patients evaluable. Histology included anaplastic astrocytoma (60) (AA), and glioblastoma multiforme (312) (GBM). All scans were forwarded to the RTOG central office and evaluated by a single reviewer without knowledge of outcome. Response at 4 months post initiation of therapy was evaluated by computed tomography or magnetic resonance image and compared with overall survival.
For patients with no tumor on the 4 month scan the median survival was 20.3 months and the 2 year survival 43%. Patients with partial or minor response had a median survival of 18.1 and 14.2 months and 2 year survival of 37% and 29%. Patients with progression had a median survival of 8.6 months and 2 year survival of 10%.
Response rates were similar in both arms.
Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC.
The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response.
Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response.
AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.
Patients with untreated squamous cell cancer of the head and neck region were randomized to receive either a boost of 25-30 Gy using photon-beam irradiation (photons) or an equivalent boost using neutron-beam irradiation (neutrons). All patients received an initial 45-50 Gy of wide-field photon irradiation. A total of 57 patients was evaluable on the neutron arm and 58 were evaluable on the photon arm. The proportion of patients with complete responses was 60 and 64% on the neutron and photon arms, respectively. The locally disease-free proportion at 2 years was estimated to be 20 and 31%, and the 2-year survival was estimated to be 32 and 41%, respectively. These differences are not statistically significant. There was a higher rate of severe complications on the neutron arm, 16 versus 7%. Thus, there was no evidence that a neutron boost produces better initial tumor clearance, local tumor control, or survival than a photon boost, and it may produce more complications.
RTOG Protocol 81-08, a feasibility study of hyperfractionated radiation therapy (HFX) with 1.2 Gy twice daily separated by 4-6 hours for non-small-cell cancer of the lung (NSCCL), was completed in 1983. Encouraging short-term results in a recently closed trial of HFX for NSCCL (RTOG 83-11) led to assessment of long-term outcome in the earlier trial. Of 120 evaluable patients who were assigned to total doses from 50.4 Gy to 74.4 Gy, all 5 of the 5-year survivors came from the 79 patients assigned to receive 69.6 Gy. The 5-year survival rates for the 79 patients were 14.3 +/- 9.4% for clinical RTOG Stage II, 5.9 +/- 4.0% for Stage III, and 3.2 +/- 3.2% for Stage IV. Combined Stage II and III 5-year survival rates were 8.3 +/- 4.0% for HFX 69.6 Gy compared to 5.6 +/- 1.5% for standard once-a-day irradiation in concurrent RTOG trials.
In an effort to investigate the antitumor activity of new cisplatin analogues, 1,2-diaminocyclohexane-(4-carboxyphthalato) platinum (II) (DACCP) was administered in a phase II disease-oriented trial to patients with advanced colorectal carcinoma. Six patients had not received prior chemotherapy, while four had received one drug, and two had received more than one drug. Primary sites of disease were in the liver only (8 patients), liver and lung (2 patients), and intra-abdominal (2 patients). Liver radionuclide scans and CT scans were the main parameter for evaluation. The drug was administered intravenously every 4 weeks at a dose of 640 mg/m2. There were no responses in 12 adequately treated patients. One patient had stable disease for 5 months. Nausea and vomiting was milder than that seen with cisplatin. A peripheral neuropathy was seen in four patients. Fever occurred in two patients and urticaria in one patient. No patient had significant drug-induced anemia, and renal dysfunction was not observed. DACCP at this dose and schedule demonstrated no efficacy as a single agent in the treatment of colorectal carcinoma.
Sixty-two patients with biopsy-proven, measurable disseminated malignant melanoma received either the combination IFN-alpha 2A with BCNU (30 patients) or the combination cimetidine with BCNU (32 patients) in parallel noncomparative Phase II trials. From patients receiving IFN-alpha 2A plus BCNU, we observed a 7% response rate: 1 complete response (CR) and 1 partial response (PR) (soft tissue disease with durations of 6.9 and 11.5+ months, respectively). Median time to progression (MTP) was 1.8 months and median survival time (MST) was 3.8 months. Myelosuppression and a flu-type illness were the most common toxicities. From patients receiving cimetidine plus BCNU, the response rate was 16%: 4 PRs (soft tissue disease, 3.8 months; visceral, 2.1, 4.0+, and 9.7 months) and 1 CR (soft tissue, 14.3+ months). MTP and MST were 1.9 and 5.5 months, respectively. Myelosuppression and nausea/vomiting were the most common side effects. Although each of these regimens had great conceptual allure, neither offered any durable impact on the natural history of disseminated malignant melanoma. Nevertheless, alternative combinations of biological response modifiers (BRMs) and BRMs with biochemical modulators or cytotoxic agents may provide some useful alternatives for further clinical investigations.
A phase II study of BCNU and PALA was undertaken in advanced large bowel carcinoma. Thirty patients with advanced metastatic colorectal carcinoma were treated with the combination BCNU (200 mg/m2) every 6 weeks, and PALA (5.0 g/m2) every 3 weeks. Fifteen patients had received no prior chemotherapy and 15 had been previously treated with one or more cytotoxic agents. Only one patient met the criteria for a partial response, and this response was of only 3 months' duration. It would seem unlikely that the combination of BCNU and PALA holds the potential of response greater than BCNU alone and that further trials of this treatment regimen for this tumor type seem unwarranted.
Characteristics of 1336 successive lung cancer patients diagnosed between 1977 and 1986 according to the Tumor Registry of the University of Miami and Jackson Memorial Hospitals were 92% smokers, 69% men, and 68% white. The histologic subtypes were 32% squamous cell carcinoma, 26% adenocarcinoma, 19% small-cell carcinoma, 12% large-cell carcinoma, 8% adenosquamous carcinoma, and 3% bronchioalveolar carcinoma. Age distribution was as follows: younger than 45, 8%; 45-54, 21%; 55-64, 36%; 65-74, 25%; and 75 years or older, 10%. Local stage constituted 15%; regional, 26%; and distant 60%. Women had a higher number of nonsmokers and adenocarcinoma. Black patients presented with lung carcinoma at a younger age than white patients. Younger patients and black patients presented with more advanced stages than older patients and white patients. The significant factors predictive of better survival were local stage and white race. Patients with bronchioloalveolar carcinoma had a better survival rate (p less than 0.02) than the other histologic subtypes, probably because of a higher incidence of local stage. There were no differences in survival between the other histologic subtypes. There were significant increases in adenocarcinoma (p less than 0.01) and adenosquamous histologies (p less than 0.025) and in distant stage (p less than 0.0001); but there were no significant changes in the age and sex distribution, smoking history, and survival rate at our center over the 10-year study period.
It is currently unclear whether the addition of chemotherapy to standard radiation therapy improves clinical outcome in patients with locoregionally advanced nasopharyngeal cancer. A meta-analysis was performed to evaluate the impact of integrating chemotherapy with external beam radiation therapy in this clinical setting. Using previously described methods, a protocol was developed outlining a meta-analysis examining the influence of chemoradiation versus radiation alone (control arm) in locoregionally advanced nasopharyngeal carcinoma. The outcomes of interest were disease-free/progression-free and overall survival. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from all available randomized controlled trials was pooled using a fixed effects model (Peto). Results were expressed as summary relative risks. Statistical tests for heterogeneity were performed. If statistical heterogeneity was demonstrated, sensitivity analyses were performed to evaluate possible sources of heterogeneity across the included studies. The literature search identified six randomized controlled trials enrolling more than 1,500 patients. All trials compared standard radical external beam radiation therapy (control arm) with radiation plus chemotherapy delivered either adjuvantly, neoadjuvantly, or concurrently with radiation. Pooling all six studies using disease-free/progression-free survival as the endpoint demonstrated that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the summary relative risk for overall survival at 2 years after treatment with the addition of chemotherapy to the treatment regimen was 0.80 (0.63-1.02), reflecting a 20% increase in 2-year survival. This finding was marginally non-statistically significant. Three- and 4-year survival was increased by 19% and 21%, respectively, with the data for 4-year survival being statistically significant. The addition of chemotherapy to standard radical radiation therapy for locoregionally advanced nasopharyngeal cancer increases both disease-free/progression-free and overall survival by 19 to 40% at 2 to 4 years after treatment, depending on the endpoint of interest. Future trials are needed to confirm these results and determine the most effective regimen for integrating chemotherapy with radiation therapy in this setting.
To evaluate the efficacy of recombinant human thyroid stimulating hormone [rhTSH (versus hypothyroidism)] in thyroid ablation with an activity of 1.1 GBq (30 mCi) (131)I.
A total of 102 patients with thyroid cancer who fulfilled the following criteria were studied: submitted to total thyroidectomy with complete tumor resection; tumor ≤4 cm without extrathyroid invasion or lymph node metastases; negative anti-thyroglobulin (anti-Tg) antibodies. Thirty-two patients (group A) received 0.9 mg of rhTSH for 2 consecutive days followed by (131)I administration and 70 patients (group B) were prepared by levothyroxine withdrawal for 4 weeks. The groups were similar in sex, age, and tumor characteristics.
Ablation was successful (stimulated Tg<1 ng/mL and negative diagnostic whole-body scanning and neck ultrasonography 9 to 12 mo after ablation) in 27 patients of group A (84.3%) and in 58 of group B (83%). Considering patients with Tg greater than 1 ng/mL immediately before (131)I administration, the rates were 72.2% in group A and 75% in group B. In group A, the ablation rate was similar for patients who discontinued levothyroxine-T4 3 days before (131)I administration and those maintained on hormone therapy. The mean follow-up was 29.6 months in group A and 55 months in group B. Stimulated Tg (after rhTSH) was undetectable in 29 patients of group A (90.6%) and in 61 of group B (87%) and 1 patient of group B presented cervical metastases at the last assessment.
Low (131)I activity after rhTSH is effective for remnant ablation in patients who are at low risk of recurrence.
The purpose of this report is to determine whether any specific magnitude in the prostate specific antigen (PSA) bounce predicted for a clinically poorer outcome.
Between May 1989 and August 1999, 568 prostate cancer patients were treated with 3-dimensional conformal radiotherapy (RT). All patients had at least 5 years of follow up, 6 post-RT PSA measurements and received no hormonal therapy as part of their initial management. The median follow up was 85 months. The median RT dose was 74 Gy. A bounce was defined by a minimum rise in PSA of 0.4 ng/mL over a 6-month period, followed by a drop of PSA of any magnitude. The analysis of the optimal PSA bounce cut-point was based upon a recursive partitioning approach (RPA) for censored data using the log-rank test for nodal separation of freedom from biochemical failure (FFBF) as defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. Cox multivariate regression analysis (MVA) was used to confirm independent predictors of outcome among clinical and treatment related factors: PSA bounce as defined by the RPA, pretreatment PSA (continuous), Gleason score (2-6 versus 7-10), T stage (T1c/T2ab versus T2c/T3), and total radiation dose (continuous).
There were 154 patients (27%) experienced a bounce with a median magnitude of 0.6. The RPA resulted in an optimal PSA bounce cut-point of 1.4 ng/mL such that 5-year Kaplan-Meier estimates of FFBF were 71%, 59%, and 38% for nonbouncers, a bounce < or =1.4 ng/mL and >1.4 ng/mL, respectively. Twenty-one (14%) of the 154 patients who experienced a bounce had a PSA bounce magnitude >1.4 ng/mL. Stepwise MVA demonstrated that the PSA bounce grouped as above was an independent predictor of FFBF (P = 0.0013), freedom from distant metastases (P = 0.0028) and cause specific survival (P = 0.0266). Lower RT dose (P < 0.0001) was the only independent predictor of a PSA bounce >1.4 ng/mL.
Using recursive partitioning techniques, a clinically significant PSA bounce occurred when the magnitude of the bounce was >1.4 ng/mL. This is important information to aid clinicians in determining management after RT.
Fotemustine is a new nitrosourea which has shown some efficacy on disseminated malignant melanoma (DMM) (24.2% response rate (RR) among 153 patients in a Phase II trial) but little activity on hepatic metastasis (8.8% RR). In order to improve those poor results, hepatic intra-arterial infusion (HIAI) of fotemustine was performed. After two years, thirteen patients, all in good general condition, were evaluable. Seven were pretreated and six had extrahepatic metastasis on entry into the study. All patients had a surgically implanted intra-arterial catheter. The induction cycle consisted of 100 mg/m2/week for 3-4 weeks, followed by 5 weeks rest and maintenance therapy of 100 mg/m2 every 3 weeks for stabilized or responding patients. Two complete responses (CR) (72+ and 145+ weeks) and six partial responses (PR) (7-18.5 weeks) were observed. The hepatic RR reached 61.5%. A RR of 42.8% was registered on preexisting EHM (one CR and one PR on cerebral lesions). Nevertheless, this treatment is limited by the high progression rate of 46.1% in extrahepatic disease. Toxicity was mainly hematologic (grade III-IV), comprising 36% neutropenia and 15% thrombopenia. Hepatic intra-arterial infusion of fotemustine is efficient therapy for liver metastases of DMM, but combination schedules (IV + HIA) are warranted.
To evaluate the clinical characteristics and long-term outcome of pediatric patients with optic glioma.
Patients and methods:
A total of 101 patients with optic glioma newly diagnosed between 1975 and 2008 were evaluated retrospectively. COPP (cyclophosphamide, vincristine, procarbazine, prednisolone) and cisplatin plus etoposide were the most commonly used chemotherapy regimens. Radiotherapy was administered in patients with progressive or unresponsive disease.
The median age at the time of diagnosis was 6 years, and the male/female ratio was 1.15. The most common referral complaint was strabismus. The most common site of optic glioma was the hypothalamic-chiasmatic region (31.7%). Fifty-three patients (52.5%) had neurofibromatosis type 1 (NF-1). Treatment consisted of surgery, radiotherapy, and chemotherapy. Forty-nine patients (48.5%) underwent surgery, which was predominantly subtotal resection, radiotherapy was administered to 39.4%, and 30 patients received chemotherapy. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 65.8% and 88.4%, respectively, and the 10-year PFS and OS were 54.2% and 83.4%, respectively, with an 8-year median follow-up. OS was significantly lower in patients with hypothalamo-chiasmatic involvement and significantly higher in patients with NF-1. The 5- and 10-year PFS rates were significantly higher in patients 10 years or older at diagnosis (P=0.0001) and in patients with intraorbital involvement (P=0.032). Eighteen patients (17.8%) died of disease.
Patients with NF-l and those older than 10 years have a better prognosis, whereas patients younger than 3 years and those with hypothalamic-chiasmatic optic glioma have a worse outcome. Further studies are needed to find appropriate treatment strategies.
To determine the effect of high-grade prostate cancer (Gleason pattern 5) on the prognosis of patients treated with Pd-103 brachytherapy.
A total of 499 higher-risk patients [Gleason score 7 or higher or prostate-specific antigen (PSA) 10-20 ng/mL] treated on a prospective protocol with Pd-103 and supplemental external beam radiation were studied. All prostate biopsies were reviewed for Gleason grade by 2 pathologists (L.T. and J.V.). Along with assignment of a Gleason score based on established criteria, the presence of any pattern 5 cancer was separately noted and photographed for future review. Freedom from biochemical failure was defined as a serum PSA < or = 0.5 ng/mL at last follow-up.
The biochemical control rate at 3 years for all 499 patients was 86%, with 348 patients followed beyond that time. Patients without pattern 5 cancer had an 89% rate of biochemical control at 3 years, versus 72% in the 87 patients with pattern 5 cancer (P = 0.0001). In Cox multivariate regression analysis, which included Gleason score, highest Gleason pattern, and pretreatment PSA, the Gleason score was the single most important predictor of biochemical control (P < 0.0001).
The presence of pattern 5 disease is a risk factor for biochemical failure. But in sharp contrast to prior studies, Pd-103 brachytherapy-based radiation appears to provide such patients with a high likelihood of cancer eradication.
To determine whether treatment gap between supplemental beam radiation and brachytherapy implant affects rectal morbidity and likelihood of cure in the treatment of intermediate-risk prostate cancer.
Five hundred sixty-eight patients with AJCC clinical stage T1c-T2a prostate cancer, Gleason score 7 to 9 and/or prostate-specific antigen (PSA) 10 to 20 ng/mL, were randomized to implantation with Pd-103 (90 vs. 115 Gy) with 44 Gy versus 20 Gy preimplant supplemental beam radiation, respectively. Treatment-related morbidity was monitored by mailed questionnaires, using a modified Radiation Therapy Oncology Group rectal morbidity criteria at 1, 3, 6, 12, 18, and 24 months. Patients who reported grade 1 or worse rectal morbidity were interviewed by telephone to clarify details regarding their rectal bleeding.
Persistent rectal bleeding occurred in 36 of the 548 evaluable patients (7%). The mean gap among rectal bleeders was 3.8 days and among nonbleeders was 4.8 days (P = 0.236). Higher R100 and external beam dose of 44 Gy were significant predictors of rectal bleeding on univariate and multivariate analysis. Log-rank analysis did not demonstrate any improvement in biochemical failure free survival (BFFS) with shorter gap interval. On univariate analysis, Gleason score >7, PSA >10, D90 <100%, and treatment gap were all predictive of biochemical failure. On multivariate analysis, only Gleason score, PSA, and D90 remained significant predictors of BFFS.
Shorter gap intervals between supplemental beam radiation and brachytherapy implant are safe. Shorter gap intervals do not improve BFFS; however, they do allow for treatment completion in a more timely fashion.
We have analyzed biochemical control versus multiple dosimetric parameters for a relatively homogeneous group of low-risk patients treated with I-125 or Pd-103.
As of January 2006, 602 patients with clinical stage T1c-T2a prostate carcinoma have been randomized to treatment with either I-125 or Pd-103 brachytherapy. This report focuses on 265 patients who had CT-based dosimetry available, and have a minimum of 2 years of follow-up. Standard postimplant dosimetric parameters were calculated including the V100 and D90, as well as the V50, V75, V150, V200, V300, D50, D75, and D200. Treatment margins were calculated using the premarket Dose Calc Test Application provided by Varian BrachyTherapy.
Almost every DVH-based dosimetric parameter was higher for patients with PSA evidence of disease control compared with those with PSA failure, regardless of isotope. Kaplan-Meier univariate analysis indicates that nearly all dosimetric parameters among patients implanted with Pd-103 were strongly predictive of biochemical control, while parameters in the I-125 group all trended to lower values for patients with biochemical failure.
Our demonstration of some predictive value of nearly all dosimetric parameters is in contrast to the impression one is left with from prior reports, which explicitly or implicitly portray a unique role for D90 or V100. We think that it is important for clinical investigators to look at other dosimetric parameters as part of ongoing clinical investigations because it is likely that dosimetric guidelines can be refined to improve our ability to rate implant quality.
The records of all patients treated at UCLA with stage I through stage III testicular seminoma, diagnosed in 1956-1983, were reviewed. Histologic subtype, therapeutic protocol, survival, and the incidence of subsequent primary malignancies are examined in this presentation. The 10 year cause-specific survival is 93% for stage I and 70% for stage II patients. Of the four patients initially seen with stage III disease, three have achieved long-term disease-free survival after combined irradiation and chemotherapy. Irradiation of the whole pelvis was not associated with improved control for those patients with previous pelvic surgery. Four patients complained of gynecomastia after therapy, and since none of these patients had elevated human chorionic gonadotropin levels, the gynecomastia was attributed to gonadal failure.
The Mayo Clinic regimen of leucovorin 20 mg/m followed immediately by 5-fluorouracil 425 mg/m administered for 5 consecutive days every 4 weeks is commonly used in the treatment of colorectal cancer. This study was aimed at prospectively determining the incidence and pattern of severe toxicity associated with this regimen. We evaluated prospectively 243 patients with colorectal cancer treated in our department with the Mayo Clinic regimen for the incidence of severe toxicity (defined as toxicity requiring hospitalization). Of the 243 patients, 32 (13%) were hospitalized for chemotherapy-related toxicity. Major toxicities included neutropenic fever in 21 (9%), grade III/IV mucositis in 25 (10%) and grade III/IV diarrhea in 20 (8%). There were five (2%) treatment-related deaths. Female patients exhibited a higher incidence of severe toxicity (18%) and toxic death (4/105) than did male patients (9% and 1/138, respectively). Elderly patients (> or =70 years) had a higher incidence of severe toxicity than younger patients did (24% versus 7%, < 0.001). Toxic death occurred in 4 of 89 patients aged 70 years or more compared to 1 of 154 in younger patients. Most episodes of severe toxicity (56%) and toxic deaths (4/5) were observed after the first cycle. We conclude that the Mayo Clinic regimen can be associated with severe toxicity, usually occurring after the first cycle. Female gender and advanced age predict severe toxicity; therefore, dose reduction in high-risk patients should be considered, especially during the first cycle.
A phase II study of the dolastatin 15 analog LU 103793 was conducted by the North Central Cancer Treatment Group in patients with advanced non-small-cell lung cancer (SCLC). Previously untreated patients received this agent at a dosage of 2.5 mg/m2 as a 5-minute intravenous infusion for 5 consecutive days every 3 weeks. Between September 1997 and July 1998, 17 patients were accrued in this study. Forty-two treatment cycles were administered with relatively modest toxicity. No responses were seen. This agent appears to be inactive in the treatment of advanced non-SCLC.
To analyze the role of genotype in patients with diffuse large B-cell lymphoma primary of breast (DLBCL-PB) treated with chemotherapy or immunochemotherapy.
We carried out a retrospective analysis in 104 patients with DLBCL-PB who were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or immunochemotherapy: R-CHOP (adding rituximab) and also carried out an analysis of genotype, studied with immunohistochemistry, as a prognostic factor.
Seventy-seven percent of patients showed the non-GCB (germinal center B) genotype. Patients treated with CHOP had a complete response of 70%; actuarial curves at 5 years showed that disease-free survival was 66 % and overall survival was 52% and that it was not statistically different than patients treated with R-CHOP: 78%, 61%, and 53%, respectively. When genotype was analyzed to assess the impact in prognosis, no statistical differences were observed. Patients treated with R-CHOP and non-GCB genotype have a complete response of 77%, disease-free survival of 56%, and overall survival of 66% that were not statistically different than patients with GCB: 80%, 60%, and 60% respectively, (P: 0.81, 0.5, and 0.66, respectively).
We confirm that the non-GCB genotype is most frequent in DLBCL-PB, but the addition of rituximab did not improve outcome in primary breast lymphoma with non-GCB phenotype.
In this Phase I study, thirteen women with advanced cervix cancer were treated with mitolactol (dibromodulcitol) plus cisplatin to determine a maximum tolerable dose schedule. Response was not an objective of this study, but four partial responses were seen in nine patients with measurable lesions. In general, the therapy was well tolerated, but of the ten patients treated at the first dose level (cisplatin 50 mg/m2 intravenously on day 1 plus mitolactol 180 mg/m2 orally on days 2-6 every 3-4 weeks), 5 required de-escalations and 8 required delays because of toxicity. All three patients treated with cisplatin plus a higher dose of mitolactol (270 mg/m2 x 5) required dose reductions and delays for hematologic toxicity. The first dose level appears tolerable by patients with, and promising in treating, advanced cervix cancer.
The survival of patients with locally advanced cancer of the cervix (stage IIB, IIIB, and IVA) treated with conventional intracavitary radium remains unsatisfactory. Over 50% of these patients are local failures and die with uncontrolled tumor in the pelvis. In 1978, we began performing transperineal interstitial implants to the parametria in patients with advanced disease. One hundred six evaluable patients (34 IIB, 67 IIIB, and five IVA) received one (99) or two interstitial implants (7) following 40-50 Gy of external supervoltage external irradiation. In addition, seven patients underwent exploratory staging laparotomies concurrently with the first implant procedure. Mean follow-up is 23 months and range is 12-60 months. Control of the pelvic tumor has been documented in 85%, 75%, and 40% of stage IIB, IIIB and IVA patients, respectively. Seven patients developed distant metastases and three died of intercurrent disease with no evidence of pelvic relapse. Nineteen patients (18%) developed radiation-related complications: proctitis or cystitis (six), rectal stenosis (six), ulceration and necrosis of the vaginal wall (one), and recto- or vesicovaginal fistula (six). It is noteworthy that 7/11 patients (64%) who had radioactive sources placed on the surface of the vaginal obturator as a substitute for an intrauterine tandem developed severe complications. We conclude that transperineal interstitial irradiation is both safe and an effective modality in the treatment of advanced cancer of the cervix.
For two decades, from 1964 to 1984, 309 patients suffering from choroidal melanoma were treated with 106Ru/106Rh applications, following confirmation of diagnosis by a variety of tests. A total of 216 patients (69.9%) were treated successfully and have been under observation for a mean period of 6.7 years after irradiation. 188 patients were followed for more than five years. Results indicate that enucleation for choroidal melanoma, especially in cases of eyes with good vision, may no longer be the standard treatment for this disease. This appears particularly true inasmuch as almost 50% of all patients with large choroidal melanomas who have enucleation die from metastases within 5 years of the operation. Therefore, conservative methods such as photocoagulation, irradiation, and microsurgical excision have been used with more or less success to destroy tumor and save a functioning eye.
Three major assumptions emerged from these clinical and endocrine long-term studies. First, buserelin, given pernasally in the conventional doses, and Decapeptyl microcapsules administered intramuscularly in 5-week intervals are equally effective in terms of their long-term castration effect in previously untreated patients with prostatic carcinoma. However, Decapeptyl causes complete LH and subsequent testosterone down-regulation 1 week earlier than buserelin. Furthermore, this treatment is more convenient, and the compliance is better. Both LHRH analogues are equally well tolerated. Second, in groups of prostate cancer patients with far advanced disease treated with palliative intention, only true subjective or objective remission should be considered a positive treatment response. Third, our results comparing PAP and PSA as the two most useful tumor markers with the corresponding testosterone levels suggest a close correlation.
The purpose of this report is to assess the prognostic factors that could influence management and clinical outcome of malignant fibrous histiocytoma (MFH) of soft tissues. Between 1975 and 1998, 109 patients diagnosed with MFH of the soft tissues, seen at King Faisal Specialist Hospital and Research Center, have been reviewed. Of the 109 patients, 75 were men and 34 were women. The median age at presentation was 48 years (range: 3-94). Seven patients (6%) had regional nodal disease and 10 other patients (9%) with distant metastases were excluded from survival analysis. The remaining 92 patients had localized disease and had surgery as the primary treatment modality with or without radiotherapy and/or chemotherapy. Extremities were the most common location (58%). Tumors less than 5 cm represented 32%, whereas 68% had tumors 5 cm or more. Low-grade tumors constituted 46%, and the remaining 54% were high grade. Thirty-seven percent of patients had positive surgical margins histologically after complete gross resection. The 5- and 10-year relapse-free survival (RFS) rates were 39% and 36%, respectively. Isolated local recurrence occurred in 20 patients (22%), isolated metastatic disease without local recurrence in 9 patients (10%), and combined local and metastatic disease occurred in 20 patients (22%). The overall 5- and 10-year overall survival (OS) rates were 50% and 43%, respectively. On multivariate analysis, tumor size and radiation dose were significant factors for RFS (p = 0.04 and 0.0005, respectively). In terms of OS, size, histologic grade, and surgical margins were significant factors on multivariate analysis (p = 0.001. 0.006, and 0.0001, respectively). Complete surgical resection at the time of primary tumor presentation is likely to afford the best chance for RFS and OS. Radiation therapy plays an important role, in combination with surgery for better local control, particularly in high-grade lesions, and in cases with positive surgical margins after wide complete gross excision. The role of adjuvant chemotherapy remains investigational.
Cases of 109 patients with metastases from cancer of unknown primary (CUP) were retrospectively analyzed. The highest survival rates were observed in patients with high performance status and metastases limited to the cervical lymph nodes. With other metastatic presentations, the survival was generally very short. Tumor markers did not demonstrate diagnostic value. The primary tumor was revealed by autopsy in 43 of 64 cases. Lungs were the most common primary site, followed by the gastrointestinal tract. Extensive clinical investigations during the initial diagnostic period were, as a rule, fruitless. Patients with CUP require efficacious treatment, but need to be investigated with adequate measures.
Reported is an analysis of overall survival at 10 years of 102 patients with advanced squamous cell carcinoma of the head and neck (SCCHN) who were enrolled in a prospective phase II trial of high-dose cisplatin, 5-fluorouracil (5-FU), and high-dose leucovorin (PFL) induction chemotherapy followed by surgery and/or definitive radiation therapy (RT) between 1987 and 1991. Initially, 14 patients underwent primary site (PS) and neck surgery irrespective of the clinical response to PFL. The high rate of clinical and pathologic complete response (CR) to PFL prompted a switch from PS surgery to definitive RT. Of 102 patients, 18 (17.6%) who completed PFL and local-regional treatment for SCCHN between 1988 to 1991 were alive in December 2000. Among these, 1 of 14 patients (7%) who had undergone PS resection and 17 of 85 (20%) who were treated after PFL with definitive RT but without PS surgery were alive at 10 years. Median survival time was higher in the nonsurgical group (98.9 vs. 51.9 months). Subset analysis suggested that patients with oropharyngeal PS had the longest median survival (108.6 months). The oropharyngeal patients represented the 61% (11/18) of the long-term survivors with organ preservation. An organ preservation approach for patients with advanced SCCHN who demonstrated PS CR to chemotherapy demonstrated a trend to improved overall survival.
Delayed diarrhea is the main toxicity of irinotecan at the currently recommended dose of 350 mg/m2 30-minute intravenous infusion, once every 3 weeks. This phase II, multicenter, open-label, randomized study was primarily designed to evaluate the effect of a 15-day Tiorfan (racecadotril) treatment on the incidence and severity of irinotecan-induced delayed diarrhea. One hundred thirty-six patients with metastatic colorectal cancer who failed to respond to a 5-fluorouracil-based treatment received 714 cycles of irinotecan. The patients were randomly allocated either to group A (68 patients) and received Tiorfan (300 mg/day) from D0 to D15 or to group B (68 patients) with no prophylactic treatment. Delayed diarrhea occurred in 197 of 355 cycles (55%) in Group A and 203 of 344 cycles (59%) in Group B. grade III-IV diarrhea was reported in 17 of 40 compliant patients (42%) in group A and 31 of 68 evaluable patients (45%) in group B. No difference was observed between the two groups for delayed diarrhea characteristics, incidence, or severity. The response rate in 99 evaluable patients was 12.1% (6.4%-20.2%). This study has shown that Tiorfan given prophylactically at 300 mg/day has no effect on delayed diarrhea.
The medical records of 414 patients with metastatic breast carcinoma treated between 1978 and 1986 were reviewed and 44 women were identified as having stage IV disease when the primary breast lesion was detected. Of these 44 women, 25 had metastatic disease limited to the skeleton while 19 had extraosseous lesions only. The clinical features, response to therapy, and survival were analyzed and compared for both groups. The median survival of those patients with bone-only metastases was 52 months as compared with 13 months for those with extraskeletal lesions (p = 0.0025). The response rate to first-line systemic therapy was similar for both groups (47% for bone metastases and 44% for extraosseous metastases). The median duration of response was 14 months (range, 3-55 months) for patients with bone disease and 8 months (range, 4-43 months) for those with extraskeletal lesions. We conclude that patients with metastatic breast cancer confined to the skeleton at initial diagnosis tend to follow an indolent, chronic course with prolonged survival. Therefore the increase in response rate with aggressive chemotherapy should be balanced against its higher morbidity. Further studies are needed to confirm whether the better prognosis of these patients is determined by the anatomical confinement of the disease to the skeleton or merely reflects the influence of other prognostic factors.
The chemotherapy regimen suitable for advanced colorectal cancer patients previously treated with 5 fluorouracil (5FU); oxaliplatin and irinotecan remains an unresolved issue. The poor response rates and progression-free survival achieved with FOLFIRI in the second-line of therapy and the schedule-dependent activity of irinotecan, prompted us to assess the efficacy and tolerability of FOLFIRI3 regimen in patients with metastatic colorectal cancer (CRC) previously exposed to irinotecan and oxaliplatin.
Twenty-seven metastatic CRC patients previously exposed to irinotecan and/or oxaliplatin were treated with the FOLFIRI3 regimen. They received an irinotecan injection at 100 mg/m(2) before and at the end of a 2400 mg/m(2) 5FU continuous infusion. Two hundred and six cycles of chemotherapy were delivered in an outpatient basis.
FOLFIRI3 regimen was well tolerated. Grade 3 of 4 adverse events included nausea and vomiting (18%), diarrhea (11%), anemia (7%), and neutropenia (7%). Partial responses were observed in 2 patients and 10 patients achieved stable diseases. From the start of FOLFIRI3, time to progression was 4.47 months (0-11 months) and median overall survival was 8.9 months (0.72-21.4 months). Interestingly, FOLFIRI3 treatment was associated to a clinical benefit in 7 out of 17 patients who previously progressed "on-therapy" or less than 3 months after the completion of a previous FOLFIRI chemotherapy.
These results suggest that fractionated irinotecan administration might restore the clinical benefit of this molecule in patients resistant to FOLFIRI.
Among the minority of patients with pleural mesothelioma and no known exposure to asbestos, there have been case reports suggesting a possible association with previous radiotherapy. The association between radiotherapy for primary breast cancer and the subsequent occurrence of mesothelioma was investigated in women entered into 11 National Surgical Adjuvant Breast and Bowel Project (NSABP) prospective clinical trials for breast cancer.
Follow-up information was obtained on 22,140 patients entered into 11 NSABP clinical trials for treatment of primary breast cancer between 1971 and 1994. Postoperative radiotherapy was administered to 9342 patients, mainly after lumpectomy. Postlumpectomy patients were treated with radiotherapy just to the ipsilateral breast and without regional nodal irradiation. There were 12,798 patients who did not have postoperative radiotherapy, and almost all had mastectomy.
Three pleural mesotheliomas were identified, and all occurred in the ipsilateral thorax of the irradiated patients (P = 0.009). All had received postlumpectomy breast irradiation for ductal carcinoma in situ. None had a known previous exposure to asbestos.
There appears to be a small but statistically significant increased risk of developing mesothelioma following radiotherapy administered for primary breast cancer. However, in absolute numbers, the risk is too small to be considered a contraindication to administering radiotherapy when indicated.
To determine the prognostic role of a K-ras mutation in tumor tissue of patients with refractory colon cancer who received irinotecan hydrochloride (CPT-11).
DNA was extracted from paraffin-stored tumor tissue of 35 patients with progressive colon cancer failing treatment with 5-fluorouracil who subsequently received CPT-11 (100 mg/m2 i.v. per week x 4 weeks with 2 weeks off per course). The first exon of the K-ras gene was amplified by polymerase chain reaction by using K-ras-specific primers followed by mutant enrichment sequencing. Survival differences of patients with a K-ras mutation were compared with those of patients with a normal K-ras status.
A total of 21 patients had a normal K-ras sequence and 14 patients had a K-ras mutation [GAT, n = 7; TGT, n = 3; and GCT, AGT, GTT, GAC (codon 13), n = 1 each]. Median survival of patients with a normal ras sequence from time of treatment with CPT-11 was 332 days compared with 169 days for patients with a K-ras mutation (p = 0.0036). No differences in age, sex, cancer stage, surgical treatment, or chemotherapy treatment were observed.
Determination of the presence of a K-ras mutation may predict survival in patients with progressive colon cancer after treatment with 5-fluorouracil who receive CPT-11.
The aim of this study was to evaluate the activity and toxicity of a combination regimen of CPT-11 and mitomycin-c as second-line chemotherapy for pretreated patients with advanced, metastatic, or both, gastric adenocarcinoma.
Patients with pretreated metastatic disease or early relapsed after adjuvant chemotherapy were enrolled. Entry criteria included histologic/cytologic diagnosis of gastric adenocarcinoma, age 18 to 75 years, performance status > or =70 (Karnofsky scale), bi-dimensionally measurable disease. Patients received CPT-11 and mitomycin-c at the dosage of 150 mg/m2 on days 1 and 15, and 8 mg/m2 on day 1, respectively, every 4 weeks. The disease evaluation was done every 3 cycles.
Among the 38 patients we observed, 1 (3%) complete response and 11 (29%) partial responses for an overall response rate of 32% according to an intent-to-treat analysis. The median duration of response was 6.5 months. The median time to progression was 4 months with a median overall survival 8 months. All patients were evaluable for toxicity and the only grade 3-4 observed toxicities were leukopenia (8%), neutropenia (21%), and anemia (5%).
The combination of CPT-11 and mitomycin-c is an active and well tolerated second-line treatment in pretreated gastric cancer patients. Further studies are needed to test its role in first-line treatment.
The combination of CPT-11 with 5-fluorouracil (5-FU) in advanced colorectal cancer (ACC) represents an attractive approach. A phase II study was conducted to assess the tolerance and efficacy of CPT-11 in combination with leucovorin-modulated bolus plus infusional 5-FU given according to the de Gramont regimen in chemonaive patients with ACC. Fifty-four patients with histologically confirmed ACC were enrolled. The patients' median age was 65 years; 30 (55.5%) patients were men; performance status (World Health Organization) was 0 in 27 (50%) patients, 1 in 22 (41%), and 2 in 5 (9%). Patients received leucovorin (200 mg/m2/d) as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at 400 mg/m2/d, and then as a 22-hour continuous infusion at 600 mg/m2/d, repeated on 2 consecutive days. CPT-11 (180 mg/m2; 30-minute intravenous infusion) was administered on day 1, simultaneously with leucovorin administration. This cycle was repeated every 2 weeks. Complete response was achieved in 4 patients (8%) and partial response in 19 (37%) (overall response rate: 45%; 95% CI: 24-50.5%). Stable disease was achieved in 16 (31%) patients and progressive disease in 13 (25%). The median duration of response and the median TTP were 5 and 8 months, respectively. After a median follow-up period of 11 months, 33 (61%) patients are still alive; the median overall survival has not yet been reached. Thrombocytopenia and anemia were very rare. Grade III/IV neutropenia developed in 19 patients (36%); febrile neutropenia developed in 4 patients, and 1 of them died of sepsis. Grade IV diarrhea was seen in 7 (13%) patients, and 4 of them required hospitalization. Grade III and IV mucositis was observed in two (4%) and one (2%) patients, respectively. Other toxicities were mild. The combination of CPT-11 and bolus plus infusional 5-FU is a relatively well-tolerated and effective first-line treatment in ACC. Final results from large phase III trials are awaited to clarify whether the CPT-11/5-FU combinations should be considered as "standard" first-line treatment in ACC.
This phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation was initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer.
Patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas received 2 cycles of induction irinotecan (100 mg/m2 IV) and gemcitabine (1000 mg/2 IV) on days 1 and 8 of each 3-week cycle. Following the induction, patients without disease progression received gemcitabine administered twice weekly (40 mg/m2/day) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy over 5.5 weeks).
From April 2000 to August 2003, 20 patients were entered into this study, 17 of whom were evaluable for treatment response. Characteristics included a median age of 67 years (range, 44-87 years) and 14 men (70%). Grades III and IV hematologic toxicity occurred in 25% and 5% of patients respectively and was primarily thrombocytopenia. No grade IV gastrointestinal toxicities or deaths due to therapy were observed. All therapy was completed in 8 patients, 7 patients were removed due to progression, 2 due to toxicity, 2 refused further treatment, and 1 was removed per the treating physician. The median time to progression and median survival was 5.1 months (95% CI, 3.2-6.7) and 8.8 months (95% CI, 6.4-10.1) respectively. Four patients (20%) were alive at 12 and 18 months.
Induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation is feasible in patients with locally advanced pancreatic cancer. This regimen, however, has only modest activity and should not be explored further.
Between November 1979 and October 1981, 110 consecutive patients with previously untreated, biopsy-proven squamous cell carcinoma of the head and neck, were treated by chemotherapy prior to scheduled surgery and/or radiotherapy. Two regimens of chemotherapy were used. The first 57 patients received cis-platinum, 20 mg/m2/day for 5 consecutive days and bleomycin 5 mg/m2/day as a continuous infusion over the same 5 days every 3 weeks (Regimen A). The next 53 patients received the same schedule and dose of cis-platinum, bleomycin 2.5 mg/m2 every 12 hours for the same 5 consecutive days and mitomycin C6 mg/m2 on day 1 of each cycle every 3 weeks (Regimen B). The number of courses administered prior to surgery and/or radiotherapy ranged from 1-4 depending on the otorhinolaryngologist's assessment of the optimal time for locoregional treatment. The overall response rate in regimen A was 78% (45/57) compared to 90% for regimen B (48/53). Complete responses were seen in 10/57 (18%) and 13/53 (25%) patients in regimens A and B, respectively. Eight of 57 patients in regimen A and 6/53 in regimen B refused further treatment and follow-up, and 7/53 patients in regimen B chose to pursue chemotherapy (in which methotrexate replaced bleomycin) rather than undergo surgery and/or radiotherapy. Five of these seven patients are surviving disease-free from 7-12 months. In regimen A, 31/57 patients are surviving with a median survival exceeding 15 months. In regimen B, 46/53 patients are surviving up to 14 months. Nausea and vomiting induced by cis-platinum were the major side effects, seen to a variable degree in all patients. No cis-platinum-induced renal toxicity was observed with the 5-day regimen and none of the patients had symptomatic bleomycin-induced pneumonitis. One patient had a bleomycin-induced skin rash which did not require discontinuation of therapy.
The objective of this study was to assess the role of various clinical and treatment factors involved in the long-term incidence of nonocular second primary tumors following retinoblastoma. The study was based on 111 patients treated between 1963 and 1977 according to the same radiotherapy protocol (electron beam radiotherapy) alone or in combination with triethylene melamine (TEM). Various statistical methods were used to obtain the actuarial survival curve, the cumulative incidence of second primary tumors, and comparisons of patient groups and subgroups. The 5-, 10-, 20-, and 30-year survival rates were 75%, 70%, 63%, and 55% with a follow-up of 23 to 35 years. The study reports the various parameters concerning 111 children and 17 second primary tumors: sex, age at treatment, histology of the retinoblastoma and second primary tumors, site of second tumors (anatomic and compared with irradiation field), radiation dose, time to onset, and chemotherapy with or without TEM. The results are discussed and compared with the data reported in the literature. Electron beam radiotherapy at a dose of 45 Gy does not eliminate the risk of nonocular second primary tumors. TEM also does not modify survival or the overall incidence of second primary tumors, but significantly increases the risk of second primary tumors outside the irradiation field.
A prospective pilot study was performed in order to determine the efficacy of 111InCyt103 (ONCOScintr CR/OV) in the detection of the presence and location, or absence of disease among patients with epithelial ovarian cancer who demonstrated no clinical or biochemical (Ca 125: < 35 mu/ml) evidence of disease at the end of first-line therapy. Among 15 patients who underwent second-look laparotomy, the overall accuracy of the test was 60%. The test demonstrated a sensitivity of 62.5% and a specificity of 57.1%. The predictive value of a positive test was 62.5% and of a negative test was 57.1%. The correct location of disease was predicted in 57% of patients with macroscopically appreciable tumors. ONCOScintr CR/OV offers little appreciable advantage over current modalities in discriminating between the presence or absence of disease among patients with epithelial ovarian cancer who demonstrate no clinical evidence of disease at the end of first-line therapy.
Small bowel adenocarcinoma is a rare cancer that has generally been considered resistant to chemotherapy, although little has been published on the role of chemotherapy. A retrospective analysis was conducted of patients with advanced small bowel adenocarcinoma to explore chemotherapy use, and gain knowledge for ongoing management and future clinical trials.
All patients with advanced adenocarcinoma of the small bowel treated at Princess Margaret Hospital (PMH) between 1986 and 2004 were identified through the cancer registry. The medical records were reviewed for patient characteristics, treatment and outcome data. Survival statistics were estimated using the Kaplan Meier survival curves and Cox proportional regression model.
Data on 113 patients was reviewed. Forty-four patients received palliative chemotherapy with an overall response rate (ORR) of 36% during a first or second line regimen (9% complete responses and 27% partial responses). Newer chemotherapy regimens including gemcitabine and irinotecan combinations appeared to have higher ORR, than older fluorouracil-based regimens. Some patients responded to more than one line of chemotherapy. Palliative chemotherapy predicted for overall survival (OS) in a multivariate analysis (HR 0.47, P = 0.035).
Chemotherapy appears to have activity in adenocarcinoma of the small bowel. Prospective trials evaluating patient benefit are required to confirm this activity using newer systemic therapies, until such time retrospective reviews such as this will continue to guide treatment decisions.