Showing papers in "Journal of Clinical Oncology in 1988"

Regimen-related toxicity in patients undergoing bone marrow transplantation.

Abstract: Bone marrow transplantation is associated with significant morbidity and mortality, some of which is due to high-dose chemoradiotherapy. In order to quantitate toxicity that was felt to be due to the preparative regimen (termed regimen-related toxicity [RRT]), a system was developed in which toxicities were graded from 0 (none) to 4 (fatal). One hundred ninety-five patients who underwent marrow transplantation for leukemia were studied retrospectively to determine whether toxicities that were clinically felt to be due to the preparative regimen were influenced by other factors such as disease status, graft-versus-host disease (GVHD) prophylaxis, and allogenicity. All patients developed grade I toxicity in at least one organ, and 30 developed grades III-IV (life-threatening or fatal) RRT. RRT was more common in relapsed patients v remission patients (P = .04), in those receiving 15.75 Gy total body irradiation (TBI) v 12.0 Gy TBI (P = .028), and in those receiving allogeneic marrow v autologous marrow (P = .0029). Autologous marrow recipients did not develop grades III-IV toxicity in this study. A multivariate analysis controlling for autologous marrow grafting showed that the dose of TBI was the only statistically significant predictor of grades III-IV RRT. Those patients who developed grade III RRT were unlikely to survive 100 days from transplant, though not all deaths could be attributed to RRT. Patients who developed grade II toxicity in three or more organs were more likely to die within 100 days than those developing grade II toxicity in two or less organs (P = .0027). This system was generally able to distinguish RRT from other toxicities observed in marrow recipients.

Fluorouracil: biochemistry and pharmacology.

Abstract: Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.

Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial.

Abstract: The survival benefit of combination chemotherapy to patients with advanced non-small-cell carcinoma of the lung (NSCLC) is controversial. To study this question, the National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a prospective randomized trial comparing best supportive care (BSC) to two chemotherapy regimens, vindesine and cisplatin (VP), and cyclophosphamide, doxorubicin, and cisplatin (CAP). Between February 1983 and January 1986, 23 centers across Canada entered 251 patients on study. Eighteen centers participated in the three-arm schema (150 patients); centers choosing not to participate in a study with a no-chemotherapy arm followed a two-arm schema comparing VP with CAP (101 additional patients). Altogether, 233 patients were eligible. Patients had measurable or evaluable disease, with either distant metastases (82.5%) or bulky limited disease considered inoperable or unsuitable for radical radiotherapy. The treatment groups were comparable in terms of age, sex, performance status, histology, disease extent, and weight loss. The overall response rates (complete response [CR] plus partial response [PR]) on the chemotherapy arms were CAP, 15.3%, and VP, 25.3% (P = .06). Patients on the three-arm portion of the trial had a median survival of 32.6 weeks when treated with VP, 24.7 weeks with CAP, and 17 weeks with BSC. The significance of the differences in survival, adjusted for prognostic factors, is as follows: chemotherapy v BSC, P = .02; VP v BSC, P = .01; and CAP v BSC, P = .05. Toxicity on the chemotherapy arms was significant, with leukopenia of severe or greater degree occurring in 37.8% (CAP) and 40.0% (VP), severe vomiting in 12.2% (CAP) and 23.3% (VP), and severe neurotoxicity in 15.6% (VP).

International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma.

Abstract: Neuroblastoma is one of the most common tumors in childhood. However, it often has been difficult to compare clinical and laboratory studies of this disease due to a lack of uniform criteria for diagnosis, staging, and response. An international group of conferees addressed each of these issues and reached a consensus. Specific criteria for making a diagnosis of neuroblastoma are defined. A new neuroblastoma staging system is proposed that takes into account the most important elements of current but incompatible systems. Finally, criteria for response to treatment are standardized. The criteria proposed herein represent an international consensus of essentially every major pediatric oncology group or organization in the United States, Europe, and Japan. The staging system should be referred to as the International Neuroblastoma Staging System, and the response criteria as the International Neuroblastoma Response Criteria. Implementation of these criteria will greatly facilitate the comparison of clinical and laboratory studies by different groups and countries. Furthermore, these criteria should serve as a foundation on which future modifications or improvements can be based.

A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma.

Abstract: We determined the therapeutic effect of fluorouracil (5-FU) in combination with folinic acid (FA) in patients with measurable recurrent or metastatic carcinoma of the colon or rectum by comparing it to standard 5-FU therapy in a prospective randomized controlled trial. Patients were randomized to receive either FA, 200 mg/m2/d for five consecutive days, or nothing. All patients received 5-FU, 370 mg/m2/d for five days on the first course, with subsequent dose modifications to maintain equal toxicity in the two arms. One hundred thirty patients were entered on trial and only five were excluded from the analysis because they did not meet the eligibility criteria or they refused therapy after randomization. The two treatment arms were balanced for 11 clinical characteristics. Patients were evaluated for response at the end of every two treatment courses and toxicity after every course of therapy. Median follow-up was 1.45 years. Dose-limiting toxicity was mucositis and diarrhea on this treatment schedule, although neutropenia was apparent. The response rate was 33% (21 of 63 patients) in the 5-FU and FA arm and was 7% (four of 61 patients) in the 5-FU arm (P less than .0005). Time to disease progression was significantly different in the combination arm as compared with the single-agent arm (P = .023). Overall survival was significantly longer for patients treated with 5-FU and FA as compared with those receiving 5-FU alone (P = .05). The median survival was 12.6 months for patients receiving the combination, and 9.6 months for those receiving 5-FU alone. Our results indicate that the combination of 5-FU and FA is effective treatment for patients with metastatic or recurrent carcinoma of the rectum and colon who have not received prior chemotherapy.

Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study.

Abstract: Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.

Relative worth of estrogen or progesterone receptor and pathologic characteristics of differentiation as indicators of prognosis in node negative breast cancer patients: findings from National Surgical Adjuvant Breast and Bowel Project Protocol B-06.

Abstract: This study correlates the disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of 1,157 histologically node negative breast cancer patients with the estrogen and/or progesterone receptor (ER, PR) and with the nuclear or histologic grade (NG, HG) of their tumors. All were treated by operation without systemic adjuvant therapy. The DFS, DDFS, and S were significantly greater (P = .005, .004, less than .001) in patients with ER positive than ER negative tumors but the magnitude of the differences after 5 years of follow-up was slight (8% in both DFS and DDFS and 10% in S). Differences of that magnitude are insufficient to discriminate clearly between patients who should or should not receive systemic therapy. As with ER, there were outcome differences in favor of PR positive tumors but only in S was the difference significant (8% at 5 years; P = .002). When combined with ER, PR made no independent contribution in the outcome prediction. Regression analysis indicated that NG was...

Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response.

Abstract: Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival (MFS) in osteosarcoma, a randomized study was undertaken with the aim of (1) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin (DOX) and cisplatin (CPDD) by administering these drugs postoperatively only after poor response with a milder preoperative regimen, and (2) improving the prognosis of patients responding poorly to the initial treatment by use of a salvage chemotherapy postoperatively. The available patients were divided into two groups. Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate (HDMTX) and the triple drug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) and were switched to DOX/CPDD postoperatively in case of poor response. DOX/CPDD was used besides HDMTX for initial treatment in the control arm, and BCD alternatively with CPDD/ifosfamide (IFO) for postoperative salvage treatment. The response rate of the study arm was significantly inferior to the control arm (26% v 60%; P less than .001). The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm (41%); it was unchanged in the control arm (53%) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy (52%). The actuarial 4-year MFS rate of good responders was 73% in the study arm, 79% in the control arm, and not significantly different from that of the COSS-80 study (84%), although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study. The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm (49% v 68%; P less than .1) and also inferior to the COSS-80 study (68%; P less than .01), indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment.

High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer.

Abstract: To evaluate the effect of high-dose chemotherapy in the treatment of metastatic breast cancer, we performed a phase II trial of a single treatment with high-dose cyclophosphamide (5,625 mg/m2), cisplatin (165 mg/m2), and carmustine (600 mg/m2), or melphalan (40 mg/m2) and bone marrow support as the initial chemotherapy for metastatic breast cancer. Twenty-two premenopausal patients with estrogen receptor negative, measurable metastatic disease were treated. Twelve of 22 patients (54%) obtained a complete response at a median 18 days. The overall response rate is 73% (complete and partial response). Median duration of response in the patients achieving complete response was 9.0 months with a median duration of survival for complete responders that is currently undefined. Relapse occurred predominantly at sites of pretreatment bulk disease or within areas of previous radiation therapy. Toxicity was frequent and five patients died of therapy-related complications. The results indicate that a single treatment...

A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer.

Abstract: This study was designed to assess the role of dosage of chemotherapy for treatment of metastatic breast cancer. One hundred thirty-three patients without prior chemotherapy for metastatic disease were randomly allocated to receive two different dose levels of cyclophosphamide (C), methotrexate (M), and fluorouracil (F), administered intravenously (IV) every 3 weeks. Patients were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by interval from primary surgery to first recurrence. Doses on the higher-dose arm were 600 mg/m2 (C,F) and 40 mg/m2 (M) with escalation if possible; doses on the lower-dose arm were 300 mg/m2 (C,F) and 20 mg/m2 (M) without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival measured from initiation of chemotherapy (median survival, 15.6 months v 12.8 months, P = .026 by log-rank test), but the effect of dose was of borderline significance (P approximately 0.12) when adjusted for a chance imbalance between the two arms in the time from first relapse to randomization, using the Cox proportional hazards model. Response rates (International Union Against Cancer [UICC] criteria) for patients with measurable disease were higher-dose arm: 16/53 (30%) and lower-dose arm: 6/53 (11%), (P = .03). Only one of 37 patients responded on crossover from the lower- to the higher-dose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. A series of 34 linear analogue self-assessment scales were used to make detailed quality of life assessments on a subset of 49 patients. These scales confirmed greater toxicity in the immediate posttreatment period, but also a trend to improvement in general health and some disease-related indices, in patients receiving higher-dose chemotherapy. This trial suggests that better palliation is achieved by using full-dose chemotherapy.

Ovarian function following marrow transplantation for aplastic anemia or leukemia.

Abstract: One hundred eighty-seven women between 13 and 49 years of age had ovarian function evaluated from 1 to 15 years (median, 4) after marrow transplant for aplastic anemia or leukemia. Among 43 women transplanted for aplastic anemia following 200 mg/kg cyclophosphamide (CY), all 27 less than 26 years of age, but only five of 16 greater than 26 years of age recovered normal ovarian function. Nine of the 43 have had 12 pregnancies, resulting in eight live births, and two elective and two spontaneous abortions. All eight children are normal. Nine of 144 women transplanted for leukemia following 120 mg/kg CY and 9.20 to 15.75 Gy total body irradiation (TBI) recovered ovarian function. Two of these nine have had three pregnancies, resulting in two spontaneous and one elective abortion. The probability of having ovarian failure was 0.35 by 7 years for patients receiving CY alone and was 1.00 at 1 year for patients receiving CY plus TBI (P less than .0001). By 7 years after transplant the probabilities of having normal ovarian function were 0.92 after CY alone and 0.24 after CY plus TBI (P less than .0001). Multivariate analysis showed that TBI was the only factor significantly influencing ovarian failure and that both TBI and greater patient age at transplant were significantly associated with a decreased probability of recovering normal ovarian function. These data demonstrate that after high-dose CY, recovery of ovarian function occurs in younger women and in a minority of older women, but after CY and TBI, recovery occurs in only a few younger women and none of the older women.

Malignancy-associated Sweet's syndrome: review of the world literature.

Abstract: Sweet's syndrome is an acute febrile neutrophilic dermatosis in which approximately 20% of the reported patients have an associated cancer. We review the 79 patients with malignancy-associated Sweet's syndrome documented in the world literature. The most common underlying neoplasm was acute myelogenous leukemia (AML). Lymphomas, chronic leukemias, myelomas, myelodysplastic syndromes, and a variety of solid tumors have also been observed. The onset of Sweet's syndrome either preceded or coincided with the discovery of a previously undiagnosed cancer in greater than 60% of malignancy-associated Sweet's syndrome patients. In contrast to patients with the idiopathic form of the disease, those with a malignancy often presented with more severe cutaneous lesions, cytopenias, and/or immature cells in the peripheral blood. Extracutaneous sites of involvement included the eyes, muscles and joints, kidneys, lungs, and liver. All the manifestations of Sweet's syndrome improved dramatically with corticosteroid therapy, regardless of the response of the associated neoplasm to tumor-directed therapy.

Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis.

Abstract: A consecutive group of 259 patients with inoperable adenocarcinoma of the lung (ACL) were observed to define risk groups for and frequency of brain metastases together with prognosis. All patients received chemotherapy in a three-armed randomized trial. Brain metastases were diagnosed in 25 patients before protocol entry and in 37 during treatment. Brain autopsy was performed in 87 patients and was positive in 38 (44%). Eleven of these (29%) were not diagnosed clinically. Patients younger than 60 years had a somewhat higher overall frequency of brain metastases than older patients. Patients with initial performance status above 60% and patients responding to chemotherapy had higher risk for developing brain metastasis during treatment than other patients, probably because of the increasing cumulated risk for this complication with prolonged survival. Median survival after onset of brain metastases was 73 days and survival was significantly shorter for these patients than for patients without this complication at days 0, 90, 180, and 365 after protocol entry. Thus, brain metastases is a frequent complication in ACL and the frequency increases with prolonged survival. Survival after development of brain metastases is short and it is questionable whether the inclusion of this subgroup of ACL patients into experimental cytostatic treatments is justified.

Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985.

Abstract: All mesothelioma patients identified by a computer search of pathologic diagnoses at the Dana-Farber Cancer Institute (DFCI) between 1965 and 1985 were the subjects of this analysis. A total of 180 patients were identified, 136 with pleural and 37 with peritoneal mesothelioma. There were five pericardial and two testicular primaries. Of the two decades included in the study, later patients were significantly older, with a more advanced disease stage, and a lower performance status than those accrued early in the study. Factors at diagnosis associated with a significantly prolonged survival for all patients with mesothelioma included a 0 to 1 performance status, absence of chest pain, age less than 50 years, and epithelial histology. Factors at diagnosis associated with prolonged survival for the subset of patients with pleural mesothelioma included epithelial histology, 0 to 1 performance status, the absence of chest pain, an interval of greater than 6 months from onset of symptoms, and treatment with chemotherapy and pleuropneumonectomy. This last result must be interpreted with caution, since this was not a randomized study.

Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection.

Abstract: To evaluate the role of mediastinal irradiation (RT) following surgery for invasive thymomas, a clinical and pathologic review of 117 patients with the diagnosis of thymoma was completed. Fourteen cases were excluded because of the lack of histologic criteria for a thymic tumor, and the remaining 103 were classified according to a staging system as follows: stage I, completely encapsulated (43); stage II, extension through the capsule or pericapsular fat invasion (21); stage III, invasion of adjacent structures (36); and stage IV, thoracic dissemination or metastases (3). The 5-year actuarial survival and relapse-free survival rates were 67% and 100% for stage I, 86% and 58% for stage II, and 69% and 53% for stage III. No recurrences occurred among stage I patients after total resection without RT. However, eight of 21 patients with invasive (stage II or III) thymomas had mediastinal recurrence as the first site of failure following total resection without RT. The 5-year actuarial mediastinal relapse rate of 53% in this group compares unfavorably with the mediastinal relapse rate seen among stage II or III cases following total resection with RT (0%) or following subtotal resection/biopsy with RT (21%). Despite attempted salvage therapy, five of eight patients with mediastinal relapse following total resection alone died of progressive disease. No significant difference was observed in the local relapse rate, overall relapse rate, or survival between those patients undergoing biopsy and RT v subtotal resection and RT for invasive thymomas (stages II and III). Total resection alone appears to be inadequate therapy resulting in an unacceptably high local failure rate with poor salvage therapy results.

Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4-year multicenter randomized study.

Abstract: To evaluate the effect of adjuvant chemotherapy in patients with local-regional nasopharyngeal carcinoma (NPC) (squamous or undifferentiated) in complete remission at the end of curative radiotherapy (RT) 229 patients were randomized from 1979 to 1983 in a multicenter study to no further therapy (116 patients) or a combination of vincristine, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (VCA) for six monthly cycles (113 patients). The RT and RT + VCA groups were well balanced for median age (50 v 49 years), histology (undifferentiated carcinoma, 73% v 70%), tumor extent (tumor limited to nasopharynx, 57% v 57%), and nodal extent (negative nodes 26% v 24%, nodes in the lower cervical levels, 17% v 16%). RT was delivered to the nasopharynx, the base of the skull, and bilateral cervical nodes using a split course technique over 10 weeks up to the dose of 60 to 70 Gy in involved sites and 50 Gy to negative nodes. Response to RT was evaluated within 65 days post-RT treatment. Analysis at 48 months did not show significant difference between the two treatment groups in terms of relapse-free survival (RT, 55.8%, RT + VCA, 57.7%, P = .45) and overall survival (RT, 67.3%, RT + VCA, 58.5%, P = .13). The pattern of relapse was similar in the two treatment arms. Distant metastases were the cause of treatment failure in about 50% of relapsing patients. Although the results of the present study did not show any benefit from VCA administered after curative RT, combined systemic chemotherapy should be further explored due to the high incidence of local and distant failure after intensive RT.

Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer.

Abstract: The effectiveness of BCG in preventing disease progression in patients with superficial bladder cancer is evaluated. Long-term follow-up of high-risk patients treated in a previously reported randomized control trial of intravesical plus percutaneous BCG shows that progression occurred in 41/43 (95%) of control and 23/43 (53%) of BCG-treated patients. Muscle invasive and/or metastatic disease occurred with equal frequency in the two groups, but was significantly delayed by BCG treatment (P = .012). Cystectomies were required in 18/43 (42%) control and 11/43 (26%) BCG-treated patients. Median time to cystectomy was 8 months for control v 24 months for BCG-treated patients. Based on initial treatment, survival was improved by BCG therapy (P = .032) (median follow-up 6 years). These results suggest that in high-risk patients intravesical BCG can delay disease progression, prolong the period of bladder preservation, and increase overall survival.

The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma.

Abstract: Non-Hodgkin's lymphoma (NHL) is a malignancy that occurs frequently in the elderly with a median age greater than 60 years. However, most chemotherapy trials have included predominantly patients less than 60 years of age. We treated 157 patients with diffuse aggressive NHL between September 1982 and May 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), procarbazine, bleomycin, vincristine, and prednisone (CAP/BOP). There were no treatment exclusions for age. Patients in this study ranged in age from 15 to 91 years (median, 63) with 112 patients greater than or equal to 60 years of age. The overall complete remission (CR) rate was 65% with no significant difference for age less than 60 (76%) v age greater than or equal to 60 (61%) (P = .18). With a median 36-month follow-up (range, 22 to 65 months), the overall 5-year survival was 42%. The patients less than 60 years old had a 62% 5-year survival in contrast to a 34% 5-year survival in those patients greater than or eq...

The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group.

Abstract: The prognostic importance of tumor size was studied in 510 patients with malignant glioma (80% with glioblastoma multiforme) in the Valid Study Group of Study 80-01 of the Brain Tumor Study Group (now the Brain Tumor Cooperative Group [BTCG]). The endpoint was length of survival from randomization, which occurred within 3 weeks of definitive surgery. Following randomization, patients were scheduled to receive radiotherapy (RT) (6,020 cGy) during a 7-week period, along with continuing courses of chemotherapy. Computed tomographic (CT) scan information was available for 124 patients preoperatively, 300 patients postoperatively (preradiation), and 218 patients 9 weeks post-RT (+/- 3 weeks). Tumor size was determined as area (length x width) on the contrast-enhanced scan and survival was compared by log rank statistics. Preoperative tumor area was unrelated to survival (P = .48), but postoperative area was significantly prognostic (P less than .0001); the smaller the residual tumor, the longer the patient lived. Patients with a 75% or greater resection, as determined by measuring the difference between the preoperative and the postoperative scans, tended to have better survival, but the difference was not significant (P = .16). The post-RT area was strongly related to survival (P less than .00001). The percent change in area between the pre- and post-RT scans was also prognostic. Tumor size was of prognostic importance independent of the other known prognostic variables: age, Karnofsky performance score, and whether the tumor was glioblastoma or anaplastic astrocytoma. We conclude that the amount of tumor remaining after surgery is an important baseline variable at the start of RT, and that the tumor size 9 weeks following RT is also prognostic. Surgical resection is most important when it leaves the least amount of residual tumor.

Treatment of the patient with stage M0 soft tissue sarcoma.

Abstract: During the period 1971 to 1985, 220 patients with soft tissue sarcoma of the extremities, torso, and head-neck region were managed by radiation and resectional surgery at the Massachusetts General Hospital (MGH). Actuarial 5-year local control and disease-free survival rates were 86% and 70%, respectively. The success rate improved during this time period. Namely, the local control rates for 1971 to 1975, 1976 to 1980, and 1981 to 1985 were 81%, 81%, and 94%, respectively. For the same time periods, the 5-year disease-free survival rates were 64%, 70%, and 76%. One hundred thirty-one patients were treated with postoperative radiation, and 89 with preoperative radiation. In the most recent 5-year period, the local control rates were 91% and 97% for the two groups (number of patients being 50 and 57 in the post- and preoperative groups, respectively). Treatment by preoperative radiation appears to have a major advantage for patients with very large sarcomas, ie, greater than 15 cm in maximum dimension. None of our patients with local control of grade 1 sarcoma have developed distant metastasis (DM). In contrast, among patients with grade 2 or 3 sarcomas, there is a relentless and progressive increase in the frequency of DM with size of the primary lesion, namely, 6% at less than or equal to 2.5 cm, congruent to 60% at 15 to 20 cm, and congruent to 80% at greater than 20 cm.

Sensitive and specific monoclonal antibody recognition of human lung cancer antigen on preserved sputum cells: a new approach to early lung cancer detection.

Abstract: Murine monoclonal antibodies (Mabs) to a glycolipid antigen of small-cell (SCC) and a protein antigen of non-small-cell lung cancer (NSCC) were applied to preserved sputum specimens from individuals who participated in The Johns Hopkins Lung Project (JHLP). In that study, undertaken in 1973 to evaluate the efficacy of sputum cytology screening, half of the high-risk participants (5,226 men, greater than or equal to 45 years of age, currently smoking greater than or equal to 1 pack of cigarettes per day) were randomly assigned to produce specimens for cytopathological analysis. During regular screenings over the next 5 to 8 years, 626 (12%) showed moderate (or greater) atypia. Sixty-nine of these (26 who progressed to cancer, 43 who did not) were randomly selected for a blinded improved Mab immunostaining protocol in the present study. Satisfactory specimens with morphologic atypia immunostained positively in 14 of the 22 patients who eventually progressed to cancer (sensitivity 64%), and were nonreactive ...

Histopathology of childhood sarcomas, Intergroup Rhabdomyosarcoma Studies I and II: clinicopathologic correlation.

Abstract: Histopathologic material from 1,782 patients registered in the Intergroup Rhabdomyosarcoma Study Committee (IRS)-I and -II were reviewed by the IRS Pathology Committee in order to provide a uniform approach to classification and correlate patient survival with tumor type. Categories considered eligible were the four types of rhabdomyosarcoma (RMS) (criteria of Horn and Enterline), extraosseous Ewing's tumor (EOE), and a group of somewhat variable undifferentiated sarcomas designated small round cell sarcoma, type indeterminate (STI). Tumors that were clearly sarcomas but were unclassifiable also were included (NOS). The committee diagnoses were embryonal (Emb) RMS in 877 (54%), alveolar (Alv) RMS in 343 (21%), botryoid (Botr) RMS in 88 (5%), pleomorphic (Pleo) RMS in 11 (1%), STI in 135 (8%), and EOE in 84 (5%). One in nine were mixtures of types, eg, Emb and Alv. Five percent of the sarcomas could not be classified because of inadequate material. In general, there was close agreement (94%) between the review committee and institutional pathologists in the diagnosis of RMS, but not in the specific types, particularly Alv RMS (41%) and STI (36%). This observation is important, since patients with Alv RMS and STI tumors had decreased survival compared with the other histologies. The prognosis varied by histology, with Botr having the best, Alv RMS and STI the worst, and Emb RMS and EOE an intermediate prognosis.

A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors.

Abstract: Standard chemotherapy for disseminated germ cell tumors (GCT) cures most patients but causes considerable acute toxicity, including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis. In addition, chronic and delayed toxicities, particularly Raynaud's phenomenon, have been reported in 6% to 37% of treated patients. In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin, a randomized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin (VAB-6) and etoposide + cisplatin (EP) was conducted on 164 eligible patients with good-prognosis GCT. Seventy-nine of 82 (96%) patients receiving VAB-6 and 76/82 (93%) receiving EP achieved a complete remission (CR) with or without adjunctive surgery. Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma. With a median follow-up of 24.4 months in the VAB...

Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Abstract: Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay...

Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers.

Abstract: From 1965 to 1985, 262 patients with malignant pleural mesothelioma were treated with cytostatics only; radiotherapy (RT); RT and cytostatics; or decortication plus RT plus cytostatics. The median survival (MS) from diagnosis was 9.6 months. This was similar for all comparable treatment groups. In a univariate analysis, significant favorable prognostic factors were good performance status (PS), duration of symptoms greater than 6 months at the time of diagnosis, early stage of disease, white race, and female sex. In a multivariate analysis, PS, race, duration of symptoms, and stage were of significance for a favorable prognosis. Age, pain as first symptom, histologic subtype, and RT dose were not of prognosis significance in this study. The stepwise addition of treatment modalities did not increase survival, which remained the same as that reported for untreated patients. Therefore, phase II trials of new agents offer the only hope for advance in the treatment of this disease.

Quality of life in stage II breast cancer: an instrument for clinical trials.

Abstract: A questionnaire has been developed for use as an outcome measure in clinical trials of adjuvant chemotherapy in women with stage II breast cancer. The selection of items for this Breast Cancer Chemotherapy Questionnaire (BCQ) was based on the problems and experiences felt to be most important by women undergoing adjuvant chemotherapy. The BCQ consists of 30 questions that focus on loss of attractiveness, fatigue, physical symptoms, inconvenience, emotional distress, and feelings of hope and support from others. The BCQ, other instruments that evaluate quality-of-life (Spitzer, Karnofsky, and Rand), and patient and physician global assessments were administered serially to 418 patients taking part in a randomized trial comparing a 12-week regimen and a 36-week regimen of adjuvant chemotherapy. The validity of the BCQ is supported by its correlation with the Rand Emotional (r = .58), Rand Physical (r = .60), and Spitzer (r = .62) questionnaires. The BCQ correlated more strongly with global ratings of both p...

The role of elective lymph node dissection in melanoma: rationale, results, and controversies.

Abstract: Elective lymph node dissection (ELND) for patients with clinically occult metastatic melanoma in regional lymph nodes has the goal of curing metastases with a surgical treatment. This is in contrast to the low probability for surgical cure in patients with clinically detectable lymph node metastases. The rationale for elective node dissection is based on a hypothesis that melanoma metastasizes sequentially via lymph nodes and then to distant sites. A subgroup of melanoma patients with high risk for regional node micrometastases but low risk for distant micrometastases has been identified from prognostic factors analysis of large patient series, as well as surgical results of nonrandomized clinical trials. However, two nonrandomized surgical trials have failed to show a survival benefit for ELND. These studies were largely performed in female patients with extremity melanomas and there were limitations that preclude a definitive conclusion. No randomized trials have been conducted involving melanomas of the trunk or head and neck. Two prospective randomized surgical trials are now being conducted in North America and in Europe. Until the results of these trials are available, physicians are encouraged to enter patients into these ongoing clinical trials or consider ELND in selected patients where the benefit-risk ratio justifies it. Factors to be considered in this decision include intermediate tumor thickness (ie, 1 to 4 mm thickness), anatomic site, histology (ulceration and growth pattern), and the risk of the operation in individual patient settings.

Dose-response in the treatment of breast cancer: a critical review.

Abstract: In animal tumor models the dose-response curve for cytotoxic agents, especially cyclophosphamide, may be steep, but the slope and shape of this curve depends not only on the drug used but on the schedule of drug administration, the specific tumor type, tumor cell kinetics, and tumor mass. It might be anticipated from these studies that the human tumors most sensitive to dose effects would be leukemia, lymphoma, small-cell carcinoma of the lung, and testicular tumors rather than the low growth fraction, relatively less responsive tumors such as breast cancer. However, the clinical evidence for a steep dose-response curve in any tumor type is limited. For breast cancer such evidence is largely retrospective or derived from uncontrolled trials. The data available from randomized trials makes it seem unlikely that small, or even moderate, reductions in drug dose for nontrivial reasons will compromise the survival of patients with either early or metastatic disease. In spite of promising data from small trials...

Cisplatin as first-line therapy for metastatic breast cancer.

Abstract: Cisplatin has had only minimal activity when used as second- and third-line chemotherapy for metastatic breast cancer (MBC). There have been no phase II studies in the United States evaluating cisplatin in patients with MBC with no prior chemotherapy. We therefore treated 20 consecutive patients with cisplatin 30 mg/m2/d for four days every 3 weeks for a maximum of six courses. We obtained partial responses in nine of 19 evaluable patients (47%), with responses in liver, lung, and soft tissue indicator lesions. Our data suggest that cisplatin has substantial single-agent activity as front-line therapy in MBC, and should be considered for inclusion in first-line combination chemotherapy regimens.