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Background: Multiple myeloma is considered to be a drug responsive disease; however, there is no cure for this disease and virtually all patients will develop drug resistance. One form of drug resistance that has been documented is the multidrug resistance phenotype or MDR., Methods: A randomized trial of the combination of vincristine, doxorubicin, and dexamethasone (VAD) and VAD plus oral verapamil (VAD/v) in drug refractory multiple myeloma patients was performed by the Southwestern Oncology Group. Verapamil was used as a chemosensitizing agent to attempt to overcome or prevent MDR and improve the therapeutic outcome., Results: Response rates between the two treatment arms were similar with an overall response rate of 41% for the VAD alone arm and 36% for the VAD/v arm. Overall survival of patients was also similar with a median survival of 10 months for the VAD arm and 13 months for the VAD/v arm. The toxicity profile was also similar for both treatments, with myelosuppression being the dose-limiting toxicity. No significant correlation was observed between expression of P-glycoprotein, serum verapamil levels, and response to therapy., Conclusions: No beneficial effect was observed from the addition of oral verapamil to the VAD chemotherapy regimen for the treatment of drug-resistant myeloma patients. More effective and less toxic chemosensitizers are needed to study the role of chemosensitizers in reversing MDR in the clinic.

Background: Prednisone is an active drug in the treatment of multiple myeloma. The optimal dose, frequency, and role of glucocorticoid receptors (GR) in response to prednisone is unknown., Purpose: The purposes of this study were (1) to estimate the response rate of alternate-day high dose prednisone in patients with relapsing and refractory multiple myeloma; (2) to measure the rate of GR levels; and (3) to correlate the response of prednisone with GR status., Patients and Methods: Between 8/86 and 1/90, 127 patients were entered onto the study with 121 evaluable for response. The number of GR sites/cell was determined on mononuclear cells isolated from pretreatment bone marrow aspirates using a one point GR binding assay. Patients received prednisone 100 mg po qod x 2 weeks, followed by 50 mg po qod x 10 weeks., Results: The overall response rate was 10% (95% CI: 5-15%) with a median survival of 11.8 months. The GR sites/cell ranged from 0-53,212 with a mean of 8,371 sites/cells. Stratification of GR sites into 0-2,500, 2,501-6,000 and > 6,000 sites/cells was associated with a response rate of 6%, 27% and 4% respectively (p = 0.009). The median survival of patients in these categories was 8.1, 14.9 and 10.6 months respectively. This was not significant by the logrank test (p = 0.11). Although myeloma patients with intermediate levels of GR sites/cell initially responded more favorably to prednisone, their long-term survival was not significantly improved., Conclusions: Alternate-day high-dose prednisone was well tolerated and may provide palliative benefit for a subset of patients with relapsing and refractory multiple myeloma. The survival of patients on this study was comparable to that reported with other but more toxic doses of glucocorticoids.

From June 1988 to November 1990 the Southwest Oncology Group initiated nine protocols for the phase II evaluation of recombinant human tumor necrosis factor alpha (rhuTNF alpha) in cancer patients. Patients with diverse metastatic malignancies including breast, colon, gastric, pancreatic, endometrial, and bladder cancers, as well as multiple myeloma and various sarcomas received 150 micrograms/m2 of rhuTNF alpha daily for 5 days every other week. Of 147 patients entered in the study, 127 were eligible and were evaluated for toxicity and response. Of 124 patients known to have completed treatment, 92 (74%) went off study for progression, 21 (17%) for toxicity, and 12 (10%) for other causes, mainly that of worsening medical condition. Thirteen percent of patients experienced grade 4 or fatal toxicity. The most serious toxicities were pulmonary failure and coagulopathies. The predominant grade 3 toxicities were symptomatic (chills, fever, malaise, headache, myalgia, and nausea or vomiting). Only one partial remission was seen in a patient with metastatic bladder cancer lasting 4 months (rate 0.8%, exact 95% confidence interval 0-4%). At the study dose and schedule, rhuTNF alpha does not appear to have significant antitumor activity. The biological basis for this finding is discussed.

Disseminated soft-tissue sarcomas are a group of uncommon malignancies generally treated in a uniform manner. This study questioned the impact of schedule on response rate and toxicity in patients with metastatic soft-tissue sarcoma treated with the two-drug combination doxorubicin and dacarbazine. Patients were randomly assigned to receive either bolus therapy with doxorubicin at a dose of 60 mg/m2 and dacarbazine at a dose of 750 mg/m2 intravenously on day 1 (118 patients) or infusional therapy with doxorubicin at 60 mg/m2 and dacarbazine at 750 mg/m2 delivered by continuous intravenous infusion for 96 hours on days 1-4 (122 patients). Chemotherapy was to be repeated every 3 weeks. A unique feature of this cooperative group protocol was a provision for surgical resection of residual disease in patients with a partial response or with stable disease following chemotherapy. Similar overall response rates (17% in both treatment arms) and complete response rates (5% in both treatment arms) were observed. For patients receiving bolus therapy, the median response duration was 19.6 months for those in complete remission and 6.6 months for those in partial remission. For patients receiving infusional therapy, the median response duration was 12.6 months for those in complete remission and 9.3 months for those in partial remission. Examination of dose intensity received when combining treatment arms revealed a weak doxorubicin dose-response relationship. There was no difference in median survival times between the two treatment arms (bolus therapy, 10.6 months; infusional therapy, 10.5 months; logrank P = .97). Analysis of toxic effects favored infusional therapy. Significant reductions in cardiac toxicity (all events, P = .04; clinical events, P = .01) and nausea and emesis (P = .04) were seen in infusional therapy. Of 47 patients eligible for cytoreductive surgery following chemotherapy, 12 received surgery, and of those 12, eight were rendered disease free. The use of a 96-hour continuous intravenous infusion of doxorubicin-dacarbazine was comparable therapeutically with bolus dosing of these two agents and was better tolerated by the patients.

This study involved the administration of amonafide intravenously 300 mg/m2 daily times five days every three weeks to 16 refractory and relapsed myeloma patients. Doses were escalated to toxicity. These doses caused severe thrombocytopenia and granulocytopenia in seven patients. No responses were seen in this heavily pretreated group of patients.

Based on a preliminary trial that suggested that CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and PVB (cisplatinum, vinblastine, bleomycin), are at least partially non-cross-resistant, the Southwest Oncology Group treated patients with unfavorable histology, non-Hodgkin's lymphoma with CHOP and PVB. In the first study, 76 eligible patients were given three courses of CHOP, with complete or partial responders receiving three courses of PVB followed by three further courses of CHOP. Nonresponders after the initial three cycles of CHOP, received six courses of PVB. In the second study, 154 eligible patients were treated with alternating cycles of the two drug regimens. The overall objective antitumor response (CR + PR) was 77% for the first study and 58% for the second. The complete remission rates were 48% and 38%, respectively. The overall survival for both studies is similar. These results are interpreted in terms of the Goldie-Coldman hypothesis.

Six hundred fourteen previously untreated patients with multiple myeloma were evaluated on this phase III Southwest Oncology Group (SWOG) trial. For remission induction, two noncross-resistant drug combinations (vincristine, melphalan, cyclophosphamide, and prednisone [VMCP] and vincristine, carmustine [BCNU], Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and prednisone [VBAP]) were administered with either a direct alternating or a syncopated schedule. Pretreatment serum beta-2 microglobulin (beta 2M) was the single most important prognostic factor for survival (P less than .0001). There was no difference in toxicity, response, or survival by induction chemotherapy schedule (P greater than .7). For consolidation, 180 eligible and responsive patients were randomized to receive either an additional year of VMCP or sequential hemibody radiation (HBI) with vincristine and prednisone (VP) administered between the two HBI courses. Relapse-free survival (26 months) and overall survival (median, 36 months) were better with VMCP than with HBI (median, 20 months and 28 months; P = .04 and .018, respectively). HBI was also evaluated on a nonrandomized basis in 66 patients who achieved either a partial response (PR) or who were nonresponders to induction therapy. While HBI converted 24% of the PR patients to remission status, this effect was only seen in 5% of nonresponding patients. The survival of responsive and nonresponding patients receiving HBI was similar. All HBI groups had an inferior outcome to those receiving VMCP consolidation. Myelosuppression was also significantly worse after HBI. Survival from the time of relapse did not differ between patients randomized to receive VMCP or HBI. Thus HBI induced less durable remissions, but did not render patients less amenable to postrelapse chemotherapy. Our findings do not support the use of HBI in either chemotherapy responsive or nonresponding patients with multiple myeloma.

Thirty-one patients with multiple myeloma refractory to therapy or relapsing after response to initial therapy were treated with Fludarabine Phosphate utilizing a daily intravenous schedule for five consecutive days. There were no objective responses seen and only one patient showed clinical improvement. Myelosuppression manifest as leucopenia and granulocytopenia was the primary toxicity seen. Fludarabine Phosphate is inactive in previously treated myeloma patients when given by the daily intravenous route.

Fifty-two patients with progressive resistant multiple myeloma were entered in this Southwest Oncology Group Phase II study, using weekly intravenous Aclacinomycin A. Of forty-three evaluable patients for response, there was one partial remission of 2 years duration and two sustained clinical improvements with 25% reduction in paraprotein. Major toxicity seen was severe myelosuppression and significant nausea and vomiting requiring dose reduction and delay of the scheduled treatment. Cardiac arrhythmia was seen in one patient. Chronic daily schedule or continuous IV infusion is recommended for future study.

Thirty-three patients with relapsing or refractory multiple myeloma were treated with 6-Thioguanine (6TG) at a dose of 1 g/M2, with therapy given over four hours every three weeks. The major toxicity seen was myelotoxicity; thrombocytopenia was more commonly noted than neutropenia. One patient achieved a PR, two were clinically improved. 6TG in this short infusion schedule proved to be myelotoxic, but demonstrated little activity in previously treated myeloma patients.

Fifty-five patients with myeloma who had relapsed on or were resistant to melphalan and/or cyclophosphamide with prednisone received vincristine, carmustine, doxorubicin, and prednisone (VBAP) plus cisplatin and bleomycin at 21-day intervals. Eighteen (32.7%) patients responded. The response rate was 38.5% (15 responses among 39 patients) in relapsing patients. Three (18.8%) of 16 patients with resistant myeloma responded. Granulocytopenia was the most frequent toxic effect, and was severe in 12 (22%) patients. Severe thrombocytopenia occurred in seven (13%) patients and severe nausea and vomiting occurred in eight (15%). One patient with previously normal renal function developed renal failure on this regimen. The median survival (100 weeks) in those patients responding to treatment was significantly longer than that in patients not responding (25 weeks; P = 0.001). VBAP plus cisplatin and bleomycin was at least as effective as VBAP but had greater toxicity, expense, and inconvenience; it therefore is not preferable to VBAP.

Thirty-five fully evaluable patients with advanced multiple myeloma, refractory to standard chemotherapeutic agents, were entered into a phase II trial with mitoxantrone at a starting dose of 12 mg/m2 iv every 3 weeks. There was one (3%) partial response (lasting 2 1/2 months) in a patient who had received treatment with five different agents, including doxorubicin (total dose, 150 mg/m2). Four additional patients (11%) showed objective evidence of clinical improvement, lasting 4-7 months. Mitoxantrone was well-tolerated with no drug-induced deaths and only moderate to severe leukopenia as the dose-limiting toxicity in the majority of patients. Although mitoxantrone had a low level of activity in this heavily pretreated patient population, consideration should be given to future trials incorporating mitoxantrone into a new drug combination.

A prospective randomized trial comparing streptozotocin, mitomycin C, and 5-FU (SMF) with mitomycin C and 5-FU (MF) in patients with advanced pancreatic cancer was performed. In patients with measurable disease the response rates were 34% (19/56) to SMF, and 8% (5/60) to MF (P = 0.009). Median survivals were similar, however, 18 versus 17 weeks (P = 0.356). Median survival of patients responding to chemotherapy was 33 weeks, and for nonresponders it was 17 weeks (P = 0.002). In patients with nonmeasurable disease, median survivals were 21 weeks (SMF) and 18 weeks (MF) (P = 0.797). Patients surviving greater than or equal to 48 weeks, however, appeared to be increased in the SMF arm (14 patients) compared to the MF (7 patients). Toxicity was moderate for both regimens, with SMF having greater gastrointestinal and renal toxicity. Chemotherapy with SMF appears to produce objective responses in patients with pancreatic cancer, but does not improve survival compared to MF.

The paraproteinemias, a large heterogeneous group of diseases, are best characterized by the type of immunoglobulin moiety (paraprotein) produced. For the most common disorder, myeloma, response to treatment with alkylating agents has been objectively shown. Waldenström's macroglobulinemia and heavy-chain disease are more closely related to lymphoma than to myeloma. Some patients with paraproteinemia have a benign course with a constant, abnormal, immunoglobulin level.

Six months after right-sided spontaneous pneumothorax developed in a 56-year-old man, squamous cell carcinoma was discovered in the ipsilateral lung. Fifteen cases of bronchogenic carcinoma presenting as spontaneous pneumothorax have been reported in the English language literature. Possible pathogenetic mechanisms include: direct tumor invasion of pleura; rupture of a subpleural bleb (in an area of obstructive emphysema) or an emphysematous bulla (in an overexpanded portion of the lung associated with lobar or segmental collapse); or unknown. Patients with spontaneous pneumothorax who fail to achieve complete expansion after three weeks of therapy or who have persistent roentgenographic pulmonary infiltration should undergo further investigation for bronchogenic carcinoma.

The first steps in managing a patient with suspected anemia are to confirm the diagnosis and to determine the morphologic type. The normocytic normochromic type has many causes, two of the most common being chronic disease and drug therapy. The anemia of chronic disease is often mistaken for iron-deficiency anemia and treated with iron supplements.

The effect of certain disease parameters on remission and survial time was evaluated in 482 patients with multiple myeloma treated with intermittent courses of melphalan-prednisone combinations. Increasing degrees of anemia, hypercalcemia, azotemia, and high serum myeloma protein levels were associated with progressive lifespan shortening. The short survival of patients with anemia and hypercalcemia was associated with short remissions in responding patients with these abnormalities. The extent of tumor mass was defined from specific laboratory parameters reported by Durie to be associated with large numbers of plasma cells. More advanced stages of myeloma were associated with higher frequencies and degrees of normal immunoglobulin depression. The response rate was not affected by the tumor mass grade, but increasing tumor mass was associated with a shorter lifespan. Greater degrees of tumor reduction were associated with longer remission and survival times. Patients in whom a marked tumor reduction was rapid had shorter survival and remission times than patients who responded more slowly.

Patients with advanced transitional cell bladder carcinoma were randomized to receive either adriamycin alone, or adriamycin plus DDP. Overall response (CR + PR) was 8/41 (19%) for adriamycin alone versus 16/37 (43%) for the combination (p = 0.02). Median response duration was 14 weeks for adriamycin versus 25 weeks for the combination (p = 0.17). Median survival was 28 weeks on adriamycin versus 31 weeks on the combination (p = 0.82). Median survival of responders was 43 weeks, and for patients with stable disease it was 29 weeks. This was significantly better than for those with increasing disease at 15 weeks (p = 0.02). Increased frequency of leukopenia and gastrointestinal toxicity were seen with the combination. Cardiotoxicity and nephrotoxicity were not prohibitive.

In January, 1972, the Southwest Oncology Group initiated two randomized studies for patients with advanced breast cancer. The study for patients with prior chemotherapy showed a 33% response rate with adriamycin. The study for patients without previous chemotherapy consisted of three treatment regimens; a weekly repeated combination of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone; these same five drugs given in courses of 5 days repeated every 4 weeks; and adriamycin as a single agent every 3 weeks. For the 283 evaluable patients, the response rates were: weekly combination 63/106 (59%); intermittent combination 39/98 (40%); and adriamycin 31/79 (39%). The median duration of response was 8 months for weekly combination, 10 months for intermittent therapy and only 4 months for adriamycin. Leukopenia was the dose-limiting toxicity with all three regimens. The weekly combination is the most effective therapy for patients with advanced disease. Extensive trails of combinations that include adriamycin are underway.

Previously untreated patients with multiple myeloma were entered on a randomized clinical trial to determine whether the use of alternating combination chemotherapy, including vincristine, doxorubicin, alkylating agents, and prednisone (160 patients) was more effective than conventional chemotherapy with melphalan and prednisone (77 patients), and whether the addition of the immunomodulating agent levamisole to maintenance chemotherapy enhanced the survival of patients achieving remission. The treatment groups were well matched for all major factors. The more aggressive chemotherapy was more effective at inducing remission, with a significantly higher proportion of patients achieving at least 75% tumor mass regression (53% with alternating combinations versus 32% with melphalan-prednisone, p = 0.002). Furthermore, the median survival was increased to 43 months with alternating combination chemotherapy as compared to 23 months with melphalan-prednisone (p = 0.004). After six to 12 months of induction therapy, 84 patients achieving remission were rerandomized to receive maintenance chemotherapy alone or with the addition of levamisole. The survival from the start of maintenance therapy was longer in patients receiving the added levamisole than with chemotherapy alone (p = 0.01). These findings support the use of aggressive multiagent chemotherapy for remission induction in patients with advanced-stage multiple myeloma.

One-hundred-fourteen evaluable patients with metastatic soft tissue or bony sarcoma with measurable disease were treated with Adriamycin (doxorubicin) administered intravenously at a dose of 60 mg/M2 on day 1, followed by DTIC (dacarbazine) at a dose of 750 mg/M2; courses were administered at 3-week intervals. Ten complete remissions and 17 partial remissions were observed. The most responsive cell type was malignant fibrous histiocytoma with a response rate of 54%. This treatment schedule was very well tolerated, with only moderate myelosuppression and moderate nausea and vomiting. Cardiac toxicity was identified in three patients, with two patients demonstrating electrocardiogram (EKG) changes and arrhythmias and only one patient developing heart failure. The 24% overall response rate suggests no compromise in activity on this schedule, with a significant reduction in toxicity.

In the first study of combined chemotherapy and radiation therapy for small cell lung cancer by the Southwest Oncology Group, 17 patients survived more than five years after treatment was initiated (4.6 percent). Late relapse, or a second primary malignancy three to six years after diagnosis, accounted for death in five of these patients. Late recurrences involved the chest, bone, and liver; none occurred in the central nervous system. Disease-free survival continues in 10 patients (6 percent of those with limited disease and 1 percent of those with extensive-stage diseases) at a minimal follow-up in excess of six years. One definite case of chronic treatment-related toxicity occurred: congestive cardiomyopathy after 450 mg/m2 of doxorubicin, successfully managed with digitalis and diuretics. One severe neurologic problem (orthostatic hypotension with preterminal dementia) and two less severe neurologic complications (occasional falling episodes without documented cause and cerebrovascular accident) may be treatment-related. Progressive pulmonary disability, post-herpetic pain syndromes, organic brain syndrome, and hematologic abnormalities have not been observed to date. Nitrosourea administration and/or co-administration of a nitrosourea or methotrexate during the induction phase of treatment with radiotherapy to the brain may account for the higher incidence of complications observed by others in long-term survivors.

Fifty-one previously untreated patients with metastatic colorectal cancer were treated with a combination of 5-fluorouracil, methyl-CCNU, and Baker's antifol. Six of 34 fully evaluable patients achieved a response. There were no apparent benefits obtained with this combination compared to treatment with 5-fluorouracil alone.

The incidence of lung cancer, the most common visceral malignancy, is increasing in the elderly patient. Careful preoperative preparation and postoperative care will allow some of these patients to have surgical resections. Radiotherapy and chemotherapy offer benefits for those patients who cannot have a curative surgical resection.