Ruby Phelps

A Randomized Trial Comparing Combination Electron-Beam Radiation and Chemotherapy with Topical Therapy in the Initial Treatment of Mycosis Fungoides

Mycosis fungoides is a T-cell lymphoma that arises in the skin and progresses at highly variable rates. Nonradomized studies have suggested that early aggressive therapy may improve the prognosis in this usually fatal disease. We studied 103 patients with mycosis fungoides, who, after complete staging, were randomly assigned to receive either combination therapy, consisting of 3000 cGy of electron-beam radiation to the skin combined with parenteral chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine (n = 52) or sequential topical treatment (n = 51). The prognostic factors were well balanced in the two groups. Combined therapy produced considerable toxicity: 12 patients required hospitalization for fever and transient neutropenia, 5 had congestive heart failure, and 2 were later found to have acute nonlymphocytic leukemia. Patients receiving combined therapy had a significantly higher rate of complete response, documented by biopsy, than patients receiving conservative therapy (38 percent vs. 18 percent; P = 0.032). After a median follow-up of 75 months, however, there was no significant difference between the treatment groups in disease-free or overall survival. We conclude that early aggressive therapy with radiation and chemotherapy does not improve the prognosis for patients with mycosis fungoides as compared with conservative treatment beginning with sequential topical therapies.

Histopathologic staging at initial diagnosis of mycosis fungoides and the Sézary syndrome. Definition of three distinctive prognostic groups.

STUDY OBJECTIVE To determine the optimal staging evaluation at the time of initial diagnosis of mycosis fungoides or the Sézary syndrome. DESIGN Retrospective review of a uniformly staged inception cohort. SETTING Single-institution tertiary care center. PATIENTS 152 consecutive patients who had mycosis fungoides with or without the Sézary syndrome within 6 months of the initial definitive diagnosis. INTERVENTION A detailed staging evaluation including physical examination, routine laboratory studies, chest roentgenogram, lymphangiogram, peripheral blood smear, lymph node biopsy, bone marrow aspirate or biopsy, and liver biopsy in selected patients. MEASUREMENTS AND MAIN RESULTS Univariate adverse prognostic features at initial diagnosis in patients with mycosis fungoides included (P less than 0.01) one or more cutaneous tumors or generalized erythroderma, adenopathy, blood smear involvement with Sézary cells, lymph node effacement, eosinophilia, and visceral involvement. Important, independent prognostic factors in a multivariate analysis are the presence of visceral disease and type of skin involvement. CONCLUSIONS A staging system based on histopathologic evaluation of skin, lymph nodes, blood, and visceral sites provides more comprehensive prognostic information than clinical evaluation of skin disease and adenopathy. Patients may be divided at initial presentation into three prognostic groups: good-risk patients, who have plaque-only skin disease without lymph node, blood, or visceral involvement (median survival, greater than 12 years); intermediate-risk patients, who have cutaneous tumors, erythroderma, or plaque disease with node or blood involvement but no visceral disease or node effacement (median survival, 5 years); and poor-risk patients, who have visceral involvement or node effacement (median survival, 2.5 years).

Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer

PURPOSE We performed a prospective randomized clinical trial to determine whether higher doses of etoposide and cisplatin (EP) yield more complete responses or longer survival in small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS Ninety patients with previously untreated extensive-stage SCLC fulfilled criteria for randomization to standard-dose versus high-dose EP. Another 25 patients at risk of excessive toxicity from high-dose treatment were given standard-dose therapy. During cycles 1 and 2 of EP, patients on standard-dose treatment received intravenous etoposide 80 mg/m2 on days 1 to 3 and cisplatin 80 mg/m2 on day 1 every 3 weeks; high-dose treatment consisted of etoposide 80 mg/m2 on days 1 to 5 and cisplatin 27 mg/m2 on days 1 to 5 every 3 weeks. All patients received standard-dose EP in cycles 3 and 4. In cycles 5 through 8, completely responding patients continued standard-dose EP; all other patients received either cyclophosphamide, doxorubicin, and vincristine, or (if possible) a combination drug program based on in vitro drug sensitivity testing of tumor-cell lines established from individual patients. RESULTS Despite 68% higher doses and a 46% higher dose-rate intensity actually given to patients randomized to receive high-dose relative to those randomized to receive standard-dose EP, complete response rates (23% v 22%; P = .99) and median survival durations (10.7 and 11.4 months, respectively; P = .68) were virtually identical. Complete responses occurred in 4% of patients and the median survival duration was 5.8 months in nonrandomized patients. Leukopenia (P < .0001), thrombocytopenia (P < .0001), febrile neutropenia (P = .01), and weight loss (P = .02) were significantly more common in patients randomized to receive high-dose compared with standard-dose EP. CONCLUSION No therapeutic benefits resulted from increasing planned doses by 67% for the first two cycles of EP in patients with extensive-stage SCLC. Higher doses were associated with substantially worse toxicities.

Smoking Cessation after Successful Treatment of Small-Cell Lung Cancer Is Associated with Fewer Smoking-related Second Primary Cancers

Combination chemotherapy for small-cell lung cancer results in objective responses in 80% to 90% of patients and in 3% to 13% of 2-year cancer-free survivors [1-7]. Relapses 2 years after initiation of therapy occur in approximately one third of 2-year survivors [1, 6, 7]. In addition, deaths from second malignancies, particularly of the lung, and from nonmalignant smoking-related medical problems have been reported in patients with small-cell lung cancer who survive free of cancer for more than 2 years [3, 5, 7-10]. Consequently, the overall 5-year survival rate for all patients with small-cell lung cancer is low, reported as 2.4% to 6% [1, 5, 7-9, 11, 12]. To estimate the risk for second primary cancers in survivors of small-cell lung cancer, we evaluated all patients with this malignancy who remained disease free for 2 years after the initiation of therapy at the National Cancer Institute. The potential change in the risk for a second cancer during follow-up was studied to determine whether the risk increases or decreases with time. In addition, the influence of smoking cessation on the development of subsequent primary smoking-related cancers is undefined [13-20]. Smoking history in our patient population was therefore carefully assessed, and the effect of smoking cessation was evaluated. Methods Patients From April 1973 to December 1989, 540 consecutive patients with histologically confirmed, previously untreated small-cell lung cancer were treated in National Cancer Institute intramural therapeutic trials. All had primary small-cell carcinoma of the lung with evaluable tumor lesions; none were treated in an adjuvant setting after surgical resection. The majority of patients were assigned a performance status, metastatic sites identified, and they were classified as having either limited- or extensive-stage disease as previously defined [21, 22]. The patients began treatment with combination chemotherapy with or without radiotherapy using various regimens that have been reported previously [11, 21-29]. The current status of all patients was determined. The locations of the initial small-cell lung cancers were identified by reviewing reports of chest roentgenograms, thoracic computed tomography, fiberoptic bronchoscopies, mediastinoscopies, and thoracotomies in all patients who were free of cancer for 2 or more years after the initiation of chemotherapy. The sites of subsequent intrathoracic cancer were localized by reviewing reports of chest roentgenograms, thoracic computed tomography, fiberoptic bronchoscopies, thoracotomies, and autopsies. Chest roentgenograms and computed tomographic scans from patients with second primary non-small-cell lung cancers were compared with pretreatment radiotherapy chest roentgenograms showing treatment ports. All initial and subsequent pathologic material was reviewed by one of two pathologists from our institution. The diagnosis of small-cell lung cancer was made and confirmed using the previously defined histologic criteria [30, 31]. Smoking history in all 55 2-year cancer-free survivors was repeatedly determined by a combination of patient follow-up visits, chart and protocol database review, and contact of either patients alive at the time of manuscript preparation or relatives of deceased patients. Smoking cessation was defined as completely stopping smoking by the end of treatment, which was usually of 6 months duration. Definitions The upper aerodigestive tract includes the epithelial regions of the head and neck, lung, and esophagus [13, 32-34]. Smoking-related cancers include cancers of the lung, head and neck, esophagus, bladder, pancreas, kidney, and possibly the stomach [35]. A second primary non-small-cell lung cancer after an initial small-cell lung cancer occurs when 1) tumor histologic findings show non-small-cell lung cancer without small-cell elements; 2) no evidence suggests local or distant recurrence of small-cell lung cancer; and 3) the second cancer is identified more than 2 years after diagnosis of the original small-cell lung cancer [3, 36, 37]. Statistical Analysis For estimation of the expected values of second cancer development, the period of risk began 2 years after diagnosis of the small-cell lung cancer and ended with the date of death, date of last follow-up, or date of diagnosis of a second cancer, whichever occurred first. Person-years of observation were accumulated using the computer program of Monson [38]. Age, sex, and time-specific rates for mortality obtained from the National Mortality Statistics and for cancer incidence obtained from the Surveillance, Epidemiology, and End Results (SEER) program were applied to the appropriate person-years of observation, had this population experienced the same rates prevailing in the national or SEER populations, respectively. Statistical methods for risk estimation were based on the assumption that the observed number of second cancers followed a Poisson distribution [39]. Test of significance and confidence intervals (CIs) for the relative risk (observed and expected) were calculated by using exact Poisson probabilities. To determine the absolute risk, or excess cases of cancer per 1000 persons per year, the number of expected cases was subtracted from the number observed; the difference was divided by the number of person-years of observation and multiplied by 104. Trends and homogeneity were tested as described by Breslow and colleagues [39]. Results Patient characteristics at time of initiation of treatment for both the entire patient population and for the 2-year cancer-free survivors are summarized in Table 1. Of the 540 patients, 55 (10%) were alive and free of cancer 2 or more years after the initiation of treatment protocols Figure 1, corresponding to 22% of 204 patients with limited-stage and 3% of 336 patients with extensive-stage disease. Eighty-six of the patients did not have a performance status assigned or metastatic sites identified prospectively. Compared with the entire patient population, the 2-year cancer-free survivors had a higher percentage of women, of patients with limited-stage disease, and of fully ambulatory patients (Eastern Cooperative Oncology Group performance status, 0-1). These favorable prognostic factors are thoroughly described in the literature [40-43]. The other 485 patients died or had relapsed with small-cell lung cancer within 2 years. The median follow-up from initiation of therapy was 6.1 years (range, 2.1 to 15.1 years) for the 55 patients. Ten patients have remained free of cancer since initial treatment. Five other patients remain alive; three developed second primary cancers that were successfully treated; and two relapsed with small-cell lung cancer, one achieving a prolonged second complete response (>3 years) after recurrence and the other currently receiving salvage chemotherapy. Of the 55 patients, 40 have died: 16 from recurrent small-cell lung cancer, 13 from second primary cancers, 1 from a suspected second primary lung cancer (lung mass without histologic confirmation), and 10 from other causes. Table 1. Patient Characteristics Figure 1. Flow diagram of the outcome of 540 patients with small-cell lung cancer treated at the National Cancer Institute from 1973 to 1989. Eighteen of the 55 patients developed recurrent small-cell lung cancer 2.1 to 12.2 years (median, 3.2 years) after beginning chemotherapy (see Figure 1). The histopathologic features of 4 of the 18 (22%) recurrent small-cell lung cancer tumors included subpopulations of cells with prominent nucleoli but were still in the histologic spectrum of small-cell lung cancer [30]. Eighteen of the 55 2-year cancer-free survivors developed one or more second primary cancers 3.5 to 13.3 years (median, 7.5 years) after beginning therapy for small-cell lung cancer. One of the 18 patients with a second primary cancer had invasive squamous cell carcinoma of the lip, which metastasized to the regional lymph nodes. Another patient died of a central nervous system disorder but had an incidental esophageal cancer discovered at postmortem examination. These cancers were not included in the calculations of the relative risk because incidence data are not available from SEER on nonmelanoma skin cancer and on incidental cancers discovered at postmortem examination (Table 2). The sarcoma was included with other lung cancers because the SEER incidence rates are based on the classification of cancers by site of origin, not by histologic findings. Table 2. Incidence of Second Primary Cancers after at Least 2 Years of Survival with Small-Cell Lung Cancer* The risk for development of a second cancer more than 2 years after the diagnosis of small-cell lung cancer increased by approximately four times, mostly due to the 16-fold increase in second non-small-cell lung cancers (nine squamous; one adenocarcinoma, one large cell carcinoma, and one sarcoma; and one suspected second primary cancer without histologic confirmation) (Table 2). A patient who developed an adenocarcinoma of the lung 12 years after the initial diagnosis of small-cell lung cancer had an initial biopsy specimen with predominant small-cell lung cancer histologic features and an adenocarcinoma component. The patient who developed a squamous cell cancer of the head and neck 8.9 years after the initiation of treatment for small-cell lung cancer had mixed small-cell/large-cell histologic features. The other 53 patients had only small-cell lung cancer in their biopsy specimens at presentation. Seven cancers developed in the lung contralateral to the original small-cell lung cancer, two in a different lobe of the ipsilateral lung, three in the same lobe, and one site could not be accurately determined because of the presence of massive bilateral pleural effusions. The relative risk for a second primary non-small-cell lung cancer compared with that in the general population increased significantly over time from 6 times at 2 to 4 years to 36 t

Female patients with small cell lung cancer live longer than male patients

PURPOSE The incidence of lung cancer is rising in women in the United States, and recent reports have suggested that female patients treated for small cell lung cancer have an improved survival compared with their male counterparts. In view of these findings, we decided to determine if, in our patient population, women live longer than men and if a higher proportion of female patients are entering our trials. PATIENTS AND METHODS The survival of women entering therapeutic clinical trials for small cell lung cancer from 1973 through 1986 at the National Cancer Institute-Navy Medical Oncology Branch was evaluated and compared with the survival of similarly treated men during the same time period. RESULTS The survival of female patients was longer than that of male patients (median of 13 months versus 10 months). Cox proportional hazards modeling incorporating multiple prognostic factors indicated that women survived significantly longer than men (p = 0.002) when adjustment for other significant factors was made. This survival advantage for women was consistent in both early and late time periods analyzed. In addition, women constituted a larger proportion of patients entering clinical trials in the later time period, as is consistent with the rising incidence of lung cancer in women nationwide. CONCLUSION We believe it will be important that comparisons of current clinical trials with older trials that enrolled fewer women control for the favorable prognostic factor of the female sex.

Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome.

PURPOSE This phase II study was undertaken to assess the efficacy and toxicity of alternating administration of pentostatin (deoxycoformycin [DCF]) and interferon alfa-2a (IFN) in patients with advanced or refractory mycosis fungoides (MF) or the Sézary syndrome (SS). PATIENTS AND METHODS Forty-one patients underwent therapy with alternating cycles of DCF 4 mg/m2 intravenously (IV) days 1 through 3 and IFN 10 million U/m2 intramuscularly (IM) day 22, and 50 million U/m2 intramuscularly (IM) days 23 through 26. Twenty-nine patients had not responded to prior chemotherapy or total-skin electron-beam irradiation (TSEB), six had not responded to topical therapies, and six had no previous treatment. RESULTS Two patients achieved a complete response (CR) and 15 achieved a partial response (PR), for an overall response rate of 41% (95% confidence interval, 26% to 58%). No responses were observed in the seven patients with visceral involvement. The median progression-free survival of patients who responded was 13.1 months. IFN-related constitutional symptoms were reported in 39% of patients; severe toxicities included cardiomyopathy in one patient, acute and chronic pulmonary dysfunction in four, and reversible mental status changes in two. Seven patients developed herpes zoster during therapy and six had staphylococcal bacteremia. CONCLUSION These results suggest that the combination of DCF and IFN is an active regimen in MF patients without visceral involvement.

Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years.

In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.

Phase II trial of intermittent high-dose recombinant interferon alfa-2a in mycosis fungoides and the Sézary syndrome.

We previously demonstrated that recombinant interferon alfa-2a (IFN-alfa) in a dose of 50 X 10(6) U million units (MU)/m2 intramuscularly (IM) three times per week has efficacy against mycosis fungoides (MF) and the Sézary syndrome (SS). However, this regimen given to patients with refractory disease was uniformly complicated by toxicities requiring major dose reductions. The present study was designed to determine if intermittent high-dose IFN-alfa would preserve efficacy and decrease toxicity in a similar patient population. Twenty-four patients with advanced disease refractory to one or more standard therapies received IFN-alfa, 10 MU/m2 IM on day 1 followed by 50 MU/m2 IM on days 2 to 5 every 3 weeks; after the first four cycles, stable and partially responding patients underwent dose escalation to twice the starting dose. One complete (CR) and six partial responses (PRs) were observed (response rate, 29%; 95% confidence interval, 13% to 51%) lasting 4 to 19 months (median, 8 months). No improvement in objective response was seen in the eight patients who received dose escalation. Dose reductions were necessary in eight of 22 patients receiving one or more cycles of therapy. Weighted mean dose rate intensity for patients on this study over the first four cycles of treatment was 65.5 MU/m2/wk compared with 73.2 MU/m2/wk over the first 12 weeks of treatment in patients from the previous study, in which all 19 patients receiving more than 1 week of treatment required dose reduction. IFN-alfa is effective against previously treated MF and the SS and is better tolerated on this intermittent schedule.

Tumor cell lines established in vitro: an independent prognostic factor for survival in non-small-cell lung cancer.

OBJECTIVE To determine the relation between in-vitro establishment of tumor cell lines and survival in patients with non-small-cell lung cancer. DESIGN Cohort study. SETTING Single-institution tertiary care center. PATIENTS One hundred twenty-three consecutive patients with non-small-cell lung cancer from whom a viable tumor specimen could be obtained. INTERVENTION Tumor tissue was removed at the time of entry into a therapeutic protocol. The tumor tissue was processed in the laboratory for attempted cell-line establishment. Patients classified as potentially curable (stages I, II, and IIIA) were treated with surgical resection, radiation therapy, or a combination. Patients suitable for palliative therapy only (stages IIIB and IV) were treated with radiation therapy with or without chemotherapy. Chemotherapy was based on in-vitro drug sensitivity when available. Cell-line establishment was correlated to clinical outcome. MEASUREMENTS AND MAIN RESULTS Univariate analysis of survival was done using the log-rank test; multivariate analysis was done by Cox modeling step-up and step-down techniques. Cell lines were established from the tumor specimens of 25 patients (20%). Those patients experienced a median survival of 7 months compared with 18 months in patients from whom cell lines could not be established (P less than 0.001). In the 61 patients with potentially curable disease, 8 patients (13%) with cell lines established had a median survival of 8 months compared with 32 months for those without cell lines established (P = 0.001). In the 62 palliative group patients, the median survival of the 17 patients (27%) from whom tumor cell lines were established was 5 months compared with 7 months for those without cell lines (P = 0.15). Multivariate analysis in both groups showed cell-line establishment to be a significant indicator of prognosis (P less than 0.0001 for curable group; P less than 0.01 for palliative group). CONCLUSION In-vitro tumor growth is related to decreased patient survival, which in turn reflects the biologic aggressiveness of cancers giving rise to these tumor cell lines.

Limited stage small cell lung cancer treated with concurrent hyperfractionated chest radiotherapy and etoposide/cisplatin

Abstract Forty-one previously untreated patients with limited-stage small cell lung cancer (SCLC) entered a combined-modality study. Patients were initially treated with etoposide and cisplatin and concurrent chest radiotherapy. Patients then received two more cycles of etoposide/cisplatin followed by four cycles of individualized chemotherapy based on in vitro drug sensitivity testing if available, or a standard regimen of vincristine/doxorubicin/cyclophosphamide. Forty patients have completed therapy and are evaluable for response. Twenty-nine (73%) had a complete response and the remaining 11 (27%) achieved partial response. The median potential follow-up is now 3 years (range 4 months to 5 years). The median projected actuarial survival is 27 months with an actuarial survival of >90% at 1 year and 65% at 2 years. Four of 41 patients (10%) have died from treatment toxicity, including three who died of combined-modality pneumonitis and one of neutropenic sepsis. The median projected actuarial survival is nearly twice as long as in our previous combined-modality treatment regimens for limited-stage small cell lung cancer.