To learn more about the natural history of low-grade non-Hodgkin's lymphoma, we have studied 83 patients in whom the advanced disease was initially managed without therapy. Actuarial survival was 82 per cent at 5 years and 73 per cent at 10 years. The median time until therapy was required was three years. Spontaneous regressions occurred in 19 untreated patients (23 per cent), including 30 per cent of patients with nodular, poorly differentiated lymphocytic lymphoma. Histologic transformation to an intermediate-grade or high-grade lymphoma occurred both before and after primary therapy. The actuarial risk of transformation among the initially untreated patients was similar to that in a group of patients treated at this institution immediately after diagnosis. Neither the time to histologic transformation nor the incidence of transformation was influenced by when therapy was started.

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We estimated the risk of second cancers among 1507 patients with Hodgkin's disease treated at Stanford University Medical Center since 1968. Eight-three second cancers occurred more than one year after diagnosis, as compared with 15.9 expected on the basis of rates in the general population (relative risk, 5.2; 95 percent confidence interval, 4.2 to 6.5). The mean (+/- SE) 15-year actuarial risk of all second cancers was 17.6 +/- 3.1 percent, of which 13.2 +/- 3.1 percent was due to solid tumors. The risk of leukemia appeared to reach a plateau level of 3.3 +/- 0.6 percent at 10 years, whereas non-Hodgkin's lymphoma continued to increase, to 1.6 +/- 0.7 percent by the end of the follow-up period. The risk of solid tumors did not vary significantly according to treatment category, with the array of neoplasms resembling that previously observed in populations exposed to radiation and in immunosuppressed groups. The risk of leukemia, although elevated after radiation therapy alone (relative risk, 11; 95 percent confidence interval, 1.2 to 38), was much higher after either adjuvant chemotherapy (relative risk, 117; 95 percent confidence interval, 69 to 185) or chemotherapy alone (relative risk, 130; 95 percent confidence interval, 26 to 380). These data suggest that the risk of solid tumors after therapy for Hodgkin's disease continues to increase with time.

Key Points This study is a retrospective analysis of long-term outcomes of patients with FL treated at Stanford University for 4 decades. Study results showed significant improvement in OS in patients with FL despite no change in event-free survival after first-line therapy.

In selected stage I and II follicular NHL patients, deferred therapy is an acceptable approach, as more than half of our patients remained untreated at a median of 6 or more years, and survival was comparable to that seen in reports with immediate treatment.

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The probability of maintaining ovarian function, becoming pregnant, and delivering a normal child is important to young women anticipating successful therapy for Hodgkin's disease. In this study, reproductive function was retrospectively examined in 103 women 40 years old or younger who had undergone treatment for Hodgkin's disease with total-lymphoid irradiation (TLI) alone, combination chemotherapy, or combined TLI and chemotherapy. Infertility was directly related to gonadal exposure to therapy and to age at treatment. Twenty women became pregnant after receiving total-nodal irradiation or combination chemotherapy or both. No fetal wastage occurred, and no birth defects were seen in the 24 infants born to these women. Even after intensive treatment programs, women successfully treated for Hodgkin's disease have become pregnant and delivered phenotypically normal children.

These data confirm our preliminary report that Stanford V chemotherapy with RT to bulky disease sites is highly effective in locally extensive and advanced Hodgkin's disease. It is most important to compare this approach with standard doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the ongoing intergroup trial (E2496) to determine whether Stanford V with or without RT represents a therapeutic advance.