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Second Malignancies After Treatment of Hodgkin's Disease: The Influence of Treatment, Follow-Up Time, and Age

PURPOSE In the period 1968 through 1988, The Norwegian Radium Hospital (NRH) treated an unselected population of 1,152 patients with Hodgkins disease (HD) that comprised more older patients (mean age, 43 years) than most other institutions. We considered it important to evaluate these patients for development of second cancers (SCs). PATIENTS AND METHODS The Norwegian Cancer Registry identified previously untreated patients with HD treated at NRH who had developed a SC more than 1 year after diagnosis of HD. The relative risk ratio (RR) (observed/expected cases) and the cumulative risk were calculated. RESULTS Sixty-eight patients had developed a SC, including nine acute nonlymphocytic leukemias (ANLLs), eight non-Hodgkins lymphomas (NHLs), and 51 solid tumors, including 11 lung cancers. The RR of SC and leukemia was 1.86 (95% confidence interval [CI], 1.4 to 2.4) and 24.3 (95% CI, 11.1 to 46.2), respectively. The RR of SC was highest in younger patients (< 41 years, RR = 3.8). No significant association between splenectomy and development of ANLL was found. The influence of treatment and follow-up time on the development of SC agrees with data from other large cancer institutions. CONCLUSION (1) The low RR of developing a SC in this study is probably due to the number of older patients included, who have a lower RR of developing a SC due to less aggressive treatment, shorter follow-up time, and higher incidence of cancer in the expected background population. (2) The low RR and cumulative risk of developing ANLL may be due to the limited use of extensive chemotherapy (CT) in our hospital in the earlier years.

High incidence of serious side effects of high-dose dexamethasone treatment in patients with epidural spinal cord compression.

SummaryTwenty-eight consecutive patients were given high-dose dexamethasone (96 mg i.v. loading dose, decreasing doses to zero in 14 days) and radiotherapy for epidural spinal cord compression due to malignant disease. There were eight events classified as side effects of the dexamethasone treatment. Four of these were considered as serious (one fatal ulcer with haemmorhage, one rectal bleeding and one gastrointestinal perforation from undetermined origins, and one perforation of the sigmoid colon) giving a total rate of serious side effects of 14.3 percent. Due to the high incidence of serious side effects of the high dexamethasone dose, the regimen was abandoned in favor of a standard dexamethasone dose of 16 mg daily reduced to zero in 14 days. There were three events classified as side effects, but none were considered as serious in 38 consecutive patients receiving this dose. The differences both in total number of side effects and number of serious side effects are statistically significant. There was no significant difference in the number of ambulant patients in the group that received the high dexamethasone dose. We conclude that the high dexamethasone dose in our experience gives an unacceptably high incidence of serious side effects and we have therefore abandoned the regimen in favour of a more standard dexamethasone dose.

Standard CHOP-21 as first line therapy for elderly patients with Hodgkin's lymphoma

There is no consensus on the optimal chemotherapy regimen for Hodgkins lymphoma patients ≥ 60 years. We present our institutions results of 5 years, using CHOP-21 as standard for this patient group. Twenty-nine patients with a median age of 71 years (range, 60 – 91) were included in this cohort. Fifty-five percent had known co-morbidities. Stage I/IIA patients (38%) were treated with 2 – 4 cycles of CHOP followed by radiotherapy. Stage IIB – IV patients (62%) received 6 – 8 cycles of CHOP and for the majority (13/18 pts) no radiotherapy. Two treatment-related deaths occurred. Febrile neutropenia was the most common toxicity (31%). The complete response rate after CHOP +/− radiotherapy was 93%. With a median follow-up of 41 months, five patients have relapsed and four have died from Hodgkins lymphoma. So far, no relapses have occurred after 2 years from the end of therapy. Overall survival and progression-free survival at 3 years were 79% and 76%, respectively. We conclude that CHOP-21 is a well-tolerated and effective treatment for elderly patients with Hodgkins lymphoma.

A 10-year experience with splenectomy in patients with malignant non-Hodgkin's lymphoma at the Norwegian Radium Hospital.

Background. Splenectomy is a major surgical intervention that has many implications for patients with malignant non‐Hodgkins lymphoma. As debated during the last few decades, the therapeutic benefit must outweigh the surgical risk and the loss of cellular immunity. A more liberal attitude toward splenectomy developed during the years 1980‐1990 at the Norwegian Radium Hospital, as illustrated by the higher number of operations performed in the last 5 years (21 patients) compared to the first 5 years (14 patients).

Late Medical Sequelae After Therapy for Supradiaphragmatic Hodgkin's Disease

A total of 221 consecutive early stage Hodgkins disease (HD) patients were given mantle field irradiation only or in combination with chemotherapy in 1971-1991. In 1994 these patients responded to a mailed self-report questionnaire covering items on late medical symptoms. Of 200 patients (91%) who reported that their thyroid function had been tested, 110 patients (55% of those tested) had thyroid hypofunction at follow-up in 1994. Ninety-five patients (86% of patients with biochemical hypothyreosis) had started hormonal substitution. In 1993 and 1994, 101 of these patients who had received mantle field irradiation in 1980-1988 were called in for interview, clinical examination and thyroid function tests. Eighteen patients (18%) had started hormonal substitution treatment earlier, but 58 (70%) of the other 83 patients were found to have biochemical hypothyreosis. Of the 221 patients who completed the questionnaire, 66 patients (30%) reported dyspnoea on exertion for more than 3 years after treatment, 8 patients (4%) reported a history of myocardial infarction, 6 patients (3%) reported pericardial disease and 25 patients (11%) heart valve disease. Increased expenses incurred for dental care were reported by 106 patients (48%), increasing to 55% when Waldeyers ring had been irradiated. The consequences of late sequelae after mantle field irradiation for future treatment are discussed.

Combined Intra-arterial and Systemic Chemotherapy for Recurrent Malignant Brain Tumors

Seventy-nine patients harboring recurrent brain tumors received four cycles of infraophthalmic carotid injections of 160 mg of carmustine. Two milligrams of intravenous vincristine and 50 mg of oral procarbazine was also administered three times daily for 1 week in conjunction with each BCNU treatment. The response rate was 60% with a median survival for patients with astrocytomas, anaplastic astrocytomas, and glioblastomas of 32, 20, and 6.5 months, respectively. The median survival of the responding patients was 20 months, and the survival at 30 months was 45%. The survival in patients not responding to treatment was 5 months, reflecting the natural history of the tumor. There have been no deaths related to the treatment procedure. No incidents of severe or permanent eye complications or leukoencephalopathy were observed. Based on multivariate survival analysis, only patients with a good performance status who are not steroid dependent are candidates for this treatment.

Prognostic factors in malignant gliomas with special reference to intra-arterial chemotherapy.

Survival was analyzed in 173 patients with malignant gliomas to study the importance of possible pretreatment prognostic factors. Seventy-nine of these patients received preirradiation intra-arterial chemotherapy with BCNU combined with vincristine intravenously and procarbazine orally; the others received only postoperative whole-brain irradiation. To judge by univariate and multivariate analyses the most important pretreatment prognostic factors were histology, corticosteroid dependency, pretreatment performance status and frontal lobe location of the tumors. Patients with anaplastic astrocytoma, not corticosteroid-dependent, with pretreatment performance status of 0-2 and with a frontal lobe location of the tumor seemed to benefit most from preirradiation chemotherapy.

Tissue specificity of the epidermal chalones

SummaryAn increasing body of evidence indicates that the rate of cell renewal in labile and stable cell populations is regulated according to a negative feedback principle. Water extracts of such tissues contain mitosis-inhibiting substances (chalones) that probably represent the chemical signals in these cell populations. Tissue specificity is one of the theoretical prerequisites of the chalones but has not been proven in many cases. The present study is an attempt to evaluate the tissue specificity of some chalones, with special emphasis on the chalones found in keratinizing epithelia.As an assay system for such a study the epidermis, the epithelium of the forestomach, and the epithelium of the crypts of jejunum and colon were chosen since they represent steady state systems with a well defined proliferating pool. The stathmokinetic method was used to estimate the effects of aqueous extracts of skin, forestomach, glandular stomach, lung, kidney, liver, spleen and striated muscle on the mitotic rate. Autoradiography and liquid scintillation counting were performed to measure the effect of the extracts of skin, forestomach, glandular stomach, and small intestine on DNA synthesis.Five mg of skin extract inhibited the mitotic activity of the epidermis (70%) and the forestomach (25%) three hours after i.p. injection. An inhibiting effect on the epithelial cells of the crypts of jejunum and colon was very slight and statistically non-significant. Five mg forestomach extract inhibited the mitotic activity of the epidermis (58%) and of the forestomach (44%). The effect on the jejunum and colon was slight and statistically non-significant. The results supported the concept of tissue specificity of the G2 factor (M chalone) in keratinizing epithelia, regardless of their ectodermal or endodermal origin. It cannot be excluded that epidermis and forestomach each have their respective organ-specific chalones because the effect was most pronounced in the organ from which each extract was made.Both skin and forestomach extracts (10 mg) inhibited the incorporation of tritiated thymidine (3HTdr) into DNA (pulse labelling) of epidermis and forestomach after a certain delay (eight hours after i.p. injection). No effect was found on jejunum or colon. This supported the concept of tissue specificity of the G1 factor (S chalone) in keratinizing epithelia.Five mg of glandular stomach extract inhibited the mitotic count of epidermis and forestomach, but did not show any depression of the incorporation of 3HTdr into DNA of the same organs. No effect was found in jejunum or colon. These results are discussed in relation to the recent findings of Elgjo and Edgehill (1973) demonstrating a mitotis-inhibiting effect of dermal extract on epidermis, but no effect on DNA synthesis. The G2 factor seems to be also present in small amounts in adjacent structures of epidermis and forestomach. This may be due to diffusion.No statistically significant inhibition of the mitotic count was found in any of the assay systems after i.p. injection of 5 mg of extracts made from lung, liver, kidney, spleen or striated muscle, respectively.The results support the hypothesis that squamous cell epithelia produce and contain inhibiting substances (chalones) which act specifically on the progenitor cells in keratinizing epithelia.Other possible mechanisms of action of the extracts are discussed.

Primary malignant lymphoma of the brain. A report of 24 cases from the Norwegian Radium Hospital.

Between 1975 and 1987, 24 patients with primary central nervous system lymphoma were seen and treated at the Norwegian Radium Hospital. The overall median survival was 24 months. Patients with poor performance status (WHO 3-4) had a median survival of 3 months whereas patients with good performance status (WHO 0-2) had a median survival of 40 months (p < 0.0001). Patients who were not steroid-dependent after operation had a better survival than those patients who were steroid-dependent (p = 0.02). Nine patients were still living without evidence of disease at last follow-up, 18-130 months after the initial treatment.

Combined intra-arterial chemotherapy followed by radiation in astrocytomas

SummarySeventy-five patients harboring astrocytomas received 4 cycles of infra-ophtalmic carotid injections of BCNU, combined with vincristine intravenously and procarbazine orally. All of the patients thereafter, received radiation therapy. The five year survival was 73% for all patients. The age of the patients had no significant impact on survival.The treatment results were compared with the results of 57 patients with astrocytomas who were treated with surgery followed by radiation in the same period. These 57 patients had a 5 year survival of 45% with a five year survival in patients >- 40 years and patients < 40 years of 70% and 22%, respectively (p < 0.05).In multivariate survival analysis of the BCNU group and radiation group together, treatment group and corticosteroid dependency were the only prognostic factors. No leukoencephalopathy was seen during the treatment or in the follow-up of the patients.We conclude that pre-radiation infra-arterial chemotherapy can be given without significant morbidity and produces an improvement in survival in patients older than 40 years.