Lynda R. Mandell

The role of postoperative radiotherapy after resection of single brain metastases

To assess the value of whole brain radiotherapy (WBRT) after complete resection of a single brain metastasis we reviewed the records of 98 patients who had elective craniotomy between 1978 and 1985. Seventy-nine patients received postoperative WBRT (Group A) and 19 patients no radiotherapy (RT) (Group B). Neurological relapse was designated as local (i.e., at the site of the original metastasis) or distant (i.e., elsewhere in the brain). Postoperative WBRT significantly prolonged the time to any neurological relapse (P = 0.034) with a 1-year recurrence rate of 22% in Group A and 46% in Group B patients; however, it did not specifically control either local or distant cerebral recurrence. Recurrence of metastatic brain disease was not affected by location of the original lesion; however, meningeal relapse occurred in 38% of cerebellar lesions, but only in 4.7% of supratentorial metastases (P = 0.003). The total radiation dose or fractionation scheme of RT did not affect survival nor time to neurological relapse. The median survival was 20.6 and 14.4 months for Groups A and B, respectively (not statistically different). Forty-eight percent of Group A and 47% of Group B patients survived for 1 year or longer; however, 11% of patients who had received RT and survived 1 year developed severe radiation-induced dementia. All patients with radiation-related cerebral damage received hypo-fractionated RT with high daily fractions as commonly designed for rapid palliation of macroscopic brain metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

The treatment of single brain metastasis from non‐oat cell lung: Carcinoma surgery and radiation. Versus radiation therapy alone

Between 1978–1980, 104 patients with single brain metastases (SBM) from non‐small cell lung carcinoma (NSCLC) were treated at Memorial Sloan‐Kettering Cancer Center (MSKCC). These included 35 patients treated with surgical resection and radiation (S + ERT) and 69 patients treated with conventional external beam radiation therapy alone (ERT). Surgical resection was combined with whole brain (WBRT) and focal radiation in 83% and 17% of patients, respectively. In the ERT group, all patients received WBRT. Both treatment groups were similar with regard to age, sex, stage distribution, location and size of SBM, and time to relapse from initial diagnosis of NSCLC. The histologic examination, however, revealed adenocarcinoma predominating in those patients receiving S + ERT and epidermoid carcinoma in those receiving ERT. Follow‐up treatment, symptomatic, and CTT response rates were evaluated. With S + ERT, the overall subjective and objective responses were 80% and 87%, respectively, and with ERT, 83% and 72% (of the 47 patients available for follow‐up CT scans), respectively. Survival data indicate a significant advantage of S + ERT over ERT with a median survival of 16 months versus 4 months (P < 0.0001). Three major factors, however, may have contributed to this difference: (1) patients in the S + ERT group generally received more aggressive initial treatment to the primary disease in the lung (72%) compared to the ERT group (36%); (2) in the S + ERT group, extracranial disease was absent at the time of SBM diagnosis in 49% of the S + ERT group compared to 26% in the ERT group; and (3) distant metastases were present in only 6% of the surgical patients yet, they were present in 49% of those treated with radiation alone. In one subset of patients, however—those with a radically treated primary and no extracranial disease—S + ERT resulted in a median survival of 33 months with 33% of the population still alive with no evidence of disease compared to 12 months and 0%, respectively, with ERT alone. Moreover, intracranial relapse was the cause of death in only one S + ERT patient (9%), yet it accounted for 50% of the ERT deaths. These data suggest that an aggressive approach to SBM in such favorable prognostic patients may indeed improve survival. Cancer 58:641‐649, 1986.

RECURRENT STAGE I ENDOMETRIAL CARCINOMA: RESULTS OF TREATMENT AND PROGNOSTIC FACTORS

Recurrences of clinical Stage I endometrial carcinoma after initial treatment are rare. They are nonetheless a serious complication, uniformly associated with poor survival outcome. Between 1969-1980, 20 patients with clinical Stage I endometrial carcinoma were treated for recurrent tumor at the time of first relapse. Nonpapillary adenocarcinoma represented 70% of the primary tumors (pure adenocarcinoma, 50%; adenosquamous, 15%, clear cell, 5%) and papillary adenocarcinoma, 30%. The most common presenting symptom was vaginal bleeding, occurring in 95% of patients. The median time to recurrence after completion of primary treatment was 9.5 mo: Adenocarcinoma relapsed at a median time of 33 mo, adenosquamous, 6 mo and papillary adenocarcinoma, 4 mo. The vagina was the site of relapse in 65% of patients, the abdomen in 20%, the pelvis in 10% and the lung in 5%. Ninety-five percent of recurrences were treated with curative intent. Complications were seen in three patients, small bowel obstruction (2 pts) and vaginal vault necrosis (1 pt); however, these patients responded effectively to conservative treatment. Minimum follow-up of 4 years was available in 18 pts (90%). Actuarial 4 yr overall and NED survival was 50%, respectively, with a median survival of 39 mo to date. There have been no deaths from further recurrence of endometrial cancer beyond 39 mo. Significant prognostic factors for 4 year survival were 1) recurrence site--vagina, 82% (9/11 pts) vs extravagina, 0% (0/7 pts; median survival: 8 mo) [p = .0001]; and 2) histologic cell type--non-papillary carcinoma, 75% (9/12 pts) vs papillary adenocarcinoma, 0% (0/6 pts; median survival: 8 mo) [p = .002]. Our review suggests that: (1) Histology and site of relapse are important prognosticators of treatment outcome; (2) Long term survival may be achieved in vaginal recurrences with aggressive local treatment; and (3) There may be a role for multimodality ovarian type treatment in overall management of recurrent papillary adenocarcinoma, a cell type that appears to exhibit a tendency towards extrapelvic spread refractory to definitive loco-regional treatment.

Factors predictive of mortality in pediatric extremity rhabdomyosarcoma

In order to examine factors predictive of fatal outcome in children presenting with histologically confirmed extremity rhabdomyosarcoma, we performed a retrospective analysis of our institutional experience from 1970 to 1985. Thirty-five patients were identified and staged according to international criteria (TNM). Variables evaluated for their predictive effect on fatal outcome included (1) tumor invasiveness, (2) tumor size, (3) anatomic location of the primary, (4) regional lymph node involvement, (5) distant metastases at presentation, (6) complete surgical resection, (7) use of amputation, and (8) alveolar histologic subtype. Significant predictors of mortality included (1) tumor invasiveness (P less than or equal to .0001), (2) regional node involvement (P less than or equal to .0002), (3) distant metastases at the time of presentation (P less than or equal to .001), (4) alveolar histology (P less than or equal to .001), (5) size of primary (P less than or equal to .007), and (6) completeness of surgical resection (P less than or equal to .05). In multivariate analysis, local tumor invasiveness was the most important predictor of fatal outcome with an associated relative risk of 18. We conclude that local tumor invasiveness is the most important determinant of clinical stage.

Reduced incidence of the somnolence syndrome in leukemic children with steroid coverage during prophylactic cranial radiation therapy. Results of a pilot study.

Chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL) include a remission induction period with high, daily doses of prednisone among other agents. A period of central nervous system (CNS) prophylaxis follows, during which steroids are often tapered entirely before cranial radiation (CRT) is completed or even initiated. The somnolence syndrome (SS) has been described 4 to 6 weeks after completion of CRT in up to 60% of the children with doses as low as 1800 cGy. A pilot study of continuous steroid coverage during CRT in childhood ALL was conducted. From July 1984 to July 1986, 38 children entered on Children Cancer Study Group ALL protocols received CRT of 1800 cGy (180 cGy × 10). All patients received oral prednisone throughout the entire course of CRT at daily doses varying from 3.0 to 60.0 mg/m2. The overall incidence of the SS was 13% (five patients). The development of the syndrome was steroid dose‐dependent: ⩾ mg/m2/d (one of 32 patients), 3% incidence; < 15 mg/m2 (four of six patients), 67% incidence. The presence of headache during CRT was also steroid dose‐related: > ⩾ mg/m2, one of 32 patients; < 15 mg/m2, six of six patients. Of the seven patients with headache during CRT, five developed the SS. The two patients (both of the < 15 mg/m2 group) who did not develop the SS were the only cases treated with increased steroid doses at the onset of headache symptoms. Steroid coverage at a dose of ⩾ mg/m2 during CRT appears to significantly reduce the incidence of acute radiation reactions and the SS. A prospective randomized study is planned to confirm these initial findings.

Postoperative vaginal radiation in endometrial cancer using a remote afterloading technique

Carcinoma of the endometrium is the most common malignancy of the female genital tract. In early stage endometrial cancer, surgery remains the primary mode of treatment while radiation therapy plays an adjuvant role. Prophylactic vaginal radiation has been shown to reduce significantly the incidence of vaginal recurrences. Between the years 1969-1976, 330 patients with FIGO Stages I and II endometrial cancer were treated according to a standard departmental policy in which 40 Gy of external radiation was given to high risk Stage I and all Stage II patients in combination with surgery and intravaginal radiation. Stage I was considered high risk if the tumor was of high grade or exhibited deep myometrial invasion. Vault radiation was delivered with a remote afterloading technique to a point .5 cm from the surface of the applicator; a total dose of 21 Gy was delivered in three fractions spaced two weeks apart over four elapsed weeks. With this regimen, the mucosal surface received a total equivalent dose of 40 Gy. These treatments were given on an outpatient basis without the need for any sedation or analgesics. All patients, regardless of stage, grade, or depth of myometrial invasion received adjuvant post-operative vaginal radiation. The minimum follow-up was 5 years, with a median follow-up of 8.5 years. The overall pelvic and/or vaginal recurrence rate was 2.7%. The incidence of vaginal complications was 3.7%. It appears that the remote afterloading treatment (RAT) for vaginal radiation is a very cost-effective therapeutic alternative, which produces minimal early or late complications and gives complete protection from radiation exposure to the medical staff. The advantages of a remote afterloading technique in delivering vaginal vault radiation in endometrial cancer are discussed in this paper.

PRELIMINARY RESULTS OF ALTERNATING COMBINATION CHEMOTHERAPY (CT) AND HYPERFRACTIONATED RADIOTHERAPY (HART) IN ADVANCED RHABDOMYOSARCOMA (RMS)

In an attempt to reduce treatment (Rx) related acute toxicity and improve protocol compliance without compromising local control nor overall survival, a Phase II single arm pilot employing alternating intensive multiagent CT and radiotherapy (RT) in children with gross residual or metastatic RMS was begun at Memorial Sloan-Kettering Cancer Center (MSKCC) in 1984. Hyperfractionated radiotherapy (HART) was adopted to allow for timely delivery of both the RT and CT. From July, 1984 through July, 1986 12 patients (pts), aged 2 to 23 yr (median 10 yr) were enrolled on study. CT treatment was delivered over approximately 14 months and included 2 induction and 5 maintenance cycles. The induction CT consisted of two repetitive cycles of Vincristine, Dactinomycin, Cyclophosphamide, Adriamycin, Bleomycin, and Methotrexate; the maintenance CT included the same agents as reduced drug doses. The HART was delivered to the primary site during cycle I of induction at fractions of 150 cGy BID to a total dose of 5400 cGy in 2 courses of 3000 cGy and 2400 cGy, respectively. One hundred percent of patients completed the recommended dose of HART; 0% required unplanned interruptions of HART due to treatment toxicity. With a median follow-up (f/u) from diagnosis of surviving patients of 25 months (range 20-30), the local control rate is 83% (10/12 pts) and the overall survival, 58% (7/12 pts). The median time (MT) to any failure, local or metastatic, is 9 months (mo); and to death, 14 mo. Comparison of results with 12 historical controls with concomitant split-course standard fractionation RT (180-200 cGy/per fraction) and T6 CT during a MSKCC trial from 1975-1984, matched by site and stage of primary, revealed that 9 pts (75%) completed the recommended dose of RT, and 7 pts (58%) required interruptions of RT. With a median f/u of 78 mo (range 34-109), the local control rate was 75% (9/12 pts) and the overall survival, 42% (5/12 pts). The MT to any failure was 14 mo; and to death, 18 mo. These results indicate that the mode of alternating CT and HART (HART T6) as employed in this pilot study is well tolerated. It appears to offer a significant improvement in protocol compliance over previous protocols using concomitant CT and RT without any apparent compromise in local primary control or survival rates with a median f/u suggestive of adequate elapsed time for the appearance of most relapses and deaths in advanced RMS.

Primary nasal-paranasal oropharyngeal lymphoma in the pediatric age group.

Nasal‐paranasal oropharyngeal (NPOP) non‐Hodgkins lymphoma (NHL) is a disease of the very young (median age, 5 years) and of the aging adult (median age, 50‐60 years). Of a total of 208 pediatric patients with NHL studied, 20 (9.6%) had primary NPOP. Sixty percent of the patients had Stage I and II disease. Primary sites were maxillary sinus in eight patients; tonsils in eight; posterior pharynx in two; mandible in one; and orbit in one patient. Histologically, the disease is different than that of the adults since most patients had B‐cell lymphomas of the diffuse undifferentiated type (Rappaport) or small cell non‐cleaved types (Lukes‐Collins, Kiel, and Working Formulation). None of these patients had gastrointestinal involvement. All patients were treated with the LSA2‐L2 regimen and radiation therapy was given to primary unresectable tumors and regional metastases. The lymphoma event‐free survival was 75%, with a median observation period of 99+ months. In staging systems that refer mostly to amount of disease outside of the primary (such as ours, Murphys, and the Ann Arbor staging systems) stage did not correlate well with disease‐free survival. In the TNM staging of 1977, a staging system that refers to size of primary tumor as well as regional and systemic disease, stage correlated better with prognosis and survival. In our staging system, eight of 12 patients (66.7%) with Stage I and II disease; four of four with Stage III; two of two with Stage IVA; and zero of two with Stage IVB survived. In the TNM staging system, three of three patients with Stage II and III disease and 12 of 18 patients (67%) with Stage IV disease survived. All recurrences occurred early suggesting that early intensification of chemotherapy may produce better results.

Mortality in Pediatric Paratesticular Rhabdomyosarcoma: A Multivariate Analysis

We performed a retrospective analysis of 28 children presenting with confirmed paratesticular embryonal rhabdomyosarcoma to examine factors predictive of fatal outcome. Complete surgery, defined as radical inguinal orchiectomy with clear microscopic margins plus radical, retroperitoneal lymph node dissection with extirpation of all gross disease, was performed in 21 patients (75 per cent). All patients received chemotherapy and 20 received radiation therapy according to protocol. Of the patients 16 have survived for more than 5 years with no evidence of disease. Univariate analysis revealed that only the presence of parenchymal metastases at diagnosis (p less than or equal to 0.040) and unresectability (p less than or equal to 0.003) were significant predictors of fatal outcome. Multivariate analysis showed that unresectability was the most important predictor of mortality with an estimated relative risk of 5.8.

The influence of extensive bone erosion on local control in non-orbital rhabdomyosarcoma of the head and neck

To investigate a recent report suggesting extensive bone erosion (EBE) as an important prognostic factor in head and neck rhabdomyosarcoma, a retrospective review was performed of 32 patients with gross residual and/or metastatic non-orbital head and neck rhabdomyosarcoma treated between the years 1971-1987. Treatment consisted of surgery, radiation therapy (median primary dose, 5000 cGy) and combination chemotherapy according to the Memorial Sloan-Kettering Cancer Center (MSKCC) T2 and T6 protocols. The MSKCC staging system was used: Stage II, 23 patients; Stage III, 6 patients; and Stage IV, 3 patients. With a median follow-up of 48 months (range 17 months to 13 years), the overall survival and local control rates were 72% (23/32) and 75% (24/32), respectively. Local control was achieved in 11/11 patients without extensive bone erosion (Stages II, 9/9; III, 1/1; IV, 1/1) as compared to 13/21 patients (Stages II, 10/14; III, 2/5; IV, 1/2) with extensive bone erosion (p = 0.02). Our data appear to support the recently reported finding that extensive bone erosion is an important predictor of local failure.