Howard E. Rockette

A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum

PURPOSE: National Surgical Adjuvant Breast and Bowel Project Protocol R-03 was designed to determine the worth of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. METHODS: Thus far, 116 patients of an eventual 900 with primary operable rectal cancer have been randomized to receive multimodality therapy to begin preoperatively (59 patients) or identical therapy beginning after curative surgery (57). All patients received seven cycles of 5-fluorouracil (FU)/leucovorin (LV) chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In Cycles 2 and 3, FU and low-dose LV chemotherapy was given during the first and fifth week of radiation therapy (5,040 cGy). The preoperative arm (Group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (Group 2) received all radiation and chemotherapy after surgery. Primary study end points included disease-free survival and survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. RESULTS: Overall treatment-related toxicity was similar in both groups. Although seven preoperative patients had events after randomization that precluded surgery, eight events occurred during an equivalent follow-up period in the postoperative group. No patient was deemed inoperable because of progressive local disease. Sphincter-saving surgery was intended in 31 percent of Group 1 patients and 33 percent of Group 2 patients at the time of randomization. Such surgery was actually performed in 50 percent of the preoperatively treated patients and 33 percent of the postoperatively treated patients. The use of protective colostomy in patients undergoing sphincter-sparing surgery and the development of perioperative complications in all surgical patients were similar in both groups. There was evidence of tumor downstaging in evaluable patients under-going preoperative therapy, with 8 percent of Group 1 patients having had a pathologic complete response. CONCLUSION: These data do suggest that the preoperative chemotherapy and radiation therapy regimen used are, at least, as safe and tolerable as standard postoperative treatment. There is presently a trend to tumor downstaging and sphincter preservation in the preoperative arm. Whether this arm will have greater or lesser survival and long-term toxicity awaits the completion of this relevant study.

Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A Randomized, Placebo-phase Trial

OBJECTIVE To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients. METHODS Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ≥20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8. RESULTS Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial. CONCLUSION Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design.

Detection and significance of occult axillary node metastases in patients with invasive breast cancer.

Blocks of axillary lymph nodes from 78 patients with invasive breast cancer, which after “routine”pathological examination were regarded as negative for metastases, were step‐sectioned at 20 u intervals. Occult metastases were detected in 24% of the cases. A significant association between such metastases and a lack of or slight degree of an intraductal carcinomatous component of the dominant cancer was noted. There was no relationship between occult metastases and 15 other histopathological and 3 clinical features investigated, including an average 5 year survival rate. Similarly there was no correlation between any of the possible discriminants investigated in the 24% of patients who have died of their diseases or are living with recurrence regardless of the presence of occult metastases. Factors accounting for the lack of universal survival in patients with Stage I (and those with occult metastases that might be designated as Stage 1 1/2) remain enigmatic. It is concluded that attempts to detect occult metastases by extending histopathological methods may be more academic than practical or therapeutically significant. Cancer 42:2025–2031, 1978.

Treatment of Acute Otitis Media in Children under 2 Years of Age

BACKGROUND Recommendations vary regarding immediate antimicrobial treatment versus watchful waiting for children younger than 2 years of age with acute otitis media. METHODS We randomly assigned 291 children 6 to 23 months of age, with acute otitis media diagnosed with the use of stringent criteria, to receive amoxicillin-clavulanate or placebo for 10 days. We measured symptomatic response and rates of clinical failure. RESULTS Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7; among children who received placebo, 28% had initial resolution of symptoms by day 2, 54% by day 4, and 74% by day 7 (P=0.14 for the overall comparison). For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, as compared with 14%, 36%, and 53% with placebo (P=0.04 for the overall comparison). Mean symptom scores over the first 7 days were lower for the children treated with amoxicillin-clavulanate than for those who received placebo (P=0.02). The rate of clinical failure--defined as the persistence of signs of acute infection on otoscopic examination--was also lower among the children treated with amoxicillin-clavulanate than among those who received placebo: 4% versus 23% at or before the visit on day 4 or 5 (P<0.001) and 16% versus 51% at or before the visit on day 10 to 12 (P<0.001). Mastoiditis developed in one child who received placebo. Diarrhea and diaper-area dermatitis were more common among children who received amoxicillin-clavulanate. There were no significant changes in either group in the rates of nasopharyngeal colonization with nonsusceptible Streptococcus pneumoniae. CONCLUSIONS Among children 6 to 23 months of age with acute otitis media, treatment with amoxicillin-clavulanate for 10 days tended to reduce the time to resolution of symptoms and reduced the overall symptom burden and the rate of persistent signs of acute infection on otoscopic examination. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00377260.).

Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience.

Since 1971, 8,483 women with primary breast cancer participated in seven trials evaluating adjuvant chemotherapy. Leukemia occurred in only three of 2,068 patients treated by operation alone. The cumulative risk was 0.06% after 10 years in those free of metastases or a second primary tumor, and 0.27% in those with tumor. Thus, leukemia is not an important factor in the natural history of breast cancer. Five of 646 women receiving postoperative regional radiation developed leukemia, an overall risk of 1.39 +/- .49% at 10 years. Twenty-seven cases of leukemia (0.5%) and seven of myeloproliferative syndrome (0.1%) were recorded in 5,299 patients who received L-phenylalanine mustard (L-PAM)-containing regimens. The maximum cumulative risk of leukemia in chemotherapy recipients (leukemia of any type and myeloproliferative syndrome) was 1.68 +/- .33% at 10 years following operation. The risk excluding those with myeloproliferative syndrome was 1.29 +/- .28%. The risk of leukemia in patients free of metastases or a second primary was 1.11 +/- .30% at 10 years, and when combined with myeloproliferative syndrome, it was 1.54 +/- .36%; risks not significantly greater than observed following radiation (P = .58 and .29). No cases of leukemia were observed during the 2 years of chemotherapy and none have occurred after the seventh postoperative year. Comparisons with the surveillance, epidemiology, and end results tumor registries (SEER) data indicate an increased relative risk of acute myelogenous leukemia following postoperative regional radiation (P less than .01) and adjuvant chemotherapy (P less than .001). The findings indicate that hematologic disorders are side effects of both radiation and alkylating agents used in the adjuvant treatment of primary breast cancer. The risk of such events is lower than that reported following treatment of other solid tumors and hematologic malignancies by chemotherapy. The benefit from adjuvant chemotherapy for breast cancer exceeds the risk of leukemia. Since chemotherapy is not uniformly beneficial, efforts should be directed toward identifying responders so that only those who will benefit are exposed to the risk.

Effect of early or delayed insertion of tympanostomy tubes for persistent otitis media on developmental outcomes at the age of three years.

BACKGROUND A main indication for the insertion of tympanostomy tubes in infants and young children is persistent otitis media with effusion, reflecting concern that this condition may cause lasting impairments of speech, language, cognitive, and psychosocial development. However, evidence of such relations is inconclusive, and evidence is lacking that the insertion of tympanostomy tubes prevents developmental impairment. METHODS We enrolled 6350 healthy infants from 2 to 61 days of age and evaluated them regularly for middle-ear effusion. Before the age of three years 429 children with persistent effusion were randomly assigned to have tympanostomy tubes inserted either as soon as possible or up to nine months later if effusion persisted. In 402 of these children we assessed speech, language, cognition, and psychosocial development at the age of three years. RESULTS By the age of three years, 169 children in the early-treatment group (82 percent) and 66 children in the late-treatment group (34 percent) had received tympanostomy tubes. There were no significant differences between the early-treatment group and the late-treatment group at the age of three years in the mean (+/-SD) scores on the Number of Different Words test, a measure of word diversity (124+/-32 and 126+/-30, respectively); the Percentage of Consonants Correct-Revised test, a measure of speech-sound production (85+/-7 vs. 86+/-7); the General Cognitive Index of McCarthy Scales of Childrens Abilities (99+/-14 vs. 101+/-13); or on measures of receptive language, sentence length, grammatical complexity, parent-child stress, and behavior. CONCLUSIONS In children younger than three years of age who have persistent otitis media, prompt insertion of tympanostomy tubes does not measurably improve developmental outcomes at the age of three years.

Correlation of estrogen receptor and pathologic characteristics of invasive breast cancer.

Estrogen receptor (ER) status was correlated with a large number of pathological and clinical characteristics of 178 invasive breast cancers. Positive ER was found to be significantly associated with high nuclear and low histologic grades, absence of tumor necrosis, presence of marked tumor elastosis, and older patients. These pathologic parameters enumerated are either directly or indirectly related to tumor differentiation suggesting that ER represents another index of this latter. Multivariate analyses disclosed that both age and tumor differentiation are associated with the ER status. Well‐differentiated tumors were more frequently ER+ in older women. Inclusion of an estimate of tumor necrosis as well as patient age appears to allow for further discrimination of ER status in poorly differentiated lesions. Considerations relative to ER and tumor differentiation provide a possible explanation for the dichotomy of response to adjuvant chemotherapy observed in pre and postmenopausal women.

Pathologic findings from the national surgical adjuvant breast project (protocol no. 4). V. significance of axillary nodal micro- and macrometastases

Two‐hundred seventy eight of 565 patients treated by radical mastectomy for invasive breast cancer in a prospective, randomized clinical trial exhibited axillary nodal metastases. Patients in whom the largest nodal metastasis measured ≤2 mm in its greatest diameter were regarded as having micrometastases and those in whom the lesions were ≤2 mm as having macrometastases. Contingency table analysis disclosed that the group with macrometastases had a greater likelihood that they would be clinically assessed as stage II, their primary tumors would be ≤2 cm, they would have 4 or more positive nodes, extension of the metastasis through the nodal capsule would have occurred and uninvolved nodes would exhibit a germinal center predominance pattern. Life table analyses failed to reveal any significant difference in survival between patients with micrometastases and those without nodal metastases although both of these groups exhibited significantly greater survival than patients with macrometastases. On the other hand, treatment failure rates were more comparable in patients with micrometastases to those with macrometastases rather than absent nodal involvement. Multivariate analysis revealed that these apparent effects on survival and treatment failure rates in patients with micro and macrometastases were more directly related to the number of nodes involved with metastases rather than the size of the latter. A subset of patients with micrometastases in whom the metastases measured ≥1.3 mm was identified who exhibited survival and treatment failure rates similar to those of the negative node patients. The data, although based on a relatively small sample size, suggest metastases ≥1.3 mm may exert an influence independent of number of nodes involved. The excellent prognosis of patients with these occult nodal metastases (≥1.3 mm) warrants the designation of the stage of their disease as 1 1/2. Cancer 42:2032–2038, 1978.

Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial

To determine the efficacy of amoxicillin prophylaxis and of tympanostomy tube insertion in preventing recurrences of acute otitis media, we randomized 264 children 7 to 35 months of age who had a history of recurrent otitis media but were free of middle ear effusion to receive either amoxicillin prophylaxis, bilateral tympanostomy tube insertion or placebo. The average rate of new episodes per child year of either acute otitis media or otorrhea was 0.60 in the amoxicillin group, 1.08 in the placebo group and 1.02 in the tympanostomy tube group (amoxicillin vs. placebo, P < 0.001; tubes vs. placebo, P = 0.25). The average proportion of time with otitis media of any type was 10.0% in the amoxicillin group, 15.0% in the placebo group and 6.6% in the tympanostomy tube group (amoxicillin vs. placebo, P = 0.03; tubes vs. placebo, P < 0.001). At the 2-year end point, the rate of attrition was 42.2% in the amoxicillin group, 45.5% in the placebo group and 26.7% in the tympanostomy tube group. Adverse drug reactions occurred in 7.0% of the amoxicillin group and persistent tympanic membrane perforations developed in 3.9% of the tympanostomy tube group. The observed degree of efficacy of amoxicillin prophylaxis and of tympanostomy tube insertion must be viewed in light of the fact that study subjects proved not to have been at as high risk for acute otitis media as had been anticipated and in view of the differential attrition rates. We conclude that in the age group we studied, amoxicillin prophylaxis is the preferred first measure in attempting to prevent recurrences of acute otitis media and that tympanostomy tube insertion is a reasonble next alternative.

Risk Factors for Speech Delay of Unknown Origin in 3-Year-Old Children

One hundred 3-year-olds with speech delay of unknown origin and 539 same-age peers were compared with respect to 6 variables linked to speech disorders: male sex, family history of developmental communication disorder, low maternal education, low socioeconomic status (indexed by Medicaid health insurance), African American race, and prolonged otitis media. Abnormal hearing was also examined in a subset of 279 children who had at least 2 hearing evaluations between 6 and 18 months of age. Significant odds ratios were found only for low maternal education, male sex, and positive family history; a child with all 3 factors was 7.71 times as likely to have a speech delay as a child without any of these factors.