Franco Milani

Improved five year survival after combined radiotherapy-chemotherapy for stage I-II non-hodgkin's lymphoma

Abstract In order to improve the prognosis of patients with localized non-Hodgkins lymphomas (NHL) who are treated with radiotherapy (RT), a prospective controlled study utilizing a combined modality approach was carried out in patients with pathologic Stage 1[-II NHL. After treatment with regional RT, patients in complete remission were randomized to receive either no further therapy or 6 cycles of cyclophosphamide, vincristine and prednisolone (CVP). At 5 years from completion of irradiation, the relapse-free survival was 46.3% after RT and 72.1% after RT plus CVP ( P = 0.005). The corresponding findings for the overall survival calculated from the beginning of irradiation were 55.8 and 82.8% respectively ( P = 0.03). The favorable effects of adjuvant chemotherapy on relapse-free survival were statistically significant only in the subgroup with diffuse histology. In patients who relapsed after RT alone, the salvage therapy failed to induce a high incidence of second durable remission. Adjuvant chemotherapy is indicated to improve the cure rate in pathologic stage I-II NHL with diffuse histology when regional RT is utilized.

Radiotherapy-induced ear toxicity

Despite their particular functional consequences, radiotherapy-induced ear injuries remain under-evaluated and under-reported. These reactions may have acute or late character, may affect all structures of the hearing organ, and result in conductive, sensorineural or mixed hearing loss. Up to 40% of patients have acute middle ear side effects during radical irradiation including acoustic structures and about one-third of patients develop late sensorineural hearing loss (SNHL). Total radiotherapy dose and tumour site seem to be among the most important factors associated with the risk of hearing impairment. Thus, reduction in radiation dose to the auditory structures should be attempted whenever possible. New radiotherapy techniques (3-dimensional conformal irradiation, intensity modulated radiotherapy, proton therapy) allow better dose distribution with lower dose to the non-target organs. Treatment of acute and late external otitis is mainly conservative and includes the anti-inflammatory agents (applied topically and systematically). Post-radiation chronic otitis media and the eustachian tube pathology may be managed with tympanic membrane incision with insertion of a tympanostomy tube (grommet), although the benefit of such approach is controversial and some authors advocate a more conservative approach. In these patients the functional deficit can be alleviated by application of bone conduction hearing aids such as, e.g., the bone anchored hearing aid (BAHA). There is no standard therapy for post-irradiation sudden or progressive SNHL yet corticosteroid therapy, rheologic medications, hyperbaric oxygen or carbogen therapy are usually employed (as for idiopathic SNHL), although controversial data on the efficacy of these treatment modalities have been published. In selected cases with bilateral profound hearing loss or total deafness, cochlear implants may prove effective. Further improvements in radiotherapy techniques and progress in otologic diagnostics and therapy may allow better prevention and management of radiation-related acoustic injury.

Malignant Lymphomas of Waldeyer's Ring: Natural History and Survival after Radiotherapy

The natural history of 292 consecutive cases of reticulum cell sarcoma and lymphosarcoma of Waldeyers ring and the survival rate after radiotherapy are reported. In our institute since 1928 from 30 to 35% of pharyngeal neoplasms have been lymphomas, and of these 55% have been reticulum cell sarcomas, 21% lymphosarcomas, and 1% Hodgkins disease. This high incidence may probably be ascribed to the fact that in all malignant lymphomas, irrespective of the clinical presentation, a systematic biopsy of the whole Waldeyers ring was carried out. Pharyngeal lymphomas were confined to Waldeyers ring in 19·6% of cases, with initial spread to contiguous cervical nodes in 43·8%, to distant nodes in 24·2%, and to extranodal tissues in 12·4%. Lymphography showed abnormal retroperitoneal lymph nodes in 38·3% of cases. There was gastrointestinal involvement either initially or later in 17·6% of cases. High-energy radiation therapy to both sides of the neck was the treatment of choice for local and regional disease. It achieved a five-year survival rate of 41·9% in the group of 97 patients treated during the past decade. The incidence of relapse (recurrence and new manifestations) was highest in the first year after treatment.

Prolonged venous infusion of cisplatin and concurrent radiation therapy for lung carcinoma. A feasibility study

Fifty patients with non resectable and/or inoperable bronchogenic carcinoma were entered into a feasibility study of cisplatin (CDDP) given in continuous infusion with concurrent radiation therapy. The radiation therapy regimen consisted of 2 Gy given 5 days a week in the first 3 and last 2 weeks of a 7‐week split course (50 Gy of total dose). The CDDP (daily dose of 4 to 6 mg/m2) was administered to cover the days of radiation treatment by means of a central venous catheter and a portable pump. Less than 1% of predicted duration of infusion was lost due to complications related to venous access and pump. Toxicity was moderate. The overall probability of a locoregional major response (complete + partial) within 1 month after treatment completion was 86%. Twenty‐three patients underwent resection. The 1‐year actuarial probability of survival was 64%. The high response and survival rates warrant further studies on concurrent CDDP continuous infusion and radiation therapy in inoperable lung carcinoma.

Preoperative concomitant cisplatin/VP16 and radiotherapy in stage III non-small cell lung cancer

PURPOSE To evaluate the therapeutic effectiveness of a combined chemoradiotherapy program, followed by surgery in selected cases, in Stage III non-small cell lung cancer. METHODS AND MATERIALS Between August 1988 and February 1990, 43 patients Staged IIIa-b (UICC 1987, 58% IIIb) have been treated with concomitant chemotherapy (cisplatin 15 mg/m2 and VP16 75 mg/m2, 5 days a week on week 1 and 5) and radiotherapy (40 Gy split course, 2 Gy/day on week 1, 2, 5, and 6), followed by attempted curative thoracotomy or more cycles of full dose chemotherapy with the same two drugs. RESULTS Planned chemoradiotherapy has been given to 91% of patients; 13/43 patients have been operated, with 12 complete resections and three (7%) pathological complete responses. Toxicity was significant, with two postoperative deaths and two fatal radiation pneumonitis. Crude progression-free survival rate is 21% at 30 months, with nine patients (21%) alive and free from progression at follow-up times ranging from 31 to 49 months. Subset survival analysis showed a possibly greater therapeutic effect for non-squamous histology as compared to squamous carcinoma. CONCLUSION These results are encouraging in a cohort of patients with quite advanced disease (58% Stage IIIb).

Laser Microsurgery for Superficial TI–T2 Basal Cell Carcinoma of the Eyelid Margins

BACKGROUND Basal cell carcinoma (BCC), the most common malignancy of the eyelid margins, poses therapeutic problems. Surgery, radiation therapy, and cryotherapy are the currently accepted methods for the treatment of this affliction. To verify the technical and clinical effectiveness of the surgical laser method, a specific approach was developed by performing laser-combined procedures under microscopic control. METHODS A series of 26 patients underwent carbon dioxide (CO2) laser microsurgical excision of 27 primary superficial BCCs of the eyelid margins. Eighteen tumors were T1 and 9 were T2. The lesions were located at the lid margins in 18 and at the canthus in 9 cases. The eyelash line was involved in all cases, whereas intermarginal space was involved in 17 cases, without extension to the conjunctival border. Six lesions were in the lacrimal region. Median linear extent of the lesion was 5 mm (range, 4-10 mm). Treatment was performed with the patient under local anesthesia in a Day Hospital regimen. The authors used the microscope-mounted CO2 laser as a scalpel to excise the tumor mass, thus obtaining the specimen for histologic evaluation. The authors treated the deep and lateral resection margins with laser vaporization and left the wound bed to heal by secondary intention. RESULTS No significant complications were observed. As full-thickness eyelid resections were avoided, the authors noted conservation of lid function and cosmetic aspect in all patients. With a median follow-up of 73 months (range, 18-118), only one patient had tumor recurrence after 22 months. This tumor, located at the outer canthus, had a second microsurgical laser excision, and the patient is disease free 51 months after the last treatment. CONCLUSIONS Laser microsurgery appears to be a safe and effective treatment method for primary superficial T1 and T2 BCC of the eyelid margins without conjunctival extension.

Assessment of carotid artery dose in the treatment of nasopharyngeal cancer with IMRT versus conventional radiotherapy

PURPOSE To determine the radiation dose to the carotid artery in nasopharyngeal cancer patients treated with intensity-modulated radiotherapy (IMRT) and to compare it to the dose delivered by a conventional three-field (3F) technique. MATERIALS AND METHODS Sixteen patients with nasopharyngeal cancer who were treated at UCSF with IMRT were selected for this analysis. 3F plans were reconstructed for comparison. The carotid arteries were retrospectively contoured, and the dose received by each of the 32 carotid arteries was determined for both IMRT and 3F plans. A subset of 8 patients with N0/N1 nodal disease was selected for IMRT replanning using additional constraints to reduce the dose to the arteries. RESULTS Using the standard prescription doses for IMRT and 3F plans, the dose delivered to 95% of the tumor volume was significantly higher in the IMRT plans, reflecting the greater conformality of this technique. The median mean dose to the carotid arteries was 65.7Gy with IMRT vs. 58.4Gy with 3F (p<0.001). After the application of dose constraints to the carotid arteries, it was possible to reduce the mean carotid dose to 54Gy in the IMRT replans. CONCLUSIONS IMRT achieves a higher tumoricidal dose and superior clinical target volume coverage, but results in an increase in the carotid artery dose as compared to conventional 3F technique. With careful IMRT planning, it is possible to constrain the carotid dose for a subset of patients with low-risk neck disease. Further study is necessary to quantify the long-term clinical impact of this intervention.

Determination of platinum in plasma of patients affected by inoperable lung carcinoma treated with radiotherapy and concurrent low-dose continuous infusion ofcis-dichlorodiammine platinum(II)

Platinum microquantities were determined in plasma of patients affected by lung carcinoma during treatment with radiotherapy (RT) and concurrent low-dose continuous infusion ofcis-dichlorodiammineplatinum(II) (CDDP). RT was given at 50 Gy in continuous course; CDDP was continuously infused at 4 mg/m2 daily for 100h/week for 5 weeks, and the infusions were separated by 68h of rest. The percentage of free drug versus total drug in plasma was about 3%. It did not vary with therapy duration and was not significantly different from that found in 5-day continuous infusions at much higher daily doses. Never-theless, maximal values of free Pt in plasma were very low and agreed with the low level of CDDP toxicity encountered on the present administration schedule.

Preferential sites and methods of diffusion of malignant lymph nodes studied on the basis of 500 cases

The preferential sites and mode of spread in 500 consecutive untreated patients with malignant lymphomas (200 Hodgkins diseases, 150 lymphosarcomas and 150 reticulum cell sarcomas) have been studied. After a detailed diagnosis all patients with primary involvement of lymph nodes and spleen were staged according to the international four-stage clinical classification proposed at Rye in 1965. The lymphoreticular sarcomas with primary onset in Waldeyers ring were staged according to the T.N.M. classification as modified in Milano by the National Cancer Institute in 1965. Patients with involvement of viscera or tissues without apparent disease in the lymph nodes, spleen or pharynx were listed separately. Primary involvement in Hodgkins disease was confined in 99.5 % to lymph nodes and spleen. In lymphosarcoma and in reticulum cell sarcoma there was a high primary involvement of Waldeyers ring (20 % and 53 % respectively) and in other extranodal sites (11–12%). Besides the cervical regions the distribution of lymph node involvement in Hodgkins disease was predominantly in the mediastinum (20%) and in the paraaortic area (20%), while in lymphoreticular sarcomas mainly in the axillary (16%), iliac (23%) and inguinal (17%) regions. In the lymphoreticular sarcomas with primary onset in Waldeyers ring the disease on first admission was limited to the pharynx and to the neek nodes in 73 % of cases. Study of the mode of spread showed that in untreated Hodgkins disease the number of cases with contiguous involvement was 66 % while in lymphoreticular sarcomas it was only 35 %. Further, after localized radiation therapy Hodgkins disease has a higher (72%) tendency to recur in adjacent lymphoid regions than lymphoreticular sarcomas with primary involvement in nodes and spleen (45%). The therapeutic implications of this study are discussed. The most important conclusion is that prophylactic irradiation should be given to localized Hodgkins disease and not to lymphoreticular sarcomas with the exception of those arising in Waldeyers ring.

Non-resectable Stage IIIa-b lung carcinoma: a Phase II study on continuous infusion of cisplatin and concurrent radiotherapy (plus adjuvant surgery)

Thirty-eight patients with non-resectable non-small-cell Stage IIIa-b lung cancer were treated in a Phase II study with radiotherapy (50 Gy in a 25-fraction split-course) plus con-current continuous infusion of cisplatin given at a daily dose of 6 mg/m2, with the aim of investigating its radiopotentiation properties. Treatments were given on an outpatient basis by means of a central venous catheter and a portable pump. Adjuvant surgery was undertaken when feasible. Toxicity was mild to moderate. The probability of a partial or complete locoregional response at 4 weeks after treatment completion was 83% (confidence limits at 95%: 13). Eighteen patients were resected. Overall 1-, 2- and 3-year progression-free survival probabilities were 42, 24 and 21%. These figures were 63, 37 and 24% in observed survival curves. Patients with squamous-cell tumors had observed survival rates of 82, 50 and 28% at 1, 2 and 3 years, compared to 42, 19 and 19% in patients with non-squamous histology. The high response and survival rates obtained at a low price according to toxicity require further investigation.