Combined modalities

In an attempt to reduce relapse rate and late toxicity, combined-modality therapy using lower doses of radiation and an abbreviated course of chemotherapy has been evaluated.16 The goal of decreased relapse rate has been achieved, but no overall survival benefit has been documented. A limitation of this approach is exposing patients to the additive toxicities of chemotherapy. Trials that have investigated this approach typically have incorporated between two and four cycles of a standard regimen for HL, such as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with involved-field radiation. At present, combined-modality therapy is considered to be a standard of care for stage I/II HL. 

For early-stage diffuse, aggressive NHL, combined-modality therapy was tested versus a longer course of chemotherapy.22 Overall survival favored the CHOP/radiation arm for 5 years (82% versus 72%). There was a trend toward increased toxicity, particularly hematologic and cardiac toxicity, in the CHOP alone arm. The results of this trial have established combined-modality therapy as first-line treatment for early-stage NHL. Unique presentations of NHL, such as CNS primary disease, may incorporate radiation into treatment algorithms.23... 

SCLC is very radiosensitive. Radiotherapy has been combined with chemotherapy to treat limited disease SCLC. This combined-modality therapy prevents local tumor recurrences but only modestly improves survival over chemotherapy alone. 

Treatment options include radiation therapy, chemotherapy, or both (combined-modality therapy). The therapeutic role of surgery is limited, regardless of stage. 

Although the delivery of radiation and chemotherapy as sole modalities is definitely more complex than outlined above, there needs to be guiding principles that will allow for their successful integration in combined modality therapy. Peckham and Steele introduced several key concepts that govern the interactions of both radiation and chemotherapy when they are administered together in an attempt to improve the therapeutic effect of their separate administrations (27). 

Toxicity independence definitely emerges as a real concern in the planning of combined modality therapy. As originally outlined, if two partially effective agents can be combined without having to alter their levels substantially, an improved therapeutic... 

The evidence presented earlier, on the effects of combined modality therapy in carcinoma of the anal canal, may exploit to some extent the properties of mitomycin C as a hypoxic cell cytotoxin. This strategy remains valid, as many human tumors are less well oxygenated than the tissues from which they arose. The literature suggests that not only are these hypoxic tumors more difficult to control locally with therapy but that they may possess a more malignant phenotype with a higher propensity for distant spread. Tirapazamine is a drug developed and introduced into the clinic for its ability to target... 

UFT was studied in combination with radiation therapy in patients with locally advanced, inoperable gastric carcinoma. Tsukiyama et al. (66) evaluated combined modality therapy (CMT) consisting of UFT and mitomycin-C administered together with radiation therapy, and reported local control in 70% of patients with advanced inoperable gastric cancer. 

The results of the intergroup trial compound the concept of radiosensitization, since a lower dose of radiation in the combined-modality group improved local control compared with the radiation-alone group. The chemotherapy also decreased the risk of micrometastasis. Despite the better outcome with chemoradiotherapy, the overall prognosis of these patients remains poor. No randomized trials comparing chemoradiotherapy with esophagectomy have been performed it seems that chemoradiotherapy provides a reasonable alternative to esophagectomy in selected patients. 

Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 1988 80 751-755. 

The Role of Platinum Complexes in Combined Modality Therapy... 

The initial combination modality clinical studies with cisplatin and fractionated radiation therapy was carried out in head and neck cancer with weekly cisplatin (120-160 mg/m2) and conventional single daily fraction radiation (95). In a follow-up intergroup study, patients were randomized to radiation therapy alone or to radiation therapy plus 20 mg/ m2/wk cisplatin (96). Both studies showed no major increase in normal tissue toxicity in the radiation field and showed an increase in response rate. There was no increase in complete response rate or in survival. Bachaud et al.(97) carried out a randomized study comparing radiation therapy alone with concurrent cisplatin (50 mg/m2) and radiation therapy in postoperative patients. This trial produced a significant reduction in local recurrence and improved disease-free survival with 59% of the patients receiving the full planned dose of cisplatin. 

Weirberg A, Yashar J, Posner M, et al. Combined modality therapy for stage Ilia non-small cell carcinoma of the lung. ProcAmer Soc Clin Oncol 1992 11 293. 

Socinski et al. have reported on their phase I/II experience with dose-escalated thoracic radiation in the setting of a combined modality approach to locally advanced NSCLC (55,64). Two cycles of carboplatin and paclitaxel (AUC 6 and 225 mg/m2/3h q21d) were followed on d 43 by weekly carboplatin and paclitaxel (AUC 2 and 45 mg/ m2/3h x 6) and thoracic radiotherapy (TRT), 50 Gy was delivered to the prechemotherapy tumor volume and areas of suspected microscopic spread in the mediastinum with a 1.0-2.0 cm margin. Boost volumes included the primary tumor volume and all radiographically positive nodes with a 1.0 cm margin. The total dose of radiation was escalated through four cohorts of patients 60,66,70,74 Gy without reaching any of the planned toxicity endpoints. The overall response to the therapy was 50% (3% CR, 47%... 

Within the multiple subsites of this tumor grouping, most work has been done in esophageal cancer. The large majority of these patients have been treated with paclitaxel in combination with radiation (Table 3). The experience with docetaxel is essentially limited to patients treated on phase I trials for thoracic malignancies that used radiation in combination with docetaxel (68,111). The situation is much the same for both pancreatic and gastric cancers as well. The rationale for looking at combination therapy that incorporates paclitaxel is much the same as in other disease sites, i.e., its activity in systemic disease (112), its potent preclinical radiosensitizing properties (38), and evidence from randomized trials that there is a benefit to combined modality therapy that includes at least radiation and chemotherapy (113-116). 

The initial experience with the taxanes and especially with paclitaxel in the realm of combined modality therapy has had a substantial impact on the treatment of cancers both in the United States and worldwide. Paclitaxel delivered in concert with radiation provides a classical model of the development of clinically applicable treatment strategies from laboratory-based studies. The initial in vitro works of Tishler (39) and Choy (40) have translated in a very tangible way into approaches that are clinically applicable and in the next generation of randomized clinical trials their efficacy will be compared to more traditional chemotherapies in the combined modality setting. While the experience to date with both paclitaxel and docetaxel has been largely positive, the mortality rates in many of the solid tumor types remind us that much more needs to be done. 

Choy H. Taxanes in combined modality therapy for solid tumors. Crit Rev Oncol Hematol 2001 37(3) 237-247. 

Choy H, LaPorte K, Knill-Selby E, et al. Esophagitis in combined modality therapy for locally advanced non-small cell lung cancer. Semin Radiat Oncol 1999 9(2 Suppl l) 90-96. 

Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993 ll(2) 336-344. 

Burmeister BH, Denham JW, O Brien M, et al. Combined modality therapy for esophageal carcinoma preliminary results from a large Australasian multicenter study. Int J Radiat Oncol Biol Phys 1995 32(4) 997-1006. 

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