Radiation Oncology Synopsis

Advanced Head and Neck Cancers

Radiobiology, Fraction Schemes and Related Studies

Radiobiologic concepts have led to the investigation of new classes of fractionation schemes: hyperfractionation and accelerated fractionation.

RTOG 9003 Compared Leading Fractionation Schemes for Head and Neck Cancer Sites

This study looked at:

This study include OP, OC, hypopharynx and supraglottinc larynx Stage III or Stage II if hypopharyx, or base of tongue.

DCB (54.5%) and HF (54.4%) arms (delayed concomitant boost and hypofractionated arms) demonstrated significantly better 2 year local-regional control compared to conventional fractionation.

Scheme LRC-2 years Disease Free Survival Grade 3/4 Toxicity
Conventional Fractionation 46% 31.7% 35%
Delayed Concommitant Boost 54.5% 54.5% 59%
Hyperfractionation 54.4% 37.6% 55%

Note that although acute/subacute toxicity at 3 months was elevated in the hypofractionated and delayed concomitant boost arms by 6-24 months chronic toxicity was equivalent to conventional fractionation.

DAHANCA 6 and 7 - Overgaard Stage I-IV Head and neck randomized to accelerated radiation therapy emplying 6 weekly fractions v. 5 weekly fractions.

Total doses in both arms were 66-68 Gy.at 2 Gy/fraction. Confluent mucositis was higher in the 6 day/week fractionation scheme, but late effects were equivalent. Accelerated regimen demonstrated improved local regional control 76% v. 64% and disease specific survival of 73% v. 66%. Overall survival was not improved in the shortend course.

Radiation and Chemotherapy Data

VA Laryngeal Cancer Study Trial

Induction Chemotherapy followed by conventional fractionation radiotherapy resulted in 66% larynx preservation and overall survival equivalent to surgery. Superceded by concurrent chemotherapy/radiotherapy studies. (Forestiere RTOG 9911).

Forestiere, RTOG 9911 Concurrent chemotherapy

This study demonstrated that patients requiring laryngectomy treated to radiation alone (70 Gy at 2 Gy/fx 35 treatments in 7 weeks); the VA Laryngeal regimen (Induction chemotherapy followed by radiation therapy or concurrent CDDP (100 gm/m2 weeks 1, 4 and 7) with 70 Gy, 2 Gy/fx that VA arms and concurrent Chemo/RT arms had better laryngectomy free survival compared with conventional RT alone. Arm C (Concurrent CDDP/RT) had a statistically superior 5 year larynx preservation rate compared with the other arms. No differences in overall survival was seen.

RTOG 9111 Three Arm Organ Preserving Trial for patients requiring Total Laryngectomy
Study Arm Conventional Radiation Alone Induction Chemotherapy (VA Laryngeal) Concurrent Chemo-Radiation
Laryngectomy Free Survival- 33.9% 46.6% 44.6%
5 Year Larynx Preservation Rate 65.7% 70.5% 83%

GORTEC 9404 (French intergroup) Phase III

The French Intergroup study was restricted to oropharyngeal cancer and compared conventionally fractionated radiation therapy to concurrent chemo-radiation therapy for locally advanced oropharyngeal cancer.

The study used carboplatin (70 mg/m2/day) and 5FU (600 mg/m2/day) on weeks 1, 4, and 7.

Acute toxicities were worse in the combined (radiotherapy/chemotherapy) treatment arm:

Treatment times and interruptions were similar in both groups.Severe cervical fibrosis was quadrupled in the combined arm at 12% v. 3%.

Prognostic factors on multivariate analysis: Hb < 12.5 g/dl, Stage IV disease, and Radiation therapy alone were predictors of short survival and loco-regional failure.

At 5 years, median follow-up, the combined modality arm demonstrated higher 5 year local-regional control at 47.6% v. 24.7%, better Disease Free Survival at 26.6% v. 14.6% and better overall survival at 22.4% v. 15.8%. There was no difference in the rate of distant metastases at 18%. This trial demonstrated a 20% improvement in survival and local-regional control with the addition of carboplatin/5FU to radiation therapy.

Bonner: Cetuximab (Erbitux) Trials

Multi-center trial of cetuximab, a mono-clonal antibody against EGFR compared Stage III/IV patients with radiation alone or cetuximab combined with radiation therapy. 60% had oro-pharyngeal cancers. At median follow-up of 54 months, the addition of cetuximab improved 3 year LRC rate: 47% v. 34%, Progression free survival: 42% v. 31% and Overall Survival 55% v. 45%. The risk of mucositis and severe late side effects did not differ between the two groups.

Harrison: Phase 2 trial of locally advanced unresectable head and neck cancer with concurrent CDDP and concomitant boost

This trial looked at 82 patients with unresectable OP cancer with 40% having base of skull involvement. The treatment consisted of concurrent CDDP with 70 Gy delivered over 6 weeks. Radiation was BID during the last 2 weeks.

70% of those with base of skull involvement were locally controlled. The initial response rate was 94% and 60% had a complete response. At 3 years,

This compares favorably to standard fractionation in local control Survival was better than expected in the poor prognosis group. CDDP was given at 100 mg/m2/day on weeks 1 and 4 or daily carboplatin (10 - 17.5 mg/m2.

German Multicenter RCT: HF accelerated RT with Carboplatin and 5-FU

This study demonstrated that Stage III - IV patients benefited from hyperfractonated accelerated radiation and chemotherapy (carbo/5FU) compared to radiation alone. Chemotherapy increased mucositis. Response at 6 weeks was similar at 92% and 40% complete response. with chemotherapy. With RT alone, 88% response and 34% complete response.

At 22 months median followup, 1-2 year respective rates of local-regional control were 69% (RT/chemo) compared with 58% and 45% with RT alone. (=0.14).

This study also looked at G-CSF and found that G-CSF reduced LRC 55% v. 38% and decreased mucositis. This contradicts RTOG 9901 which was a blinded study that failed to show any improvement in radiation-induced mucositis rates with GM-CSF.

Induction Chemotherapy

GORTEC 2000-01 compared docetaxel, CDDP and 5FU (TPF) to CDDP and 5FU ((CPF). TPF demonstrated an imprivement in overall response at 82.8% v. 60.8% and an initial larynx preservation rate of 80% v. 57.6% and 3 year LP of 73% v.63%, but thise results were inferior to RTOG 9111 which demonstrated larynx preservation rate of 83.6% for concrurent chemo-radiation therapy which was significantly better than both induction chemotherapy and radiation alone and no difference in overall survival.

Wayne State had the most successful induction chemotherapy regimen consisiting of CDDP + continuous infusion 5FU x 5 days for 3 cycles follwed by chemo-radiation. A transient complete response rate was 30-50%

MACH-NC Meta-analysis

The MACH-NC meta-analysis covered more than 30 trials over 5000 patients. This analysis failed to show a survival adevantage with inductino chemotherapy at 5 years. There was a benefit in trials using platinum/5FU based cehmotherapy with a HR 0.88. The MACH meta-analysis also showed an 8% OS benefit with concurrent chemoradiation.

Special Management Considerations

Advanced Tonsillar Cancer Stage III and IV

Stage III and IV tonsillar cancer are those who have large tumors (> 4 cm) or with invasion into the lingual surface of the epiglottis. (T3) or any tumors meeting those characteristics or less with nodes between 3 and 6 cm, (N2a), multiple ipsilateral nodes all less than 6 cm (N2b), or contralateral or bilateral lymph nodes none more than 6 cm. Stge IV tumors are T4 with invasion into the larynx, extrinsic muscles of the tongue, medial pterygoid, hard palate or mandible and very advanced disease including invasion into the lateral pterygoid muscle, pterygoid plates, lateral nasopharynx or base of skull or encasing the carotid artery -- inoperable). These also include N3 nodal disease > 6 cm.

Definitive radiation with a neck dissection for node positive patients is used. For locally advanced lesions, the studies above have shown the addition of chemotherapy to radiation with or without planned neck dissection is the present standard of care in patients with advanced neck disease.

Combined surgery with post-operative RT is becomine far less frequently advocated. Post surgical functional outcomes can be poor and there is no clear cancer advantage.

Surgery and Post-Op RT

In the past surgery with definitive resection was recommended in advanced disease. Roswell Park examined tonsillar cancer treated with single modality surgery v. radiation in Stage III patients (T1-2/N1 and T3/N0-1 and up). Surgery did better in 5 year disease free survival at 47% v 27% compared with radiation alone. A greater precentage of patients were Stage IV in the radiation arm at 75% and split-course treatment was delivered to about half which is known to be inferior to continuous course. .

Surgery in advanced tonsillar cancer frequently resultsw in close or positive margins and multiple positive neck nodes. In these cases, post-operative treatment is important. Zelefsky and Foote have both reported long term treatment resulsts showing improved local control at doses ≥ 60 Gy. Foote noted that the main pattern of failure was above the clavicles, (39% in surgery alone v. 31% in surgery plus post-op RT. The RT group had more locally advanced disease. 5 year OS rates with clinical Stage III/IV disease who received surgery and postoperative adjuvant RT were 100% and 78% compared with 56% adn 43% Based on this data, post operative radiation is necessary in locally advanced tonsillar cancers.

Some studies indicate that brachytherapy may provide an advantage if there is extension to the tongue, when combined with external beam radiation.

Recurrent Disease Salvage Therapy

Surgical salvage is better if the tummors are anterior tonsillar pillar. Actuarial 3 year survival after salvage was 38% and at 5 years 24%. There is higer postoperative mortality (8% v. 1.4%). Tumor extension into the base of tongue is a negative predictive factor.

Advanced BOT Cancer Managment

Traditionally major resection was recommended for advanced BOT disease. This procedure entails total laryngectomy , bone and tongue resection followed by post-op radiation. More recently (modern era) advances in radiation and chemotherapy has surplanted surgery from initial therapeutic considerations.

Presently, improved quality of life and oncologic outcome demands have shifted the focus from surgery to combined chemo/radiation therapy for organ preservation with or without selective neck dissection in moderately advanced lesions as the standard of care. Most patients can be offered primary radiation therapy wiht chemotherapy that provide local control equivalent to or better than surgery, and with better quality of life. Primary surgery is not commonly employed in most centers.

Outcomes and Results

Advanced BOT tumors require multiple modality treatment. For surgery alone Dupont reported on T3/T4 lesions treated by surgical resection alone. 82% had positive neck nodes. At 2 years local control was 27% and overall survival was 20%. 44% required laryngectomy. Of the patients who had a unilateral neck dissection, neck failure was 53%. (70% contralateral and 30% ipsilateral).

Definitive radiation therapy experience spans 50 years. Definitive RT in advanced tumors produces as local control rate of 50% compared with 75 - 90% for surgery with post operative RT.

Harrison reported on Stage III-IV patients who were treated with EBRT + brachytherapy and neck dissection in a larynx preservation study. These patients would have required laryngectomy . The treatment was neoadjuvant chemotherapy followed by EBRT and brachytherapy impant between 1981 - 1995.

Neoadjuvant Chemotherapy followed by EBRT and brachtherapy in larynx preservation
Local Control 88%
Regional Control 96%
Distant Mets Free Survival 80% (5 yrs) 67% (10 yrs)
Overall Survival 86% (5yrs) 52% (10 yrs)
Surgical Salvage LC 94%

Surgery and Postoperative Adjuvant Radiation Therapy

MSKCC/Zelefsky reported long term treatment results for BOT and tonsillar fossa carcinomas with surgery plus radiation. Indications for post-operative radiotherpy include:

The 7 year actuarial local control rates were 81% for BOT carcinomas, 94% for T3 and 75% for T4 lesions. For patients with postive or close margins with doses ≥ 60 Gy the long term control rate was 93%, Breaks are bad: The actuarial control rate with a treatmen break was 64% if a break was required with 93% for those who required no break. OS-7 years was 52% and DFS was 64%. Distant metastases rates at 7 years was 30%.

Post-op Chemotherapy with Radiation EORTC 22931 Phase III

This trial demonstrated a benefit to concurrent chemtherapy and radiation compared to radiation alone. Radiation was 66 Gy at 2 Gy/fraction with or without CDDP (100 mg/m2/cycle x 3 cycles. At 60 months patients did better with cheomradiation. PFS-5yr was 5% v. 40% and 5 year local regional relapse was 18% v. 31%. Distant mets were the same at 21%

An RTOG 9501 study had similar findings except the overall survival at 2 years was not different. Based on these studies, post-operative concurrent chemotherapy and radiation therapy are the standards for post-operative patients with high risk features.

Recurrence Salvage Therapy

Treatment Sequalae adn Complications

Surgical Resection

Sequelae are grouped into intraoperative, immediate and delayed post-operative complcations. Intraopearative mortality for tumor and neck dissection is low (< 5%). Primary intra-operative complications include damage to CN V, VII, XI) and vascular, lymphatic and pulmonary complications. Delayed complications include fistua, dysarthria, mandibular necrosis, trismus, exposure of teh carotid artery, lymphedema, and decreased muscular functions. Extensive resections can affect speech and swallowing. Laryngectomy is performed to prevent aspiration, increasing functional morbidity.

BOT propels food. Reconstruction of the anterior florro of mouth inhibits tonue-tip and lateral movement and reduces teh ablity to chew, and initiate swallowing.

Salvage surgical procedures after chemo and definitive RT have higher rates of major wound complications if performed in less than 1 year of initial treatment. The incidence drops from 77% (< 1 year) to 20% incidence (> 1 year).

Radiation

Acute inflammation of the salavary gland occurs in 5% within 24 hours of the first treatment. This resolves in 24-48 hours. Skin erytherma, desquamation and hyperpigmentation occurs. Desquamation can be moist if the basal cell layer is overwhelmed. After 35-40 Gy, acute xerostomia and alatered taste occurs.

Radiation induced dysphagia. Avi Eisbruch studied radiation dysphagia. He found via VFSS and eosphagography functional abnormalities using pre- and post-treatment studies and CT scans. The vast majority of patients had no oral phase problems. Multiple abnormalities were found in the pharyngeal phase. These abnormalities affected every patient in the study. Eisbruch identified dysphagia and aspiration related structures (DARS). These structures were found to be:

In the second phase, Eisbruch generated additional treatment plans of those treated with standard IMRT based on RTOG guidelines to create a dysphagia/aspiration-optimized IMRT plan. This plan minimzed the portions fo the DARS that lay outside of the PTV receiving ≥ 50 Gy without compriomising the PTV doses. Eisbruch showed it is possible to reduce the mean V50 using a modified IMRT plan compared with 3DCRT and standard IMRT planning to both the pharyngeal constrictors (69% v. 90%) and the larynx. This may allow reduction in treatment related dysphagia.

Retrospective studies of dose-response relationship for DARS including the constrictor muscles, larynx and hypopharynx. Threshold doses appear to be 45 - 54 Gy above which severe dysphagia and stricture is reported based on VSFF and quality of life questionanareis (EORTC Q-30) and MDACC dysphagia inventory.

Prudence is required in implementing DARS sparing, There has not been prospective validiation of this data. Caution is required, especially in patients with retropharyngeal node risk.

Long term complications at doses exceeding 60 Gy include soft-tissue and bone ulceration and necrosis. Avasculalr soft tissue necrosis can progress to bone exposure and bone injury. For minor cases, debridement is used. In advanced cases, hyperbaric oxygen has been used.

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